WO2016186967A1 - Benzimidazole and imadazopyridine carboximidamide compounds having activity as inhibitors of indoleamine 2,3-dioxygenase - Google Patents

Benzimidazole and imadazopyridine carboximidamide compounds having activity as inhibitors of indoleamine 2,3-dioxygenase Download PDF

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Publication number
WO2016186967A1
WO2016186967A1 PCT/US2016/032152 US2016032152W WO2016186967A1 WO 2016186967 A1 WO2016186967 A1 WO 2016186967A1 US 2016032152 W US2016032152 W US 2016032152W WO 2016186967 A1 WO2016186967 A1 WO 2016186967A1
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WO
WIPO (PCT)
Prior art keywords
hydroxy
carboximidamide
fluorophenyl
chloro
amino
Prior art date
Application number
PCT/US2016/032152
Other languages
French (fr)
Inventor
Mark J. BARTLETT
Julian Andrew CODELLI
Britton Kenneth CORKEY
Jennifer Leigh COSMAN
Kristyna ELBEL
Jennifer Alissa Loyer-Drew
David Sperandio
Joshua Van Veldhuizen
Hai Yang
Suet Chung YEUNG
Original Assignee
Gilead Sciences, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to AU2016263083A priority Critical patent/AU2016263083B2/en
Priority to CA2985642A priority patent/CA2985642A1/en
Priority to EA201792259A priority patent/EA201792259A1/en
Priority to NZ736709A priority patent/NZ736709A/en
Application filed by Gilead Sciences, Inc. filed Critical Gilead Sciences, Inc.
Priority to CN201680040764.0A priority patent/CN107849024A/en
Priority to KR1020177035775A priority patent/KR20180004811A/en
Priority to ES16730065T priority patent/ES2761824T3/en
Priority to BR112017024331-8A priority patent/BR112017024331A2/en
Priority to JP2017559523A priority patent/JP2018515541A/en
Priority to MX2017014613A priority patent/MX2017014613A/en
Priority to EP16730065.6A priority patent/EP3294732B1/en
Publication of WO2016186967A1 publication Critical patent/WO2016186967A1/en
Priority to IL255294A priority patent/IL255294A0/en
Priority to HK18104140.1A priority patent/HK1244796A1/en
Priority to HK18107798.9A priority patent/HK1248235A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The present disclosure provides indoleamine 2,3 -dioxygenase 1 (IDO1) inhibitors of Formula I: or pharmaceutically acceptable salts thereof, in which X, L, n, m, R1, R2a, R2b, Rn, Rm, and R1 are as defined herein, as well as pharmaceutical compositions that include a compound of Formula I, or pharmaceutically acceptable salts thereof, and methods of using the same to treat conditions mediated by IDO1.

Description

Attorney Docket No.: 1115.PF
BENZIMIDAZOLE AND IMADAZOPYRIDINE CARBOXIMIDAMIDE COMPOUNDS
Field
[0001] The present disclosure relates generally to inhibitors of indoleamine 2,3- dioxygenase 1 (IDO1) activity and methods of use and manufacture thereof.
Background
[0002] Catabolism of the essential amino acid tryptophan by the inducible heme- containing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is a central pathway maintaining the immunosuppressive microenvironment in many cancers. IDO1 catalyzes the degradation of tryptophan to kynurenine, and its effects on immune suppression are due to decreased tryptophan availability and the generation of tryptophan metabolites resulting in multipronged negative effects on cytotoxic T lymphocytes, as well as expansion of immunosuppressive regulatory T cells. IDO1 is elevated in multiple cancers, is induced by chemotherapy, targeted therapy, or immunotherapy. IDO1 expression in the tumor microenvironment is correlated with poor prognosis in a variety of cancers. IDO1 inhibitors are positioned to potentiate the efficacy of multiple oncology therapeutics including immunotherapies, targeted agents, and chemotherapies. Indeed, epacadostat (INCB24360), a potent and selective IDO1 inhibitor, entered clinical trials and is demonstrating activity in combination with ipilimumab (anti-CTLA4) in melanoma.
[0003] In addition to the above, IDO1 has been shown to play a role in chronic infections, HIV and AIDS, autoimmune diseases or disorders (e.g., rheumatoid arthritis), and immunologic tolerance, prevention of fetal rejection in utero. Inhibition of IDO1 may also be an important treatment strategy for patients with neurological or neuropsychiatric diseases or disorders, such as depression.
[0004] A need remains for additional therapeutic agents useful to treat proliferative disorders or diseases that are mediated by IDO1.
Summary
[0005] The present disclosure provides compounds that function as inhibitors of IDO1. The disclosure also provides compositions, including pharmaceutical 1
604642.1 Attorney Docket No.: 1115.PF compositions, kits that include the compounds, and methods of using and making the compounds. The compounds provided herein are useful in treating diseases, disorders, or conditions that are mediated by IDO1. The disclosure also provides compounds for use in therapy. The disclosure further provides compounds for use in a method of treating a disease, disorder, or condition that is mediated by IDO1. Moreover, the disclosure provides uses of the compounds in the manufacture of a medicament for the treatment of a disease, disorder or condition that is mediated by IDO1.
[0006] In one aspect, provided is a compound having the structure of Formula I:
Figure imgf000004_0001
wherein
R1 is mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, wherein two of the optional substituents can join to form an additional partially saturated heterocyclic ring; and
wherein each C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, - N(R20)(R22) and C3-6 cycloalkyl;
X is N or CR2c;
R2a, R2b, and R2c are independently hydrogen, hydroxyl, halo, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, or C1-6 alkyl;
R2d and R2e are independently hydrogen, C1-6 haloalkyl, C1-6 haloalkoxy, or C1-6 alkyl;
n and m are independently 0, 1, 2, or 3; 2
604642.1 Attorney Docket No.: 1115.PF each Rn and Rm are independently hydrogen, hydroxyl, halo, C1-6 alkoxy, C1-6 alkyl, C3-6 cycloalkyl, aryl, heterocyclyl, or heteroaryl; or two Rn or Rm join to form a C3-6 cycloalkyl; and
wherein each C1-6 alkoxy, C1-6 alkyl, C3-6 cycloalkyl aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, - N(R20)(R22), C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, C1-6 alkyl, and C3-6 cycloalkyl;
L is a bond, -NR3-, -C(O)-NR3-, -NR3-C(O)-, -NR3SO2-, -NR3SO2-NR3-, - SO2NR3-, -O-, -S-, or–S(O)t-, where t is 0, 1 or 2;
each R3 is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, aryl, heterocyclyl, or heteroaryl; and
Rt is hydrogen, C1-6 alkyl, C1-6 alkoxy, -C(O)R20, -C(O)OR20, -NC(O)OR20, - N(R20)(R22), -C(O)N(R20)(R22), -SO2R20, -N(R20)SO2(R21), -N(R20)SO2- N(R21)(R22), -SO2N(R20)(R22), C3-15 cycloalkyl, aryl, heteroaryl, or heterocyclyl, provided that when Rt is C1-6 alkoxy, -NC(O)OR20, - N(R20)(R22), -N(R20)SO2(R21), -N(R20)SO2-N(R21)(R22), or - SO2N(R20)(R22), and m is 0, then L is a bond;
wherein said C1-6 alkyl, C1-6 alkoxy, C3-15 cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO2, C1- 6 haloalkyl, C1-6 haloalkoxy, -C(O)R20, -N(R20)(R22), -SO2R20, - N(R20)SO2(R21), -N(R20)SO2-N(R21)(R22), -SO2N(R20)(R22), C3-6 cycloalkyl, -CN, C1-6 alkoxy, C1-6 alkyl, and heterocyclyl; and wherein said heterocyclyl is optionally substituted with one or two oxo;
wherein said C3-6 cycloalkyl, C1-6 alkyl or C1-6 alkoxy is optionally substituted with one, two, or three substituents
independently selected from hydroxyl, halo, -NO2, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, - N(R20)(R22), -SO2R20, -N(R20)SO2(R22), -N(R20)SO2- N(R21)(R22)-, and -SO2N(R20)(R22); and said C1-6 alkyl is optionally substituted with aryl; 3
604642.1 Attorney Docket No.: 1115.PF R20, R21, and R22 are independently selected from hydrogen, C1-6 alkyl, C1-6
haloalkyl, C3-6 cycloalkyl, aryl, heterocyclyl, and heteroaryl; wherein said aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three halogen;
or a pharmaceutically acceptable salt, isomer, or mixture thereof. [0007] Some embodiments provide a method of using the compounds of Formula I, or additional Formula(s) described throughout, in the treatment of a disease or condition in a mammal, particularly a human, that is amenable to treatment by an IDO1 inhibitor.
[0008] In certain embodiments, the disclosure provides pharmaceutical
compositions comprising a therapeutically effective amount of a compound of the disclosure (e.g. a compound of Formula I or additional Formulas described throughout), and at least one pharmaceutically acceptable excipient.
[0009] The inventions of this disclosure are described throughout. In addition, specific embodiments of the invention are as disclosed herein.
Detailed Description
Definitions and General Parameters
[0010] The following description sets forth exemplary methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.
[0011] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
[0012] A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named.
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604642.1 Attorney Docket No.: 1115.PF [0013] The prefix“Cu-v” indicates that the following group has from u to v carbon atoms. For example,“C1-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.
[0014] Reference to“about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term“about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term“about X” includes description of“X”. Also, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to "the compound" includes a plurality of such compounds and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art.
[0015] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), or 1 to 4 carbon atoms (i.e., C1-4 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec- butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3- hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example,“butyl” includes n-butyl (i.e. -(CH2)3CH3), sec-butyl (i.e. -CH(CH3)CH2CH3), isobutyl (i.e. - CH2CH(CH3)2) and tert-butyl (i.e. -C(CH3)3); and“propyl” includes n-propyl (i.e. - (CH2)2CH3) and isopropyl (i.e. -CH(CH3)2).
[0016] “Alkenyl” refers to an aliphatic group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).
[0017] “Alkynyl” refers to an aliphatic group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms
5
604642.1 Attorney Docket No.: 1115.PF (i.e., C2-4 alkynyl). The term“alkynyl” also includes those groups having one triple bond and one double bond.
[0018] “Alkoxy” refers to the group“alkyl-O-”. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.“Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.
[0019] “Acyl” refers to a group -C(=O)R, wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include formyl, acetyl,
cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.
[0020] “Amido” refers to both a“C-amido” group which refers to the group - C(═O)NRyRz and an“N-amido” group which refers to the group -NRyC(═O)Rz, wherein Ry and Rz are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may be optionally substituted.
[0021] “Amino” refers to the group -NRyRz wherein Ry and Rz are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, or heteroaryl; each of which may be optionally substituted.
[0022] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 12 carbon ring atoms (i.e., C6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C6-10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is heteroaryl.
[0023] “Cyano” or“carbonitrile” refers to the group -CN.
[0024] “Cycloalkyl” refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term“cycloalkyl” includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 6
604642.1 Attorney Docket No.: 1115.PF ring carbon atoms (i.e., C3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
[0025] “Halogen” or“halo” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).
[0026] “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group. The term“heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, - S(O)2-, and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As used herein, heteroalkyl include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
[0027] “Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl include 1 to 20 ring carbon atoms (i.e., C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8 heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with aryl as defined above. 7
604642.1 Attorney Docket No.: 1115.PF [0028] “Heterocyclyl” or“heterocyclic ring” refers to an unsaturated non-aromatic cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. As used herein,“heterocyclyl” or“heterocyclic ring” refers to rings that are saturated or partially saturated unless otherwise indicated, e.g., in some embodiments“heterocyclyl” or“heterocyclic ring” refers to rings that are partially saturated where specified. The term“heterocyclyl” or“heterocyclic ring” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond). A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. As used herein, the term“bridged- heterocyclyl” refers to a four- to ten-membered cyclic moiety connected at two non-adjacent atoms of the heterocyclyl with one or more (e.g., 1 or 2) four- to ten-membered cyclic moiety having at least one heteroatom where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. As used herein,“bridged-heterocyclyl” includes bicyclic and tricyclic ring systems. Also as used herein, the term“spiro-heterocyclyl” refers to a ring system in which a three- to ten-membered heterocyclyl has one or more additional ring, wherein the one or more additional ring is three- to ten-membered cycloalkyl or three- to ten-membered heterocyclyl, where a single atom of the one or more additional ring is also an atom of the three- to ten-membered heterocyclyl. Examples of the spiro- heterocyclyl include bicyclic and tricyclic ring systems, such as 2-oxa-7- azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl.
[0029] “Hydroxy” or“hydroxyl” refers to the group -OH.
[0030] “Oxo” refers to the group (=O) or (O).
[0031] “Sulfonyl” refers to the group -S(O)2R, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.
8
604642.1 Attorney Docket No.: 1115.PF [0032] Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent“alkyl” group, a divalent“aryl” group, etc., may also be referred to as an“alkylene” group or an“alkylenyl” group, an“arylene” group or an“arylenyl” group, respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g. arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.
[0033] The terms“optional” or“optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term“optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.
[0034] The term“substituted” means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom’s normal valence is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. For example, the term “substituted aryl” includes, but is not limited to,“alkylaryl.” Unless specified otherwise,
9
604642.1 Attorney Docket No.: 1115.PF where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.
[0035] In some embodiments, the term“substituted alkyl” refers to an alkyl group having one or more substituents including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In additional embodiments,“substituted cycloalkyl” refers to a cycloalkyl group having one or more substituents including alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl;“substituted heterocyclyl” refers to a heterocyclyl group having one or more substituents including alkyl, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl;“substituted aryl” refers to an aryl group having one or more substituents including halo, alkyl, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano; “substituted heteroaryl” refers to an heteroaryl group having one or more substituents including halo, alkyl, haloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano and “substituted sulfonyl” refers to a group -S(O)2R, in which R is substituted with one or more substituents including alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.
[0036] Some of the compounds exist as tautomeric isomers. Tautomeric isomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.
[0037] Any formula or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass
number. Examples of isotopes that can be incorporated into compounds of the disclosure
10
604642.1 Attorney Docket No.: 1115.PF include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl and 125I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 3H, 13C and 14C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.
[0038] The disclosure also included compounds of Formula I in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of Formula I when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.
[0039] Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index. An 18F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula I.
[0040] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as "H"
11
604642.1 Attorney Docket No.: 1115.PF or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.
[0041] In many cases, the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
[0042] The term“pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, mono, di or tri cycloalkyl amines, mono, di or tri arylamines or mixed amines, etc. Specific examples of suitable amines include, by way of example only,
isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N- ethylpiperidine, and the like.
[0043] Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
[0044] As used herein,“pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known 12
604642.1 Attorney Docket No.: 1115.PF in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
Supplementary active ingredients can also be incorporated into the compositions.
[0045] “Treatment” or“treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
[0046] “Prevention” or“preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
[0047] “Subject” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.
[0048] The term“therapeutically effective amount” or“effective amount” of a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition responsive to inhibition of IDO1 activity. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of
13
604642.1 Attorney Docket No.: 1115.PF the disease or condition, and the manner of administering, which can readily be determined by one or ordinary skill in the art.
[0049] The term“inhibition” indicates a decrease in the baseline activity of a biological activity or process.“Inhibition of activity of IDO1” or variants thereof refers to a decrease in activity in IDO1 as a direct or indirect response to the presence of a compound of the present application relative to the activity IDO1in the absence of the compound of the present application.“Inhibition of IDO1” refers to a decrease in IDO1 activity as a direct or indirect response to the presence of a compound described herein relative to the activity of IDO1 in the absence of the compound described herein. In some embodiments, the inhibition of IDO1 activity may be compared in the same subject prior to treatment, or other subjects not receiving the treatment.
Compounds
[0050] Provided herein are compounds that function as inhibitors of IDO1. In one aspect, provided is a compound having structure of Formula I:
Figure imgf000016_0001
wherein
R1 is mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, wherein two of the optional substituents can join to form an additional partially saturated heterocyclic ring; and
wherein each C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, - N(R20)(R22) and C3-6 cycloalkyl; 14
604642.1 Attorney Docket No.: 1115.PF X is N or CR2c;
R2a, R2b, and R2c are independently hydrogen, hydroxyl, halo, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, or C1-6 alkyl;
R2d and R2e are independently hydrogen, C1-6 haloalkyl, C1-6 haloalkoxy, or C1-6 alkyl;
n and m are independently 0, 1, 2, or 3;
each Rn and Rm are independently hydrogen, hydroxyl, halo, C1-6 alkoxy, C1-6 alkyl, C3-6 cycloalkyl, aryl, heterocyclyl, or heteroaryl; or two Rn or Rm join to form a C3-6 cycloalkyl; and
wherein each C1-6 alkoxy, C1-6 alkyl, C3-6 cycloalkyl aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, - N(R20)(R22), C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, C1-6 alkyl, and C3-6 cycloalkyl;
L is a bond, -NR3-, -C(O)-NR3-, -NR3-C(O)-, -NR3SO2-, -NR3SO2-NR3-, - SO2NR3-, -O-, -S-, or–S(O)t-, where t is 0, 1 or 2;
each R3 is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, aryl, heterocyclyl, or heteroaryl; and
Rt is hydrogen, C1-6 alkyl, C1-6 alkoxy, -C(O)R20, -C(O)OR20, -NC(O)OR20, - N(R20)(R22), -C(O)N(R20)(R22), -SO2R20, -N(R20)SO2(R21), -N(R20)SO2- N(R21)(R22), -SO2N(R20)(R22), C3-15 cycloalkyl, aryl, heteroaryl, or heterocyclyl, provided that when Rt is C1-6 alkoxy, -NC(O)OR20, - N(R20)(R22), -N(R20)SO2(R21), -N(R20)SO2-N(R21)(R22), or - SO2N(R20)(R22), and m is 0, then L is a bond;
wherein said C1-6 alkyl, C1-6 alkoxy, C3-15 cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO2, C1- 6 haloalkyl, C1-6 haloalkoxy, -C(O)R20, -N(R20)(R22), -SO2R20, - N(R20)SO2(R21), -N(R20)SO2-N(R21)(R22), -SO2N(R20)(R22), C3-6 cycloalkyl, -CN, C1-6 alkoxy, C1-6 alkyl, and heterocyclyl; and wherein said heterocyclyl is optionally substituted with one or two oxo;
wherein said C3-6 cycloalkyl, C1-6 alkyl or C1-6 alkoxy is optionally substituted with one, two, or three substituents
15
604642.1 Attorney Docket No.: 1115.PF independently selected from hydroxyl, halo, -NO2, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, - N(R20)(R22), -SO2R20, -N(R20)SO2(R22), -N(R20)SO2- N(R21)(R22)-, and -SO2N(R20)(R22); and said C1-6 alkyl is optionally substituted with aryl;
R20, R21, and R22 are independently selected from hydrogen, C1-6 alkyl, C1-6
haloalkyl, C3-6 cycloalkyl, aryl, heterocyclyl, and heteroaryl; wherein said aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three halogen;
or a pharmaceutically acceptable salt, isomer, or mixture thereof.
[0051] In some embodiments, R1 is bicyclic aryl or heteroaryl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3- 6 cycloalkyl, wherein two of the optional substituents can join to form an additional partially saturated heterocyclic ring; and wherein each C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, -N(R20)(R22), and C3-6 cycloalkyl.
[0052] In some embodiments, R1 is bicyclic aryl or heteroaryl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, C1- 6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl.
[0053] In some embodiments, the compound is selected from the group consisting of:
N'-hydroxy-N-naphthalen-2-yl-1H-imidazo[4,5-b]pyridine-7-carboximidamide; N'-hydroxy-N-naphthalen-1-yl-1H-imidazo[4,5-b]pyridine-7-carboximidamide; N-(4-chloronaphthalen-1-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(3-chloronaphthalen-2-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; 16
604642.1 Attorney Docket No.: 1115.PF N-(1-benzofuran-4-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(1-benzofuran-6-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(1-benzofuran-7-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; and N-(1-benzofuran-5-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide. [0054] In some embodiments, R1 is phenyl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, wherein two of the optional substituents can join to form an additional partially saturated heterocyclic ring; and wherein each C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, -N(R20)(R22), and C3-6 cycloalkyl.
[0055] In some embodiments, R1 is phenyl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, -CHF2, -O- CHF2, -CF3, -O-CF3, C1-4 alkoxy, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, and C3-6 cycloalkyl, and wherein two of the optional substituents can join to form an additional partially saturated heterocyclic ring.
[0056] In some embodiments, at least one of R2a, R2b, and, when present, R2c are not hydrogen. In some embodiments, R2a is not hydrogen. In some embodiments, R2b is not hydrogen. In some embodiments, R2c is not hydrogen.
[0057] In some embodiments, the compound is selected from the group consisting of:
N-(3-chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-1H-benzimidazole-4- carboximidamide; N-(3-chloro-4-fluorophenyl)-7-fluoro-N'-hydroxy-3H-benzimidazole-4- carboximidamide; 17
604642.1 Attorney Docket No.: 1115.PF 7-chloro-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-benzimidazole-4- carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-7-(trifluoromethyl)-1H-benzimidazole-4- carboximidamide; N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(2-morpholin-4- ylethylamino)-3H-benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(methylaminomethyl)- 1H-benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-7-methyl-3H-benzimidazole-4- carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-7-methyl-3H-benzimidazole-4- carboximidamide; N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4- carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-7-(trifluoromethoxy)-3H-benzimidazole- 4-carboximidamide; and N-(3-chloro-4-fluorophenyl)-5-fluoro-N'-hydroxy-3H-benzimidazole-4- carboximidamide. [0058] In some embodiments, L is a bond.
[0059] In some embodiments, Rt is C1-6 alkyl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO2, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, -CN, and C1-6 alkoxy.
[0060] In some embodiments, the compound is selected from the group consisting of:
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(methoxymethyl)-1H-imidazo[4,5- b]pyridine-7-carboximidamide;
18
604642.1 Attorney Docket No.: 1115.PF N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-hydroxyethyl)-1H-imidazo[4,5- b]pyridine-7-carboximidamide; 2-(chloromethyl)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide; N-[4-fluoro-3-(trifluoromethyl)phenyl]-N'-hydroxy-2-(hydroxymethyl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(hydroxymethyl)-1H-imidazo[4,5- b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(1-hydroxyethyl)-1H-imidazo[4,5- b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2,2,2-trifluoro-1-hydroxyethyl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-[cyclopropyl(hydroxy)methyl]-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-hydroxypropan-2-yl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide; and 2-(aminomethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide. [0061] In some embodiments, Rt is C3-15 cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein said cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO2, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, -CN, C1-6 alkoxy and C1-6 alkyl.
[0062] In some embodiments, the compound is selected from the group consisting of:
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-morpholin-4-ylethyl)-3H- imidazo[4,5-b]pyridine-7-carboximidamide; 19
604642.1 Attorney Docket No.: 1115.PF N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(pyrrolidin-1-ylmethyl)-3H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(piperidin-1-ylmethyl)-3H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-pyridin-3-yl-1H-imidazo[4,5- b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(1H-pyrrol-2-yl)-1H-imidazo[4,5- b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2S)-pyrrolidin-2-yl]-1H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(1H-pyrazol-5-yl)-1H-imidazo[4,5- b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(1H-imidazol-2-yl)-1H-imidazo[4,5- b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-cyclopropyl-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-thiophen-2-yl-3H-imidazo[4,5- b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(morpholin-4-ylmethyl)-3H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[hydroxy(phenyl)methyl]-1H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-methyl-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(3-chloro-4-fluorophenyl)-2-ethyl-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; 20
604642.1 Attorney Docket No.: 1115.PF N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-piperidin-1-ylethyl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-pyrrolidin-1-ylethyl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide; and N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(5-methyl-1H-imidazol-2-yl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide. [0063] In some embodiments, Rt is hydrogen.
[0064] In some embodiments, the compound is selected from the group consisting of:
N-(3-ethynylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
N-(3-ethynyl-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-[3-(difluoromethyl)phenyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N'-hydroxy-N-[3-(trifluoromethoxy)phenyl]-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N'-hydroxy-N-phenyl-1H-imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-ethylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide;
N-[4-fluoro-3-(trifluoromethoxy)phenyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine- 7-carboximidamide; N-(4-fluoro-3-methoxyphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(5-bromo-2-fluorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7- carboximidamide; 21
604642.1 Attorney Docket No.: 1115.PF N-(3-bromo-5-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N'-hydroxy-N-[3-(trifluoromethyl)phenyl]-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-[3-fluoro-5-(trifluoromethyl)phenyl]-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(3-bromophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
N-(3-bromo-4-fluorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(3-chlorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
N-[4-fluoro-3-(trifluoromethyl)phenyl]-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(4-fluoro-3-prop-1-ynylphenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(3-bromo-4-chlorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(3,4-dichlorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(4-chlorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide; N-(4-bromophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide; N-(4-fluorophenyl)-N'-hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-cyano-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide;
22
604642.1 Attorney Docket No.: 1115.PF N'-hydroxy-N-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-7- carboximidamide; N'-hydroxy-N-(3-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(4-fluoro-3-propan-2-ylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N'-hydroxy-N-(4-methylphenyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(5-chloro-2-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(5-bromo-2,4-difluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(5-chloro-2,4-difluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(2,5-dichlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(3,5-dichloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(3-chlor2,4-difluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(3-cyclopropyl-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(4-fluoro-3-phenylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide;
23
604642.1 Attorney Docket No.: 1115.PF N-(3-but-1-ynyl-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-[3-(2-cyclopropylethynyl)-4-fluorophenyl]-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide; and N'-hydroxy-N-[4-(trifluoromethoxy)phenyl]-1H-imidazo[4,5-b]pyridine-7- carboximidamide. [0065] In some embodiments, L is -NR3.
[0066] In some embodiments, Rt is C1-6 optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO2, C1-6 haloalkyl, C1-6 haloalkoxy, -N(R20)(R22), -SO2R20, C3-6 cycloalkyl, -CN, and C1-6 alkoxy.
[0067] In some embodiments,, the compound is selected from the group consisting of:
N-(3-chloro-4-fluorophenyl)-2-[2-(dimethylamino)ethyl]-N'-hydroxy-3H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[2-(methylamino)ethyl]-3H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-((2-methoxyethyl)amino)ethyl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide N-(3-chloro-4-fluorophenyl)-2-[(2,2-dimethylpropylamino)methyl]-N'-hydroxy- 1H-imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[2-(2-methoxyethylamino)ethyl]-3H- imidazo[4,5-b]pyridine-7-carboximidamide; ethyl N-[7-[(Z)-N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl]-1H- imidazo[4,5-b]pyridin-2-yl]carbamate; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(methylamino)-1H-imidazo[4,5- b]pyridine-7-carboximidamide;
24
604642.1 Attorney Docket No.: 1115.PF N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2,2,2-trifluoroethylamino)-1H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-(dimethylamino)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-[2-(diethylamino)ethyl]-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-[2-(dimethylamino)-1-hydroxyethyl]-N'-hydroxy- 1H-imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2-methylpropylamino)methyl]-1H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(methylaminomethyl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-[2-[2,2-difluoroethyl(methyl)amino]ethyl]-N'- hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(propan-2-ylamino)-1H-imidazo[4,5- b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-[(2,2-difluoroethylamino)methyl]-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[[(3-hydroxy-2,2- dimethylpropyl)amino]methyl]-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(propan-2-ylamino)methyl]-3H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-(ethylaminomethyl)-N'-hydroxy-3H-imidazo[4,5- b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-(ethylamino)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide;
25
604642.1 Attorney Docket No.: 1115.PF N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(3-methoxypropylamino)methyl]-3H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-[(dimethylamino)methyl]-N'-hydroxy-3H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[[3- methoxypropyl(methyl)amino]methyl]-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2-methoxyethylamino)methyl]-3H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2,2,2-trifluoroethylamino)methyl]- 3H-imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-[[2-(dimethylamino)ethylamino]methyl]-N'- hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(3-hydroxypropylamino)methyl]-1H- imidazo[4,5-b]pyridine-7-carboximidamide; N-[[7-[(Z)-N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl]-3H- imidazo[4,5-b]pyridin-2-yl]methyl]acetamide; N-(3-chlorophenyl)-N'-hydroxy-2-(methylamino)-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[2-[2- methoxyethyl(methyl)amino]ethyl]-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(3-chloro-4-fluorophenyl)-2-[2-(diethylamino)ethylamino]-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide; and N-(3-chlorophenyl)-2-((dimethylamino)methyl)-4,5-difluoro-N'-hydroxy-1H- benzo[d]imidazole-7-carboximidamide.
26
604642.1 Attorney Docket No.: 1115.PF [0068] In some embodiments, L is -NR3 and Rt is C3-15 cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein said cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -NO2, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, -CN, and C1-6 alkoxy.
[0069] In some embodiments, the compound is selected from the group consisting of:
N-(3-chloro-4-fluorophenyl)-2-(cyclopropylamino)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-(cyclopropylmethylamino)-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-phenylethylamino)-1H- imidazo[4,5-b]pyridine-7-carboximidamide; 2-anilino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(3-chloro-4-fluorophenyl)-2-[(3,3-difluorocyclobutyl)amino]-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(pyrimidin-2-ylamino)methyl]-3H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-(cyclobutylamino)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(1,3-thiazol-2- ylmethylamino)methyl]-1H-imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-[(cyclopropylmethylamino)methyl]-N'-hydroxy- 3H-imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(pyridin-2-ylmethylamino)methyl]- 3H-imidazo[4,5-b]pyridine-7-carboximidamide;
27
604642.1 Attorney Docket No.: 1115.PF 2-[(benzylamino)methyl]-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[[(2- methoxyphenyl)methylamino]methyl]-1H-imidazo[4,5-b]pyridine-7- carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2-pyridin-2-ylethylamino)methyl]- 3H-imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-[(cyclopropylamino)methyl]-N'-hydroxy-3H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(pyridin-3-ylmethylamino)methyl]- 3H-imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(oxan-2-ylmethylamino)methyl]-1H- imidazo[4,5-b]pyridine-7-carboximidamide; 2-(anilinomethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-imidazo[4,5- b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(oxan-3-ylmethylamino)methyl]-1H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(pyrimidin-2-ylmethylamino)methyl]- 3H-imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(3-morpholin-4- ylpropylamino)methyl]-3H-imidazo[4,5-b]pyridine-7-carboximidamide;
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(oxan-4-ylamino)methyl]-1H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(pyridin-4-ylmethylamino)methyl]- 3H-imidazo[4,5-b]pyridine-7-carboximidamide;
28
604642.1 Attorney Docket No.: 1115.PF N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(pyrazin-2-ylmethylamino)methyl]- 1H-imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(oxolan-3-ylmethylamino)methyl]- 1H-imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2-pyrimidin-2-ylethylamino)methyl]- 3H-imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-[2-[cyclopropylmethyl(methyl)amino]ethyl]-N'- hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-morpholin-4-ylethylamino)-1H- imidazo[4,5-b]pyridine-7-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(1-methylpiperidin-2- yl)methylamino]-1H-imidazo[4,5-b]pyridine-7-carboximidamide; and N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(1-methylpyrrolidin-3-yl)amino]-1H- imidazo[4,5-b]pyridine-7-carboximidamide. [0070] In some embodiments, L is -NR3 and Rt is hydrogen.
[0071] In some embodiments, the compound is selected from the group consisting of:
2-(2-aminoethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-imidazo[4,5- b]pyridine-7-carboximidamide; and 2-amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide. [0072] In some embodiments, L is–SO2NR3-.
[0073] In some embodiments, the compound is selected from the group consisting of:
2-(benzenesulfonamidomethyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide, and
29
604642.1 Attorney Docket No.: 1115.PF N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(methanesulfonamidomethyl)-3H- imidazo[4,5-b]pyridine-7-carboximidamide.
[0074] In some embodiments, X is–N-.
[0075] In some embodiments, X is–CR2c-.
[0076] In some embodiments, the compound is selected from the group consisting of:
N-(3-chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-1H-benzimidazole-4- carboximidamide; N-(3-chloro-4-fluorophenyl)-7-fluoro-N'-hydroxy-3H-benzimidazole-4- carboximidamide; 7-chloro-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-benzimidazole-4- carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-7-(trifluoromethyl)-1H-benzimidazole-4- carboximidamide; N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(2-morpholin-4- ylethylamino)-3H-benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(methylaminomethyl)- 1H-benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-7-methyl-3H-benzimidazole-4- carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-7-methyl-3H-benzimidazole-4- carboximidamide; N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4- carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-7-(trifluoromethoxy)-3H-benzimidazole- 4-carboximidamide;
30
604642.1 Attorney Docket No.: 1115.PF N-(3-chloro-4-fluorophenyl)-5-fluoro-N'-hydroxy-3H-benzimidazole-4- carboximidamide; N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(hydroxymethyl)-3H- benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-morpholin-4-yl-3H- benzimidazole-4-carboximidamide; N-(3-chlorophenyl)-6,7-difluoro-N'-hydroxy-2-(1-methylpiperidin-3-yl)-3H- benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-benzimidazole-4-carboximidamide; 6-chloro-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-benzimidazole-4- carboximidamide; 7-bromo-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-benzimidazole-4- carboximidamide; N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-[(3- methoxypropylamino)methyl]-1H-benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-[3-(dimethylamino)propyl]-6,7-difluoro-N'- hydroxy-3H-benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-[2-(dimethylamino)ethyl]-6,7-difluoro-N'- hydroxy-1H-benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(methylamino)-3H- benzimidazole-4-carboximidamide; N-(3-bromo-4-fluorophenyl)-2-[2-(dimethylamino)ethyl]-6,7-difluoro-N'- hydroxy-1H-benzimidazole-4-carboximidamide; N-(3-bromophenyl)-2-[2-(dimethylamino)ethyl]-6,7-difluoro-N'-hydroxy-1H- benzimidazole-4-carboximidamide;
31
604642.1 Attorney Docket No.: 1115.PF N-(3-chlorophenyl)-2-[2-(dimethylamino)ethyl]-6,7-difluoro-N'-hydroxy-1H- benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-[3-(dimethylamino)propylamino]-6,7-difluoro-N'- hydroxy-3H-benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(2-methoxyethylamino)- 3H-benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-[2-(dimethylamino)ethylamino]-6,7-difluoro-N'- hydroxy-3H-benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-[2-(diethylamino)ethylamino]-6,7-difluoro-N'- hydroxy-3H-benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-[(propan-2- ylamino)methyl]-1H-benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-[(dimethylamino)methyl]-6,7-difluoro-N'-hydroxy- 1H-benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-(ethylaminomethyl)-6,7-difluoro-N'-hydroxy-1H- benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-[2-(dimethylamino)ethylamino]-7-fluoro-N'- hydroxy-3H-benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-[2-(methylamino)ethyl]- 1H-benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-[2-(diethylamino)ethyl]-6,7-difluoro-N'-hydroxy- 1H-benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-7-fluoro-N'-hydroxy-2-(2- methylsulfonylethylamino)-3H-benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(2- methylsulfonylethylamino)-3H-benzimidazole-4-carboximidamide; 32
604642.1 Attorney Docket No.: 1115.PF N-(3-chloro-4-fluorophenyl)-2-[(cyclopropylmethylamino)methyl]-6,7-difluoro- N'-hydroxy-1H-benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-7-fluoro-N'-hydroxy-2-(3-morpholin-4- ylpropylamino)-3H-benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(2-pyrrolidin-1- ylethylamino)-3H-benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-2-[2-(4,4-difluoropiperidin-1-yl)ethylamino]-6,7- difluoro-N'-hydroxy-3H-benzimidazole-4-carboximidamide; N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(1-morpholin-4-ylpropan- 2-ylamino)-3H-benzimidazole-4-carboximidamide; 2-(aminomethyl)-N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-1H- benzimidazole-4-carboximidamide; 2-amino-N-(3-chloro-4-fluorophenyl)-7-fluoro-N'-hydroxy-3H-benzimidazole-4- carboximidamide; 2-amino-N-(3-bromo-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-3H- benzimidazole-4-carboximidamide; 2-amino-N-(3-bromophenyl)-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4- carboximidamide; 2-amino-N-(3-chlorophenyl)-6,7-difluoro-N'-hydroxy-3H-benzimidazole-4- carboximidamide; 2-amino-N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-3H- benzimidazole-4-carboximidamide; 2-amino-N-(3-bromophenyl)-7-fluoro-N'-hydroxy-3H-benzimidazole-4- carboximidamide; 2-amino-N-(3-bromo-4-fluorophenyl)-7-fluoro-N'-hydroxy-3H-benzimidazole-4- carboximidamide; 33
604642.1 Attorney Docket No.: 1115.PF 2-amino-N-(3-chlorophenyl)-7-fluoro-N'-hydroxy-3H-benzimidazole-4- carboximidamide; 2-amino-6,7-difluoro-N-[4-fluoro-3-(trifluoromethyl)phenyl]-N'-hydroxy-3H- benzimidazole-4-carboximidamide; 2-amino-7-fluoro-N-[4-fluoro-3-(trifluoromethyl)phenyl]-N'-hydroxy-3H- benzimidazole-4-carboximidamide; N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-(((3- methoxypropyl)amino)methyl)-1H-benzo[d]imidazole-7-carboximidamide; N-(3-chlorophenyl)-2-(((cyclopropylmethyl)amino)methyl)-4,5-difluoro-N'- hydroxy-1H-benzo[d]imidazole-7-carboximidamide; N-(3-chlorophenyl)-2-((dimethylamino)methyl)-4,5-difluoro-N'-hydroxy-1H- benzo[d]imidazole-7-carboximidamide; N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((isopropylamino)methyl)-1H- benzo[d]imidazole-7-carboximidamide; N-(3-chlorophenyl)-2-((ethylamino)methyl)-4,5-difluoro-N'-hydroxy-1H- benzo[d]imidazole-7-carboximidamide; N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-(hydroxymethyl)-1H- benzo[d]imidazole-7-carboximidamide; N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((methylamino)methyl)-1H- benzo[d]imidazole-7-carboximidamide; 2-(aminomethyl)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-1H- benzo[d]imidazole-7-carboximidamide; and N-(3-chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-2-((2- morpholinoethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide. [0077] In some embodiments, L is–C(O)-NR3-.
34
604642.1 Attorney Docket No.: 1115.PF [0078] In some embodiments, the compound is selected from the group consisting of:
ethyl N-[7-[(Z)-N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl]-1H- imidazo[4,5-b]pyridin-2-yl]carbamate; N-[[7-[(Z)-N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl]-3H- imidazo[4,5-b]pyridin-2-yl]methyl]acetamide; and propan-2-yl N-[7-[(Z)-N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl]- 1H-imidazo[4,5-b]pyridin-2-yl]carbamate. [0079] In some embodiments, L is N, m is 1, and n is 0.
[0080] In some embodiments, L is N, m is 2, and n is 0.
[0081] In some embodiments, L is N, m is 3, and n is 0.
[0082] In one embodiment, the compound of Formula I is represented by Formula IA or IB:
Figure imgf000037_0001
IA IB.
,
,
Figure imgf000037_0002
35
604642.1 Attorney Docket No.: 1115.PF
, ,
Figure imgf000038_0001
36
604642.1 Attorney Docket No.: 1115.PF
, and
Figure imgf000039_0001
[0084] In one embodiment, R1 is .
Figure imgf000039_0002
[0085] In one embodiment, the compound of Formula I is represented by Formula II:
Figure imgf000039_0003
II.
[0086] In one embodiment, the compound of Formula I is represented by Formula IIA or IIB:
Figure imgf000039_0004
IIA IIB.
37
604642.1 Attorney Docket No.: 1115.PF [0087] In one embodiment, the compound of Formula I is represented by Formula III:
Figure imgf000040_0001
III. [0088] In one embodiment, the compound of Formula I is represented by Formula IV:
Figure imgf000040_0002
[0089] In one embodiment, the group of any Formula described herein is selected from the grou
Figure imgf000040_0003
n, (1-methylpiperidin- 2-yl)methylamino, (1-methylpyrrolidin-3-yl)amino, (2-pyrimidin-2- ylethylamino)methyl, (2S)-pyrrolidin-2-yl, (isopropyloxycarbonyl)amino, (1,3-thiazol-2- ylmethylamino)methyl, 1H-imidazol-2-yl, 1H-pyrazol-5-yl, 1H-pyrrol-2-yl, 1- hydroxyethyl, 2-(2-methoxyethylamino)ethyl, 2-(diethylamino)ethyl, 2- (diethylamino)ethylamino, 2-(dimethylamino)-1-hydroxyethyl, 2-(dimethylamino)ethyl, 2-(dimethylamino)ethylamino, [2-(dimethylamino)ethylamino]methyl, 2- (methylamino)ethyl, 2,2,2-trifluoro-1-hydroxyethyl, 2,2,2-trifluoroethylamino, (2,2,2- trifluoroethylamino)methyl, 2-[2,2-difluoroethyl(methyl)amino]ethyl, (2,2- difluoroethylamino)methyl, (2,2-dimethylpropylamino)methyl, 2-[2- methoxyethyl(methyl)amino]ethyl, 2-[cyclopropylmethyl(methyl)amino]ethyl, 2- 38
604642.1 Attorney Docket No.: 1115.PF aminoethyl, 2-hydroxyethyl, 2-hydroxypropan-2-yl, (2-methoxyethylamino)methyl, [(2- methoxyphenyl)methylamino]methyl, 2-morpholin-4-ylethyl, 2-morpholin-4- ylethylamino, 2-phenylethylamino, 2-piperidin-1-ylethyl, (2-pyridin-2- ylethylamino)methyl, 2-pyrrolidin-1-ylethyl, 3-(dimethylamino)propyl, (3,3- difluorocyclobutyl)amino, [(3-hydroxy-2,2-dimethylpropyl)amino]methyl, (3- hydroxypropylamino)methyl, [3-methoxypropyl(methyl)amino]methyl, (3- methoxypropylamino)methyl, 3-morpholin-4-ylpropylamino, (3-morpholin-4- ylpropylamino)methyl, 5-methyl-1H-imidazol-2-yl, 2-methylsulfonylethylamino, 2-(4,4- difluoropiperidin-1-yl)ethylamino, 1-morpholin-4-ylpropan-2-ylamino, 3- (dimethylamino)propylamino, 2-methoxyethylamino, 2-pyrrolidin-1-ylethylamino, 1- methylpiperidin-3-yl, aminomethyl, (dimethylamino)methyl,acetamidomethyl, amino, aminomethyl, anilino, anilinomethyl, benzenesulfonamidomethyl, (benzylamino)methyl, chloromethyl, cyclobutylamino, cyclopropyl, cyclopropyl(hydroxy)methyl,
cyclopropylamino, (cyclopropylamino)methyl, cyclopropylmethylamino,
(cyclopropylmethylamino)methyl, dimethylamino, ethoxy carbonyl amino, ethyl, ethylamino, ethylaminomethyl, hydroxy(phenyl)methyl, hydroxymethyl,
methanesulfonamidomethyl, methoxymethyl, methyl, methylamino, methylaminomethyl, (methylpropylamino)methyl, morpholin-4-yl, morpholin-4-ylmethyl, (oxan-2- ylmethylamino)methyl, (oxan-3-ylmethylamino)methyl, (oxan-4-ylamino)methyl, (oxolan-3-ylmethylamino)methyl, piperidin-1-ylmethyl, propan-2-ylamino, (propan-2- ylamino)methyl, (pyrazin-2-ylmethylamino)methyl, pyridin-3-yl, (pyridin-3- ylmethylamino)methyl, (pyridin-4-ylmethylamino)methyl, (pyrimidin-2-ylamino)methyl, (pyrimidin-2-ylmethylamino)methyl, pyrrolidin-1-ylmethyl, and thiophen-2-yl.
[0090] In one embodiment, the group f any Formula described herein is selected from the grou
Figure imgf000041_0001
39
604642.1 Attorney Docket No.: 1115.PF
,
Figure imgf000042_0001
40
604642.1 Attorney Docket No.: 1115.PF
, ,
Figure imgf000043_0001
41
604642.1 Attorney Docket No.: 1115.PF
, ,
Figure imgf000044_0001
Attorney Docket No.: 1115.PF , , ,
Figure imgf000045_0001
Attorney Docket No.: 1115.PF
,
Figure imgf000046_0001
Attorney Docket No.: 1115.PF
,
Figure imgf000047_0001
Attorney Docket No.: 1115.PF
, ,
Figure imgf000048_0001
,
Figure imgf000048_0002
46
604642.1 Attorney Docket No.: 1115.PF
, ,
Figure imgf000049_0001
604642.1 Attorney Docket No.: 1115.PF
, ,
Figure imgf000050_0001
,
Figure imgf000050_0002
48
604642.1 Attorney Docket No.: 1115.PF
,
Figure imgf000051_0001
49
604642.1 Attorney Docket No.: 1115.PF
,
,
,
Figure imgf000052_0001
, la IIA or IIB:
Figure imgf000052_0002
IIA IIB wherein R2a, R2b, X, Rm, Rn, m, n, and Rt are as defined herein and each R1a is independently hydroxyl, halo, -CN, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 alkoxy, C1-6 50
604642.1 Attorney Docket No.: 1115.PF alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, or two of the optional substituents can join to form an additional partially saturated heterocyclic ring, and s is 0, 1, 2 or 3. [0095] In some embodiments, each R1a is independently hydroxyl, halo, -CN, C1-6 haloalkoxy, or C1-6 haloalkyl. In some embodiments, each R1a is independently halo or - CF3. In some embodiments, each R1a is independently halo. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. [0096] In general, the specific compounds exemplified herein are named using ChemBioDraw Ultra. However, it is understood that other names may be used to identify compounds of the same structure. In particular, the compounds may also be named using other nomenclature systems and symbols that are commonly recognized in the art of chemistry including, for example, Chemical Abstract Service (CAS) and International Union of Pure and Applied Chemistry (IUPAC). Other compounds or radicals may be named with common names, or systematic or non-systematic names.
[0097] For example, the compound of Example 10 (shown below) may be referred to as N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7- carboximidamide or N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-3H- benzimidazole-4-carboximidamide, where both names provide the structure below.
Figure imgf000053_0001
are also all tautomeric forms of the compounds of any Formula described herein. Tautomeric isomers are in equilibrium with one another. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both. Non-limiting examples of benzimidazole and imidazo[4,5-b]pyridine tautomers are shown below: 51
604642.1 Attorney Docket No.: 1115.PF
Figure imgf000054_0001
[0099] Provided are also compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof, in which from 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molecule. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof when administered to a mammal. See, e.g., Foster,“Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.
[00100] Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein.
“Pharmaceutically acceptable” or“physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use. “Pharmaceutically acceptable salts” or“physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. 52
604642.1 Attorney Docket No.: 1115.PF [00101] A“solvate” is formed by the interaction of a solvent and a compound.
Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.
[00102] A“prodrug” is a biologically inactive derivative of a drug that upon administration to the human body is converted to the biologically active parent drug according to some chemical or enzymatic pathway.
[00103] In certain embodiments, provided are optical isomers, racemates, or other mixtures thereof of the compounds described herein or pharmaceutically acceptable salts or a mixture thereof. In those situations, the single enantiomer or diastereomer, i.e., optically active form, can be obtained by asymmetric synthesis or by resolution of the racemate. Resolution of racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high pressure liquid chromatography (HPLC) column. In addition, provided are also Z- and E- forms (or cis- and trans- forms) of the
hydroxyamidine compounds described herein. Specifically, Z- and E- forms are included even if only one designation is named for both carbon-carbon double bonds as well as the hydroxyamidine bond.
[00104] Compositions provided herein that include a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof may include racemic mixtures, or mixtures containing an enantiomeric excess of one enantiomer or single diastereomers or diastereomeric mixtures. All such isomeric forms of these compounds are expressly included herein the same as if each and every isomeric form were specifically and individually listed.
[00105] In certain embodiments, provided herein are also crystalline and amorphous forms of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof.
[0100] In certain embodiments, provided are also chelates, non-covalent complexes, and mixtures thereof, of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof. A“chelate” is formed by the coordination of a compound to a metal ion at two (or more) points. A“non-covalent complex” is formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule. For example, complexation can 53
604642.1 Attorney Docket No.: 1115.PF occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding). Therapeutic Uses of the Compounds
[0101] The methods described herein may be applied to cell populations in vivo or ex vivo.“In vivo” means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and biopsies thereof. In this context, the invention may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the invention may be used ex vivo to determine the optimal schedule and/or dosing of administration of an IDO1 inhibitor for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the invention may be suited are described below or will become apparent to those skilled in the art. The selected compounds may be further
characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art. [0102] In some embodiments, the compounds described herein may be used to treat subjects who have or are suspected of having disease states, disorders, and conditions (also collectively referred to as“indications”) responsive or believed to be responsive to the inhibition of IDO1 activity. In some embodiments, the compounds described herein may be used to inhibit the activity of an IDO1 polypeptide. In some embodiments, the compounds described herein may be used to inhibit excessive or destructive immune reactions or growth or a proliferation of a cell, such as a cancer cell, or inhibit immunosuppression. [0103] Example indications suitable for treatment with compounds described here include, without limitation cancer, viral infection such as HIV infection, HBV infection, HCV infection, other infections (e.g., skin infections, GI infection, urinary
54
604642.1 Attorney Docket No.: 1115.PF tract infections, genito-urinary infections, and systemic infections), depression, neurodegenerative disorders such as Alzheimer's disease and Huntington's disease, trauma, age-related cataracts, organ transplantation (e.g., organ transplant rejection), and autoimmune diseases. [0104] Examples of autoimmune diseases include, but are not limited to, asthma, collagen diseases such as rheumatoid arthritis, systemic lupus erythematosus. Sharp's syndrome, CREST syndrome (calcinosis, Raynaud's syndrome, esophageal dysmotility, sclerodactyly, telangiectasia), dermatomyositis, vasculitis (Morbus Wegener's) and Sjögren's syndrome, renal diseases such as Goodpasture's syndrome, rapidly- progressing glomerulonephritis and membrano-proliferative glomerulonephritis type II, endocrine diseases such as type-I diabetes, autoimmune polyendocrinopathy-candidiasis- ectodermal dystrophy (APECED), autoimmune parathyroidism, pernicious anemia, gonad insufficiency, idiopathic Morbus Addison's, hyperthyreosis, Hashimoto's thyroiditis and primary myxedema, skin diseases such as pemphigus vulgaris, bullous pemphigoid, herpes gestationis, epidermolysis bullosa and erythema multiforme major, liver diseases such as primary biliary cirrhosis, autoimmune cholangitis, autoimmune hepatitis type-1, autoimmune hepatitis type-2, primary sclerosing cholangitis, neuronal diseases such as multiple sclerosis, myasthenia gravis, myasthenic Lambert-Eaton syndrome, acquired neuromyotomy, Guillain-Barre syndrome (Muller-Fischer syndrome), stiff-man syndrome, cerebellar degeneration, ataxia, opsoclonus, sensoric neuropathy and achalasia, blood diseases such as autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura (Morbus Werlhof), infectious diseases with associated autoimmune reactions such as AIDS, allergic inflammation, inflammatory bowel disease, psoriasis and systemic lupus erythematosusor, malaria and Chagas disease. [0105] In some embodiments, the compounds described herein may be used for treating cancer, viral infection, depression, a neurodegenerative disorder, trauma, age- related cataracts, organ transplant rejection, or an autoimmune disease. [0106] In other embodiments, the disease to be treated is a solid tumor. In particular embodiments, the solid tumor is from pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck
55
604642.1 Attorney Docket No.: 1115.PF cancer, melanoma, neuroendocrine cancers, CNS cancers, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, or soft tissue sarcoma. In some embodiments, the solid tumor is from non-small cell lung cancer, small-cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, or breast cancer.. [0107] In some embodiments, the disease is an autoimmune disease. In particular embodiments, the autoimmune disease is systemic lupus erythematosus (SLE), myestenia gravis, rheumatoid arthritis (RA), acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis (MS), psoriasis, Sjoegren’s syndrome, psoriasis, autoimmune hemolytic anemia, asthma, or chronic obstructive pulmonary disease (COPD). In other embodiments, the disease is inflammation. In yet other embodiments, the disease is excessive or destructive immune reactions, such as asthma, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease (COPD), and lupus. [0108] Provided is a method for treating a subject, who has or is suspected of having a disease or condition responsive or believed to be responsive to the inhibition of IDO1 activity by administering to the subject the compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof. Provided is also a method of inhibiting kinase activity of a IDO1 polypeptide by contacting the polypeptide with the compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof. Provided is also a method of inhibiting a growth or a proliferation of cancer cells of hematopoietic origin comprising contacting the cancer cells with an effective amount of a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof. [0109] In one embodiment, the compounds of the present application may be used in combination with one or more additional therapeutic agent that are being used and/or developed to treat cancers or inflammatory disorders. The one or more additional therapeutic agent may be a chemotherapeutic agent, an immunotherapeutic agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-cancer agent, an anti- proliferation agent, an anti-fibrotic agent, an anti-angiogenic agent, a therapeutic antibody, or any combination thereof. 56
604642.1 Attorney Docket No.: 1115.PF [0110] The one or more additional therapeutic agent may be an inhibitor to PI3K such as PI3Kγ, PI3Kβ, PI3Kδ, and/or PI3Kα, Janus kinase (JAK) such as JAK1, JAK2 and/or JAK3 , spleen tyrosine kinase (SYK), Bruton’s tyrosine kinase (BTK), bromodomain containing protein inhibitor (BRD) such as BRD4, a lysyl oxidase protein (LOX), lysyl oxidase-like protein (LOXL) such as LOXL1-5, matrix metalloprotease (MMP) such as MMP 1-10, adenosine A2B receptor (A2B), isocitrate dehydrogenase (IDH) such as IDH1, apoptosis signal-regulating kinase (ASK) such as ASK1, serine/threonine kinase TPL2, discoidin domain receptor (DDR) such as DDR1 and DDR2, histone deacetylase (HDAC), protein kinase C (PKC), or any combination thereof. [0111] A phosphoinositide 3-kinase inhibitor (PI3K inhibitor) functions by inhibiting one or more of the phosphoinositide 3-kinase enzymes, including but not limited to PI3Kγ, PI3Kβ, PI3Kδ, and PI3Kα. Non-limiting examples of PI3K inhibitors include wortmannin, demethoxyviridin, LY294002, idelalisib, perifosine, PX-866, IPI- 145, BAY 80-6946, BEZ235, RP6530, TGR 1202, INK1117, GDC-0941, BKM120, XL147 (also known as SAR245408), XL765 (also known as SAR245409), Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, CAL263, RP6503, PI-103, GNE-477, CUDC-907 and AEZS-136. In some embodiments, the PI3K inhibitor is a PI3Kδ inhibitors, such as idelalisib, IPI-145, RP6530, and RP6503, as well as those disclosed in U.S. Patent No.8,569,296, and PCT publications WO 2014/006572 and WO
2015/001491. [0112] In some embodiments, the one or more additional therapeutic agent may be an MMP9 inhibitor, or an agent that inhibits the expression and/or activity of MMP9. A representative protein sequence for MMP9 is GenBank Accession No. NP_004985. The inhibitor can be small molecule or biologic. For instance, Gu et al., The Journal of Neuroscience, 25(27): 6401-6408 (2005) discloses a specific MMP9 inhibitor, SB-3CT (CAS 292605-14-2). Further, siRNA, antisense RNA and antibodies have also been demonstrated to inhibit the expression or activity of MMP9 and are within the scope of the present disclosure. In one embodiment, an MMP9 inhibitor is a monoclonal anti- MMP9 antibody. In some embodiment, the one or more additional therapeutic agent includes an MMP9 inhibitor and a nucleoside analog such as gemcitabine.
57
604642.1 Attorney Docket No.: 1115.PF [0113] One, two, three, or more of the therapeutic agents (e.g. a PI3K inhibitor, a JAK inhibitor, a SYK inhibitor, a BTK inhibitor, a BRD4 inhibitor, a LOXL2 inhibitor, a MMP9 inhibitor, a A2B inhibitor, an IDH inhibitor, an ASK inhibitor, a TPL2 inhibitor, a DDR1 inhibitor, a TBK inhibitor, a HDAC inhibitor, a PKC inhibitor) may be further used or combined with a chemotherapeutic agent, an immunotherapeutic agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-cancer agent, an anti- fibrotic agent, an anti-angiogenic agent, a therapeutic antibody, or any combination thereof. [0114] Chemotherapeutic agents may be categorized by their mechanism of action into, for example, the following groups: anti-metabolites/anti-cancer agents, such as pyrimidine analogs (floxuridine, capecitabine, and cytarabine); purine analogs, folate antagonists and related inhibitors, antiproliferative/antimitotic agents including natural products such as vinca alkaloid (vinblastine, vincristine) and microtubule such as taxane (paclitaxel, docetaxel), vinblastin, nocodazole, epothilones and navelbine,
epidipodophyllotoxins (etoposide, teniposide); DNA damaging agents (actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, Cytoxan, dactinomycin, daunorubicin, doxorubicin, epirubicin, iphosphamide, melphalan, merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, procarbazine, taxol, taxotere, teniposide, etoposide, triethylenethiophosphoramide); antibiotics such as dactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin), idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin; enzymes (L- asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine); antiplatelet agents;
antiproliferative/ antimitotic alkylating agents such as nitrogen mustards
cyclophosphamide and analogs, melphalan, chlorambucil), and (hexamethylmelamine and thiotepa), alkyl nitrosoureas (BCNU) and analogs, streptozocin), trazenes- dacarbazinine (DTIC); antiproliferative/antimitotic antimetabolites such as folic acid analogs (methotrexate); platinum coordination complexes (cisplatin, oxiloplatinim, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide, nilutamide) and aromatase inhibitors (letrozole, anastrozole); anticoagulants (heparin, synthetic heparin salts and other inhibitors of thrombin); fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel; 58
604642.1 Attorney Docket No.: 1115.PF antimigratory agents; antisecretory agents (breveldin); immunosuppressives tacrolimus sirolimus azathioprine, mycophenolate; compounds (TNP-470, genistein) and growth factor inhibitors (vascular endothelial growth factor inhibitors, fibroblast growth factor inhibitors); angiotensin receptor blocker, nitric oxide donors; anti-sense oligonucleotides; antibodies (trastuzumab, rituximab); cell cycle inhibitors and differentiation inducers (tretinoin); inhibitors, topoisomerase inhibitors (doxorubicin (adriamycin), daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan and mitoxantrone, topotecan, irinotecan, camptothesin), corticosteroids (cortisone, dexamethasone, hydrocortisone, methylpednisolone, prednisone, and prenisolone); growth factor signal transduction kinase inhibitors; dysfunction inducers, toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, or diphtheria toxin, and caspase activators; and chromatin. [0115] As used herein the term "chemotherapeutic agent" or "chemotherapeutic" (or "chemotherapy," in the case of treatment with a chemotherapeutic agent) is meant to encompass any non-proteinaceous (i.e., non-peptidic) chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; emylerumines and memylamelamines including alfretamine,
triemylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimemylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (articularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CBI-TMI); eleutherobin; pancratistatin; a
sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, ranimustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammaII and calicheamicin phiI1, see, e.g., Agnew, Chem. Intl. Ed. Engl, 33:183-186 (1994); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related 59
604642.1 Attorney Docket No.: 1115.PF chromoprotein enediyne antibiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carrninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo- L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino- doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti- metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as demopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replinisher such as frolinic acid; aceglatone;
aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformthine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone;
mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; fluoropyrimidine; folinic acid; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK(r); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-tricUorotriemylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol;
mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiopeta; taxoids, e.g., paclitaxel (TAXOL(r) and docetaxel (TAXOTERE(r)); chlorambucil; gemcitabine (Gemzar(r)); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitroxantrone; vancristine; vinorelbine (Navelbine(r)); novantrone;
teniposide; edatrexate; daunomycin; aminopterin; xeoloda; ibandronate; CPT-11;
topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; FOLFIRI (fluorouracil, leucovorin, and irinotecan) and pharmaceutically acceptable salts, acids or derivatives of any of the above. One or more chemotherapeutic agent are used or included in the present application. For example,
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604642.1 Attorney Docket No.: 1115.PF gemcitabine, nab-paclitaxel, and gemcitabine/nab-paclitaxel are used with the JAK inhibitor and/or PI3Kδ inhibitor for treating hyperproliferative disorders. [0116] Also included in the definition of "chemotherapeutic agent" are anti- hormonal agents that act to regulate or inhibit hormone action on tumors such as anti- estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NolvadexTM), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston(r)); inhibitors of the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate (Megace(r)), exemestane, formestane, fadrozole, vorozole (Rivisor(r)), letrozole (Femara(r)), and anastrozole (Arimidex(r).); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprohde, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above. [0117] The anti-angiogenic agents include, but are not limited to, retinoid acid and derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN(r), ENDOSTATIN(r), suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproternase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor- 2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulphate (clupeine), sulfated chitin derivatives (prepared from queen crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism, including for example, proline analogs ((1-azetidine-2-carboxylic acid (LACA), cishydroxyproline, D,L-3,4-dehydroproline, thiaproline, .alpha.-dipyridyl, beta-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone;
methotrexate, mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chimp-3, chymostatin, beta-cyclodextrin tetradecasulfate, eponemycin; fumagillin, gold sodium thiomalate, d-penicillamine (CDPT), beta-1-anticollagenase-serum, alpba-2-antiplasmin, bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthronilic acid disodium or "CCA", thalidomide; angiostatic steroid, cargboxynaminolmidazole; metalloproteinase inhibitors such as BB94. Other anti-angiogenesis agents include antibodies, preferably monoclonal antibodies against these angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF and Ang-1/Ang-2. See Ferrara N. and
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604642.1 Attorney Docket No.: 1115.PF Alitalo, K. "Clinical application of angiogenic growth factors and their inhibitors" (1999) Nature Medicine 5:1359-1364. [0118] The anti-fibrotic agents include, but are not limited to, the compounds such as beta-aminoproprionitrile (BAPN), as well as the compounds disclosed in U.S. Pat. No.4,965,288 to Palfreyman, et al., issued Oct.23, 1990, entitled "Inhibitors of lysyl oxidase," relating to inhibitors of lysyl oxidase and their use in the treatment of diseases and conditions associated with the abnormal deposition of collagen; U.S. Pat. No.4,997,854 to Kagan, et al., issued Mar.5, 1991, entitled "Anti-fibrotic agents and methods for inhibiting the activity of lysyl oxidase in situ using adjacently positioned diamine analogue substrate," relating to compounds which inhibit LOX for the treatment of various pathological fibrotic states, which are herein incorporated by reference.
Further exemplary inhibitors are described in U.S. Pat. No.4,943,593 to Palfreyman, et al., issued Jul.24, 1990, entitled "Inhibitors of lysyl oxidase," relating to compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine; as well as, e.g., U.S. Pat. No. 5,021,456; U.S. Pat. No.5,5059,714; U.S. Pat. No.5,120,764; U.S. Pat. No.5,182,297; U.S. Pat. No.5,252,608 (relating to 2-(1-naphthyloxymemyl)-3-fluoroallylamine); and U.S. Patent Application No.2004/0248871, which are herein incorporated by reference. Exemplary anti-fibrotic agents also include the primary amines reacting with the carbonyl group of the active site of the lysyl oxidases, and more particularly those which produce, after binding with the carbonyl, a product stabilized by resonance, such as the following primary amines: emylenemamine, hydrazine, phenylhydrazine, and their derivatives, semicarbazide, and urea derivatives, aminonitriles, such as beta- aminopropionitrile (BAPN), or 2-nitroethylamine, unsaturated or saturated haloamines, such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3- bromopropylamine, p-halobenzylamines, selenohomocysteine lactone. Also, the anti- fibrotic agents are copper chelating agents, penetrating or not penetrating the cells.
Exemplary compounds include indirect inhibitors such compounds blocking the aldehyde derivatives originating from the oxidative deamination of the lysyl and hydroxylysyl residues by the lysyl oxidases, such as the thiolamines, in particular D- penicillamine, or its analogues such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2- amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2- aminoethyl)dithio)butanoic acid, sodium-4-((p-1-dimethyl-2-amino-2-
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604642.1 Attorney Docket No.: 1115.PF carboxyethyl)dithio)butane sulphurate, 2-acetamidoethyl-2-acetamidoethanethiol sulphanate, sodium-4-mercaptobutanesulphinate trihydrate. [0119] The immunotherapeutic agents include and are not limited to therapeutic antibodies suitable for treating patients; such as abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, daratumumab, drozitumab, duligotumab, dusigitumab, detumomab, dacetuzumab, dalotuzumab, ecromeximab, elotuzumab, ensituximab, ertumaxomab, etaracizumab, farietuzumab, ficlatuzumab, figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab, iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, moxetumomab, narnatumab, naptumomab, necitumumab, , nimotuzumab, nofetumomabn, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab, radretumab, rilotumumab, rituximab, robatumumab, satumomab, sibrotuzumab, siltuximab, simtuzumab, solitomab, tacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, tucotuzumab, ublituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, CC49 and 3F8. The exemplified therapeutic antibodies may be further labeled or combined with a radioisotope particle, such as indium In 111, yttrium Y 90, iodine I-131. [0120] The application also provides method for treating a subject who is undergoing one or more standard therapies, such as chemotherapy, radiotherapy, immunotherapy, surgery, or combination thereof. Accordingly, one or more therapeutic agent or inhibitors may be administered before, during, or after administration of chemotherapy, radiotherapy, immunotherapy, surgery or combination thereof. [0121] In certain embodiments, the subject may be a human who is (i) substantially refractory to at least one chemotherapy treatment, or (ii) in relapse after treatment with chemotherapy, or both (i) and (ii). In some of embodiments, the subject 63
604642.1 Attorney Docket No.: 1115.PF is refractory to at least two, at least three, or at least four chemotherapy treatments (including standard or experimental chemotherapies). [0122] In certain embodiments, the subject is refractory to at least one, at least two, at least three, or at least four chemotherapy treatment (including standard or experimental chemotherapy) selected from fludarabine, rituximab, obinutuzumab, alkylating agents, alemtuzumab and other chemotherapy treatments such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone); R-CHOP (rituximab-CHOP); hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine); R-hyperCVAD (rituximab-hyperCVAD); FCM (fludarabine, cyclophosphamide, mitoxantrone); R-FCM (rituximab, fludarabine, cyclophosphamide, mitoxantrone); bortezomib and rituximab; temsirolimus and rituximab; temsirolimus and Velcade®; Iodine-131 tositumomab (Bexxar®) and CHOP; CVP (cyclophosphamide, vincristine, prednisone); R-CVP (rituximab-CVP); ICE (iphosphamide, carboplatin, etoposide); R-ICE (rituximab-ICE); FCR (fludarabine, cyclophosphamide, rituximab); FR (fludarabine, rituximab); and D.T. PACE
(dexamethasone, thalidomide, cisplatin, Adriamycin®, cyclophosphamide, etoposide). [0123] Other examples of chemotherapy treatments (including standard or experimental chemotherapies) are described below. In addition, treatment of certain lymphomas is reviewed in Cheson, B.D., Leonard, J.P.,“Monoclonal Antibody Therapy for B-Cell Non-Hodgkin’s Lymphoma” The New England Journal of Medicine 2008, 359(6), p.613-626; and Wierda, W.G.,“Current and Investigational Therapies for Patients with CLL” Hematology 2006, p.285-294. Lymphoma incidence patterns in the United States is profiled in Morton, L.M., et al.“Lymphoma Incidence Patterns by WHO Subtype in the United States, 1992-2001” Blood 2006, 107(1), p.265-276. [0124] Examples of immunotherapeutic agents treating lymphoma or leukemia include, but are not limited to, rituximab (such as Rituxan), alemtuzumab (such as Campath, MabCampath), anti-CD19 antibodies, anti-CD20 antibodies, anti-MN-14 antibodies, anti-TRAIL, Anti-TRAIL DR4 and DR5 antibodies, anti-CD74 antibodies, apolizumab, bevacizumab, CHIR-12.12, epratuzumab (hLL2- anti-CD22 humanized antibody), galiximab, ha20, ibritumomab tiuxetan, lumiliximab, milatuzumab, ofatumumab, PRO131921, SGN-40, WT-1 analog peptide vaccine, WT1126-134 peptide vaccine, tositumomab, autologous human tumor-derived HSPPC-96, and
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604642.1 Attorney Docket No.: 1115.PF veltuzumab. Additional immunotherapy agents includes using cancer vaccines based upon the genetic makeup of an individual patient’s tumor, such as lymphoma vaccine example is GTOP-99 (MyVax®). [0125] Examples of chemotherapy agents for treating lymphoma or leukemia include aldesleukin, alvocidib, antineoplaston AS2-1, antineoplaston A10, anti- thymocyte globulin, amifostine trihydrate, aminocamptothecin, arsenic trioxide, beta alethine, Bcl-2 family protein inhibitor ABT-263, BMS-345541, bortezomib (Velcade®), bryostatin 1, busulfan, carboplatin, campath-1H, CC-5103, carmustine, caspofungin acetate, clofarabine, cisplatin, Cladribine (Leustarin), Chlorambucil (Leukeran), Curcumin, cyclosporine, Cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostin), cytarabine, denileukin diftitox, dexamethasone, DT PACE, docetaxel, dolastatin 10, Doxorubicin (Adriamycin®, Adriblastine), doxorubicin hydrochloride, enzastaurin, epoetin alfa, etoposide, Everolimus (RAD001), fenretinide, filgrastim, melphalan, mesna, Flavopiridol, Fludarabine (Fludara), Geldanamycin (17-AAG), ifosfamide, irinotecan hydrochloride, ixabepilone, Lenalidomide (Revlimid®, CC-5013), lymphokine-activated killer cells, melphalan, methotrexate, mitoxantrone hydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen (Genasense) Obatoclax (GX15-070), oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991, PEGylated liposomal doxorubicin hydrochloride, pegfilgrastim, Pentstatin (Nipent), perifosine, Prednisolone, Prednisone, R-roscovitine (Selicilib, CYC202), recombinant interferon alfa, recombinant interleukin-12, recombinant interleukin-11, recombinant flt3 ligand, recombinant human thrombopoietin, rituximab, sargramostim, sildenafil citrate, simvastatin, sirolimus, Styryl sulphones, tacrolimus, tanespimycin, Temsirolimus (CCl-779), Thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, Velcade® (bortezomib or PS-341), Vincristine (Oncovin), vincristine sulfate, vinorelbine ditartrate, Vorinostat (SAHA), vorinostat, and FR (fludarabine, rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CVP (cyclophosphamide, vincristine and prednisone), FCM (fludarabine, cyclophosphamide, mitoxantrone), FCR (fludarabine, cyclophosphamide, rituximab), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine), ICE (iphosphamide, carboplatin and etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone), R-CHOP (rituximab
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604642.1 Attorney Docket No.: 1115.PF plus CHOP), R-CVP (rituximab plus CVP), R-FCM (rituximab plus FCM), R-ICE (rituximab-ICE), and R-MCP (Rituximab-MCP). [0126] In some embodiments, the cancer is melanoma. Suitable agents for use in combination with the compounds described herein include, without limitation, dacarbazine (DTIC), optionally, along with other chemotherapy drugs such as carmustine (BCNU) and cisplatin; the "Dartmouth regimen", which consists of DTIC, BCNU, cisplatin and tamoxifen; a combination of cisplatin, vinblastine, and DTIC, temozolomide or YERVOY™. Compounds according to the invention may also be combined with immunotherapy drugs, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF) in the treatment of melanoma. [0127] Compounds described here may also be used in combination with vaccine therapy in the treatment of melanoma. Anti-melanoma vaccines are, in some ways, similar to the anti-virus vaccines which are used to prevent diseases caused by viruses such as polio, measles, and mumps. Weakened melanoma cells or parts of melanoma cells called antigens may be injected into a patient to stimulate the body's immune system to destroy melanoma cells. [0128] Melanomas that are confined to the arms or legs may also be treated with a combination of agents including one or more compounds described herein, using a hyperthermic isolated limb perfusion technique. This treatment protocol temporarily separates the circulation of the involved limb from the rest of the body and injects high doses of chemotherapy into the artery feeding the limb, thus providing high doses to the area of the tumor without exposing internal organs to these doses that might otherwise cause severe side effects. Usually the fluid is warmed to 102º to 104º F. Melphalan is the drug most often used in this chemotherapy procedure. This can be given with another agent called tumor necrosis factor (TNF). [0129] The therapeutic treatments can be supplemented or combined with any of the abovementioned therapies with stem cell transplantation or treatment. One example of modified approach is radioimmunotherapy, wherein a monoclonal antibody is combined with a radioisotope particle, such as indium In 111, yttrium Y 90, iodine I-131. Examples of combination therapies include, but are not limited to, Iodine-131
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604642.1 Attorney Docket No.: 1115.PF tositumomab (Bexxar®), Yttrium-90 ibritumomab tiuxetan (Zevalin®), Bexxar® with CHOP. [0130] Other therapeutic procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, infusion of stem cells, bone marrow ablation with stem cell support, in vitro-treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technique, pharmacological study, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and
nonmyeloablative allogeneic hematopoietic stem cell transplantation. Anti-HBV Combination Therapy [0131] In certain embodiments, a method for treating or preventing an HBV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a
therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents. In one embodiment, a method for treating an HBV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents. [0132] In certain embodiments, the present disclosure provides a method for treating an HBV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HBV infection. [0133] In one embodiment, pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional 67
604642.1 Attorney Docket No.: 1115.PF therapeutic agents, and a pharmaceutically acceptable carrier, diluent or excipient are provided. [0134] In one embodiment, kits comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents are provided. [0135] In the above embodiments, the additional therapeutic agent may be an anti-HBV agent. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of HBV combination drugs, HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), interferon alpha receptor ligands, hyaluronidase inhibitors, recombinant IL-7, hepatitis B surface antigen (HBsAg) inhibitors, compounds targeting hepatitis B core antigen (HbcAg), cyclophilin inhibitors , HBV therapeutic vaccines, HBV prophylactic vaccines, HBV viral entry inhibitors, NTCP (Na+-taurocholate cotransporting polypeptide) inhibitors, antisense
oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA), miRNA gene therapy agents, endonuclease modulators, inhibitors of ribonucleotide reductase, hepatitis B virus E antigen inhibitors, recombinant scavenger receptor A (SRA) proteins, Src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, short synthetic hairpin RNAs (sshRNAs), HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and“antibody-like” therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives), CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core or capsid protein inhibitors), stimulators of retinoic acid-inducible gene 1, stimulators of NOD2, stimulators of NOD1, Arginase-1 inhibitors, STING agonists, PI3K inhibitors, lymphotoxin beta receptor activators, Natural Killer Cell Receptor 2B4 inhibitors, Lymphocyte-activation gene 3 inhibitors, CD160 inhibitors, cytotoxic T- lymphocyte-associated protein 4 inhibitors, CD137 inhibitors, Killer cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyte attenuator inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG- Interferon Lambda, recombinant thymosin alpha-1, BTK inhibitors, modulators of TIGIT, modulators of CD47, modulators of SIRPalpha , modulators of ICOS, modulators 68
604642.1 Attorney Docket No.: 1115.PF of CD27, modulators of CD70, modulators of OX40, modulators of NKG2D, modulators of Tim-4, modulators of B7-H4, modulators of B7-H3, modulators of NKG2A, modulators of GITR, modulators of CD160, modulators of HEVEM, modulators of CD161, modulators of Axl, modulators of Mer, modulators of Tyro, gene modifiers or editors such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), Hepatitis B virus replication inhibitors compounds such as those disclosed in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), US20090047249 (Gilead Sciences), US8722054 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma),
US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma),
US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma),
US20140088085 (VentirxPharma), US20140275167 (Novira therapeutics),
US20130251673 (Novira therapeutics), US8513184 (Gilead Sciences), US20140030221 (Gilead Sciences), US20130344030 (Gilead Sciences), US20130344029 (Gilead Sciences), US20140343032 (Roche), WO2014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen), US20140330015 (Ono pharmaceutical),
US20130079327 (Ono pharmaceutical), US20130217880 (Ono pharmaceutical), and other drugs for treating HBV, and combinations thereof. [0136] In certain embodiments, the additional therapeutic is selected from the group consisting of HBV combination drugs, HBV DNA polymerase inhibitors, toll-like receptor 7 modulators, toll-like receptor 8 modulators, Toll-like receptor 7 and 8 modulators, Toll-like receptor 3 modulators, interferon alpha receptor ligands, HBsAg inhibitors, compounds targeting HbcAg, cyclophilin inhibitors, HBV therapeutic vaccines, HBV prophylactic vaccines, HBV viral entry inhibitors, NTCP inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA) , hepatitis B virus E antigen inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus, thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core or capsid protein inhibitors), stimulators of retinoic acid-inducible gene 1, stimulators of NOD2, 69
604642.1 Attorney Docket No.: 1115.PF stimulators of NOD1, recombinant thymosin alpha-1, BTK inhibitors, and hepatitis B virus replication inhibitors, and combinations thereof. [0137] In certain embodiments a compound disclosed herein is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HBV. In certain embodiments, the tablet can contain another active ingredient for treating HBV, such as HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), modulators of tlr7, modulators of tlr8, modulators of tlr7 and tlr8, interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis B surface antigen (HBsAg) inhibitors, compounds targeting hepatitis B core antigen (HbcAg), cyclophilin inhibitors , HBV viral entry inhibitors, NTCP (Na+-taurocholate cotransporting polypeptide) inhibitors, endonuclease modulators, inhibitors of ribonucleotide reductase, hepatitis B virus E antigen inhibitors, Src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, CCR2 chemokine antagonists, thymosin agonists, nucleoprotein inhibitors (HBV core or capsid protein inhibitors), stimulators of retinoic acid-inducible gene 1, stimulators of NOD2, stimulators of NOD1, Arginase-1 inhibitors, STING agonists, PI3K inhibitors, lymphotoxin beta receptor activators, Natural Killer Cell Receptor 2B4 inhibitors, Lymphocyte-activation gene 3 inhibitors, CD160 inhibitors, cytotoxic T- lymphocyte-associated protein 4 inhibitors, CD137 inhibitors, Killer cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyte attenuator inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, BTK inhibitors, modulators of TIGIT, modulators of CD47, modulators of SIRP alpha, modulators of ICOS, modulators of CD27, modulators of CD70, modulators of OX40, modulators of NKG2D, modulators of Tim-4, modulators of B7-H4, modulators of B7- H3, modulators of NKG2A, modulators of GITR, modulators of CD160, modulators of HEVEM, modulators of CD161, modulators of Axl, modulators of Mer, modulators of Tyro, and Hepatitis B virus replication inhibitors, and combinations thereof. [0138] In certain embodiments, such tablets are suitable for once daily dosing. [0139] In certain embodiments, the additional therapeutic agent is selected from one or more of:
70
604642.1 Attorney Docket No.: 1115.PF (1) Combination drugs selected from the group consisting of tenofovir disoproxil fumarate + emtricitabine (TRUVADA®); adefovir + clevudine, ABX- 203+lamivudine+PEG-IFNalpha, ABX-203+adefovir+PEG-IFNalpha and GBV- 015; (2) HBV DNA polymerase inhibitors selected from the group consisting of besifovir, entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil , tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ester, telbivudine (Tyzeka®), pradefovir, Clevudine, emtricitabine (Emtriva®), ribavirin, lamivudine (Epivir-HBV®), phosphazide, famciclovir, SNC-019754, FMCA, fusolin, AGX-1009 and metacavir; (3) Immunomodulators selected from the group consisting of rintatolimod, imidol hydrochloride, ingaron, dermaVir, plaquenil (hydroxychloroquine), proleukin, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative
mycophenolate mofetil (MMF), WF-10, ribavirin, IL-12, polymer
polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936559 and IR-103; (4) Toll-like receptor 7 modulators selected from the group consisting of GS-9620, GSK-2245035, imiquimod, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202 RG-7863 and RG-7795; (5) Toll-like receptor 8 modulators selected from the group consisting of motolimod, resiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463; (6) Toll-like receptor 3 modulators selected from the group consisting of
rintatolimod, poly-ICLC, MCT-465, MCT-475, Riboxxon, Riboxxim and ND- 1.1; (7) Interferon alpha receptor ligands selected from the group consisting of interferon alpha-2b (Intron A®), pegylated interferon alpha-2a (Pegasys®), interferon alpha 1b (Hapgen®), Veldona, Infradure, Roferon-A, YPEG-interferon alfa-2a (YPEG- rhIFNalpha-2a), P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN- co (recombinant super compound interferon), Ypeginterferon alfa-2b (YPEG- 71
604642.1 Attorney Docket No.: 1115.PF rhIFNalpha-2b), MOR-22, peginterferon alfa-2b (PEG-Intron®), Bioferon, Novaferon, Inmutag (Inferon), Multiferon®, interferon alfa-n1(Humoferon®), interferon beta-1a (Avonex®), Shaferon, interferon alfa-2b (AXXO), Alfaferone, interferon alfa-2b (BioGeneric Pharma), interferon-alpha 2 (CJ), Laferonum, VIPEG, BLAUFERON-B, BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B PDferon-B, interferon alfa-2b (IFN,
Laboratorios Bioprofarma), alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b (Zydus-Cadila), Optipeg A, Realfa 2B, Reliferon, interferon alfa-2b (Amega), interferon alfa-2b (Virchow), peginterferon alfa-2b (Amega), Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, Layfferon, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFN alpha-2b and Interapo (Interapa); (8) Hyaluronidase inhibitors selected from the group consisting of astodrimer; (9) Modulators of IL-10; (10) HBsAg inhibitors selected from the group consisting of HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP 9AC, REP-9C and REP 9AC’; (11) Toll like receptor 9 modulators selected from CYT003; (12) Cyclophilin inhibitors selected from the group consisting of OCB-030, SCY-635 and NVP-018; (13) HBV Prophylactic vaccines selected from the group consisting of Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D/T/P/HBV/M (LBVP- 0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L, DTwP- HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B prophylactic vaccine (Advax Super D), Hepatrol-07, GSK-223192A, Engerix B®, recombinant hepatitis B vaccine (intramuscular, Kangtai Biological Products), recombinant hepatitis B vaccine (Hansenual polymorpha yeast, intramuscular, Hualan Biological Engineering ), Bimmugen, Euforavac, Eutravac, anrix-DTaP-IPV-Hep B, Infanrix-DTaP-IPV-Hep B-Hib, Pentabio Vaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep B, Comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, Heberbiovac HB, Trivac HB, GerVax,
72
604642.1 Attorney Docket No.: 1115.PF DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene, SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf, Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan6, rhHBsAG vaccine, and DTaP-rHB-Hib vaccine; (14) HBV Therapeutic vaccines selected from the group consisting of HBsAG-HBIG complex, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine (epsilonPA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2, CVI-HBV-002, AltraHepB, VGX-6200, FP-02, TG-1050, NU-500, HBVax, im/TriGrid/antigen vaccine, Mega-CD40L-adjuvanted vaccine, HepB-v, NO- 1800, recombinant VLP-based therapeutic vaccine (HBV infection, VLP
Biotech), AdTG-17909, AdTG-17910 AdTG-18202, ChronVac-B, and Lm HBV; (15) HBV viral entry inhibitor selected from the group consisting of Myrcludex B; (16) Antisense oligonucleotide targeting viral mRNA selected from the group
consisting of ISIS-HBVRx; (17) Short interfering RNAs (siRNA) selected from the group consisting of TKM- HBV (TKM-HepB), ALN-HBV, SR-008, ddRNAi and ARC-520; (18) Endonuclease modulators selected from the group consisting of PGN-514; (19) Inhibitors of ribonucleotide reductase selected from the group consisting of
Trimidox; (20) Hepatitis B virus E antigen inhibitors selected from the group consisting of
wogonin; (21) HBV antibodies targeting the surface antigens of the hepatitis B virus selected from the group consisting of GC-1102, XTL-17, XTL-19, XTL-001, KN-003 and fully human monoclonal antibody therapy (hepatitis B virus infection, Humabs BioMed); (22) HBV antibodies including monoclonal antibodies and polyclonal antibodies selected from the group consisting of Zutectra, Shang Sheng Gan Di, Uman Big (Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B, 73
604642.1 Attorney Docket No.: 1115.PF igantibe, Niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4, HBV infection, Shanghai RAAS Blood Products) and Fovepta (BT-088); (23) CCR2 chemokine antagonists selected from the group consisting of
propagermanium; (24) Thymosin agonists selected from the group consisting of Thymalfasin; (25) Cytokines selected from the group consisting of recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex); recombinant human interleukin-2 (Shenzhen Neptunus) and celmoleukin; (26) Nucleoprotein inhibitors (HBV core or capsid protein inhibitors) selected from the group consisting of NVR-1221, NVR-3778, BAY 41-4109, morphothiadine mesilate and DVR-23; (27) Stimulators of retinoic acid-inducible gene 1 selected from the group consisting of SB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI- 9198 and ORI-7170; (28) Stimulators of NOD2 selected from the group consisting of SB-9200; (29) Recombinant thymosin alpha-1 selected from the group consisting of NL-004 and PEGylated thymosin alpha 1; (30) Hepatitis B virus replication inhibitors selected from the group consisting of isothiafludine, IQP-HBV, RM-5038 and Xingantie; (31) PI3K inhibitors selected from the group consisting of idelalisib, AZD-8186, buparlisib, CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, UCB-5857, taselisib, XL-765, gedatolisib, VS- 5584, copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423, panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-040093, pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319, RP- 6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414, SAR- 260301 and CLR-1401; (32) cccDNA inhibitors selected from the group consisting of BSBI-25; 74
604642.1 Attorney Docket No.: 1115.PF (33) PD-L1 inhibitors selected from the group consisting of MEDI-0680, RG-7446, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL, STI- A1014 and BMS-936559; (34) PD-1 inhibitors selected from the group consisting of nivolumab,
pembrolizumab, pidilizumab, BGB-108 and mDX-400; (35) BTK inhibitors selected from the group consisting of ACP-196, dasatinib,
ibrutinib, PRN-1008, SNS-062, ONO-4059, BGB-3111, MSC-2364447, X-022, spebrutinib, TP-4207, HM-71224, KBP-7536 and AC-0025; (36) Other drugs for treating HBV selected from the group consisting of gentiopicrin (gentiopicroside), nitazoxanide, birinapant, NOV-205 (Molixan; BAM-205), Oligotide, Mivotilate, Feron, levamisole, Ka Shu Ning, Alloferon, WS-007, Y- 101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106,
Hepbarna, IBPB-006IA, Hepuyinfen, DasKloster 0014-01, Jiangantai
(Ganxikang), picroside, GA5 NM-HBV, DasKloster-0039, hepulantai, IMB- 2613, TCM-800B, reduced glutathione and ZH-2N; and (37) The compounds disclosed in US20100143301 (Gilead Sciences),
US20110098248 (Gilead Sciences), US20090047249 (Gilead Sciences), US8722054 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen),
WO2014/128189 (Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array
Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma),
US20140088085 (VentirxPharma), US20140275167 (Novira therapeutics), US20130251673 (Novira therapeutics) , US8513184 (Gilead Sciences),
US20140030221 (Gilead Sciences), US20130344030 (Gilead Sciences), US20130344029 (Gilead Sciences), US20140343032 (Roche), WO2014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen), 75
604642.1 Attorney Docket No.: 1115.PF US20140330015 (Ono pharmaceutical), US20130079327 (Ono pharmaceutical), and US20130217880 (Ono pharmaceutical) . [0140] In certain embodiments, a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and/or they can be selected from different classes of therapeutic agents. [0141] In a specific embodiment, a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor. In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor and at least one additional therapeutic agent selected from the group consisting of: immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), interferon alpha receptor ligands, hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, compounds targeting HbcAg, cyclophilin inhibitors , HBV therapeutic vaccines, HBV prophylactic vaccines HBV viral entry inhibitors, NTCP inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA), miRNA gene therapy agents, endonuclease modulators, inhibitors of ribonucleotide reductase, Hepatitis B virus E antigen inhibitors, recombinant scavenger receptor A (SRA) proteins, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, short synthetic hairpin RNAs (sshRNAs), HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and“antibody-like” therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives), CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core or capsid protein inhibitors), stimulators of retinoic acid-inducible gene 1, stimulators of NOD2, 76
604642.1 Attorney Docket No.: 1115.PF stimulators of NOD1, Arginase-1 inhibitors, STING agonists, PI3K inhibitors, lymphotoxin beta receptor activators, Natural Killer Cell Receptor 2B4 inhibitors, Lymphocyte-activation gene 3 inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte- associated protein 4 inhibitors, CD137 inhibitors, Killer cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyte attenuator inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG-Interferon Lambda, recombinant thymosin alpha-1, BTK inhibitors, modulators of TIGIT, modulators of CD47, modulators of SIRPalpha , modulators of ICOS, modulators of CD27, modulators of CD70, modulators of OX40, modulators of NKG2D, modulators of Tim-4, modulators of B7-H4, modulators of B7-H3, modulators of NKG2A, modulators of GITR, modulators of CD160, modulators of HEVEM, modulators of CD161, modulators of Axl, modulators of Mer, modulators of Tyro, gene modifiers or editors such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), and Hepatitis B virus replication inhibitors. [0142] In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent selected from the group consisting of: immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and“antibody-like” therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, PD-1 inhibitors, PD-L1 inhibitors, Arginase-1 inhibitors, PI3K inhibitors and stimulators of NOD2. [0143] In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent selected from the group consisting of: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigens of the hepatitis B virus, short interfering RNAs (siRNA), miRNA gene therapy agents, short synthetic hairpin RNAs (sshRNAs), and nucleoprotein inhibitors (HBV core or capsid protein inhibitors). 77
604642.1 Attorney Docket No.: 1115.PF [0144] In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor, one or two additional therapeutic agents selected from the group consisting of: immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and“antibody-like” therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, PD-1 inhibitors, PD-L1 inhibitors, Arginase-1 inhibitors, PI3K inhibitors and stimulators of NOD2, and one or two additional therapeutic agents selected from the group consisting of: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigens of the hepatitis B virus, short interfering RNAs (siRNA), miRNA gene therapy agents, short synthetic hairpin RNAs (sshRNAs), and
nucleoprotein inhibitors (HBV core or capsid protein inhibitors). [0145] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents selected from adefovir (Hepsera®), tenofovir disoproxil fumarate + emtricitabine (TRUVADA®), tenofovir disoproxil fumarate (Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide
hemifumarate, telbivudine (Tyzeka®), Clevudine®, emtricitabine (Emtriva®), peginterferon alfa-2b (PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferon alpha-2b (Intron A®), pegylated interferon alpha-2a (Pegasys®), interferon alfa-n1(Humoferon®), ribavirin, interferon beta-1a (Avonex®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alfa-2b (AXXO), Alfaferone, interferon alfa-2b (BioGeneric Pharma), Feron, interferon-alpha 2 (CJ), BEVAC, Laferonum, VIPEG, BLAUFERON-B, BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, interferon alfa-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b (Zydus-Cadila), Optipeg A, Realfa 2B, Reliferon, interferon alfa-2b (Amega), interferon alfa-2b (Virchow), peginterferon alfa-2b (Amega), Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b (Changchun Institute of Biological Products), 78
604642.1 Attorney Docket No.: 1115.PF Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Alloferon and celmoleukin; [0146] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®). [0147] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®). [0148] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: entecavir (Baraclude®), adefovir
(Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide
hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®) and at least a second additional therapeutic agent selected from the group consisting of
immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), interferon alpha receptor ligands, hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, compounds targeting HbcAg, cyclophilin inhibitors , HBV Therapeutic vaccines, HBV prophylactic vaccines, HBV viral entry inhibitors, NTCP inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA), miRNA gene therapy agents, endonuclease modulators, inhibitors of ribonucleotide reductase, Hepatitis B virus E antigen inhibitors, recombinant scavenger receptor A (SRA) proteins, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, short synthetic hairpin RNAs (sshRNAs), HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and“antibody-like” therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives), CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core or capsid protein
79
604642.1 Attorney Docket No.: 1115.PF inhibitors), stimulators of retinoic acid-inducible gene 1, stimulators of NOD2, stimulators of NOD1, recombinant thymosin alpha-1, Arginase-1 inhibitors, STING agonists, PI3K inhibitors, lymphotoxin beta receptor activators, Natural Killer Cell Receptor 2B4 inhibitors, Lymphocyte-activation gene 3 inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte-associated protein 4 inhibitors, CD137 inhibitors, Killer cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T- lymphocyte attenuator inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG-Interferon Lambd, BTK inhibitors, modulators of TIGIT, modulators of CD47, modulators of SIRPalpha , modulators of ICOS, modulators of CD27, modulators of CD70, modulators of OX40, modulators of NKG2D, modulators of Tim-4, modulators of B7-H4, modulators of B7-H3, modulators of NKG2A, modulators of GITR, modulators of CD160, modulators of HEVEM, modulators of CD161, modulators of Axl, modulators of Mer, modulators of Tyro, gene modifiers or editors such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), a and Hepatitis B virus replication inhibitors. [0149] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: entecavir (Baraclude®), adefovir
(Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide
hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®) and at least a second additional therapeutic agent selected from the group consisting of peginterferon alfa-2b (PEG-Intron®), Multiferon®, interferon alpha 1b (Hapgen®), interferon alpha- 2b (Intron A®), pegylated interferon alpha-2a (Pegasys®), interferon alfa- n1(Humoferon®), ribavirin, interferon beta-1a (Avonex®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alfa-2b
(AXXO), Alfaferone, interferon alfa-2b (BioGeneric Pharma), Feron, interferon-alpha 2 (CJ), BEVAC, Laferonum, VIPEG, BLAUFERON-B, BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, interferon alfa-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b (Zydus-Cadila), Optipeg A, Realfa 2B, Reliferon, interferon alfa-2b (Amega), interferon alfa-2b (Virchow), peginterferon alfa-2b (Amega), Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b (Changchun Institute of Biological Products), 80
604642.1 Attorney Docket No.: 1115.PF Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Alloferon and celmoleukin; [0150] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: entecavir (Baraclude®), adefovir
(Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide
hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®) and at least a second additional therapeutic agent selected from the group consisting of
immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and“antibody-like” therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, Arginase-1 inhibitors, PI3K inhibitors, PD-1 inhibitors, PD-L1 inhibitors and stimulators of NOD2. [0151] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: entecavir (Baraclude®), adefovir
(Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide
hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®) and at least a second additional therapeutic agent selected from the group consisting of HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigens of the hepatitis B virus, short interfering RNAs (siRNA), miRNA gene therapy agents, short synthetic hairpin RNAs (sshRNAs), and
nucleoprotein inhibitors (HBV core or capsid protein inhibitors). [0152] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: entecavir (Baraclude®), adefovir
(Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir,
81
604642.1 Attorney Docket No.: 1115.PF tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide
hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®), one or two additional therapeutic agents selected from the group consisting of: immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV antibodies targeting the surface antigens of the hepatitis B virus and bispecific antibodies and“antibody-like” therapeutic proteins (such as
DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab derivatives), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, PD-1 inhibitors, PD-L1 inhibitors, Arginase-1 inhibitors, PI3K inhibitors and stimulators of NOD2, and one or two additional therapeutic agents selected from the group consisting of: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigens of the hepatitis B virus, short interfering RNAs (siRNA), miRNA gene therapy agents, short synthetic hairpin RNAs (sshRNAs), and
nucleoprotein inhibitors (HBV core or capsid protein inhibitors). [0153] In certain embodiments, a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, is combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, is combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. A compound as disclosed herein (e.g., a compound of formula (I)) may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed. [0154] In certain embodiments, a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, is combined with 100-400 mg tenofovir 82
604642.1 Attorney Docket No.: 1115.PF disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 100-150; 100-200, 100-250; 100-300; 100-350; 150-200; 150- 250; 150-300; 150-350; 150-400; 200-250; 200-300; 200-350; 200-400; 250-350; 250- 400; 350-400 or 300-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 250 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 150 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. A compound as disclosed herein (e.g., a compound of formula (I)) may be combined with the agents provided herein in any dosage amount of the compound (e.g., from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed. [0155] In certain embodiments, when a compound disclosed herein is combined with one or more additional therapeutic agents as described above, the components of the composition are administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. [0156] In certain embodiments, a compound disclosed herein is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration. [0157] In certain embodiments, a compound disclosed herein is administered with one or more additional therapeutic agents. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of the compound disclosed herein and one or more additional therapeutic agents are both present in the body of the patient.
83
604642.1 Attorney Docket No.: 1115.PF [0158] Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by
administration of a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound disclosed herein. Anti-HIV Combination Therapy [0159] In certain embodiments, a method for treating or preventing an HIV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a
therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents. In one embodiment, a method for treating an HIV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents. [0160] In certain embodiments, the present disclosure provides a method for treating an HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HIV infection.
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604642.1 Attorney Docket No.: 1115.PF [0161] In one embodiment, pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent or excipient are provided. [0162] In one embodiment, kits comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents are provided. [0163] In the above embodiments, the additional therapeutic agent may be an anti- HIV agent. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gpl20 inhibitors, G6PD and NADH- oxidase inhibitors, compounds that target the HIV capsid ("capsid inhibitors"; e.g., capsid polymerization inhibitors or capsid disrupting compounds such as those disclosed in WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), and WO 2013/006792 (Pharma Resources), pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof. [0164] In further embodiments, the additional therapeutic agent is selected from one or more of: (1) HIV protease inhibitors selected from the group consisting of amprenavir,
atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfmavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L- 756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35, and AG 1859; (2) HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC- 85
604642.1 Attorney Docket No.: 1115.PF 963, MIV-150, TMC-120, rilpivirene, BILR 355 BS, VRX 840773, lersivirine (UK-453061), RDEA806, KM023 and MK-1439; (3) HIV nucleoside or nucleotide inhibitors of reverse transcriptase selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, abavavir sulfate, amdoxovir, elvucitabine, alovudine, MIV- 210, ±- FTC, D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil, apricitibine (AVX754), KP-1461, GS-9131 (Gilead Sciences) and fosalvudine tidoxil (formerly HDP 99.0003), tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide (Gilead Sciences), tenofovir alafenamide hemifumarate (Gilead Sciences), GS-9148 (Gilead Sciences), adefovir, adefovir dipivoxil, CMX-001 (Chimerix) or CMX-157 (Chimerix); (4) HIV integrase inhibitors selected from the group consisting of curcumin,
derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5- dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-1360, AR- 177, L-870812, and L-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK- 2048, BA 011, elvitegravir, dolutegravir and GSK-744; (5) HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) including, but not limited to, BI-224436, CX0516, CX05045, CX14442, compounds disclosed in WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2012/003498 (Gilead Sciences) each of which is incorporated by references in its entirety herein; (6) gp41 inhibitors selected from the group consisting of enfuvirtide, sifuvirtide, albuvirtide, FB006M, and TRI-1144; (7) the CXCR4 inhibitor AMD-070; (8) the entry inhibitor SP01A; (9) the gpl20 inhibitor BMS-488043; 86
604642.1 Attorney Docket No.: 1115.PF (10) the G6PD and NADH-oxidase inhibitor immunitin; (11) CCR5 inhibitors selected from the group consisting of aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5mAb004; (12) CD4 attachment inhibitors selected from the group consisting of ibalizumab (TMB-355) and BMS-068 (BMS-663068); (13) pharmacokinetic enhancers selected from the group consisting of cobicistat and SPI-452; and (14) other drugs for treating HIV selected from the group consisting of BAS-100, SPI- 452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimat), HRG214, VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA- 1050040 (PA-040), and combinations thereof . [0165] In certain embodiments, the additional therapeutic agent is a Toll-like receptor 8 modulator selected from the group consisting of motolimod, resiquimod, 3M- 051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463 and those disclosed in US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma),
US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (VentirxPharma), US20140275167 (Novira therapeutics),
US20130251673 (Novira therapeutics). [0166] In certain embodiments, a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt
87
604642.1 Attorney Docket No.: 1115.PF thereof, is combined with four additional therapeutic agents. The two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, or they can be selected from different classes of therapeutic agents. In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In a further
embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In an additional embodiment, a compound disclosed herein, or a
pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two HIV nucleoside or nucleotide inhibitor of reverse transcriptase. [0167] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate. [0168] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate. [0169] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent selected from the group consisting of emtricitibine and lamivudine. In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic
88
604642.1 Attorney Docket No.: 1115.PF agent selected from the group consisting of: tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitibine. [0170] In certain embodiments, when a compound disclosed herein is combined with one or more additional therapeutic agents as described above, the components of the composition are administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. [0171] In certain embdoiments, a compound disclosed herein is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration. [0172] In certain embodiments, a compound disclosed herein is administered with one or more additional therapeutic agents. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of the compound disclosed herein and one or more additional therapeutic agents are both present in the body of the patient. [0173] Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by
administration of a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered 89
604642.1 Attorney Docket No.: 1115.PF first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound disclosed herein. Kits [0174] Provided herein are also kits that include a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and suitable packaging. In one embodiment, a kit further includes instructions for use. In one aspect, a kit includes a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a label and/or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein. [0175] Provided herein are also articles of manufacture that include a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag. Pharmaceutical Compositions and Modes of Administration
[0176] Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provides herein are also pharmaceutical compositions that contain one or more of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa.17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc.3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.). [0177] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra- 90
604642.1 Attorney Docket No.: 1115.PF arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant. [0178] One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. [0179] Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders. [0180] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and
propylhydroxy-benzoates; sweetening agents; and flavoring agents. [0181] The compositions that include at least one compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug 91
604642.1 Attorney Docket No.: 1115.PF delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos.3,845,770;
4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present invention employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos.5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. [0182] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. [0183] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate. [0184] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable
pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic
92
604642.1 Attorney Docket No.: 1115.PF effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. Dosing
[0185] The specific dose level of a compound of the present application for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject. [0186] The daily dosage may also be described as a total amount of a compound described herein administered per dose or per day. Daily dosage of a compound of Formula I may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about 10 to 500 mg/day, between about 20 to 500 mg/day, between about 50 to 300 mg/day, between about 75 to 200 mg/day, or between about 15 to 150 mg/day. [0187] When administered orally, the total daily dosage for a human subject may be between 1 mg and 1,000 mg, between about 10-500 mg/day, between about 50-300 mg/day, between about 75-200 mg/day, or between about 100-150 mg/day. [0188] The compounds of the present application or the compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode 93
604642.1 Attorney Docket No.: 1115.PF described above. Also, administration or treatment with the compounds may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known in cancer chemotherapy, and are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous. [0189] In a particular embodiment, the method comprises administering to the subject an initial daily dose of about 1 to 500 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week. Synthesis of the Compounds of Formula I [0190] The compounds may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers. General Synthesis [0191] Typical embodiments of compounds described herein may be synthesized using the general reaction schemes described below. It will be apparent given the description herein that the general schemes may be altered by substitution of the starting materials with other materials having similar structures to result in products that are correspondingly different. Descriptions of syntheses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Given a desired product for which the substituent groups are defined, the necessary starting materials generally may be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. For synthesizing compounds which are embodiments described in the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of
94
604642.1 Attorney Docket No.: 1115.PF each substituent group. The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein. In general, compounds described herein are typically stable and isolatable at room temperature and pressure. Synthetic Reaction Parameters [0192] The compounds of this disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [0193] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein. [0194] Furthermore, the compounds of this disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer- enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like. [0195] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers
95
604642.1 Attorney Docket No.: 1115.PF such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). [0196] The terms“solvent”,“inert organic solvent”, or“inert solvent” refer to a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or
dichloromethane), diethyl ether, methanol, and the like). Unless specified to the contrary, the solvents used in the reactions of the present invention are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen. [0197] The term“q.s.” means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%). Compounds of Formula I [0198] The compounds of Formula I may prepared by first providing the substituted imidazo[4,5-b]pyridine or benzimidazole core, and optionally further modifying the core as desired to provide the substituents disclosed herein. [0199] Scheme 1 shows the preparation of compounds of Formula I, where m, n,
L, R1, R2a, R2b, and X are as defined herein, or a functional gro
Figure imgf000098_0001
n conditions and protection/deprotection steps as required.
96
604642.1 Attorney Docket No.: 1115.PF Scheme 1
Figure imgf000099_0001
Figure imgf000099_0002
[0200] In Scheme 1, suitably substituted 1-a and 1-b are coupled and cyclized in a suitable solvent (e.g., formic acid, ethanol, etc.) at an elevated temperature (typically about 80-100 °C) to provide the imidazo[4,5-b]pyridine or benzimidazole core 1-c. 1-c is then converted to the corresponding thioamide 1-d using Lawesson’s reagent (i.e., 2,4- bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide) under standard conditions. 1-e is obtained by cyclization of the thioamide 1-d using hydroxylamine. Hydrolysis of 1-e to obtain compound 1-f is achieved by reaction with a suitable base (e.g., NaOH). Alternately, 1-c is transformed to compound 1-f using phosphorous pentachloride, followed by treatment with aqueous hydroxylamine. [0201] Scheme 2 shows the synthesis of compounds of Formula I where Rt is hydrogen, and R1, R2a, R2b, and X are as defined herein.
97
604642.1 Attorney Docket No.: 1115.PF Scheme 2
Figure imgf000100_0001
[0202] In Scheme 2, 2-a is nitrated using fuming nitric acid to provide 2-b, which is then cyclized to provide C-2 unsubstituted imidazo[4,5-b]pyridine or benzimidazole 2- c under reducing conditions (e.g., zinc, iron, etc.). Amide 2-e is provided by reacting the corresponding ester 2-c with a suitable amine 2-d under standard amide bond forming reaction conditions, and is then converted to compounds of Formula I using the methods shown above in Scheme 1. [0203] Scheme 3 shows the synthesis of compounds of Formula I where Rt is– NH2, and R1, R2a, R2b, and X are as defined herein. Scheme 3
Figure imgf000100_0002
[0204] In Scheme 3, 3-b is obtained by reaction of 3-a with cyanogen bromide. Amide 3-d is provided by reacting the corresponding ester 3-b with a suitable amine 3-c under standard amide bond forming reaction conditions, and is then converted to compounds of Formula I using the methods shown above in Scheme 1. [0205] In certain embodiments, the process may comprise protection and deprotection/further modification of R4 (Scheme 1) to provide the desired
98
604642.1 Attorney Docket No.: 1115.PF
group in the compound of Formula I. Scheme 4 shows an
Figure imgf000101_0001
/deprotection or further modification to provide compounds of Formula I, where Rt, Rm, m, L, R1, R2a, R2b, and X are as defined herein. Scheme 4
Figure imgf000101_0002
[0206] In Scheme 4, suitably substituted 4-a can be protected to provide 4-b using a suitable proecting group PG, such as a silyl ether (see, e.g., T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein). 4-b is then converted to the corresponding thioamide 4-c and cyclized using hydroxylamine as shown above in Scheme 1 to provide 4-d. 4-d can then be coverted to compound 4-e by deprotectiona and optional further modification. For example, 4-d can be deprotected and converted to a suitable leaving group (e.g., a TMS-O- group) and then reacted with a suitable amine to provide compounds of formula 4-e where L is–NR3-. 4-e is then converted to compounds of Formula I using the methods shown above in Scheme 1. [0207] Each of the intermediates in the above schemes may be isolated and/or purified prior to the subsequent step, or used in the next step without purification and/or 99
604642.1 Attorney Docket No.: 1115.PF isolation. It will also be appreciated that the addition of any substituent may result in the production of a number of isomeric products any or all of which may be isolated and purified using conventional techniques. EXAMPLES
[0208] The following examples are included to demonstrate specific
embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. List of Abbreviations and Acronyms Abbreviation Meaning
% Percent
°C Degree Celsius
A2B Adenosine A2B receptor
Ac Acetyl
ACN/CH3CN/MeCN Acetonitrile
ADME Absorption, distribution, metabolism and excretion AlMe3 Trimethylaluminum
APECED Autoimmune polyendocrinopathy-candidiasis- ectodermal dystrophy
ASK Apoptosis signal-regulating kinase
BAPN Beta-aminoproprionitrile
BCNU Carmustine
bicarb Bicarbonate
br Broad
BRD Bromodomain containing protein inhibitor
BTK Bruton’s tyrosine kinase 100
604642.1 Attorney Docket No.: 1115.PF BTK Bruton's tyrosine kinase
CAS Chemical Abstract Service
cccDNA Covalently closed circular DNA
CCR C-C chemokine receptor
CD Cluster of differentiation
CHOP Cyclophosphamide
CNS Central nervous system
COPD Chronic obstructive pulmonary disease
CREST Calcinosis, Raynaud's syndrome, esophageal
dysmotility, sclerodactyly and telangiectasia CRISPR Clustered regularly interspaced short palindromic repeats
CVP Cyclophosphamide, vincristine, prednisone d Doublet
D Deuterium
D.T. PACE Dexamethasone, thalidomide, cisplatin, Adriamycin®, cyclophosphamide, etoposide
D/d Deuterium
DABAL-Me3 Bis(trimethylaluminum)-DABCO® adduct
DABCO® 1,4-Diazabicyclo[2.2.2]octane
DCE Dichloroethane
DCM/CH2Cl2 Dichloromethane/methylene chloride
dd Doublet of doublets
DDR Discoidin domain receptor
DIPEA/DIEA N,N-Diisopropylethylamine
DMF Dimethylformamide
DMFO Difluoromethylornithine
DMPK Drug metabolism and pharmacokinetics
DMSO Dimethylsulfoxide
DTIC Dacarbazine
EC50 The half maximal effective concentration
101
604642.1 Attorney Docket No.: 1115.PF EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide equiv/eq Equivalents
Et Ethyl
Et3N Triethylamine
EtOAc/AcOEt Ethylacetate
EtOH Ethanol
F Fahrenheit
Fab Fragment antigen-binding
FBS Fetal bovine serum
FCM Fludarabine, cyclophosphamide, mitoxantrone FCR Fludarabine, cyclophosphamide, rituximab
FOLFIRI Fluorouracil, leucovorin, and irinotecan
FR Fludarabine, rituximab
g Grams
GITR Glucocorticoid-induced TNFR-related protein
Gp Glycoprotein
h/hr Hours
HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) HbcAg Hepatitis B core antigen
HBsAg Hepatitis B surface antigen
HBV Hepatitis B virus
HBx Hepatitis B viral protein
HDAC Histone deacetylase
hex Hexanes
HOBt Hydroxybenzotriazole
HPLC High pressure liquid chromatography
hyperCVAD Hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine Hz Hertz 102
604642.1 Attorney Docket No.: 1115.PF ICE Iphosphamide, carboplatin, etoposide
ICOS Inducible T-cell COStimulator
IDH Isocitrate dehydrogenase
IDO1 Indoleamine 2,3-dioxygenase 1
IL Interleukin
INCB24360 Epacadostat
IUPAC International Union of Pure and Applied Chemistry J Coupling constant (MHz)
JAK Janus kinase
Kg/kg Kilogram
LACA 1-Azetidine-2-carboxylic acid
LCMS/LC-MS Liquid chromatography–mass spectrometry LET Linear energy transfer
LOX Lysyl oxidase protein
LOXL Lysyl oxidase-like protein
M Molar
m multiplet
M+ Mass peak
M+H Mass peak plus hydrogen
MCP Mitoxantrone, chlorambucil, and prednisolone Me Methyl
mg Milligram
MHz Megahertz
min/m Minute
miRNA MicroRNA
ml/mL Milliliter
mM Millimolar
MMF Ester derivative mycophenolate mofetil mmol Millimole 103
604642.1 Attorney Docket No.: 1115.PF MMP Matrix metalloprotease
mol Mole
MPA Mycophenolate mofetil
MS Mass spectroscopy
MS Multiple sclerosis
N Normal
NADH Nicotinamide adenine dinucleotide in reduced form NCINI Non-catalytic site, or allosteric, integrase inhibitors NCS N-Chlorosuccinimide
ng Nanograms
nM NanoMolar
NMR Nuclear magnetic resonance
NOD Nucleotide-binding oligomerization domain-containing protein
NTCP Na+-taurocholate cotransporting polypeptide
PD Programmed cell death
PdCl2(dppf) [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II), PdCl2(PPh3)2 Bis(triphenylphosphine)palladium(II) dichloride PD-L Programmed death-ligand
PEG Polyethylene glycol
PEI Polymer polyethyleneimine
PET Positron emission tomography
Ph Phenyl
PI3K Phosphoinositide 3-kinase
PKC Protein kinase C
prep Preparative
q.s. Quantity sufficient to achieve a stated function
RA Rheumatoid arthritis
R-CHOP Rituximab-CHOP (Rituximab plus CHOP) 104
604642.1 Attorney Docket No.: 1115.PF R-CVP Rituximab-CVP (Rituximab plus CVP) Rf Retention factor
R-FCM Rituximab plus FCM
R-hyperCVAD Rituximab-hyperCVAD
R-ICE Rituximab-ICE
R-MCP Rituximab-MCP
RPM Revolutions per minute
rSIFN-co Recombinant super compound interferon RT/rt Room temperature
s Second
s Singlet
SAHA Vorinostat
sat. Saturated
SEM 2-(Trimethylsilyl)ethoxymethyl
SERMs Selective estrogen receptor modulators siRNA Short interfering RNAs
SIRP Signal-regulatory protein
SLE Systemic lupus erythematosus
SPECT Single-photon emission computed tomography SRA Scavenger receptor A
Src Proto-oncogene tyrosine-protein kinase sshRNAs Short synthetic hairpin RNAs
STING Sequence To and withIN Graphics
SYK Spleen tyrosine kinase
t Triplet
TALENs Transcription activator-like effector nucleases TBAF Tetra-n-butylammonium fluoride
TCA Trichloroacetic acid
TEA Triethylamine 105
604642.1 Attorney Docket No.: 1115.PF temp. Temperature
TFA Trifluoroacetic acid
THF Tetrahydrofuran
TIGIT T cell immunoreceptor with Ig and ITIM domains
TIM T-cell immunoglobulin and mucin domain
TKM-HBV TKM-HepB
Tlr Toll-like receptor modulators
TNF Tumor necrosis factor
TPL2 Serine/threonine kinase
Vac Vacuum
w/v Weight/volume
w/w Weight/weight
YPEG-rhIFNalpha-2a PEG-interferon alfa-2a
YPEG-rhIFNalpha-2b Ypeginterferon alfa-2b
δ Chemical shift (ppm)
µg Microgram
µL/ µl Microliter
µM Micromolar
µm Micrometer
µmol Micromole
Example 1: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-4-methyl-1H- benzo[d]imidazole-7-carboximidamide
Figure imgf000108_0001
Methyl 3-formamido-4-methylbenzoate. A solution of methyl -3-amino-4- methylbenzoate (5.1 g, 31 mmol) in formic acid (42 mL) was stirred at 110 °C for 4 hr. The reaction mixture was allowed to cool to room temp. Water was added and the 106
604642.1 Attorney Docket No.: 1115.PF aqueous layer was washed three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the desired product. C10H11NO3.194.0 (M+1). O O
Figure imgf000109_0001
ethyl 3-formamido-4-methyl-2-nitrobenzoate. Methyl 3-formamido-4- methylbenzoate (5.3 g, 27 mmol) was added to fuming nitric acid at 0 °C portion wise over 45 min. The reaction mixture was stirred at 0 °C for an additional 1 h, and then ice was added and the mixture stirred for 1.5 h at room temperature. The precipitated solid was filtered, and washed with water. The solid was purified by silica gel to give the desired product. C10H10N2O5.239.0 (M+1).
Figure imgf000109_0002
Methyl 4-methyl-1H-benzo[d]imidazole-7-carboxylate. A mixture of methyl 3-formamido-4-methyl-2-nitrobenzoate (1.0 g, 4.2 mmol) and iron (1.2 g, 21 mmol) in methanol (10 mL) and acetic acid (5 mL) was stirred at 70 °C for 3 hr. To the cooled reaction mixture was added ethyl acetate and water and the mixture was filtered and the solid was washed with ethyl acetate. The aqueous layer was washed two times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the desired product. C10H10N2O2.191.1 (M+1).
Figure imgf000109_0003
chloro-4-fluorophenyl)-4-methyl-1H-benzo[d]imidazole-7- carboxamide. To a solution of the 3-chloro-4-fluoroanilinein (253 mg, 1.74 mmol) dichloroethane at 0 °C under nitrogen was added trimethylaluminum (2 M in heptane, 107
604642.1 Attorney Docket No.: 1115.PF 1.74 mL, 3.47 mmol) dropwise over 5 min. The solution was allowed to warm to room temperature and stirred for 30 min. The solution was cooled to 0 °C and to this solution was added methyl 4-methyl-1H-benzo[d]imidazole-7-carboxylate (220 mg, 1.16 mmol). The solution was stirred at 85 °C for 6 hr and, then, cooled to room temperature. To the mixture was added ethyl acetate and 10% citric acid and the resulting precipitate was filtered and dried on high vac to give the desired product. C15H11ClFN3O.304.4 (M+1).
Figure imgf000110_0001
chloro-4-fluorophenyl)-N'-hydroxy-4-methyl-1H- benzo[d]imidazole-7-carboximidamide. A mixture of N-(3-chloro-4-fluorophenyl)-4- methyl-1H-benzo[d]imidazole-7-carboxamide (154 mg, 0.507 mmol), phosphorous pentachloride (158 mg, 0.761 mmol) in phosphoryl chloride (1.5 mL) and 1,2- dichloroethane (1.5 mL) were stirred at 80 °C for 2.5 hr. The reaction mixture was concentrated and suspended in ethanol (1.5 mL) and to this mixture was added 50% hydroxylamine in water (0.311 mL, 5.07 mmol). The reaction mixture stirred for 1 hr and was concentrated. The residue was purified by preparative HPLC to give the desired product. C15H12ClFN4O.319.1 (M+1). Example 2: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-4-(trifluoromethoxy)-1H- benzo[d]imidazole-7-carboximidamide
Figure imgf000110_0002
[0214] Nitric acid (18 mL) was cooled to -10 °C in a dry ice/acetone bath and methyl 2-formamido-4-(trifluoromethoxy)benzoate (1.97 g, 7.0 mol) was added and the reaction was allowed to stir for 4 hours at -10 °C. The reaction was slowly quenched with water (20 mL) and extracted with EtOAc (3x 10 mL). Combined organic layers 108
604642.1 Attorney Docket No.: 1115.PF were washed with brine (1 x 30 mL) and concentrated in vacuo to give methyl 2- formamido-3-nitro-4-(trifluoromethoxy)benzoate as a mixture of isomers. [0215] Methyl 2-formamido-3-nitro-4-(trifluoromethoxy)benzoate (2.2 g, 7.0 mmol) was dissolved in ethanol (15 mL) and water (5 mL). Ammonium chloride (0.108 mol) was added in one portion and the reaction was allowed to stir at room temperature. Zinc powder (0.108 mol) was added portion-wise over 5 minutes and the reaction was allowed to stir 5 minutes after completion of addition. The zinc was then removed by vacuum filtration and the filtrate was concentrated in vacuo. The crude was dissolved in water (20 mL) and extracted with EtOAc (4 x 10 mL). Combined organic layers were washed with brine (1 x 50 mL), dried over sodium sulfate, and concentrated in vacuo to give methyl 3-amino-2-formamido-4-(trifluoromethoxy)benzoate. [0216] Methyl 3-amino-2-formamido-4-(trifluoromethoxy)benzoate (1.32 g, 5.0 mmol) was dissolved in formic acid (15 mL) and heated to 80 °C for 1 hour. The reaction was cooled to rt, concentrated in vacuo, and quenched with saturated sodium bicarbonate solution (10 mL). The mixture was extracted with EtOAc (4x5 mL) and combined organic layers were washed with brine (1x15 mL) and concentrated in vacuo. Crude material was purified by column chromatography to give methyl 4- (trifluoromethoxy)-1H-benzo[d]imidazole-7-carboxylate.
Figure imgf000111_0001
Chloro-4-fluorophenyl)-N'-hydroxy-4-(trifluoromethoxy)-1H- benzo[d]imidazole-7-carboximidamide. Example 2 was made analogously to Example 10 using methyl 4-(trifluoromethoxy)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 4,5-difluoro-1H-benzo[d]imidazole-7-carboxylate. C15H9ClF4N4O2. 389.0/391.1 (M+1).
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604642.1 Attorney Docket No.: 1115.PF Example 3: N-(3-Chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-1H- benzo[d]imidazole-7-carboximidamide
Figure imgf000112_0001
Example 3 (N-(3-chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-1H- benzo[d]imidazole-7-carboximidamide) was made analogously to Example 59 using 6- fluoro-1H-benzo[d]imidazole-7-carboxylic acid in place of 1H-imidazo[4,5-b]pyridine- 7-carboxylic acid. C14H9ClF2N4O. 323.1/325.0 (M+1). Example 4: N-(3-Chloro-4-fluorophenyl)-5-fluoro-N'-hydroxy-1H- benzo[d]imidazole-7-carboximidamide
Figure imgf000112_0002
ple 4 was made analogously to Example 59 using 5-fluoro-1H- benzo[d]imidazole-7-carboxylic in place of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid. C14H9ClF2N4O.323.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.87 (d, J = 15.9 Hz, 2H), 7.60 (dd, J = 8.7, 2.4 Hz, 1H), 7.20 (dd, J = 10.2, 2.4 Hz, 1H), 7.02 (t, J = 9.1 Hz, 1H), 6.95 (dd, J = 6.6, 2.7 Hz, 1H), 6.52 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H). Example 5: N-(3-Chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-1H- benzo[d]imidazole-7-carboximidamide
Figure imgf000112_0003
110
604642.1 Attorney Docket No.: 1115.PF [0220] Example 5 was made analogously to Example 59 using 4-fluoro-1H- benzo[d]imidazole-7-carboxylic acid in place of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid. C14H9ClF2N4O.323.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.75 (s, 1H), 8.27 (s, 1H), 7.16 (dd, J = 8.4, 4.6 Hz, 1H), 7.09– 6.94 (m, 2H), 6.90 (dd, J = 6.6, 2.7 Hz, 1H), 6.47 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H). Example 6: 4-Chloro-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H- benzo[d]imidazole-7-carboximidamide
Figure imgf000113_0001
ple 6 was made analogously to Example 59 using 4-chloro-1H- benzo[d]imidazole-7-carboxylic acid in place of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid. C14H9Cl2FN4O.339.1 (M+1).1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.81 (s, 1H), 8.39 (s, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 7.01 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.6, 2.7 Hz, 1H), 6.47 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H). Example 7: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-4-(trifluoromethyl)-1H- benzo[d]imidazole-7-carboximidamide
Figure imgf000113_0002
ple 7 was made analogously to Example 59 using 4- (trifluoromethyl)-1H-benzo[d]imidazole-7-carboxylic acid in place of 1H-imidazo[4,5- b]pyridine-7-carboxylic acid. C15H9ClF4N4O.373.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.97 (d, J = 5.0 Hz, 1H), 8.83 (s, 1H), 8.35 (s, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.01 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.6, 2.7 Hz, 1H), 6.46 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H).
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604642.1 Attorney Docket No.: 1115.PF Example 8: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-1H-benzo[d]imidazole-7- carboximidamide
Figure imgf000114_0001
le 8 was made analogously to Example 59 using 1H- benzo[d]imidazole-7-carboxylic acid in place of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid. C14H10ClFN4O.305.1 (M+1). Example 9: N-(3-Chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-7-methyl-3H- benzimidazole-4-carboximidamide
Figure imgf000114_0002
3,5-difluoro-4-methyl-2-nitrobenzoic acid. To a solution of concentrated nitric acid (65% in water, 7.5 mL) and sulfuric acid (15 mL) at 0 °C was added 3,5- difluoro-4-methylbenzoic acid (5.0 g, 29 mmol) in portions over 1 hr. The solution was allowed to warm to room temperature and stirred for 18 hr. The reaction mixture was poured onto ice and the resulting precipitate was filtered and dried on high vac to give the desired product (6.3 g). C8H5F2NO4.217.9 (M+1).
Figure imgf000114_0003
hloro-4-fluorophenyl)-3,5-difluoro-4-methyl-2-nitrobenzamide. To a solution of 3-chloro-4-fluoroaniline (670 mg, 4.6 mmol), 3,5-difluoro-4-methyl-2- nitrobenzoic acid (1.0 g, 4.6 mmol), and triethylamine (1.9 mL, 14 mmol) in
dichlromethane (40 mL) at 0 °C was added phosphoryl chloride (0.64 mL, 6.9 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 hr. To 112
604642.1 Attorney Docket No.: 1115.PF the reaction mixture was added saturated sodium bicarbonate and the aqueous layer was washed three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, adsorbed onto silica and purified by silica gel chromatography to give the desired product (1.6 g). C14H8ClF3N2O3.345.0 (M+1).
Figure imgf000115_0001
no-N-(3-chloro-4-fluorophenyl)-5-fluoro-4-methyl-2- nitrobenzamide. A solution of N-(3-chloro-4-fluorophenyl)-3,5-difluoro-4-methyl-2- nitrobenzamide (674 mg, 1.96 mmol) and 28% aqueous ammonium hydroxide in ethanol (2 mL) was stirred at 80 °C for 18 hr. To this solution was added water and the resulting precipitate was filtered and dried on high vac to give the desired product (583 mg). C14H10ClF2N3O3.364.0 (M+23).
Figure imgf000115_0002
oro-4-fluorophenyl)-5-fluoro-3-formamido-4-methyl-2- nitrobenzamide. A mixture of acetic anhydride (0.4 mL, 4.3 mmol) in formic acid (4 mL) was stirred for 5 min. To this solution was added 3-amino-N-(3-chloro-4-fluorophenyl)- 5-fluoro-4-methyl-2-nitrobenzamide (583 mg, 1.7 mmol). The reaction mixture stirred for 2 hr and was poured onto cold water and the resulting precipitate was filtered and dried on high vac to give the desired product (562 mg). C15H10ClF2N3O4.370.0 (M+1).
Figure imgf000115_0003
chloro-4-fluorophenyl)-5-fluoro-4-methyl-1H-benzo[d]imidazole-7- carboxamide was made analogously to Example 1 using N-(3-chloro-4-fluorophenyl)-5- 113
604642.1 Attorney Docket No.: 1115.PF fluoro-3-formamido-4-methyl-2-nitrobenzamide in place of methyl 3-formamido-4- methyl-2-nitrobenzoate. C15H10ClF2N3O.322.2 (M+1).
Figure imgf000116_0001
Chloro-4-fluorophenyl)-6-fluoro-N'-hydroxy-7-methyl-3H- benzimidazole-4-carboximidamide was made analogously to Example 1 using N-(3- chloro-4-fluorophenyl)-5-fluoro-4-methyl-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-4-methyl-1H-benzo[d]imidazole-7-carboxamide. C15H11ClF2N4O.337.0 (M+1).1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.96 (s, 1H), 8.86 (s, 1H), 7.20– 7.11 (m, 1H), 7.01 (t, J = 9.2 Hz, 1H), 6.97 (dd, J = 6.5, 2.6 Hz, 1H), 2.44 (d, J = 1.6 Hz, 3H).
Example 10: N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H- benzo[d]imidazole-7-carboximidamide
Figure imgf000116_0002
, , .
dissolved in methanol (200 mL) and sulfuric acid (20 mL) was added dropwise to the solution over 5 minutes. A reflux condenser was attached and the reaction was heated to 71 °C overnight. The reaction was then cooled to room temperature and concentrated in vacuo to approximately 50 mL of solvent. The reaction was neutralized to pH=7 with saturated potassium carbonate and then extracted with EtOAc (5 x 40 mL). Combined organic layers were washed with brine (1 x 60 mL) and concentrated in vacuo to give methyl 3-amino-4,5-difluoro-2-nitrobenzoate as a yellow solid which was used without further purification.
[0231] 3-Amino-4,5-difluoro-2-nitrobenzoate (14.5 g, 62 mmol) was dissolved in ethanol (150 mL) and water (50 mL). Ammonium chloride (0.934 mol) was added in one portion and the reaction was allowed to stir at room temperature. Zinc powder 114
604642.1 Attorney Docket No.: 1115.PF (0.934 mol) was added portion-wise over 5 minutes and the reaction was allowed to stir 5 minutes after completion of addition. The zinc was then removed by vacuum filtration and the filtrate was concentrated in vacuo. The crude was dissolved in water (60 mL) and extracted with EtOAc (4 x 40 mL). Combined organic layers were washed with brine (1 x 50 mL), dried over sodium sulfate, and concentrated in vacuo to give methyl 2,3-diamino-4,5-difluorobenzoate as a brown powder.
Figure imgf000117_0001
, , , .
dissolved in formic acid (2 mL) and heated to 100 °C in a sealed tube for 10 minutes. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in sat. sodium bicarbonate (2 mL) and extracted with EtOAc (3 x 3 mL). Combined organic layers were washed with water (1 x 5 mL) and concentrated in vacuo to give methyl 4,5-difluoro-1H-benzo[d]imidazole-7-carboxylate as a brown solid which was used without further purification.
[0233] Methyl 4,5-difluoro-1H-benzo[d]imidazole-7-carboxylate (12 mg, 0.056 mmol) was dissolved in DCE (1 mL) under an inert atmosphere. Trimethylaluminum (0.085 mL, 2.0 M in toluene) was added dropwise to the reaction followed by 3-chloro- 4-fluoroaniline (0.085 mmol). The reaction was allowed to stir at rt overnight under inert atmosphere. The reaction was quenched with sat. sodium bicarb (3 mL) and extracted with EtOAc (3 x 2mL). Combined organic layers were washed with water (1 x 4 mL) and concentrated in vacuo to give N-(3-chloro-4-fluorophenyl)-4,5-difluoro-1H- benzo[d]imidazole-7-carboxamide which was used directly in the next reaction. The crude material was dissolved in POCl3 (2 mL) and PCl5 (0.083 mmol) was added. The reaction was heated to 85 °C in a sealed tube for 12 hours. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in a pre- mixed solution of ethanol (2 mL) and hydroxylamine (0.55 mmol, 50% in water) and the reaction was allowed to stir at room temperature for 5 minutes. The reaction was concentrated in vacuo and purified by reverse-phase HPLC to afford N-(3-chloro-4- fluorophenyl)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide as a
115
604642.1 Attorney Docket No.: 1115.PF white solid. C14H8ClF3N4O. 341.1/343.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.77 (s, 1H), 8.28 (s, 1H), 7.25 (d, J = 5.5 Hz, 1H), 7.03 (t, J = 9.0 Hz, 1H), 6.96 (dd, J = 6.5, 2.8 Hz, 1H), 6.48 (d, J = 9.1 Hz, 1H).
Example 11: 6-Chloro-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H- benzo[d]imidazole-4-carboximidamide
Figure imgf000118_0001
ethyl 5-chloro-3-formamido-2-nitrobenzoate was made analogously to Example 1 using methyl 3-amino-5-chloro-2-nitrobenzoate in place of methyl 3-amino- 4-methylbenzoate. C9H7ClN2O5.281.1 (M+23).
Figure imgf000118_0002
Methyl 6-chloro-1H-benzo[d]imidazole-4-carboxylate was made analogously to Example 1 using methyl 5-chloro-3-formamido-2-nitrobenzoate in place of methyl 3-formamido-4-methyl-2-nitrobenzoate. C9H7ClN2O2.211.2 (M+1).
oro-N-(3-chloro-4-fluorophenyl)-1H-benzo[d]imidazole-4- carboxamide was made analogously to Example 1 using methyl 6-chloro-1H- benzo[d]imidazole-4-carboxylate in place of methyl 4-methyl-1H-benzo[d]imidazole-7- carboxylate. C14H8Cl2FN3O. 324.2 (M+1).
OH N H N Cl F
Figure imgf000118_0004
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604642.1 Attorney Docket No.: 1115.PF [0237] 6-chloro-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-benzo[d]imidazole- 4-carboximidamide was made analogously to Example 1 using 6-chloro-N-(3-chloro-4- fluorophenyl)-1H-benzo[d]imidazole-4-carboxamide in place of N-(3-chloro-4- fluorophenyl)-4-methyl-1H-benzo[d]imidazole-7-carboxamide. C14H9Cl2FN4O.339.0 (M+1).
Example 12: 4-Bromo-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H- benzo[d]imidazole-7-carboximidamide
Figure imgf000119_0001
ethyl 4-bromo-3-formamidobenzoate was prepared analogously to Example 9, using methyl 3-amino-4-bromobenzoate in place of 3-amino-N-(3-chloro-4- fluorophenyl)-5-fluoro-4-methyl-2-nitrobenzamide. C9H8BrNO3. 279.9/281.9 [M+23]+.
Figure imgf000119_0002
ethyl 4-bromo-3-formamido-2-nitrobenzoate. To fuming nitric acid (14 mL) at -10 °C was added methyl 4-bromo-3-formamidobenzoate (5.1 g, 20 mmol), portionwise over 90 min. The mixture was stirred at 0 °C for 1 h and then poured over ice and allowed to stir and warm to rt over 1.5 h. The solid was isolated via filtration and the filter pad was washed with water. The solid was taken up in EtOAc, washed with brine, concentrated onto silica gel, and purified via column chromatography on silica gel to yield a mixture of the desired product and its regioisomer (3.5 g). C9H7BrN2O5.
324.9/326.9 [M+23]+.
Figure imgf000119_0003
Figure imgf000119_0004
Methyl 4-bromo-1H-benzo[d]imidazole-7-carboxylate was prepared analogously to Example 1, using methyl 4-bromo-3-formamido-2-nitrobenzoate in place of methyl 3-formamido-4-methyl-2-nitrobenzoate. C9H7BrN2O2. 254.9/256.9 [M+1]+.
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604642.1 Attorney Docket No.: 1115.PF
Figure imgf000120_0001
-(3-chloro-4-fluorophenyl)-1H-benzo[d]imidazole-7- carboxamide was prepared analogously to Example 1 , using methyl 4-bromo-1H- benzo[d]imidazole-7-carboxylate in place of methyl 4-methyl-1H-benzo[d]imidazole-7- carboxylate. C14H8BrClFN3O. 368.0/369.9 [M+1]+.
Figure imgf000120_0002
-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-benzo[d]imidazole- 7-carboximidamide was prepared analogously to Example 1, using 4-bromo-N-(3-chloro- 4-fluorophenyl)-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4- fluorophenyl)-4-methyl-1H-benzo[d]imidazole-7-carboxamide. C14H9BrClFN4O.
382.9/384.9 [M+1]+.
Example 13: 2-Amino-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H- benzo[d]imidazole-7-carboximidamide
Figure imgf000120_0003
, , e (0.5 g, 2.0 mmol) was dissolved in methanol (7.0 mL) and water (2.50 mL). Cyanogen bromide (3.0 mmol) was added and the reaction was refluxed in a sealed tube for 45 mins. The reaction was allowed to cool to rt and diluted with water (4 mL) and EtOAc (4 mL). The water layer was isolated and neutralized to pH=8 with sat. sodium carbonate. The neutralized aqueous layer was extracted with EtOAc (3x4 mL) and combined organic layers were washed with brine (1x5 mL), dried over sodium sulfate, and concentrated in vacuo to give methyl 2-amino-4,5-difluoro-1H-benzo[d]imidazole-7-carboxylate as a brown solid.
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604642.1 Attorney Docket No.: 1115.PF
Figure imgf000121_0001
Figure imgf000121_0002
idazole-7-carboxylate (75 mg, 0.33 mmol) was dissolved in DCE (4 mL) under inert atmosphere and cooled to 0 °C. Trimethylaluminium (1.2 mL, 2M hexanes) was added dropwise followed by 3- chloro-4-fluoroaniline (1.0 mmol) and the reaction was then heated to 70 °C for 2 days. The reaction was cooled to rt and quenched with saturated bicarbonate solution. The reaction was extracted with EtOAc (3x3 mL) and combined organic layers were washed with brine (1x 6 mL) and concentrated in vacuo. The crude material was dried loaded on to silica gel and purified by column chromatography (EtOAc/hex) to give 2-amino-N-(3- chloro-4-fluorophenyl)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide as a white powder.
[0245] 2-Amino-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-1H- benzo[d]imidazole-7-carboxamide (20 mg, 0.0587 mmol) and Lawesson’s reagent (0.176 mmol) was dissolved in toluene (2mL) and heated to 90°C overnight. The reaction was allowed to cool to rt and precipitates were removed by vacuum filtration and the filtrate was concentrated. The crude material was purified by column chromatography
(EtOAc/hex) to give 2-amino-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-1H- benzo[d]imidazole-7-carbothioamide as a yellow oil.
[0246] 2-Amino-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-1H- benzo[d]imidazole-7-carbothioamide (20 mg, 0.0561 mmol) was dissolved in ethanol (2 mL) and hydroxylamine (50% in aqueous solution, 0.561 mmol) was added and the reaction was allowed to stir overnight at rt. The reaction was concentrated in vacuo and purified by reverse-phase HPLC to give 2-amino-N-(3-chloro-4-fluorophenyl)-4,5- difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide as a white solid.
C14H9ClF3N5O. 356.0/357.9 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.27 (dd, J = 119
604642.1 Attorney Docket No.: 1115.PF 5.8, 2.7 Hz, 1H), 7.15 (t, J = 8.6 Hz, 1H), 7.03– 6.98 (m, 2H), 6.94 (s, 1H), 6.67 (d, J = 3.8 Hz, 1H).
Example 14: 2-Amino-N-(3-bromo-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-1H- benzo[d]imidazole-7-carboximidamide
Figure imgf000122_0001
was made analogously to Example 13 using 3-bromo-4- fluoroaniline in place of 3-chloro-4-fluoroaniline. C14H9BrF3N5O. 400.0/402.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.76 (s, 1H), 7.12 (dd, J = 6.1, 2.6 Hz, 1H), 7.06 (t, J = 8.8 Hz, 2H), 6.61– 6.51 (m, 1H).
Example 15: 2-Amino-N-(3-bromophenyl)-4,5-difluoro-N'-hydroxy-1H- benzo[d]imidazole-7-carboximidamide
Figure imgf000122_0002
was made analogously to Example 13 using 3-bromoaniline in place of 3-chloro-4-fluoroaniline. C12H10BrF2N5O. 382.0/384.1 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.11– 6.96 (m, 4H), 6.69– 6.63 (m, 1H).
Example 16: 2-Amino-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-1H- benzo[d]imidazole-7-carboximidamide
Figure imgf000122_0003
was made analogously to Example 13 using 3-chloroaniline in place of 3-chloro-4-fluoroaniline. C14H10ClF2N5O. 338.0/340.1 (M+1). 1H NMR
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604642.1 Attorney Docket No.: 1115.PF (400 MHz, Methanol-d4) δ 8.69– 8.59 (m, 2H), 8.51– 8.45 (m, 1H), 8.39 (t, J = 2.1 Hz, 1H), 8.21– 8.15 (m, 1H).
Example 17: 2-Amino-4,5-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N'- hydroxy-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000123_0001
as made analogously to Example 13 using 4-fluoro-3- (trifluoromethyl)aniline in place of 3-chloro-4-fluoroaniline. C15H9F6N5O. 390.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.93 (s, 1H), 8.16 (s, 2H), 7.24– 7.10 (m, 3H), 6.83 (dt, J = 7.9, 3.5 Hz, 1H).
Example 18: 2-Amino-N-(3-bromophenyl)-4-fluoro-N'-hydroxy-1H- benzo[d]imidazole-7-carboximidamide
Figure imgf000123_0002
was made analogously to Example 15 using methyl 2- amino-4-fluoro-1H-benzo[d]imidazole-7-carboxylate in place of 2-amino-4,5-difluoro- 1H-benzo[d]imidazole-7-carboxylate. C14H11BrFN5O. 364.0/366.0 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.16 (dd, J = 8.8, 4.5 Hz, 1H), 7.09– 6.92 (m, 4H), 6.65 (d, J = 8.1 Hz, 1H).
Example 19: 2-Amino-N-(3-bromo-4-fluorophenyl)-4-fluoro-N'-hydroxy-1H- benzo[d]imidazole-7-carboximidamide
Figure imgf000123_0003
121
604642.1 Attorney Docket No.: 1115.PF [0252] Example 19 was made analogously to Example 14 using methyl 2-amino- 4-fluoro-1H-benzo[d]imidazole-7-carboxylate in place of 2-amino-4,5-difluoro-1H- benzo[d]imidazole-7-carboxylate. C14H10BrF2N5O. 382.0/384.0 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.15 (dd, J
Figure imgf000124_0001
), 7.10– 6.99 (m, 2H), 6.95 (t, J = 8.6 Hz, 1H), 6.69 (dt, J = 8.8, 3.5 Hz, 1H).
Example 20: 2-Amino-N-(3-chlorophenyl)-4-fluoro-N'-hydroxy-1H- benzo[d]imidazole-7-carboximidamide
Figure imgf000124_0002
was made analogously to Example 16 using methyl 2-amino- 4-fluoro-1H-benzo[d]imidazole-7-carboxylate in place of 2-amino-4,5-difluoro-1H- benzo[d]imidazole-7-carboxylate. C14H11ClFN5O. 320.1/322.1 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.16 (dd, J = 8.8, 4.6 Hz, 1H), 7.10– 6.99 (m, 2H), 6.89 (ddd, J = 8.0, 2.0, 0.9 Hz, 1H), 6.79 (t, J = 2.0 Hz, 1H), 6.64– 6.58 (m, 1H).
Example 21: 2-Amino-4-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy- 1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000124_0003
was made analogously to Example 17 using methyl 2-amino- 4-fluoro-1H-benzo[d]imidazole-7-carboxylate in place of 2-amino-4,5-difluoro-1H- benzo[d]imidazole-7-carboxylate. C15H10F5N5O. 372.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.93 (s, 1H), 8.32 (s, 2H), 7.24– 7.05 (m, 4H), 6.83 (dd, J = 8.5, 4.2 Hz, 1H).
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604642.1 Attorney Docket No.: 1115.PF Example 22: 2-Amino-N-(3-chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-1H- benzo[d]imidazole-7-carboximidamide
Figure imgf000125_0001
n methanol (120 mL) and sulfuric acid (2.5 mL) was added dropwise to the solution over 5 minutes. A reflux condenser was attached and the reaction was heated to 71 °C overnight. The reaction was then cooled to room temperature and concentrated in vacuo to approximately 50 mL of solvent. The reaction was neutralized to pH=7 with saturated potassium carbonate and then extracted with EtOAc (5 x 40 mL). Combined organic layers were washed with brine (1 x 60 mL) and concentrated in vacuo to give methyl 3- amino-4-fluoro-2-nitrobenzoate as a yellow solid which was used without further purification.
[0256] 3-Amino-4-fluoro-2-nitrobenzoate (2.32 g, 11.0 mmol) was dissolved in ethanol (100 mL) and water (35 mL). Ammonium chloride (0.163 mol) was added in one portion and the reaction was allowed to stir at room temperature. Zinc powder (0.163 mol) was added portion-wise over 5 minutes and the reaction was allowed to stir 5 minutes after completion of addition. The zinc was then removed by vacuum filtration and the filtrate was concentrated in vacuo. The crude was dissolved in water (20 mL) and extracted with EtOAc (4 x 10 mL). Combined organic layers were washed with brine (1 x 50 mL), dried over sodium sulfate, and concentrated in vacuo to give methyl 2,3-diamino-4-fluorobenzoate as a brown powder.
Figure imgf000125_0002
(0.1g, 0.54 mmol) was dissolved in methanol (2.0 mL) and water (1.0 mL). Cyanogen bromide (0.54 mmol) was added and the reaction was refluxed in a sealed tube for 45 mins. The reaction was allowed to cool to rt and diluted with water (4 mL) and EtOAc (4 mL). The water layer was isolated and 123
604642.1 Attorney Docket No.: 1115.PF neutralized to pH=8 with sat. sodium carbonate. The neutralized aqueous layer was extracted with EtOAc (3x4 mL) and combined organic layers were washed with brine (1x5 mL), dried over sodium sulfate, and concentrated in vacuo to give methyl 2-amino- 4-fluoro-1H-benzo[d]imidazole-7-carboxylate as a brown solid.
Figure imgf000126_0001
as made analogously to Example 13 (using methyl 2-amino- 4-fluoro-1H-benzo[d]imidazole-7-carboxylate in place of 2-amino-4,5-difluoro-1H- benzo[d]imidazole-7-carboxylate. C14H10ClF2N5O. 338.1/339.2 (M+1).1H NMR (400 MHz, Methanol-d4) δ 7.14 (dd, J = 8.8, 4.6 Hz, 1H), 7.00 (dt, J = 23.9, 9.2 Hz, 2H), 6.91 (dd, J = 6.4, 2.7 Hz, 1H), 6.64 (dt, J = 8.8, 3.4 Hz, 1H).
Example 23: N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2- morpholinoethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000126_0002
Figure imgf000126_0003
-difluoro-2-((2-morpholinoethyl)amino)-1H- benzo[d]imidazole-7-carboxylate. Dissolved methyl 2,3-diamino-4,5-difluorobenzoate (50 mg, 0.25 mmol) in THF (3 ml), to the solution was added 4-(2- isothiocyanatoethyl)morpholine (0.43 g, 0.002 mmol) and triethylamine (0.36 g, 0.003 mol). The reaction mixture was heated at 80oC overnight, then to the reaction mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.47 g, 0.002 mol), heated at 80oC for 1h. The reaction mixture was diluted with EtOAc, and washed with NaHCO3 saturated solution, organic layer was evaporated and the residue was purified with Combi-Flash column chromatography to afford 84mg desired product. C15H18F2N4O3.341.2 (M+1).
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604642.1 Attorney Docket No.: 1115.PF
Figure imgf000127_0001
rophenyl)-4,5-difluoro-2-((2-morpholinoethyl)amino)- 1H-benzo[d]imidazole-7-carboxamide. Dissolved 3-chloro-4-fluoroaniline (12.8mg, 0.088 mmol) in dichloroethane (2 ml), to the solution was added trimethylamine (0.088 ml , 2M in toluene) and triethylamine (0.36 g, 0.003 mol). Then to the raction mixture was added methyl 4,5-difluoro-2-((2-morpholinoethyl)amino)-1H-benzo[d]imidazole-7- carboxylate (20 mg, 0.06 mmol). The reaction mixture was stirred at room temperature for 2h, then the reaction mixture was diluted with EtOAc, and washed with NaHCO3 saturated solution, organic layer was evaporated and the residue was purified with Combi-Flash column chromatography to afford 27mg desired product. C20H19ClF3N5O2. 454.4 (M+1).
Figure imgf000127_0002
rophenyl)-4,5-difluoro-N'-hydroxy-2-((2- morpholinoethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide. Example 23 was made analogously to Example 107 using the general procedure for hydroxyamidine formation. C20H20ClF3N6O2.469.1 (M+1).1H NMR (400 MHz, Methanol-d4) δ 7.01– 6.85 (m, 3H), 6.67 (ddd, J = 8.9, 4.0, 2.8 Hz, 1H), 4.00 (t, J = 4.8 Hz, 4H), 3.81– 3.73 (m, 2H), 3.49– 3.36 (m, 6H).
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604642.1 Attorney Docket No.: 1115.PF Example 24: N-(3-Chlorophenyl)-4,5-difluoro-N'-hydroxy-2-(((3- methoxypropyl)amino)methyl)-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000128_0001
rophenyl)-4,5-difluoro-2-(methoxymethyl)-1H- benzo[d]imidazole-7-carboxamide was prepared analogously to Example 45, using 3- chloroaniline in place of 3-chloro-4-fluoroaniline. C16H12ClF2N3O2. 352.1 [M+1]+.
Figure imgf000128_0002
-chlorophenyl)-3-(4,5-difluoro-2-(methoxymethyl)-1H- benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one was prepared analogously to Example 45, using N-(3-chlorophenyl)-4,5-difluoro-2-(methoxymethyl)-1H- benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-4,5-difluoro- 2-(methoxymethyl)-1H-benzo[d]imidazole-7-carboxamide. C17H11ClF2N4O3. 393.0 [M+1]+.
Figure imgf000128_0003
[d]imidazol-7-yl)-4-(3- chlorophenyl)-1,2,4-oxadiazol-5(4H)-one and 4-(3-chlorophenyl)-3-(4,5-difluoro-2- (hydroxymethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one were prepared analogously to Example 45, using 4-(3-chlorophenyl)-3-(4,5-difluoro-2- (methoxymethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one in place of 4- 126
604642.1 Attorney Docket No.: 1115.PF (3-chloro-4-fluorophenyl)-3-(4,5-difluoro-2-(methoxymethyl)-1H-benzo[d]imidazol-7- yl)-1,2,4-oxadiazol-5(4H)-one. C16H8BrClF2N4O2. 440.9/442.9 [M+1]+.
C16H9ClF2N4O3. 379.0 [M+1]+.
Figure imgf000129_0001
henyl)-4,5-difluoro-N'-hydroxy-2-(((3- methoxypropyl)amino)methyl)-1H-benzo[d]imidazole-7-carboximidamide. Example 24 was prepared analogously to Example 45, using 3-(2-(bromomethyl)-4,5-difluoro-1H- benzo[d]imidazol-7-yl)-4-(3-chlorophenyl)-1,2,4-oxadiazol-5(4H)-one in place of 3-(2- (bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)- 1,2,4-oxadiazol-5(4H)-one. C19H20ClF2N5O2. 424.1 [M+1]+.
Example 25: N-(3-Chlorophenyl)-2-(((cyclopropylmethyl)amino)methyl)-4,5- difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000129_0002
as prepared analogously to Example 45 , using 3-(2- (bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chlorophenyl)-1,2,4- oxadiazol-5(4H)-one and cyclopropylmethanamine in place of 3-(2-(bromomethyl)-4,5- difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)- one and 3-methoxypropylamine, respectively. C19H18ClF2N5O. 406.1 [M+1]+.
127
604642.1 Attorney Docket No.: 1115.PF Example 26: N-(3-Chlorophenyl)-2-((dimethylamino)methyl)-4,5-difluoro-N'- hydroxy-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000130_0001
26 was prepared analogously to Example 45, using 3-(2- (bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chlorophenyl)-1,2,4- oxadiazol-5(4H)-one and dimethylamine in place of 3-(2-(bromomethyl)-4,5-difluoro- 1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-methoxypropylamine, respectively. C17H16ClF2N5O. 380.1 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 12.93 (br s, 1H), 11.00 (br s, 1H), 10.27 (br s, 1H), 8.86 (s, 1H), 7.38 – 7.23 (m, 1H), 7.06– 6.96 (m, 1H), 6.85 (t, J = 2.1 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 6.47 (dd, J = 8.2, 1.8 Hz, 1H), 4.58 (s, 2H), 2.85 (s, 6H).
Example 27: N-(3-Chlorophenyl)-4,5-difluoro-N'-hydroxy-2- ((isopropylamino)methyl)-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000130_0002
was prepared analogously to Example 45, using 3-(2- (bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chlorophenyl)-1,2,4- oxadiazol-5(4H)-one and isopropylamine in place of 3-(2-(bromomethyl)-4,5-difluoro- 1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-methoxypropylamine, respectively. C18H18ClF2N5O. 394.1 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 12.88 (br s, 1H), 11.03 (br s, 1H), 9.27 (br s, 3H), 8.85 (s, 1H), 7.31– 7.20 (m, 1H), 7.04 (t, J = 8.1 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.80 (t, J = 2.1 Hz, 1H), 6.49 (dd, J = 8.3, 1.8 Hz, 1H), 4.51– 4.43 (m, 2H), 3.54– 3.35 (m, 1H), 1.28 (d, J = 6.3 Hz, 6H). 128
604642.1 Attorney Docket No.: 1115.PF Example 28: N-(3-Chlorophenyl)-2-((ethylamino)methyl)-4,5-difluoro-N'-hydroxy- 1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000131_0001
was prepared analogously to Example 45, using 3-(2- (bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chlorophenyl)-1,2,4- oxadiazol-5(4H)-one and ethylamine in place of 3-(2-(bromomethyl)-4,5-difluoro-1H- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3- methoxypropylamine, respectively. C17H16ClF2N5O. 380.1 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 12.87 (br s, 1H), 11.01 (br s, 1H), 9.27 (br s, 2H), 8.85 (s, 1H), 7.30– 7.21 (m, 1H), 7.03 (t, J = 8.0 Hz, 1H), 6.87– 6.78 (m, 2H), 6.52– 6.45 (m, 1H), 4.54– 4.38 (m, 2H), 3.17– 2.98 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H).
Example 29: N-(3-Chlorophenyl)-4,5-difluoro-N'-hydroxy-2-(hydroxymethyl)-1H- benzo[d]imidazole-7-carboximidamide
Figure imgf000131_0002
29 was prepared analogously to Example 46, using 4-(3- chlorophenyl)-3-(4,5-difluoro-2-(hydroxymethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4- oxadiazol-5(4H)-one in place of 4-(3-chloro-4-fluorophenyl)-3-(4,5-difluoro-2- (hydroxymethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one.
C15H11ClF2N4O2. 353.0 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 11.00 (br s, 1H), 8.79 (s, 1H), 7.16 (dd, J = 12.0, 7.0 Hz, 1H), 7.07– 7.00 (m, 1H), 6.85– 6.79 (m, 2H), 6.53– 6.47 (m, 1H), 4.67 (s, 2H).
129
604642.1 Attorney Docket No.: 1115.PF Example 30: N-(3-Chlorophenyl)-4,5-difluoro-N'-hydroxy-2- ((methylamino)methyl)-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000132_0001
30 was prepared analogously to Example 45, using 3-(2- (bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chlorophenyl)-1,2,4- oxadiazol-5(4H)-one and methylamine in place of 3-(2-(bromomethyl)-4,5-difluoro-1H- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3- methoxypropylamine, respectively. C16H14ClF2N5O. 366.0 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 12.86 (br s, 1H), 11.00 (br s, 1H), 9.24 (br s, 2H), 8.84 (s, 1H), 7.30– 7.19 (m, 1H), 7.03 (t, J = 8.0 Hz, 1H), 6.88– 6.75 (m, 2H), 6.53– 6.45 (m, 1H), 4.45 (t, J = 5.6 Hz, 2H), 2.74– 2.64 (m, 3H).
Example 31: 2-(Aminomethyl)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-1H- benzo[d]imidazole-7-carboximidamide
Figure imgf000132_0002
31 was prepared analogously to Example 45, using 3-(2- (bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chlorophenyl)-1,2,4- oxadiazol-5(4H)-one and ammonia (0.5 M solution in dioxane) in place of 3-(2- (bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)- 1,2,4-oxadiazol-5(4H)-one and 3-methoxypropylamine, respectively. C15H12ClF2N5O. 352.0 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 12.77 (br s, 1H), 11.00 (br s, 1H), 8.83 (s, 1H), 8.52 (br s, 3H), 7.21 (dd, J = 12.0, 6.9 Hz, 1H), 7.04 (t, J = 8.1 Hz, 1H), 6.83 (dd, J = 7.8, 2.0 Hz, 1H), 6.80 (t, J = 2.1 Hz, 1H), 6.49 (dd, J = 8.2, 2.1 Hz, 1H), 4.34 (q, J = 5.4 Hz, 2H).
130
604642.1 Attorney Docket No.: 1115.PF Example 32: N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-morpholino- 1H-benzo-[d]imidazole-7-carboximidamide
Figure imgf000133_0001
, , . , , ) was dissolved in formic acid (120 mL) and stirred at 80 oC for 3 hours. Formic acid was subsequently removed in vacuo and methyl 4,5-difluoro-1H-benzo[d]imidazole-7- carboxylate was obtained as a brown solid. C9H6F2N2O2, 213.0 (M+1).1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.83 (dd
Figure imgf000133_0002
Hz, 1H), 3.95 (s, 3H).19F NMR (377 MHz, DMSO-d6) δ -146.16 (dd, J = 21.8, 7.2 Hz, 1F), -149.09 (dd, J = 21.8, 11.6 Hz, 1F).
[0274] To a suspension of methyl 4,5-difluoro-1H-benzo[d]imidazole-7- carboxylate (6.0 g, 28 mmol, 1 equiv) in THF (60 mL) was added a 60 wt% dispersion of NaH (1.7 g, 42 mmol, 1.5 equiv) in three portions. Once gas evolution ceased, the reaction mixture was cooled to 0 oC and SEM-Cl (6.0 mL, 34 mmol, 1.2 equiv) was added. The ice bath was subsequently removed and the reaction was stirred at room temperature for 3 hours before being quenched with saturated aqueous NH4Cl. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2 over 20 minutes). Methyl 4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- benzo[d]imidazole-7-carboxylate was isolated as a yellow solid. C15H20F2N2O3Si, 342.9 (M+1).1H NMR (400 MHz, Chloroform-d) δ 8.17 (s, 1H), 7.91 (dd, J = 11.5, 7.5 Hz, 1H), 5.68 (s, 2H), 4.06 (s, 3H), 3.64– 3.45 (m, 2H), 0.98– 0.85 (m, 2H), -0.04 (d, J = 0.6 Hz, 9H).19F NMR (377 MHz, Chloroform-d) δ -144.34 (m, 1F), -150.20 (m, 1F).
Figure imgf000133_0003
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604642.1 Attorney Docket No.: 1115.PF [0275] To a solution of methyl 4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-benzo[d]imidazole-7-carboxylate (2.2 g, 6 mmol, 1 equiv) in acetonitrile (46.2 mL) was added NCS (1.29 g, 10 mmol, 1.5 equiv). The reaction mixture was stirred at 100 oC in a sealed vessel for 12 hours. Acetonitrile was subsequently removed in vacuo and the crude product purified by silica gel chromatography (0-5% MeOH/CH2Cl2 over 20 minutes). Methyl 2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- benzo[d]imidazole-7-carboxylate was obtained as a crystalline yellow solid.
C15H19ClF2N2O3Si, 376.9/378.9 (M+1).
Figure imgf000134_0001
, 1-((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate (0.29 g, 0.46 mmol, 1 equiv) in DMSO (2 mL) was added morpholine (0.14 mL, 1.6 mmol, 3.5 equiv). The reaction was stirred at 60 oC for 3 hours before being diluted with DMF/H2O and purified by reverse phase HPLC (10-90% CH3CN/H2O over 20 mins). The TFA salt of methyl 4,5-difluoro-2-morpholino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- benzo[d]imidazole-7-carboxylate was obtained as a white solid. C19H27F2N3O4Si, 428.1 (M+1).
Figure imgf000134_0002
luorophenyl)-4,5-difluoro-2-morpholino-1H- benzo[d]imidazole-7-carboxamide was made analogously to Example 13 using methyl 4,5-difluoro-2-morpholino-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole- 7-carboxylate and 3-chloro-4-fluoroaniline in place of methyl 2-amino-4,5-difluoro-1H- benzo[d]imidazole-7-carboxylate. C18H14ClF3N4O2, 411.1/413.0 (M+1).
Figure imgf000134_0003
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604642.1 Attorney Docket No.: 1115.PF
Figure imgf000135_0001
made analogously to Example 59 using N-(3-chloro-4- fluorophenyl)-4,5-difluoro-2-morpholino-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide.
C18H15ClF3N5O2.426.1/428.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.78 (br. s, 1H), 8.82 (s, 1H), 7.04 (t, J = 9.1 Hz, 1H), 7.00 (dd, J = 6.6, 2.7 Hz, 1H), 6.93 (dd, J = 12.1, 6.9 Hz, 1H), 6.51 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.69– 3.62 (m, 4H), 3.53– 3.44 (m, 4H).
Example 33: N-(3-Chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-2-((2- (methylsulfonyl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
.814 mmol) and 1- ved in THF (4.5 mL)
Figure imgf000135_0002
and triethylamine (7.0 mmol) was added and the reaction was heated to reflux overnight. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (5.0 mmol) was added and the reaction was allowed to heat at reflux for an additional 1 hour. The reaction was allowed to cool to room temperature, quenched with water, and extracted with EtOAc (3x 3 mL). The combined organic layers were washed with brine (1x4mL), concentrated, and purified by silica gel column chromatography to give methyl 4-fluoro-2-((2- (methylsulfonyl)ethyl)amino)-1H-benzo[d]imidazole-7-carboxylate.
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Figure imgf000136_0001
made analogously to Example 22 using methyl 4-fluoro- 2-((2-(methylsulfonyl)ethyl)amino)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-amino-4-fluoro-1H-benzo[d]imidazole-7-carboxylate. C17H16ClF2N5O3S. 444.1/446/1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.85 (s, 1H), 7.12 – 6.98 (m, 3H), 6.95 (dd, J = 6.5, 2.7 Hz, 1H), 6.55 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.89 (d, J = 6.3 Hz, 2H), 3.51 (t, J = 6.1 Hz, 2H), 3.08 (s, 3H).
Example 34: N-(3-Chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-2-((2- morpholinoethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000136_0002
e analogously to Example 33 using 4-(2- lace of 1-isothiocyanato-2-(methylsulfonyl)ethane.
Figure imgf000136_0003
Example 35: N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2- (methylsulfonyl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000136_0004
made analogously to Example 39 using 2- (methylsulfonyl)ethanamine in place of N1,N1-dimethylpropane-1,3-diamine with an addition of triethylamine (1.2 eq) in the cyclization reaction. C17H15ClF3N5O3S. 134
604642.1 Attorney Docket No.: 1115.PF 462.1/464.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.82 (d, J = 4.0 Hz, 1H), 7.65 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 7.03– 6.91 (m, 2H), 6.55 (dt, J = 9.0, 3.5 Hz, 1H), 3.84 (d, J = 5.9 Hz, 2H), 3.48 (t, J = 6.4 Hz, 2H), 3.06 (s, 3H).
Example 36: N-(3-Chloro-4-fluorophenyl)-2-((2-(4,4-difluoropiperidin-1- yl)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000137_0001
e analogously to Example 39 using 2-(4,4- difluoropiperidin-1-yl)ethanamine in place of N1,N1-dimethylpropane-1,3-diamine. C21H20ClF5N6O. 503.2/505/2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.71 (s, 1H), 6.94 (dd, J = 6.5, 2.8 Hz, 1H), 6.87 (dd, J = 12.2, 6.9 Hz, 1H), 6.76 (s, 1H), 6.59 (s, 1H), 6.53 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 3.78– 3.67 (m, 2H), 3.50 (s, 4H), 3.41 (t, J = 5.7 Hz, 2H), 2.34 (dt, J = 13.6, 7.8 Hz, 4H).
Example 37: N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((1- morpholinopropan-2-yl)amino)-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000137_0002
ade analogously to Example 39 using 1- morpholinopropan-2-amine in place of N1,N1-dimethylpropane-1,3-diamine.
C21H22ClF3N6O2. 483.1/485.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.69 (s, 1H), 7.14– 6.97 (m, 2H), 6.93 (dd, J = 6.6, 2.8 Hz, 1H), 6.87 (dd, J = 12.3, 7.1 Hz, 1H), 6.58– 6.49 (m, 1H), 4.41– 4.26 (m, 1H), 3.85 (s, 4H), 3.49 (s, 2H), 3.32 (d, J = 6.3 Hz, 4H), 1.26 (d, J = 6.7 Hz, 3H). 135
604642.1 Attorney Docket No.: 1115.PF Example 38: N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2- (methylamino)-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000138_0001
lution of methyl 2-chloro-4,5-difluoro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate (0.16 g, 0.43 mmol, 1 equiv) in DMSO (1 mL) was added a 2 M solution of methylamine in methanol (0.76 mL, 1.51 mmol, 3.5 equiv) and triethylamine (0.06 mL, 0.43 mmol, 1 equiv). The reaction was stirred at 60 oC for 2 hours before being diluted with water and extracted with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-3%
MeOH/CH2Cl2). Methyl 4,5-difluoro-2-(methylamino)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was obtained as a yellow oil. C16H23F2N3O3Si.372.05 (M+1).
Figure imgf000138_0002
- - -4-fluorophenyl)-4,5-difluoro-2-(methylamino)-1H- benzo[d]imidazole-7-carboxamide was made analogously to Example 13 using methyl 4,5-difluoro-2-(methylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- benzo[d]imidazole-7-carboxylate and 3-chloro-4-fluoroaniline in place of methyl 2- amino-4,5-difluoro-1H-benzo[d]imidazole-7-carboxylate and stirring overnight at room temperature. The crude product was purified by reverse phase HPLC (10-90%
CH3CN/H2O over 20 mins) and the TFA salt of N-(3-chloro-4-fluorophenyl)-4,5- difluoro-2-(methylamino)-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C15H10ClF3N4O.355.06/356.98 (M+1).
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604642.1 Attorney Docket No.: 1115.PF
Figure imgf000139_0001
was made analogously to Example 59 using N-(3-chloro-4- fluorophenyl)-4,5-difluoro-2-(methylamino)-1H-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(methylamino)-1H- benzo[d]imidazole-7-carboximidamide was isolated as a white solid. C15H11ClF3N5O. 370.05/371.98 (M+1).1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.79 (s, 1H), 7.08 (t, J = 9.0 Hz, 1H), 7.06– 7.01 (m, 1H), 6.99 (dd, J = 6.6, 2.7 Hz, 1H), 6.53 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 2.98 (d, J = 3.7 Hz, 3H).19F NMR (377 MHz, DMSO-d6) δ -73.7, - 126.8 , -147.4 , -155.1 (TFA salt).
Example 39: N-(3-Chloro-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5- difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000139_0002
ethyl 2-chloro-4,5-difluoro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate (0.25 g, 0.66 mmol, 1 equiv) in DMSO (1.25 mL) was added N,N-dimethylpropane-1,3-diamine (0.10 mL, 0.81 mmol, 1.2 equiv). The reaction was stirred at 60 oC for 6 hours before being diluted with DMF/water and purified by reverse phase HPLC (10-90% CH3CN/H2O over 15 mins). The TFA salt of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was obtained as a yellow oil. C20H32F2N4O3Si.443.18 (M+1).
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604642.1 Attorney Docket No.: 1115.PF
Figure imgf000140_0001
ethyl 2-((3-(dimethylamino)propyl)amino)-4,5- difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate (TFA salt, 159 mg, 0.36 mmol, 1 equiv) and 3-chloro-4-fluoroaniline (209 mg, 1 mmol, 4 equiv) in DCE (7.5 mL) was added a 2 M solution of AlMe3 in toluene (1.26 mL, 3 mmol, 7 equiv) at room temperature. The reaction was stirred overnight before quenching with 2 M aqueous NaOH and extracting with ethyl acetate. The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The crude product was dissolved in CH2Cl2 (2 mL) and TFA (2 mL) was added. The SEM-deprotection was stirred overnight before being concentrated in vacuo. The crude product was purified by reverse phase HPLC (10-90% CH3CN/H2O over 15 mins). The TFA salt of N-(3-chloro- 4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1H-benzo[d]- imidazole-7-carboxamide was obtained as an off-white solid. C19H19ClF3N5O.
426.18/428.13 (M+1).
Figure imgf000140_0002
de analogously to Example 59 using N-(3-chloro-4- fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1H-benzo[d]imidazole- 7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7- carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((3- (dimethylamino)propyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7- carboximidamide was isolated as a white solid. C19H20ClF3N6O.441.12/443.09 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.72 (s, 1H), 8.74 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 7.00– 6.85 (m, 2H), 6.55 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.42 (m, 2H), 3.10 (m, 2H), 2.80 (s, 6H), 1.93 (m, 2H).19F NMR (377 MHz, DMSO-d6) δ -73.7, -127.1, - 149.4, -156.5.
138
604642.1 Attorney Docket No.: 1115.PF Example 40: N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2- methoxyethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000141_0001
, - oro-2-((2-methoxyethyl)amino)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using 2-methoxyethanamine and triethylamine (1 equiv) in place of N,N-dimethylpropane-1,3-diamine. The TFA salt of methyl 4,5-difluoro-2-((2- methoxyethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7- carboxylate was isolated as a yellow oil. C18H27F2N3O4Si.416.09/417.07 (M+1).
Figure imgf000141_0002
ophenyl)-4,5-difluoro-2-((2-methoxyethyl)amino)-1H- benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-((2-methoxyethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- benzo[d]imidazole-7-carboxylate in place of methyl 2-((3- (dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5- difluoro-2-((2-methoxyethyl)amino)-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C17H14ClF3N4O2.399.09/401.02 (M+1).
139
604642.1 Attorney Docket No.: 1115.PF [0293] Example 40 was made analogously to Example 59 using N-(3-chloro-4- fluorophenyl)-4,5-difluoro-2-((2-methoxyethyl)amino)-1H-benzo[d]imidazole-7- carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7- carboxamide . The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2- ((2-methoxyethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as a white solid. C17H15ClF3N5O2.414.09/416.01 (M+1).1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.79 (s, 1H), 8.11 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 7.04 (dd, J = 12.1, 7.0 Hz, 1H), 6.99 (dd, J = 6.6, 2.7 Hz, 1H), 6.55 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 3.56 (t, J = 5.1 Hz, 2H), 3.51 (t, J = 4.7 Hz, 2H), 3.29 (s, 3H).19F NMR (377 MHz, DMSO-d6) δ - 75.18 (6F), -126.96 (1F), -147.44 (1F), -155.18 (1F).
Example 41: N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2- (pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000142_0001
, oro-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using 2-(pyrrolidin-1-yl)ethanamine in place of N,N- dimethylpropane-1,3-diamine. The TFA salt of methyl 4,5-difluoro-2-((2-(pyrrolidin-1- yl)ethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7- carboxylate was isolated as a yellow oil. C21H32F2N4O3Si.455.21 (M+1).
Figure imgf000142_0002
rophenyl)-4,5-difluoro-2-((2-(pyrrolidin-1- yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl
140
604642.1 Attorney Docket No.: 1115.PF 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5- difluoro-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C20H19ClF3N5O.438.21/440.12 (M+1).
Figure imgf000143_0001
de analogously to Example 59 using N-(3-chloro-4- fluorophenyl)-4,5-difluoro-2-((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7- carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7- carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2- ((2-(pyrrolidin-1-yl)ethyl)amino)-1H-benzo[d]imidazole-7-carboximidamide was isolated as a white solid. C20H20ClF3N6O.453.14/455.11 (M+1).1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.84 (s, 1H), 8.70 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 7.02 (s, 1H), 6.93 (dd, J = 6.6, 2.7 Hz, 1H), 6.84 (dd, J = 12.3, 6.9 Hz, 1H), 6.53 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 4.00 (dq, J = 8.3, 7.1 Hz, 1H), 3.75-3.60 (m, 3H), 3.45-3.35 (m, 3H), 2.05-1.80 (m, 4H), 1.24 (td, J = 7.0, 0.9 Hz, 1H).19F NMR (377 MHz, DMSO-d6) δ - 74.94 (9F), -127.34 (1F), -150.32 (1F), -157.02 (1F).
Example 42: N-(3-Chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-4,5- difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000143_0002
hylamino)ethyl)amino)-4,5-difluoro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using N,N-diethylethane-1,2-diamine in place of N,N- dimethylpropane-1,3-diamine. The TFA salt of methyl 2-((2- 141
604642.1 Attorney Docket No.: 1115.PF (diethylamino)ethyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C21H34F2N4O3Si.457.22 (M+1).
Figure imgf000144_0001
- - - - enyl)-2-((2-(diethylamino)ethyl)amino)-4,5- difluoro-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 2-((2-(diethylamino)ethyl)amino)-4,5-difluoro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2- ((2-(diethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C20H21ClF3N5O.440.21/442/11 (M+1).
Figure imgf000144_0002
de analogously to Example 59 using N-(3-chloro-4- fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7- carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7- carboxamide . The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2- (diethylamino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7- carboximidamide was isolated as a white solid. C20H22ClF3N6O.455.18/457.11 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.73 (s, 1H), 8.70 (s, 1H), 7.08 (t, J = 9.1 Hz, 1H), 6.97 (s, 1H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.85 (dd, J = 12.2, 6.9 Hz, 1H), 6.53 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 3.68 (m, 2H), 3.31 (m, 2H), 3.26– 3.13 (m, 4H), 1.20 (t, J = 7.2 Hz, 6H).19F NMR (376 MHz, DMSO-d6) δ -74.9, -127.3, -150.3, -157.1. 142
604642.1 Attorney Docket No.: 1115.PF Example 43: N-(3-Chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5- difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000145_0001
- - methylamino)ethyl)amino)-4,5-difluoro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using N,N-dimethylethane-1,2-diamine in place of N,N- dimethylpropane-1,3-diamine. The TFA salt of methyl 2-((2- (dimethylamino)ethyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C19H30F2N4O3Si.429.17 (M+1).
Figure imgf000145_0002
henyl)-2-((2-(dimethylamino)ethyl)amino)-4,5- difluoro-1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2- ((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C18H17ClF3N5O.412.19/414.09 (M+1).
143
604642.1 Attorney Docket No.: 1115.PF
Figure imgf000146_0001
[0302] Example 43 was made analogously to Example 59 using N-(3-chloro-4- fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-1H-benzo[d]imidazole-7- carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7- carboxamide . The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2- (dimethylamino)ethyl)amino)-4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7- carboximidamide was isolated as a white solid. C18H18ClF3N6O.427.14/429.09 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.74 (s, 1H), 8.71 (s, 1H), 7.09 (t, J = 10.7 Hz, 1H), 7.04 (br s, 1H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.84 (dd, J = 12.2, 7.0 Hz, 1H), 6.53 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 3.69 (q, J = 5.9 Hz, 2H), 3.31 (t, J = 5.8 Hz, 2H), 2.86 (s, 6H).19F NMR (376 MHz, DMSO-d6) δ -74.99 (9F), -127.32 (1F), -150.28 (1F), -156.83 (1F).
Example 44: N-(3-Chlorophenyl)-4,5-difluoro-N'-hydroxy-2-(1-methylpiperidin-3- yl)-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000146_0002
44 was made analogously to Example 53 using 1- methylpiperidine-3-carboxylic acid in place of 3-(dimethylamino)propanoic acid . The TFA salt of 4,5-difluoro-2-(1-methylpiperidin-3-yl)-1H-benzo[d]imidazole-7-carboxylic acid was isolated as a colorless oil. C14H15F2N3O2.296.14/297.12 (M+1).
144
604642.1 Attorney Docket No.: 1115.PF H O N
Figure imgf000147_0001
of 4,5-difluoro-2-(1-methylpiperidin-3-yl)-1H- benzo[d]imidazole-7-carboxylic acid (TFA salt, 63 mg, 0.19 mmol, 1 equiv), 3- chloroaniline (0.05 mL, 0.48 mmol, 2.5 equiv), and DIPEA (0.16 mL, 0.95 mmol, 5 equiv) in DMF (1 mL) was added HATU (87 mg, 0.23 mmol, 1.2 equiv) and the reaction was stirred overnight at room temperature. The crude product was purified by reverse phase HPLC (10-90% CH3CN/H2O) and the TFA salt of N-(3-chlorophenyl)-4,5- difluoro-2-(1-methylpiperidin-3-yl)-1H-benzo[d]imidazole-7-carboxamide was obtained as a white solid. C20H19ClF2N4O.405.19/407.12 (M+1).
Figure imgf000147_0002
was made analogously to Example 59 using N-(3-chloro-4- fluorophenyl)-4,5-difluoro-2-(1-methylpiperidin-3-yl)-1H-benzo[d]imidazole-7- carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7- carboxamide . The TFA salt of N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-(1- methylpiperidin-3-yl)-1H-benzo[d]imidazole-7-carboximidamide was isolated as a white solid. C20H20ClF2N5O.420.22/422.17 (M+1).
Example 45: N-(3-Chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(((3- methoxypropyl)amino)methyl)-1H-benzo[d]imidazole-4-carboximidamide
Figure imgf000147_0003
145
604642.1 Attorney Docket No.: 1115.PF [0306] Methyl 4,5-difluoro-2-(methoxymethyl)-1H-benzo[d]imidazole-7- carboxylate. A mixture of methyl 2,3-diamino-4,5-difluorobenzoate (2.0 g, 9.9 mmol) in methoxyacetic acid (23 mL) was stirred at 120 °C for 3 hr. To the mixture was added saturated sodium bicarbonate and the aqueous layer was washed three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, absorbed onto silica and purified by silica gel chromatography to give the desired
product.C11H10F2N2O3.257.3 (M+1).
Figure imgf000148_0001
-fluorophenyl)-4,5-difluoro-2-(methoxymethyl)-1H- benzo[d]imidazole-7-carboxamide. To a solution of the 3-chloro-4-fluoroaniline in (1.30 g, 8.90 mmol) in dichloroethane (60 mL) at 0 °C under nitrogen was added
trimethylaluminum (2 M in heptane, 8.90 mL, 17.8 mmol) dropwise over 5 min. The solution was allowed to warm to room temperature and stirred for 30 min. The solution was cooled to 0 °C and to this solution was added methyl 4,5-difluoro-2- (methoxymethyl)-1H-benzo[d]imidazole-7-carboxylate (1.52 g, 5.93 mmol). The solution was stirred at 85 °C for 3 hr and, then, cooled to room temperature. Water and 10% citric acid were added and the resulting precipitate was filtered and dried on high vac to give the desired product. C16H11ClF3N3O2.370.1 (M+1).
Figure imgf000148_0002
-4-fluorophenyl)-3-(4,5-difluoro-2-(methoxymethyl)-1H- benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one. A mixture of N-(3-chloro-4- fluorophenyl)-4,5-difluoro-2-(methoxymethyl)-1H-benzo[d]imidazole-7-carboxamide (1.80 g, 4.86 mmol), phosphorous pentachloride (1.52 g, 7.29 mmol) in phosphoryl chloride (14 mL) and 1,2-dichloroethane (14 mL) was stirred at 80 °C for 2.5 hr. The 146
604642.1 Attorney Docket No.: 1115.PF reaction mixture was concentrated and suspended in ethanol (14 mL) and to this mixture was added 50% hydroxylamine in water (3.0 mL, 49 mmol). The reaction mixture stirred for 1.5 hr. Water was added to the reaction mixture and the resulting precipitate was collected by filtration and dried on high vac. The dried solid and carbonyl diimidazole (1.6 g, 9.7 mmol) was suspended in ethyl acetate (50 mL) and the reaction mixture stirred for 18 hr. The resulting solution was absorbed onto silica gel and purified by silica gel chromatography to give the desired product. C17H10ClF3N4O3.411.0 (M+1).
Figure imgf000149_0001
midazol-7-yl)-4-(3-chloro- 4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 4-(3-chloro-4-fluorophenyl)-3-(4,5- difluoro-2-(hydroxymethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one. To a mixture of 4-(3-chloro-4-fluorophenyl)-3-(4,5-difluoro-2-(methoxymethyl)-1H- benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one (937 mg, 2.28 mmol) in
dichloromethane (16 mL) at 0 °C was added a solution of 1 M boron tribromide in dichloromethane (3.42 mL, 3.42 mmol). The reaction was allowed to warm to room temperature and stirred for 18 hr. The reaction mixture was diluted with
dichloromethane and saturated sodium bicarbonate and the aqueous layer was washed three times with dichlromethane. The combined organic layers contained a precipitate that was filtered off to give 4-(3-chloro-4-fluorophenyl)-3-(4,5-difluoro-2- (hydroxymethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one (203 mg) as a white solid. The filtrate was dried over sodium sulfate, filtered, loaded onto silica gel column and purified by silica gel chromatography to give 3-(2-(bromomethyl)-4,5- difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)- one. C16H7BrClF3N4O2.459.0 (M+1). C16H8ClF3N4O3.397.1 (M+1).
Figure imgf000149_0002
147
604642.1 Attorney Docket No.: 1115.PF [0310] N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(((3- methoxypropyl)amino)methyl)-1H-benzo[d]imidazole-4-carboximidamide. A solution of 3-(2-(bromomethyl)-4,5-difluoro-1H-benzo[d]imidazol-7-yl)-4-(3-chloro-4- fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (12 mg, 0.026 mmol) and 3- methoxypropylamine (0.027 mL, 0.26 mmol) in acetonitrile (1 mL) was stirred at 65 °C for 10 min. The reaction was concentrated. The residue was brought up in
tetrahydrofuran (0.3 mL) and water (0.3 mL). To this solution was added 2 N sodium hydroxide (0.19 mL, 0.34 mmol) and the reaction mixture stirred for 10 min. To the mixture was added acetic acid (0.05 mL) and the solution was loaded directly onto a prep HPLC for purification to give the desired product. C19H19ClF3N5O2.442.1 (M+1).
Example 46: N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2- (hydroxymethyl)-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000150_0001
n of 4-(3-chloro-4-fluorophenyl)-3-(4,5-difluoro-2- (hydroxymethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one (20 mg, 0.050 mmol) in tetrahydrofuran (0.4 mL) and water (0.4 mL) was added 2 N sodium hydroxide (0.38 mL, 0.76 mmol) and the reaction mixture stirred for 10 min. To the mixture was added acetic acid (0.06 mL) and the solution was loaded directly onto a prep HPLC for purification to give the desired product. C15H10ClF3N4O2.371.0 (M+1).1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.80 (s, 1H), 7.16 (dd, J = 12.0, 7.0 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.49 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 4.63 (s, 2H).
Example 47: 2-(Aminomethyl)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- hydroxy-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000150_0002
148
. Attorney Docket No.: 1115.PF [0312] Example 47 was made analogously to Example 45 using 0.5 M ammonia in dioxane in place of 3-methoxypropylamine. C15H11ClF3N5O.370.1 (M+1).
Example 48: N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2- ((methylamino)methyl)-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000151_0001
was made analogously to Example 45 using 2 M
methylamine in tetrahydrofuran in place of 3-methoxypropylamine. C16H13ClF3N5O. 384.0 (M+1).1H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 10.92 (s, 1H), 9.21 (s, 2H), 8.82 (s, 1H), 7.34– 7.17 (m, 1H), 7.04 (t, J = 9.1 Hz, 1H), 6.90 (dd, J = 6.6, 2.7 Hz, 1H), 6.48 (dt, J = 9.0, 3.5 Hz, 1H), 4.40 (t, J = 5.8 Hz, 2H), 2.65 (s, 3H).
Example 49: N-(3-Chloro-4-fluorophenyl)-2-(((cyclopropylmethyl)amino)methyl)- 4,5-difluoro-N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000151_0002
made analogously to Example 45 using
cyclopropylmethylamine in place of 3-methoxypropylamine. C19H17ClF3N5O.424.0 (M+1).
Example 50: N-(3-Chloro-4-fluorophenyl)-2-((ethylamino)methyl)-6,7-difluoro-N'- hydroxy-1H-benzo[d]imidazole-4-carboximidamide
Figure imgf000151_0003
149
604642.1 Attorney Docket No.: 1115.PF [0315] Example 50 was made analogously to Example 45 using 2 M ethylamine in tetrahydrofuran in place of 3-methoxypropylamine. C17H15ClF3N5O.398.0 (M+1).1H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 10.92 (s, 1H), 9.25 (s, 2H), 8.82 (s, 1H), 7.33– 7.20 (m, 1H), 7.05 (t, J = 9.0 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.50 (dt, J = 9.0, 3.6 Hz, 1H), 4.43 (t, J = 5.9 Hz, 2H), 3.11– 2.95 (m, 2H), 1.21 (t, J = 7.2 Hz, 3H).
Example 51: N-(3-Chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2- ((isopropylamino)methyl)-1H-benzo[d]imidazole-4-carboximidamide
Figure imgf000152_0001
as made analogously to Example using isopropylamine in place of 3-methoxypropylamine. C18H17ClF3N5O.412.1 (M+1).1H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 10.94 (s, 1H), 9.25 (s, 2H), 8.82 (s, 1H), 7.33– 7.20 (m, 1H), 7.06 (t, J = 9.0 Hz, 1H), 6.90 (dd, J = 6.5, 2.7 Hz, 1H), 6.50 (dt, J = 9.1, 3.5 Hz, 1H), 4.49– 4.37 (m, 2H), 3.48– 3.33 (m, 1H), 1.26 (d, J = 6.5 Hz, 6H).
Example 52: N-(3-Chloro-4-fluorophenyl)-2-((dimethylamino)methyl)-6,7-difluoro- N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide
Figure imgf000152_0002
was made analogously to Example 45 using dimethylamine in place of 3-methoxypropylamine. C17H15ClF3N5O. 398.1 (M+1).1H NMR (400 MHz, DMSO-d6) δ12.93 (s, 1H), 10.93 (s, 1H), 10.28 (s, 1H), 8.83 (s, 1H), 7.40– 7.23 (m, 1H), 7.03 (t, J = 9.1 Hz, 1H), 6.95 (dd, J = 6.6, 2.7 Hz, 1H), 6.49 (dt, J = 9.0, 3.5 Hz, 1H), 4.56 (s, 2H), 2.83 (s, 6H).
150
604642.1 Attorney Docket No.: 1115.PF Example 53: N-(3-Chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro- N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide
Figure imgf000153_0001
ethylamino)ethyl)-6,7-difluoro-1H-benzo[d]imidazole-4-carboxylic acid. A mixture of methyl 2,3-diamino-4,5-difluorobenzoate (2.0g, 9.89mmol) and 3- (dimethylamino)propanoic acid (6.08g, 39.6mmol ) in concentrated hydrochloric acid was stirred at 120°C overnight in a sealed screw-top flask. The reaction was concentrated under reduced pressure. Cured product was used as is in next step without purification. C12H13F2N3O2.270.10 (M+1).
Figure imgf000153_0002
rophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-1H- benzo[d]imidazole-4-carboxamide. A mixture of 2-(2-(dimethylamino)ethyl)-6,7- difluoro-1H-benzo[d]imidazole-4-carboxylic acid (300 mg, 1.114mmol), 3-chloro-4- fluoroaniline (300 mg, 1.114mmol) , bis(2-oxo-3-oxazolidinyl)phosphinic chloride (567mg, 2.23mmol) and diisopropylethylamine (1.94mL, 11.1 mmol) in
dichloromethane (8 mL) was stirred for 2hr. The reaction mixture was filtered and absorbed onto silica gel and purified by silica gel chromatography to give the desired product. C18H16ClF3N4O.
Figure imgf000153_0003
orophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N'- hydroxy-1H-benzo[d]imidazole-4-carboximidamide. Example 53 was made analogously to Example 95 C18H17ClF3N5O.411.11 (M+1).1H NMR (400 MHz, DMSO-d6) δ 10.92
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604642.1 Attorney Docket No.: 1115.PF (s, 1H), 8.78 (s, 1H), 7.17 (dd, J = 12.0, 7.0 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.6, 2.7 Hz, 1H), 6.50 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.53 (t, J = 7.5 Hz, 2H), 3.26 (t, J = 7.6 Hz, 2H), 2.83 (s, 6H)
Example 54: N-(3-Bromo-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro- N'-hydroxy-1H-benzo[d]imidazole-4-carboximidamide
Figure imgf000154_0001
orophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-1H- benzo[d]imidazole-4-carboxamide was made analogously to Example 53 using 3-bromo- 4-fluoroaniline in place of 3-chloro-4-fluoroaniline. C18H16BrF3N4O.441.1 (M+1).
Figure imgf000154_0002
orophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N'- hydroxy-1H-benzo[d]imidazole-4-carboximidamide. Example 54 was made analogously to Example 95. C18H17BrF3N5O.456.1 (M+1).1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.76 (s, 1H), 7.17 (dd, J = 11.9, 7.0 Hz, 1H), 7.07 (dd, J = 6.1, 2.7 Hz, 1H), 7.00 (t, J = 8.8 Hz, 1H), 6.53 (ddd, J = 8.9, 4.1, 2.7 Hz, 1H), 3.53 (t, J = 7.5 Hz, 2H), 3.26 (t, J = 7.5 Hz, 2H), 2.83 (s, 6H).
Example 55: N-(3-Bromophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N'- hydroxy-1H-benzo[d]imidazole-4-carboximidamide
Figure imgf000154_0003
152
604642.1 Attorney Docket No.: 1115.PF [0323] N-(3-bromophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-1H- benzo[d]imidazole-4-carboxamide was made analogously to Example 53 using 3- bromoaniline in place of 3-chloro-4-fluoroaniline. C18H16BrF3N4O.423.1 (M+1).
Figure imgf000155_0001
yl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N'-hydroxy-1H- benzo[d]imidazole-4-carboximidamide. Example 55 was made analogously to Example 95. C18H18BrF2N5O.438.10.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.78 (s, 1H), 7.22– 7.07 (m, 1H), 7.00– 6.85 (m, 3H), 6.55– 6.40 (m, 1H), 3.54 (t, J = 7.5 Hz, 2H), 3.35– 3.20 (m, 2H), 2.84 (s, 6H).
Example 56: N-(3-Chlorophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N'- hydroxy-1H-benzo[d]imidazole-4-carboximidamide
Figure imgf000155_0002
yl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-1H- benzo[d]imidazole-4-carboxamide was made analogously to Example 53 using 3- chloroaniline in place of 3-chloro-4-fluoroaniline. C18H17ClF2N4O.379.11(M+1).
Figure imgf000155_0003
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604642.1 Attorney Docket No.: 1115.PF [0326] N-(3-chlorophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N'-hydroxy-1H- benzo[d]imidazole-4-carboximidamide. Example 56 was made analogously to Example 95 C18H18ClF2N5O.394.12 (M+1).1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.78 (s, 1H), 7.14 (dd, J = 12.0, 7.0 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H), 6.86– 6.74 (m, 2H), 6.51– 6.38 (m, 1H), 3.54 (t, J = 7.5 Hz, 2H), 3.27 (t, J = 7.5 Hz, 2H), 2.83 (s, 6H).
Example 57: N-(3-Chloro-4-fluorophenyl)-6,7-difluoro-N'-hydroxy-2-(2- (methylamino)ethyl)-1H-benzo[d]imidazole-4-carboximidamide
Figure imgf000156_0001
-4-fluorophenyl)carbamoyl)-4,5-difluoro-1H- benzo[d]imidazol-2-yl)acetate was made analogously to Example 53 using 2,3-diamino- N-(3-chloro-4-fluorophenyl)-4,5-difluorobenzamide. C18H13ClF3N3O3.412.10 (M+1).
Figure imgf000156_0002
rophenyl)-4,5-difluoro-2-(2-hydroxyethyl)-1H- benzo[d]imidazole-7-carboxamide was made analogously to Example 183 using Ethyl 2- (7-((3-chloro-4-fluorophenyl)carbamoyl)-4,5-difluoro-1H-benzo[d]imidazol-2-yl)acetate. C16H11ClF3N3O2.370.10 (M+1).
Figure imgf000156_0003
enyl)-4,5-difluoro-2-(2-((triisopropylsilyl)oxy)ethyl)- 1H-benzo[d]imidazole-7-carboxamide was made analogously to Example 183 using N- (3-chloro-4-fluorophenyl)-4,5-difluoro-2-(2-hydroxyethyl)-1H-benzo[d]imidazole-7- carboxamide. C25H31ClF3N3O2Si.526.18 (M+1).
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604642.1 Attorney Docket No.: 1115.PF
Figure imgf000157_0001
enyl)-4,5-difluoro-2-(2-((triisopropylsilyl)oxy)ethyl)- 1H-benzo[d]imidazole-7-carbothioamide was made analogously to Example 183 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(2-((triisopropylsilyl)oxy)ethyl)-1H- benzo[d]imidazole-7-carboxamide. C25H31ClF3N3OSSi.542.16 (M+1).
Figure imgf000157_0002
enyl)-3-(4,5-difluoro-2-(2- ((triisopropylsilyl)oxy)ethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one was made analogously to Example 183 using N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(2- ((triisopropylsilyl)oxy)ethyl)-1H-benzo[d]imidazole-7-carbothioamide.
C26H30ClF3N4O3Si.567.17 (M+1).
Figure imgf000157_0003
luorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)- 4,5-difluoro-1-(methylsulfonyl)-1H-benzo[d]imidazol-2-yl)ethyl methanesulfonate was made analogously to Example 112 using 4-(3-chloro-4-fluorophenyl)-3-(4,5-difluoro-2- (2-((triisopropylsilyl)oxy)ethyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-5(4H)-one. C19H14ClF3N4O7S2.567.00 (M+1). 155
604642.1 Attorney Docket No.: 1115.PF
Figure imgf000158_0001
rophenyl)-6,7-difluoro-N'-hydroxy-2-(2- (methylamino)ethyl)-1H-benzo[d]imidazole-4-carboximidamide. Example 57 was made analogously to Example 112 using 2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro- 1,2,4-oxadiazol-3-yl)-4,5-difluoro-1-(methylsulfonyl)-1H-benzo[d]imidazol-2-yl)ethyl methanesulfonate in place of 2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)-3-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-2-yl)ethyl
methanesulfonate. C16H16ClFN6O.363.11 (M+1).
Example 58: N-(3-Chloro-4-fluorophenyl)-2-(2-(diethylamino)ethyl)-4,5-difluoro- N'-hydroxy-1H-benzo[d]imidazole-7-carboximidamide
Figure imgf000158_0002
ade analogously to Example 57 using 2-(7-(4-(3-chloro-4- fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-4,5-difluoro-1-(methylsulfonyl)- 1H-benzo[d]imidazol-2-yl)ethyl methanesulfonate and diethylamine in place of 2-(7-(4- (3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-(methylsulfonyl)- 3H-imidazo[4,5-b]pyridin-2-yl)ethyl methanesulfonate and methylamine.
C20H21ClF3N5O. 440.141H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.78 (s, 1H), 7.18 (dd, J = 11.9, 6.9 Hz, 1H), 7.03 (t, J = 9.0 Hz, 1H), 6.94 (dd, J = 6.6, 2.7 Hz, 1H), 6.48 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 3.50 (t, J = 7.6 Hz, 2H), 3.24 (t, J = 7.7 Hz, 2H), 3.19 (q, J = 8.3, 7.3 Hz, 4H), 1.20 (t, J = 7.3 Hz, 6H).
156
604642.1 Attorney Docket No.: 1115.PF Example 59: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine- 7-carboximidamide
Figure imgf000159_0001
[0335] 1H-imidazo[4,5-b]pyridine-7-carboxylic acid (300 mg, 2.0 mmol), 3-chloro- 4-fluoroaniline (2.0 mmol), and HATU (2.4 mmol) were dissolved in DMF (5 mL) and DIPEA (6 mmol) was added. The reaction was allowed to stir at rt overnight. The reaction was quenched with saturated sodium bicarbonate solution (5 mL) and the reaction was extracted with EtOAc (3x5 mL). Combined organic layers were washed with brine (1x8 mL) and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hex) to give N-(3-chloro-4-fluorophenyl)-1H- imidazo[4,5-b]pyridine-7-carboxamide.
[0336] N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (122 mg, 0.42 mmol) and PCl5 (0.63 mmol) was dissolved in POCl3 (2 mL) and heated to 85 °C for 12 hours. The reaction was cooled to rt and concentrated in vacuo. The residue was dissolved in a pre-mixed solution of hydroxylamine (50% aqueous solution, 4.0 mmol) and ethanol (2 mL) and the reaction was allowed to stir at rt for 10 minutes. The reaction was concentrated in vacuo and purified by reverse-phase HPLC to give N-(3- chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide as a white solid. C13H9ClFN5O. 306.0/308.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.92 (d, J = 1.9 Hz, 1H), 8.64 (s, 1H), 8.43– 8.39 (m, 1H), 7.28– 7.23 (m, 1H), 7.03 (t, J = 9.1 Hz, 1H), 6.98– 6.92 (m, 1H), 6.51 (dt, J = 8.9, 3.4 Hz, 1H).
Example 60: N-(5-Chloro-2-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine- 7-carboximidamide
Figure imgf000159_0002
157
604642.1 Attorney Docket No.: 1115.PF [0337] Example 60 was made analogously to Example 59 using 5-chloro-2- fluoroaniline in place of 3-chloro-4-fluoroaniline. C13H9ClFN5O. 306.1/308.2 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 8.88 (s, 1H), 8.46 (d, J = 5.3 Hz, 1H), 7.35 (d, J = 5.3 Hz, 1H), 7.01– 6.95 (m, 2H), 6.92– 6.85 (m, 1H).
Example 61: N-(5-Bromo-2,4-difluorophenyl)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide
Figure imgf000160_0001
e 61 was made analogously to Example 59 using 5-bromo-2,4- difluoroaniline in place of 3-chloro-4-fluoroaniline. C13H8BrF2N5O. 368.0/370.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.71 (s, 1H), 8.59 (s, 1H), 8.36 (d, J = 4.8 Hz, 1H), 7.34– 7.21 (m, 3H).
Example 62: N-(5-Chloro-2,4-difluorophenyl)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide
Figure imgf000160_0002
e 62 was made analogously to Example 59 using 5-chloro-2,4- difluoroaniline in place of 3-chloro-4-fluoroaniline. C13H8ClF2N5O. 324.0/326.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.71 (d, J = 17.2 Hz, 2H), 8.42– 8.34 (m, 1H), 7.34 (dd, J = 10.7, 9.3 Hz, 1H), 7.28 (d, J = 5.0 Hz, 1H), 7.15 (t, J = 8.2 Hz, 1H).
Example 63: N-(3,5-Dichloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide
Figure imgf000160_0003
158
604642.1 Attorney Docket No.: 1115.PF [0340] Example 63 was made analogously to Example 59 using 3,5-dichloro-4- fluoroaniline in place of 3-chloro-4-fluoroaniline. C13H8Cl2FN5O. 340.1/342.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 10.10 (s, 1H), 9.07 (d, J = 1.1 Hz, 1H), 8.53 (s, 1H), 8.45– 8.37 (m, 1H), 7.31 (d, J = 5.2 Hz, 1H), 6.81– 6.73 (m, 2H).
Example 64: N-(3-Chloro-2,4-difluorophenyl)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide
Figure imgf000161_0001
64 was made analogously to Example 59 using 3-chloro-2,4- difluoroaniline in place of 3-chloro-4-fluoroaniline. C13H8ClF2N5O. 324.1/326.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 0H), 8.67 (s, 1H), 8.51 (s, 1H), 8.34 (dd, J = 5.0, 2.3 Hz, 1H), 7.22 (s, 1H), 7.04 (t, J = 9.0 Hz, 1H), 6.84 (s, 1H).
Example 65: N-(3-Cyclopropyl-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide
Figure imgf000161_0002
5 was made analogously to Example 59 using 3-cyclopropyl-4- fluoroaniline in place of 3-chloro-4-fluoroaniline. C16H14FN5O. 312.1 (M+1).
Example 66: N'-Hydroxy-N-(4-(trifluoromethoxy)phenyl)-1H-imidazo[4,5- b]pyridine-7-carboximidamide
Figure imgf000161_0003
6 was made analogously to Example 59 using 4- (trifluoromethoxy)aniline in place of 3-chloro-4-fluoroaniline. C14H10F3N5O2. 338.1 (M+1). 159
604642.1 Attorney Docket No.: 1115.PF Example 67: N-(Benzofuran-4-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000162_0001
67 was made analogously to Example 59 using benzofuran-4-amine in place of 3-chloro-4-fluoroaniline. C15H11N5O2. 294.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 8.92 (s, 1H), 8.86 (s, 1H), 8.34 (dd, J = 5.2, 2.7 Hz, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.16– 7.09 (m, 2H), 7.06 (dd, J = 2.3, 1.0 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 6.36 (d, J = 7.8 Hz, 1H).
Example 68: N-(Benzofuran-6-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000162_0002
68 was made analogously to Example 59 using benzofuran-6-amine in place of 3-chloro-4-fluoroaniline. C15H11N5O2. 294.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.89 (d, J = 33.4 Hz, 2H), 8.40 (d, J = 6.1 Hz, 1H), 7.79– 7.74 (m, 1H), 7.30 (dd, J = 8.6, 2.0 Hz, 1H), 7.24 (t, J = 5.9 Hz, 1H), 6.90 (t, J = 2.5 Hz, 1H), 6.76 (dd, J = 2.2, 1.1 Hz, 1H), 6.69 (dt, J = 8.4, 1.9 Hz, 1H).
Example 69: N-(Benzofuran-7-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000162_0003
e 69 was made analogously to Example 59 using benzofuran-7-amine in place of 3-chloro-4-fluoroaniline. C15H11N5O2. 294.1 (M+1).
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604642.1 Attorney Docket No.: 1115.PF Example 70: N-(benzofuran-5-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-
Figure imgf000163_0001
OH H N N
Figure imgf000163_0002
70 was made analogously to Example 59 using benzofuran-5-amine in place of 3-chloro-4-fluoroaniline. C15H11N5O2. 294.1 (M+1).
Example 71: N-(5-Bromo-2-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine- 7-carboximidamide
Figure imgf000163_0003
ple 71 was made analogously to Example 59 using acid and 5-bromo- 2-fluoroaniline in place of 3-chloro-4-fluoroaniline. C13H9BrFN5O.350.1/352.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 10.06 (s, 1H), 8.74 (s, 1H), 8.57 (s, 1H), 8.35 (d, J = 5.1 H, 1H), 7.25 (s, 1H), 7.14– 6.92 (m, 3H).
Example 72: N-(3-Bromo-5-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine- 7-carboximidamide
Figure imgf000163_0004
e 72 was made analogously to Example 59 using 5-bromo-3- fluoroaniline in place of 3-chloro-4-fluoroaniline. C13H9BrFN5O.350.1/352.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 9.08 (s, 1H), 8.55 (s, 1H), 8.37 (d, J = 5.1 Hz, 1H), 7.23 (d, J = 5.1 Hz, 1H), 6.84– 6.75 (m, 1H), 6.66 (t, J = 1.9 Hz, 1H), 6.30 (dt, J = 11.3, 2.1 Hz, 1H).
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604642.1 Attorney Docket No.: 1115.PF Example 73: N'-Hydroxy-N-(3-(trifluoromethyl)phenyl)-1H-imidazo[4,5- b]pyridine-7-carboximidamide
Figure imgf000164_0001
ple 73 was made analogously to Example 59 using 3- (trifluoromethyl)aniline in place of 3-chloro-4-fluoroaniline. C14H10F3N5O.322.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 9.13 (s, 1H), 8.77 (s, 1H), 8.43 (d, J = 5.1 Hz, 1H), 7.29 (d, J = 5.1 Hz, 1H), 7.27– 7.13 (m, 1H), 7.13– 7.02 (m, 2H), 6.90– 6.71 (m, 1H).
Example 74: N-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide
Figure imgf000164_0002
74 was made analogously to Example 59 using 2,2- difluorobenzo[d][1,3]dioxol-5-amine in place of 3-chloro-4-fluoroaniline.
[0352] N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide. C14H9F2N5O3.334.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.00 (d, J = 13.0 Hz, 1H), 8.86 (s, 1H), 8.46 (s, 1H), 8.34 (d, J = 5.0 Hz, 1H), 7.22 (d, J = 31.8 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.78 (d, J = 2.2 Hz, 1H), 6.34 (dd, J = 8.7, 2.3 Hz, 1H).
Example 75: N-(3-Fluoro-5-(trifluoromethyl)phenyl)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide
Figure imgf000164_0003
162
604642.1 Attorney Docket No.: 1115.PF [0353] Example 75 was made analogously to Example 59 using 3-fluoro-5- (trifluoromethyl)aniline in place of 3-chloro-4-fluoroaniline. C14H9F4N5O.340.1 (M+1).
Example 76: N-(2,5-Dichlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000165_0001
dichloroaniline (2.0 mmol) were dissolved in DCM (3 mL) and cooled to 0 °C.
Triethylamine (4.0 mmol) was added dropwise followed by POCl3 (2.0 mmol) and the reaction was allowed to slowly come to rt and stir for 15 mins. The reaction was quenched with saturated sodium bicarbonate solution and extracted with EtOAc (3x5 mL). Combined organic layers were washed with brine (1x7 mL) and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hex) to give N-(2,5-dichlorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide.
[0355] N-(2,5-dichlorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (40 mg, 0.13 mmol) was dissolved in POCl3 (2 mL) and PCl5 (0.195 mmol) was added. The reaction was heated to 80 °C overnight, allowed to cool to rt, and concentrated in vacuo. The crude was dissolved in a pre-mixed solution of hydroxylamine (50% in water, 1.0 mmol) and ethanol (2 mL) and allowed to stir at rt for 10 mins then concentrated in vacuo. The crude was purified by reverse-phase HPLC to give N-(2,5-dichlorophenyl)- N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. C13H9Cl2N5O. 322.0/324.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 8.80 (s, 1H), 8.71 (s, 1H), 8.48 – 8.39 (m, 1H), 7.43– 7.34 (m, 2H), 6.98 (dd, J = 8.6, 2.4 Hz, 1H), 6.69 (d, J = 3.2 Hz, 1H).
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604642.1 Attorney Docket No.: 1115.PF Example 77: N-(6-Fluoro-[1,1'-biphenyl]-3-yl)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide
Figure imgf000166_0001
fluoroaniline (11.0 mmol), and HATU (12.0 mmol) were dissolved in DMF (15.0 mL) and DIPEA (28.0 mmol) was added and the reaction was allowed to stir overnight at rt. The reaction was quenched with saturated sodium bicarb solution and the precipitate was isolated by vacuum filtration. The precipitate was washed with water followed by diethyl ether to give N-(3-bromo-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7- carboxamide as a yellow powder.
[0357] N-(3-bromo-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (150 mg, 0.448 mmol) and phenyl boronic acid (2.0 mmol) was dissolved in degassed THF (2.0 mL) and water (0.50 mL). PdCl2(dppf) (0.090 mmol) and K2CO3 (2.0 mmol) were added and the reaction was heated to 65 °C overnight. The reaction was allowed to cool to rt and quenched with saturated bicarb solution. The solution was extracted with EtOAc (3 x 4 mL) and combined organic layers were washed with brine (1x 5
((EtOAc/hex) to give N-(6-fluoro-[1,1'-biphenyl]-3-yl)-1H-imidazo[4,5-b]pyridine-7- carboxamide.
[0358] N-(6-fluoro-[1,1'-biphenyl]-3-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (100 mg, 0.301 mmol) was dissolved in POCl3, PCl5 (2.0 mmol) was added, and the reaction was heated to 80 °C overnight. The reaction was allowed to cool to rt and concentrated in vacuo. The crude was dissolved in a pre-mixed solution of
hydroxylamine (50% in water, 3.0 mmol) and ethanol (2 mL) and allowed to stir at rt for 164
604642.1 Attorney Docket No.: 1115.PF 10 mins. The reaction was purified by reverse-phase HPLC to give N-(6-fluoro-[1,1'- biphenyl]-3-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide.
C19H14FN5O. 348.2 (M+1).
Example 78: N-(3-(But-1-yn-1-yl)-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide
Figure imgf000167_0001
[0359] N-(3-bromo-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (100 mg, 0.298 mmol), PdCl2(PPh3)2 (0.015 mmol), and CuI (0.0298 mmol) were dissolved in degassed DMF (0.75 mL) and DIPEA (3.0 mmol) was added. But-1-yne was bubbled through the reaction for 5 mins and then removed. The reaction was allowed to stir overnight under an atmosphere of but-1-yne. The reaction was quenched with water and extracted with EtOAc (3x 3 mL). The combined organic layers were washed with brine (1x5 mL) and concentrated in vacuo. The crude was purified by column chromatography (EtOAc/hex) to give N-(3-(but-1-yn-1-yl)-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7- carboxamide (57 mg, 62%).
[0360] N-(3-(but-1-yn-1-yl)-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7- carboxamide (56 mg, 0.182 mmol) was dissolved in POCl3 (2 mL) and PCl5 (0.272 mmol) was added and the reaction was heated to 80 °C for 45 mins. The reaction was allowed to cool to rt and concentrated in vacuo. The material was dissolved in a pre- mixed solution of hydroxylamine (50% in water, 2.0 mmol) and ethanol (2 mL) and allowed to stir at rt for 10 mins. The reaction was purified by reverse-phase HPLC to give N-(3-(but-1-yn-1-yl)-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide. C17H14FN5O. 324.2 (M+1).
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604642.1 Attorney Docket No.: 1115.PF Example 79: N-(3-(Cyclopropylethynyl)-4-fluorophenyl)-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000168_0001
s made analogously to Example 78 using ethynylcyclopropane (5 eq) in place of but-1-yne. C18H14FN5O. 336.1 (M+1).
Example 80: N-(3-Bromophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000168_0002
henyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. To a solution of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid (0.102 g, 0.625 mmol), 3- bromoaniline (0.07 mL, 0.625 mmol), HOBt (0.101 g, 0.750 mmol) and DIEA (0.27 mL, 1.56 mmol) in DMF (3 mL) was added EDC (0.16 mL, 0.75 mmol). The mixture stirred at room temperature for 16 h. The mixture was diluted with sat. bicarb solution and the solid was isolated via filtration. The solid was suspended in 10% citric acid solution and then isolated via filtration. The filter cake was rinsed with water and dried under vacuum to yield the desired product. C13H9BrN4O. 317.0/319.0 [M+1]+.
Figure imgf000168_0003
henyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide. To a mixture of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7- carboxamide (0.062 g, 0.195 mmol) and phosphoryl chloride (0.18 mL, 1.95 mmol) in DCE (2 mL) was added phosphorus pentachloride (0.061 g, 0.293 mmol). The mixture was stirred at 80 °C for 2 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was taken up in EtOH (3 mL) and hydroxylamine (0.12 mL of a 50 w/w% solution in water, 1.96 mmol) was added. The mixture stirred 2 h at 166
604642.1 Attorney Docket No.: 1115.PF rt. The mixture was concentrated and the residue was dissolved in DMSO/water and purified via preparative HPLC to yield the desired product. C13H10BrN5O. 332.0/334.0 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 11.25 (br s, 1H), 8.94 (br s, 1H), 8.71 (br s, 1H), 8.42 (dd, J = 5.0, 2.5 Hz, 1H), 7.26 (dd, J = 5.2, 2.2 Hz, 1H), 7.01– 6.98 (m, 1H), 6.96– 6.91 (m, 2H), 6.51 (ddd, J = 4.9, 3.8, 2.2 Hz, 1H).
Example 81: N-(3-Bromo-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine- 7-carboximidamide
Figure imgf000169_0001
4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. To a solution of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid (0.097 g, 0.595 mmol), 3- bromo-4-fluoroaniline (0.114 g, 0.597 mmol), HOBt (0.099 g, 0.729 mmol) and DIEA (0.26 mL, 1.49 mmol) in DMF (3 mL) was added EDC (0.15 mL, 0.71 mmol). The mixture stirred at room temperature for 16 h. The mixture was diluted with sat. bicarb solution and the solid was isolated via filtration. The solid was taken up in DCM/MeCN, concentrated onto silica gel, and purified via flash chromatography on silica gel to give the desired product. C13H8BrFN4O. 335.0/337.0 [M+1]+.
Figure imgf000169_0002
4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide. Example 81 was synthesized analogously to Example 80, using N-(3- bromo-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3- bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. (C13H9BrFN5O. 350.0/352.0 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 11.18 (br s, 1H), 8.94 (br s, 1H), 8.69 (br s, 1H), 8.42 (d, J = 5.1 Hz, 1H), 7.26 (d, J = 5.1 Hz, 1H), 7.09 (dd, J = 6.1, 2.7 Hz, 1H), 7.00 (t, J = 8.8 Hz, 1H), 6.54 (ddd, J = 8.9, 4.1, 2.7 Hz, 1H).
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604642.1 Attorney Docket No.: 1115.PF Example 82: N-(3-Chlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000170_0001
henyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 80 using 3-chloroaniline in place of 3-bromoaniline. C13H9ClN4O. 273.0 [M+1]+
.
Figure imgf000170_0002
henyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide. Example 82 was synthesized analogously to Example 80, using N-(3- chlorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3- bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C13H10ClN5O. 288.0
[M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 11.28 (br s, 1H), 8.98 (s, 1H), 8.75 (br s, 1H), 8.43 (dd, J = 4.9, 1.5 Hz, 1H), 7.26 (dd, J = 5.1, 1.5 Hz, 1H), 6.99 (t, J = 8.1 Hz, 1H), 6.87– 6.78 (m, 2H), 6.47 (ddd, J = 8.3, 2.2, 0.9 Hz, 1H).
Example 83: N-(4-Fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide
Figure imgf000170_0003
(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridine-7- carboxamide was synthesized analogously to Example 80 using 4-fluoro-3- (trifluoromethyl)aniline in place of 3-bromoaniline. C14H8F4N4O. 325.0 [M+1]+.
Figure imgf000170_0004
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604642.1 Attorney Docket No.: 1115.PF [0369] N-(4-fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide. Example 83 was synthesized analogously to Example 80, using N-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridine-7- carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C14H9F4N5O. 340.1 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 11.18 (br s, 1H), 9.09 (s, 1H), 8.55 (br s, 1H), 8.40 (dd, J = 5.0, 1.8 Hz, 1H), 7.29 (d, J = 5.0 Hz, 1H), 7.16– 7.07 (m, 2H), 6.85– 6.79 (m, 1H).
Example 84: N-(4-Fluoro-3-(prop-1-yn-1-yl)phenyl)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide
Figure imgf000171_0001
ro-3-(prop-1-yn-1-yl)aniline. A solution of 3-bromo-4-fluoroaniline (0.254 g, 1.337 mmol) and trimethyl(prop-1-yn-1-yl)silane (0.59 mL, 4.010 mmol) in DMF (1.5 mL) was degassed by bubbling N2 for approx.5 min. CuI (0.025 g, 0.134 mmol), Pd(PPh3)2Cl2 (0.094 g, 0.134 mmol) and TBAF (4.68 mL of a 1 M solution in THF, 4.68 mmol) were added and the mixture was heated at 65 °C for 16 h. The mixture was diluted with water and extracted 3× with DCM. The combined organic layers were washed with sat. bicarb solution and brine, dried (Na2SO4), filtered and concentrated. The residue was purified via flash chromatography on silica gel to yield the desired product. C9H8FN. 150.0 [M+1]+.
Figure imgf000171_0002
rop-1-yn-1-yl)phenyl)-1H-imidazo[4,5-b]pyridine-7- carboxamide. To a solution of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid (0.030 g, 0.184 mmol), 4-fluoro-3-(prop-1-yn-1-yl)aniline (0.028 g, 0.134 mmol), HOBt (0.030 g, 0.221 mmol) and DIEA (0.08 mL, 0.46 mmol) in DMF (2 mL) was added EDC (0.05 mL, 0.22 mmol). The mixture stirred at room temperature for 16 h. The mixture was diluted with sat. bicarb solution and was extracted 3× with EtOAc. The combined organic layers were washed with 10% citric acid solution and brine, dried (Na2SO4),
169
604642.1 Attorney Docket No.: 1115.PF filtered, concentrated onto silica gel, and purified via flash chromatography on silica gel to yield the desired product. C16H11FN4O. 295.1 [M+1]+.
Figure imgf000172_0001
rop-1-yn-1-yl)phenyl)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide. Example 84 was synthesized analogously to Example 80, using N-(4-fluoro-3-(prop-1-yn-1-yl)phenyl)-1H-imidazo[4,5-b]pyridine-7- carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C16H12FN5O. 310.1 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 11.02 (br s, 1H), 8.75 (s, 1H), 8.60 (br s, 1H), 8.36 (d, J = 4.9 Hz, 1H), 7.18 (d, J = 5.0 Hz, 1H), 6.85 (t, J = 9.1 Hz, 1H), 6.78 (dd, J = 6.3, 2.8 Hz, 1H), 6.52 (ddd, J = 8.
8, 4.4, 2.9 Hz, 1H), 1.98 (s, 3H).
Example 85: N-(3-Bromo-4-chlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine- 7-carboximidamide
Figure imgf000172_0002
4-chlorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 80, using 3-bromo-4-chloroaniline in place of 4- fluoro-3-(prop-1-yn-1-yl)aniline. C13H8BrClN4O. 350.9/352.9 [M+1]+.
Figure imgf000172_0003
4-chlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide. Example 85 was synthesized analogously to Example 80 using N-(3- bromo-4-chlorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3- bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C13H9BrClN5O. 366.0/368.0 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 11.27 (br s, 1H), 9.01 (s, 1H), 8.65 (br s, 1H), 8.40 (dd, J = 5.1, 1.7 Hz, 1H), 7.25 (dd, J = 5.0, 1.5 Hz, 1H), 7.17 (d, J = 8.7 Hz, 1H), 7.11 (dd, J = 2.7, 0.8 Hz, 1H), 6.49 (dd, J = 8.7, 2.6 Hz, 1H).
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604642.1 Attorney Docket No.: 1115.PF Example 86: N-(3,4-Dichlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000173_0001
orophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. Example 86 was synthesized analogously to Example 80, using 3,4-dichloroaniline in place of 3- bromoaniline. C13H8Cl2N4O. 307.0 [M+1]+.
Figure imgf000173_0002
orophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide. Example 86 was synthesized analogously to Example 80, using N- (3,4-dichlorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3- bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C13H9Cl2N5O. 322.0
[M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 11.33 (br s, 1H), 9.09 (s, 1H), 8.71 (br s, 1H), 8.44 (dd, J = 5.2, 1.8 Hz, 1H), 7.29 (dd, J = 5.0, 1.6 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 2.7 Hz, 1H), 6.49 (dd, J = 8.8, 2.6 Hz, 1H).
Example 87: N-(4-Chlorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000173_0003
henyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. To a solution of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid (0.110 g, 0.674 mmol), 4-chloroaniline (0.088 g, 0.689 mmol), HOBt (0.109 g, 0.807 mmol) and DIEA (0.30 mL, 1.72 mmol) in DMF (3 mL) was added EDC (0.18 mL, 0.809 mmol). The mixture stirred at room temperature for 16 h. The mixture was diluted with sat. bicarb solution and the solid was isolated via filtration. The solid was suspended in approx.3 mL THF. The solid was removed via filtration and the filter cake was washed with THF. The filtrate was dried
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604642.1 Attorney Docket No.: 1115.PF (Na2SO4), filtered and concentrated under reduced pressure to yield the desired product. C13H9ClN4O. 273.0 [M+1]+.
Figure imgf000174_0001
henyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide. Example 87 was synthesized analogously to Example 80, using N-(4- chlorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3- bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C13H10ClN5O. 288.0
[M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 11.19 (br s, 1H), 8.92 (s, 1H), 8.75 (br s, 1H), 8.41 (d, J = 5.1 Hz, 1H), 7.21 (d, J = 5.1 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.8 Hz, 2H).
Example 88: N-(4-Bromophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000174_0002
henyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 80, using 4-bromoaniline in place of 3- bromoaniline. C13H9BrN4O. 339.0/341.0 [M+23]+.
Figure imgf000174_0003
henyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide. Example 88 was synthesized analogously to Example 80, using N-(4- bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3- bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C13H10BrN5O. 332.0/334.0 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 11.19 (br s, 1H), 8.89 (s, 1H), 8.72 (br s, 1H), 8.41 (d, J = 5.0 Hz, 1H), 7.21 (d, J = 5.3 Hz, 1H), 7.19 (d, J = 8.7 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H).
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604642.1 Attorney Docket No.: 1115.PF Example 89: N-(4-Fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000175_0001
henyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 80 using 5-fluoroaniline in place of 3-bromoaniline. C13H9FN4O. 257.0 [M+1]+.
Figure imgf000175_0002
henyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide. Example 89 was synthesized analogously to Example 80, using N-(4- fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3- bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C13H10FN5O. 272.1 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 11.05 (br s, 1H), 8.80 (s, 1H), 8.72 (br s, 1H), 8.39 (dd, J = 5.1, 1.3 Hz, 1H), 7.18 (d, J = 5.1 Hz, 1H), 6.88 (t, J = 8.8 Hz, 2H), 6.71 (dd, J = 9.0, 4.8 Hz, 2H).
Example 90: N-(3-Cyano-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000175_0003
luorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 80, using 3-cyano-4-fluoroaniline in place of 3- bromoaniline. C14H8FN5O. 282.0 [M+1]+.
Figure imgf000175_0004
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604642.1 Attorney Docket No.: 1115.PF [0384] N-(3-cyano-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide. Example 90 was synthesized analogously to Example 80, using N-(3- cyano-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3- bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C14H9FN6O. 297.1 [M+1]+.
Example 91: N'-Hydroxy-N-(4-(trifluoromethyl)phenyl)-1H-imidazo[4,5- b]pyridine-7-carboximidamide
Figure imgf000176_0001
methyl)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 84, using 4-(trifluoromethyl)aniline in place of 4-fluoro-3-(prop-1-yn-1-yl)aniline. C14H9F3N4O. 307.0 [M+1]+.
Figure imgf000176_0002
(4-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridine-7- carboximidamide. Example 91 was synthesized analogously to Example 80 using N-(4- (trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3- bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C14H10F3N5O. 322.1
[M+1]+.
Example 92: N'-Hydroxy-N-(3-methoxyphenyl)-1H-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000176_0003
phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 80, using 3-methoxyaniline in place of 3- bromoaniline. C14H12N4O2. 269.1 [M+1]+.
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604642.1 Attorney Docket No.: 1115.PF
Figure imgf000177_0001
(3-methoxyphenyl)-1H-imidazo[4,5-b]pyridine-7- carboximidamide. Example 92 was synthesized analogously to Example 80 , using N-(3- methoxyphenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3- bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C14H13N5O2. 284.1 [M+1]+.
Example 93: N-(4-Fluoro-3-isopropylphenyl)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide
Figure imgf000177_0002
isopropylphenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 80 , using 4-fluoro-3-isopropylaniline in place of 3-bromoaniline. C16H15FN4O. 299.0 [M+1]+.
Figure imgf000177_0003
isopropylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide. Example 93 was synthesized analogously to Example 80 , using N-(4- fluoro-3-isopropylphenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3- bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C16H16FN5O. 314.1 [M+1]+.
Example 94: N'-Hydroxy-N-(p-tolyl)-1H-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000177_0004
1H-imidazo[4,5-b]pyridine-7-carboxamide was synthesized analogously to Example 84 , using p-toluidine in place of 4-fluoro-3-(prop-1-yn-1- yl)aniline. C14H +
12N4O. 253.1 [M+1] . 175
604642.1 Attorney Docket No.: 1115.PF
Figure imgf000178_0001
xy-N-(p-tolyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 94 was synthesized analogously to Example 80 , using N-(p-tolyl)-1H- imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5- b]pyridine-7-carboxamide. C14H13N5O. 268.1 [M+1]+.
Example 95: N-(3-Ethynylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000178_0002
henyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. A solution of 1H-imidazo[4,5-b]pyridine-7-carboxylic acid (100 mg, 0.613 mmol), bis(2-oxo-3- oxazolidinyl)phosphinic chloride (312mg, 1.23mmol) and diisopropylethylamine (0.534 mL, 3.06 mmol) in dichloromethane (10 mL). was stirred for 16hr. The reaction mixture was filtered and absorbed onto silica gel and purified by silica gel chromatography to give the desired product (140 mg). C15H10N4O. 263.1 (M+1).
Figure imgf000178_0003
henyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide. A mixture of N-(3-ethynylphenyl)-1H-imidazo[4,5-b]pyridine-7- carboxamide (41 mg, 0.155 mmol), phosphorous pentachloride (48 mg, 0.233 mmol) in phosphoryl chloride (0.3mL) and 1,2-dichloroethane (0.3 mL) were stirred at 80 °C for 2 hr. The reaction mixture was concentrated and suspended in ethanol (2 mL) and to this mixture was added 50% hydroxylamine in water (0.265 mL, 4.33 mmol). The reaction mixture stirred for 1 hr and was concentrated. The residue was purified by preparative HPLC to give two products (Example 95 and Example 96). N-(3-ethynylphenyl)-N'- 176
604642.1 Attorney Docket No.: 1115.PF hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. C15H11N5O.278.07 (M+1) 1H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.90 (s, 1H), 8.78 (s, 1H), 8.43 (d, J = 5.1 Hz, 1H), 7.24 (d, J = 5.1 Hz, 1H), 7.00 (t, J = 8.1 Hz, 1H), 6.93– 6.85 (m, 2H), 6.59 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H), 4.07 (s, 1H).
Example 96: N-(3-Ethylphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000179_0001
nyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide was prepared as described in Example 95. C15H15N5O.281.10 (M+1) 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.74 (d, J = 15.8 Hz, 2H), 8.39 (d, J = 5.1 Hz, 1H), 7.19 (d, J = 5.1 Hz, 1H), 6.98– 6.87 (m, 1H), 6.64 (ddd, J = 7.5, 1.6, 0.9 Hz, 1H), 6.55– 6.43 (m, 2H), 2.34 (q, J = 7.6 Hz, 2H), 0.89 (t, J = 7.6 Hz, 3H).
Example 97: N-(3-Ethynyl-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine- 7-carboximidamide
Figure imgf000179_0002
4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using 3-ethynyl-4-fluoroaniline in place of 3- ethynylaniline. C15H9FN4O.281.00 (M+1).
Figure imgf000179_0003
4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide. Example 97 was made analogously to Example 95 C15H10FN5O. 295.09 (M+1).1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.90 (s, 1H), 8.78 (s,
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604642.1 Attorney Docket No.: 1115.PF 1H), 8.43 (d, J = 5.1 Hz, 1H), 7.26 (d, J = 5.1 Hz, 1H), 6.98– 6.89 (m, 2H), 6.62 (ddd, J = 9.0, 4.4, 2.9 Hz, 1H), 4.39 (d, J = 0.6 Hz, 1H).
Example 98: N-(3-(Difluoromethyl)phenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine- 7-carboximidamide
Figure imgf000180_0001
oromethyl)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using 3-(difluoromethyl)aniline in place of 3- ethynylaniline. C14H10F2N4O.289.10 (M+1).
Figure imgf000180_0002
methyl)phenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide. Example 98 was made analogously to Example 95 using N-(3- (difluoromethyl)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C14H11F2N5O. 304.10 (M+1) 1H NMR (400 MHz, DMSO-d6) δ, 12.51 (s, 1H), 11.17 (s, 1H), 8.92 (d, J = 25.4 Hz, 1H), 8.41 (s, 1H), 8.33 (d, J = 5.0 Hz, 1H), 7.41-7.23 (m, 1H), 7.19– 7.02 (m, 1H), 7.02– 6.80 (m, 2H), 6.73 (d, J = 8.2 Hz, 1H).
Example 99: N-Hydroxy-N-(3-(trifluoromethoxy)phenyl)-1H-imidazo[4,5- b]pyridine-7-carboximidamide
Figure imgf000180_0003
omethoxy)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using 3-(trifluoromethoxy)aniline in place of 3- ethynylaniline. C14H9F3N4O2.323.07 (M+1)
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Figure imgf000181_0001
N-hydroxy-N-(3-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-b]pyridine-7- carboximidamide. Example 99 was made analogously to Example 95 using N-(3- (trifluoromethoxy)phenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C14H10F3N5O2. 338.10 (M+1).1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 9.22 (s, 1H), 8.58 (d, J = 5.3 Hz, 1H), 7.40 (d, J = 5.3 Hz, 1H), 7.12 (td, J = 8.1, 0.5 Hz, 1H), 6.74 (ddt, J = 8.2, 2.1, 1.0 Hz, 1H), 6.69– 6.61 (m, 3H).
Example 100: N-Hydroxy-N-phenyl-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000181_0002
idazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using aniline in place of 3-ethynylaniline. C13H10N4O.239.10 (M+1).
Figure imgf000181_0003
droxy-N-phenyl-1H-imidazo[4,5-b]pyridine-7-carboximidamide.
Example 100 was made analogously to Example 95 using N-phenyl-1H-imidazo[4,5- b]pyridine-7-carboxamide. C13H11N5O.254.101H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 11.01 (s, 1H), 8.63 (s, 1H), 8.40 (d, J = 1.1 Hz, 1H), 8.34– 8.26 (m, 1H), 7.08– 6.99 (m, 2H), 6.95 (dd, J = 8.5, 7.3 Hz, 1H), 6.82– 6.76 (m, 1H), 6.73– 6.58 (m, 2H).
Example 101: N-(4-Fluoro-3-(trifluoromethoxy)phenyl)-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000181_0004
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604642.1 Attorney Docket No.: 1115.PF [0403] N-(4-fluoro-3-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-b]pyridine-7- carboxamide was made analogously to Example 95 using 4-fluoro-3- (trifluoromethoxy)aniline in place of 3-ethynylaniline. C14H8F4N4O2.341.06 (M+1).
Figure imgf000182_0001
ifluoromethoxy)phenyl)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide. Example 101 was made analogously to Example 95 using N-(4-fluoro-3-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-b]pyridine-7- carboxamide. C14H9F4N5O2.355.07 (M+1).1H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 9.10 (s, 1H), 8.77 (s, 1H), 8.45 (d, J = 5.1 Hz, 1H), 7.30 (d, J = 5.1 Hz, 1H), 7.24– 7.10 (m, 1H), 6.76– 6.70 (m, 2H).
Example 102: N-Hydroxy-N-(naphthalen-2-yl)-1H-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000182_0002
alen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using naphthalen-2-amine in place of 3-ethynylaniline. C17H12N4O.289.10 (M+1).
Figure imgf000182_0003
y-N-(naphthalen-2-yl)-1H-imidazo[4,5-b]pyridine-7- carboximidamide (Example 102) and N-(3-chloronaphthalen-2-yl)-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide (Example 103) were made analogously to Example 95 using N-(naphthalen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide give two products (N-hydroxy-N-(naphthalen-2-yl)-1H-imidazo[4,5-b]pyridine-7- carboximidamide and N-(3-chloronaphthalen-2-yl)-N'-hydroxy-1H-imidazo[4,5- 180
604642.1 Attorney Docket No.: 1115.PF b]pyridine-7-carboximidamide). C17H13N5O.304.11 (M+1) and C17H12ClN5O.
338.11(M+1).
Example 103: N-(3-Chloronaphthalen-2-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine- 7-carboximidamide
Figure imgf000183_0001
loronaphthalen-2-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide was prepared according to Example 102. C17H12ClN5O.
338.11(M+1).
Example 104: N'-hydroxy-N-(naphthalen-1-yl)-1H-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000183_0002
thalen-1-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using naphthalen-1-amine in place of 3-ethynylaniline.
C17H12N4O.289.10 (M+1).
Figure imgf000183_0003
oxy-N-(naphthalen-1-yl)-1H-imidazo[4,5-b]pyridine-7- carboximidamide (Example 104) and N-(4-chloronaphthalen-1-yl)-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide (Example 105) were made analogously to Example 95 using N-(naphthalen-1-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide give two products (N'-hydroxy-N-(naphthalen-1-yl)-1H-imidazo[4,5-b]pyridine-7- carboximidamide and N-(4-chloronaphthalen-1-yl)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide). C17H13N5O.304.11 (M+1) 181
604642.1 Attorney Docket No.: 1115.PF Example 105: N-(4-Chloronaphthalen-1-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine- 7-carboximidamide
Figure imgf000184_0001
oronaphthalen-1-yl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide. Example 105 was made analogously to Example 104. C17H12ClN5O. 338.11(M+1).
Example 106: N-(4-Fluoro-3-methoxyphenyl)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide
Figure imgf000184_0002
o-3-methoxyphenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 95 using 4-fluoro-3-methoxyanilinein place of 3- ethynylaniline. C14H11FN4O2.286.09 (M+1).
Figure imgf000184_0003
o-3-methoxyphenyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide. Example 106 was made analogously to Example 95 using 4-fluoro-3- methoxyphenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C14H12FN5O2.302.10 (M+1).
Example 107: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-methyl-1H-imidazo[4,5- b]pyridine-7-carboximidamide
Figure imgf000184_0004
182
604642.1 Attorney Docket No.: 1115.PF [0413] 2-Chloro-3-nitroisonicotinic acid. To a solution of 2-chloro-4-methyl-3- nitropyridine (5.0 g, 29 mmol) in sulfuric acid (40 mL) was added potassium dichromate (11.3 g, 38.5 mmol) in portions over 20 min. The reaction was stirred at 60 °C overnight and poured onto ice. The water was washed with ethyl acetate three times and the combined organic layers were dried over sodium sulfate, filtered and
concentrated to give the desired product. C6H3ClN2O4.203.1 (M+1).
Figure imgf000185_0001
-N-(3-chloro-4-fluorophenyl)-3-nitroisonicotinamide. To a solution of 3-chloro-4-fluoroaniline (3.84 g, 26.4 mmol), 2-chloro-3-nitroisonicotinic acid (5.34 g, 26.4 mmol) and triethylamine (11 mL, 79 mmol) in dichlromethane (100 mL) in an ice bath was added phosphoryl chloride (3.69 mL, 39.6 mmol). The ice bath was removed and the reaction stirred for 1 hr. Saturated sodium bicarbonate was added and the aqueous layer was washed three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated onto silica gel and purified by silica gel chromatography (0->100% ethyl acetate in dichloromethane) to give the desired product. C12H6Cl2FN3O3.330.0 (M+1).
Figure imgf000185_0002
-N-(3-chloro-4-fluorophenyl)-3-nitroisonicotinamide. A mixture of 2-chloro-N-(3-chloro-4-fluorophenyl)-3-nitroisonicotinamide (4.78 g, 14.5 mmol) in ethanol (15 mL) and 28% ammonium hydroxide in water (14.1 mL, 101.4 mmol) was stirred in a closed vessel at 90 °C for 1.5 hr. The reaction mixture was cooled in an ice bath and the resulting precipitate filtered and washed with cold ethanol. Dried the solid on high vac to give desired product. C12H8ClFN4O3.311.1 (M+1).
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Figure imgf000186_0001
ino-N-(3-chloro-4-fluorophenyl)isonicotinamide. A mixture of 2- amino-N-(3-chloro-4-fluorophenyl)-3-nitroisonicotinamide (3.43 g, 11.0 mmol) and 10 % Palladium on carbon (250 mg) in methanol (100 mL) was mixed in a Parr shaker at 40 psi hydrogen for 2 hr. Reaction was filtered and concentrated to give the desired product. C12H10ClFN4O.281.1 (M+1).
Figure imgf000186_0002
o-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7- carboxamide. A mixture of 2,3-diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide (1.06 g, 3.77 mmol) in acetic acid (11 mL) was stirred at 180 °C for 1 hr in a microwave. Water was added and the resulting precipitate was filtered and dried on high vac to give the desired product. C14H10ClFN4O.305.1 (M+1).
Figure imgf000186_0003
-4-fluorophenyl)-N'-hydroxy-2-methyl-1H-imidazo[4,5- b]pyridine-7-carboximidamide. A mixture of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H- imidazo[4,5-b]pyridine-7-carboxamide (132 mg, 0.433 mmol), phosphorous
pentachloride (135 mg, 0.650 mmol) in phosphoryl chloride (2 mL) and 1,2- dichloroethane (2 mL) were stirred at 80 °C for 2.5 hr. The reaction mixture was concentrated and suspended in ethanol (2 mL) and to this mixture was added 50% hydroxylamine in water (0.265 mL, 4.33 mmol). The reaction mixture stirred for 1 hr and was concentrated. The residue was purified by preparative HPLC to give the desired product. C14H11ClFN5O.320.0 (M+1).
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604642.1 Attorney Docket No.: 1115.PF Example 108: N-(3-Chloro-4-fluorophenyl)-2-ethyl-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide
Figure imgf000187_0001
4-fluorophenyl)-2-ethyl-1H-imidazo[4,5-b]pyridine-7- carboxamide was made analogously to Example 107 using propionic acid in place of acetic acid. C15H12ClFN4O.319.1 (M+1).
Figure imgf000187_0002
4-fluorophenyl)-2-ethyl-N'-hydroxy-1H-imidazo[4,5-b]pyridine- 7-carboximidamide. Example 108 was made analogously to Example 107 using N-(3- chloro-4-fluorophenyl)-2-ethyl-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N- (3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide.
C15H13ClFN5O.334.1 (M+1).
Example 109: N-(3-Chloro-4-fluorophenyl)-2-cyclopropyl-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000187_0003
fluorophenyl)-2-cyclopropyl-1H-imidazo[4,5-b]pyridine-7- carboxamide was made analogously to Example 107 using cyclopropanecarboxylic acid in place of acetic acid. C16H12ClFN4O.331.1 (M+1).
Figure imgf000187_0004
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604642.1 Attorney Docket No.: 1115.PF [0422] N-(3-chloro-4-fluorophenyl)-2-cyclopropyl-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide. Example 109 was made analogously to Example 107 using N-(3-chloro-4-fluorophenyl)-2-cyclopropyl-1H-imidazo[4,5-b]pyridine-7- carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5- b]pyridine-7-carboxamide. C16H13ClFN5O.346.1 (M+1).
Example 110: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(methoxymethyl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000188_0001
uorophenyl)-2-(methoxymethyl)-1H-imidazo[4,5-b]pyridine- 7-carboxamide was made analogously to Example 107 using methoxyacetic acid in place of acetic acid. C15H12ClFN4O2.334.9 (M+1).
Figure imgf000188_0002
uorophenyl)-3-(2-(methoxymethyl)-1H-imidazo[4,5- b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one. A mixture of N-(3-chloro-4-fluorophenyl)-2- (methoxymethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (2.62 g, 7.82 mmol), phosphorous pentachloride (2.44 g, 11.7 mmol) in phosphoryl chloride (22 mL) and 1,2- dichloroethane (22 mL) were stirred at 80 °C for 2.5 hr. The reaction mixture was concentrated and suspended in ethanol (20 mL) and to this mixture was added 50% hydroxylamine in water (4.8 mL, 78 mmol). The reaction mixture stirred for 1 hr and was concentrated. Water and aqueous saturated sodium bicarbonate were added and the solid was filtered and dried on high vac. The solid was suspended in ethyl acetate (100 mL) and to this mixture was added carbonyldiimidazole (1.90 g, 11.7 mmol). The mixture was stirred for 18 hr and concentrated. The residue was purified by silica gel chromatography to give the desired product (871 mg). C16H11ClFN5O3.376.3 (M+1).
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Figure imgf000189_0001
uorophenyl)-N'-hydroxy-2-(methoxymethyl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide. Example 110 was made analogously to Example 95 using N-(3-chloro-4-fluorophenyl)-2-(methoxymethyl)-1H-imidazo[4,5- b]pyridine-7-carboxamide. C15H13ClFN5O2.350.1 (M+1).
Example 111: 4-(3-Chloro-4-fluorophenyl)-3-(2-(hydroxymethyl)-1H-imidazo[4,5- b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one
Figure imgf000189_0002
4-(3-chloro-4-fluorophenyl)-3-(2-(methoxymethyl)-1H- imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one (400 mg, 1.07 mmol) in dichloromethane (8 mL) at 0 °C was added a solution of 1 M boron tribromide in dichloromethane (1.60 mL, 1.60 mmol). The reaction was allowed to warm to room temperature and stirred for 18 hr. The reaction mixture was diluted with
dichloromethane and saturated sodium bicarbonate and the aqueous layer was washed three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, loaded onto silica gel column and purified by silica gel chromatography to give two product: 4-(3-chloro-4-fluorophenyl)-3-(2-(hydroxymethyl)-1H-imidazo[4,5- b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one (385 mg) and 3-(2-(bromomethyl)-1H- imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one. C15H9ClFN5O3.362.0 (M+1).
Figure imgf000189_0003
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604642.1 Attorney Docket No.: 1115.PF [0427] 3-(2-(bromomethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-1,2,4-oxadiazol-5(4H)-one. C15H8BrClFN5O2.425.9 (M+1).
Example 112: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(morpholinomethyl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000190_0001
-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1- (methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate. To a solution of 4-(3-chloro-4-fluorophenyl)-3-(2-(hydroxymethyl)-1H-imidazo[4,5-b]pyridin-7-yl)- 1,2,4-oxadiazol-5(4H)-one (510 mg, 1.41 mmol) and triethylamine (1.97 mL, 14.1 mmol) in dichlromethane (20 mL) at -78 °C was added methanesulfonyl chloride (0.548 mL, 7.05 mmol) dropwise over 10 min. The reaction mixture was warmed to 0 °C and stirred for 10 min. Water was added and the aqueous layer was washed three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to give two product: (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1- (methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate (440 mg) and 4-(3-chloro-4-fluorophenyl)-3-(2-(chloromethyl)-1-(methylsulfonyl)-1H-imidazo[4,5- b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one. C17H13ClFN5O7S2.518.2 (M+1).
Figure imgf000190_0002
uorophenyl)-3-(2-(chloromethyl)-1-(methylsulfonyl)-1H- imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol-5(4H)-one was prepared from the above reaction. C16H10Cl2FN5O4S.458.0 (M+1).
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604642.1 Attorney Docket No.: 1115.PF
Figure imgf000191_0001
rophenyl)-N'-hydroxy-2-(morpholinomethyl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide. A solution of (7-(4-(3-chloro-4- fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H- imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate (27 mg, 0.052 mmol) and morpholine (0.10 mL, 1.1 mmol) in acetonitrile (1 mL) was stirred at 65 °C for 10 min. The reaction was concentrated. The residue was brought up in tetrahydrofuran (0.5 mL) and water (0.5 mL). To this solution was added 2 N sodium hydroxide (0.39 mL, 0.78 mmol) and the reaction mixture stirred for 10 min. To the mixture was added acetic acid (0.05 mL) and the solution was loaded directly onto a prep HPLC for purification to give the desired product. C18H18ClFN6O2.405.1 (M+1).
Example 113: N-(3-Chloro-4-fluorophenyl)-2-((dimethylamino)methyl)-N'-hydroxy- 1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000191_0002
uorophenyl)-2-((dimethylamino)methyl)-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide. A solution of 4-(3-chloro-4-fluorophenyl)- 3-(2-(chloromethyl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol- 5(4H)-one (30 mg, 0.065 mmol) and dimethylamine (2 M in THF, 0.655 mL, 1.3 mmol) in acetonitrile (1 mL) was stirred at 65 °C for 3 hr min. The reaction was concentrated. The residue was brought up in tetrahydrofuran (0.5 mL) and water (0.5 mL). To this solution was added 2 N sodium hydroxide (0.39 mL, 0.78 mmol) and the reaction mixture stirred for 10 min. To the mixture was added acetic acid (0.05 mL) and the solution was loaded directly onto a prep HPLC for purification to give the desired product (12 mg). C16H16ClFN6O.363.1 (M+1). 189
604642.1 Attorney Docket No.: 1115.PF Example 114: N-(3-Chloro-4-fluorophenyl)-2-((ethylamino)methyl)-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000192_0001
orophenyl)-2-((ethylamino)methyl)-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide. Example 114 was made analogously to Example 112 using 2 M ethylamine in THF in place of morpholine. C16H16ClFN6O. 363.1 (M+1).1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 11.16 (s, 1H), 9.29 (s, 2H), 8.96 (s, 1H), 8.38 (d, J = 5.0 Hz, 1H), 7.41– 6.99 (m, 2H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.51 (d, J = 8.7 Hz, 1H), 4.47 (s, 2H), 3.08 (s, 2H), 1.23 (t, J = 7.3 Hz, 3H).
Example 115: 2-((Benzylamino)methyl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy- 1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000192_0002
yl)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide. Example 115 was made analogously to Example 112 using benzylamine in place of morpholine. C21H18ClFN6O.425.1 (M+1).
Example 116: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2- ((isopropylamino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000192_0003
rophenyl)-N'-hydroxy-2-((isopropylamino)methyl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide. Example 116 was made analogously to Example 112 using isopropylamine in place of morpholine. C17H18ClFN6O.377.1 190
604642.1 Attorney Docket No.: 1115.PF (M+1).1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.28 (s, 2H), 8.96 (s, 1H), 8.38 (d, J = 5.0 Hz, 1H), 7.24– 6.96 (m, 2H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.51 (s, 1H), 4.48 (s, 2H), 3.56– 3.28 (m, 1H), 1.37– 1.15 (m, 6H).
Example 117: N-(3-Chloro-4-fluorophenyl)-2-(((cyclopropylmethyl)amino)methyl)- N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000193_0001
phenyl)-2-(((cyclopropylmethyl)amino)methyl)-N'- hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 117 was made analogously to Example 112 using cyclopropylmethylamine in place of morpholine. C18H18ClFN6O.388.9 (M+1).1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.41 (s, 2H), 8.95 (s, 1H), 8.38 (d, J = 5.0 Hz, 1H), 7.28– 6.98 (m, 2H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.52 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 4.50 (s, 2H), 2.96 (s, 2H), 1.17– 0.92 (m, 1H), 0.68– 0.48 (m, 2H), 0.42– 0.24 (m, 2H).
Example 118: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((2,2,2- trifluoroethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000193_0002
phenyl)-2-(((cyclopropylmethyl)amino)methyl)-N'- hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 118 was made analogously to Example 112 using 2,2,2-trifluoroethylamine in place of morpholine. C16H13ClF4N6O.416.7 (M+1).
191
604642.1 Attorney Docket No.: 1115.PF Example 119: N-(3-Chloro-4-fluorophenyl)-2-((cyclopropylamino)methyl)-N'- hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000194_0001
rophenyl)-2-((cyclopropylamino)methyl)-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide. Example 119 was made analogously to Example 112 using cyclopropylamine in place of morpholine. C17H16ClFN6O.374.9 (M+1).
Example 120: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((3- methoxypropyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
OH N H N Cl F
Figure imgf000194_0002
yl)-N'-hydroxy-2-(((3- methoxypropyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 120 was made analogously to Example 112 using 3-methoxypropylamine in place of morpholine. C18H20ClFN6O2.407.1 (M+1).
Example 121: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((pyridin-2- ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000194_0003
henyl)-N'-hydroxy-2-(((pyridin-2- ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 121 was made analogously to Example 112 using pyridin-2-ylmethanamine in place of morpholine. C20H17ClFN7O.426.1 (M+1).
192
604642.1 Attorney Docket No.: 1115.PF Example 122: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((3- methoxypropyl)(methyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000195_0001
yl)-N'-hydroxy-2-(((3- methoxypropyl)(methyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 122 was made analogously to Example 112 using 3-(2-(bromomethyl)-1H- imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one and 3-methoxy-N-methylpropan-1-amine in place of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo- 4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2- yl)methyl methanesulfonate and morpholine. C19H22ClFN6O2.421.2 (M+1).
Example 123: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((2- methoxybenzyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000195_0002
yl)-N'-hydroxy-2-(((2- methoxybenzyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide.
Example 123 was made analogously to Example 112 using 4-(3-chloro-4-fluorophenyl)- 3-(2-(chloromethyl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol- 5(4H)-one and 2-methoxybenzylamine in place of (7-(4-(3-chloro-4-fluorophenyl)-5- oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2- yl)methyl methanesulfonate and morpholine. C22H20ClFN6O2.455.1 (M+1).
193
604642.1 Attorney Docket No.: 1115.PF Example 124: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((2- methoxyethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000196_0001
henyl)-N'-hydroxy-2-(((2- methoxyethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 124 was made analogously to Example 112 using 2-methoxyethylamine in place of morpholine.C17H18ClFN6O2.393.1(M+1).
Example 125: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((2-(pyridin-2- yl)ethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000196_0002
l)-N'-hydroxy-2-(((2-(pyridin-2- yl)ethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 125 was made analogously to Example 112 using 2-(pyridin-2-yl)ethanamine in place of morpholine. C21H19ClFN7O.440.1 (M+1).
Example 126: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((pyridin-3- ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000196_0003
henyl)-N'-hydroxy-2-(((pyridin-3- ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 126 was made analogously to Example 112 using 3-picolylamine in place of morpholine. C20H17ClFN7O.426.1 (M+1).
194
604642.1 Attorney Docket No.: 1115.PF Example 127: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((((tetrahydro-2H-pyran- 2-yl)methyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000197_0001
henyl)-N'-hydroxy-2-((((tetrahydro-2H-pyran-2- yl)methyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 127 was made analogously to Example 112 using 4-(3-chloro-4-fluorophenyl)-3-(2- (chloromethyl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-7-yl)-1,2,4-oxadiazol- 5(4H)-one and (tetrahydro-2H-pyran-2-yl)methanamine in place of (7-(4-(3-chloro-4- fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H- imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine. C20H22ClFN6O2. 433.1 (M+1).
Example 128: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((phenylamino)methyl)- 1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000197_0002
chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl
methanesulfonate (14 mg, 0.027 mmol) and aniline (0.025 mL, 0.27 mmol) in acetonitrile (1 mL) was stirred at 65 °C for 18 hr. To the solution was added
isopropylamine (0.1 mL) and the reaction stirred at 65 °C for 5 min. The reaction was concentrated. The residue was brought up in tetrahydrofuran (0.3 mL) and water (0.3 mL). To this solution was added 2 N sodium hydroxide (0.2 mL, 0.41 mmol) and the reaction mixture stirred for 10 min. To the mixture was added acetic acid (0.05 mL) and the solution was loaded directly onto a prep HPLC for purification to give the desired product. C20H16ClFN6O.411.1 (M+1).
195
604642.1 Attorney Docket No.: 1115.PF Example 129: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((((tetrahydro-2H-pyran- 3-yl)methyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000198_0001
enyl)-N'-hydroxy-2-((((tetrahydro-2H-pyran-3- yl)methyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 129 was made analogously to Example 112 using (tetrahydro-2H-pyran-3-yl)methanamine in place of morpholine. C20H22ClFN6O2.433.1 (M+1).
Example 130: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((pyrimidin-2- ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000198_0002
henyl)-N'-hydroxy-2-(((pyrimidin-2- ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide. Example 130 was made analogously to Example 112 using pyrimidin-2-ylmethanamine in place of morpholine. C19H16ClFN8O.427.1 (M+1).
Example 131: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((3- morpholinopropyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000198_0003
alogously to Example 112 using 3- morpholinopropan-1-amine in place of morpholine. C21H25ClFN7O2.462.2 (M+1).
196
604642.1 Attorney Docket No.: 1115.PF Example 132: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((tetrahydro-2H-pyran- 4-yl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000199_0001
e analogously to Example 112 using 4-(3-chloro-4- fluorophenyl)-3-(2-(chloromethyl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-7-yl)- 1,2,4-oxadiazol-5(4H)-one and tetrahydro-2H-pyran-4-amine in place of (7-(4-(3-chloro- 4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H- imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine. C19H20ClFN6O2. 419.1 (M+1).
Example 133: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((pyridin-4- ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000199_0002
e analogously to Example 112 using 4-picolylamine in place of morpholine. C20H17ClFN7O.426.1 (M+1).
Example 134: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((pyrazin-2- ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000199_0003
e analogously to Example 112 using pyrazin-2- ylmethanamine in place of morpholine. C19H16ClFN8O.427.1 (M+1).
197
604642.1 Attorney Docket No.: 1115.PF Example 135: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((((tetrahydrofuran-3- yl)methyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
OH N H N Cl F
Figure imgf000200_0001
e analogously to Example 112 using 4-(3-chloro-4- fluorophenyl)-3-(2-(chloromethyl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-7-yl)- 1,2,4-oxadiazol-5(4H)-one and (tetrahydrofuran-3-yl)methanamine in place of (7-(4-(3- chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H- imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine. C19H20ClFN6O2. 419.1 (M+1).
Example 136: N-(3-Chloro-4-fluorophenyl)-2-(((2- (dimethylamino)ethyl)amino)methyl)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000200_0002
e analogously to Example 112 using N,N- dimethylethane-1,2-diamine in place of morpholine. C18H21ClFN7O.406.1 (M+1).
Example 137: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((2-(pyrimidin-2- yl)ethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000200_0003
alogously to Example 112 using 2-(pyrimidin-2- yl)ethanamine in place of morpholine. C20H18ClFN8O.441.1 (M+1).
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604642.1 Attorney Docket No.: 1115.PF Example 138: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((3- hydroxypropyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000201_0001
analogously to Example 112 using 3-aminopropanol in place of morpholine. C17H18ClFN6O2.393.1 (M+1).
Example 139: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(pyrrolidin-1-ylmethyl)- 1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000201_0002
ynthesized analogously to Example 112 using pyrrolidine in place of morpholine. C18H18ClFN6O. 389.1 [M+1]+.
Example 140: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(piperidin-1-ylmethyl)- 1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000201_0003
nthesized analogously to Example 112 using piperidine in place of morpholine. C19H20ClFN6O. 403.1 [M+1]+.
Example 141: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2- ((neopentylamino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000201_0004
199
604642.1 Attorney Docket No.: 1115.PF [0459] Example 141 was synthesized analogously to Example 112 using 3-(2- (bromomethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4- oxadiazol-5(4H)-one and 2,2-dimethylpropan-1-amine in place of (7-(4-(3-chloro-4- fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H- imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine, respectively. C19H22ClFN6O. 405.2 [M+1]+.
Example 142: N-(3-Chloro-4-fluorophenyl)-2-(((2,2-difluoroethyl)amino)methyl)- N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000202_0001
thesized analogously to Example 112 using 3-(2- (bromomethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4- oxadiazol-5(4H)-one and 2,2-difluoroethylamine in place of (7-(4-(3-chloro-4- fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H- imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine, respectively. C16H14ClF3N6O. 399.1 [M+1]+.
Example 143: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((3-hydroxy-2,2- dimethylpropyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000202_0002
thesized analogously to Example 112 using 3-(2- (bromomethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4- oxadiazol-5(4H)-one and 3-amino-2,2-dimethylpropan-1-ol in place of (7-(4-(3-chloro-4- fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H- imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine, respectively. C19H22ClFN6O2. 421.2 [M+1]+.
200
604642.1 Attorney Docket No.: 1115.PF Example 144: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(((thiazol-2- ylmethyl)amino)methyl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000203_0001
sized analogously to Example 112 using 3-(2- (bromomethyl)-1H-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-1,2,4- oxadiazol-5(4H)-one and thiazol-2-ylmethanamine in place of (7-(4-(3-chloro-4- fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(methylsulfonyl)-1H- imidazo[4,5-b]pyridin-2-yl)methyl methanesulfonate and morpholine, respectively. C18H15ClFN7OS. 432.1 [M+1]+.
Example 145: N-((7-(N-(3-Chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H- imidazo[4,5-b]pyridin-2-yl)methyl)acetamide
Figure imgf000203_0002
-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)-1-(methylsulfonyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl
methanesulfonate (17 mg, 0.033 mmol) and 0.5 M ammonia in dioxane (1.44 mL, 0.722 mmol) in acetonitrile (1 mL) was stirred at 65 °C for 30 min. The reaction was concentrated. The residue was brought up in tetrahydrofuran (0.5 mL) and to this solution was added triethylamine (0.021 mL, 0.15 mmol) and acetyl chloride (0.003 mL, 0.045 mmol. The reaction stirred for 3 hr and, then, more acetyl chloride (0.003 mL, 0.045 mmol) was added. The reaction stirred for 2 hr and was concentrated. The residue was brought up in tetrahydrofuran (0.3 mL) and water (0.3 mL). To this solution was added 2 N sodium hydroxide (0.22 mL, 0.44 mmol) and the reaction mixture stirred for 10 min. To the mixture was added acetic acid (0.05 mL) and the solution was loaded directly onto a prep HPLC for purification to give the desired product. C16H14ClFN6O2. 377.1 (M+1). 201
604642.1 Attorney Docket No.: 1115.PF Example 146: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(thiophen-2-yl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000204_0001
yl-2-(thiophen-2-yl)-1H-imidazo[4,5-b]pyridine. A solution of 4- methyl-3-nitropyridin-2-amine (400 mg, 2.61 mmol), thiophene-2-carbaldehyde (449 mg, 3.92 mmol) and sodium hydrosulfite (1.61 g, 7.84 mmol) in dimethyl sulfoxide (5 mL) and ethanol (5 mL) were stirred at 90 °C for 18 hr. The mixture was allowed to cool to room temperature and to this mixture was added water and the aqueous layer was washed three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, absorbed onto silica gel and purified by silica gel
chromatography to give the desired product. C11H9N3S.216.1 (M+1).
Figure imgf000204_0002
2-(thiophen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxylate. A solution of 7-methyl-2-(thiophen-2-yl)-1H-imidazo[4,5-b]pyridine (234 mg, 1.09 mmol) and selenium dioxide (482, 4.35 mmol) in pyridine (2.5 mL) was stirred at 120 °C for 24 hours. The reaction mixture was filtered through a pad of celite and the celite pad was washed with hot water and methanol. The filtrate was concentrated and the resulting residue was dried on high vac. The residue was brought up in methanol (10 mL) and to this solution was added thionyl chloride (0.55 mL, 7.6 mmol). The solution was stirred at 70 °C for 4 hours. The resulting mixture was concentrated to give the desired product. C12H9N3O2S .260.1 (M+1).
Figure imgf000204_0003
uorophenyl)-2-(thiophen-2-yl)-1H-imidazo[4,5-b]pyridine-7- carboxamide. To a soln of the 3-chloro-4-fluoroanilinein (239 mg, 1.64 mmol) dichloroethane at 0 °C under nitrogen was added trimethylaluminum (2 M in heptane, 202
604642.1 Attorney Docket No.: 1115.PF 1.57, 3.15 mmol) dropwise over 5 min. The solution was allowed to warm to room temperature and stirred for 30 min. The solution was cooled to 0 °C and to this solution was added methyl 2-(thiophen-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxylate (272 mg, 1.05 mmol). The solution was stirred at 85 °C for 18 hr and, then, cooled to room temperature. Saturated sodium bicarbonate was carefully added to the solution and the aqueous layer was washed three times with dichloromethane. The aqueous layer was acidified with 10% citric acid and the resulting precipitate was filtered and dried on high vac to give the desired product. C17H10ClFN4OS.373.1 (M+1).
Figure imgf000205_0001
uorophenyl)-N'-hydroxy-2-(thiophen-2-yl)-1H-imidazo[4,5- b]pyridine-7-carboximidamide. Example 146 was made analogously to Example 107 using N-(3-chloro-4-fluorophenyl)-2-(thiophen-2-yl)-1H-imidazo[4,5-b]pyridine-7- carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5- b]pyridine-7-carboxamide. C17H11ClFN5OS.388.1 (M+1).
Example 147: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(pyridin-3-yl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000205_0002
orophenyl)-2-(pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-7- carboxamide. A mixture of 2,3-diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide (0.150 g, 0.534 mmol) and nicotinaldehyde (0.50 mL, 5.34 mmol) in DMSO was stirred at 100 °C under air atmosphere for 16 h. Mixture was cooled to rt and diluted with water. The aqueous layer was extracted 3× with EtOAc and the combined organic layers were washed with brine, dried (Na2SO4), filtered, concentrated onto silica gel, and purified via column chromatography on silica gel to yield the final product.
C18H11ClFN5O. 368.1 [M+1]+. 203
604642.1 Attorney Docket No.: 1115.PF
Figure imgf000206_0001
synthesized analogously to Example 80 , using N-(3- chloro-4-fluorophenyl)-2-(pyridin-3-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C18H12ClFN6O. 383.1 [M+1]+.
Example 148: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(1H-pyrrol-2-yl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000206_0002
orophenyl)-2-(1H-pyrrol-2-yl)-1H-imidazo[4,5-b]pyridine- 7-carboxamide was synthesized analogously to Example 147 using 1H-pyrrole-2- carbaldehyde in place of nicotinaldehyde. C17H11ClFN5O. 356.1 [M+1]+.
Figure imgf000206_0003
synthesized analogously to Example 80 , using N-(3- chloro-4-fluorophenyl)-2-(1H-pyrrol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C17H12ClFN6O. 371.1 [M+1]+.
Example 149: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(1H-imidazol-2-yl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000206_0004
204
604642.1 Attorney Docket No.: 1115.PF [0472] Methyl 2,3-diaminoisonicotinate. A mixture of 2,3-diaminoisonicotinic acid (2.0 g, 13 mmol) in sulfuric acid (2.5 mL) and methanol (25 mL) was stirred at 120 °C in a microwave for 1 hr. To the reaction mixture was added aqueous saturated sodium bicarbonate until basic and the aqueous layer was washed three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the desired product. C7H9N3O2.168.1 (M+1).
Figure imgf000207_0001
2-(1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxylate was made analogously to Example 147 using methyl 2,3-diaminoisonicotinate and 1H- imidazole-2-carbaldehyde. C11H9N5O2.244.0 (M+1).
Figure imgf000207_0002
uorophenyl)-2-(1H-imidazol-2-yl)-1H-imidazo[4,5- b]pyridine-7-carboxamide was made analogously to Example 146 using methyl 2-(1H- imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxylate in place of methyl 2-(thiophen- 2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxylate. C16H10ClFN6O.357.2 (M+1).
Figure imgf000207_0003
s made analogously to Example 107 using N-(3-chloro-4- fluorophenyl)-2-(1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7-carboxamide. C16H11ClFN7O.372.1 (M+1).1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.92 (s, 1H), 8.33 (d, J = 5.1 Hz, 1H), 7.44 (s, 2H), 7.18 (d, J = 5.1 Hz, 1H), 7.02 (t, J = 9.1 Hz, 1H), 6.96 (dd, J = 6.5, 2.7 Hz, 1H), 6.56 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H).
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604642.1 Attorney Docket No.: 1115.PF Example 150: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(1H-pyrazol-5-yl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000208_0001
orophenyl)-2-(1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridine- 7-carboxamide was synthesized analogously to Example 147 using 1H-pyrazole-5- carbaldehyde in place of nicotinaldehyde. C16H10ClFN6O. 357.1 [M+1]+.
Figure imgf000208_0002
orophenyl)-N'-hydroxy-2-(1H-pyrazol-5-yl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide. Example 150 was synthesized analogously to Example 80 , using N-(3-chloro-4-fluorophenyl)-2-(1H-pyrazol-5-yl)-1H-imidazo[4,5- b]pyridine-7-carboxamide in place of N-(3-bromophenyl)-1H-imidazo[4,5-b]pyridine-7- carboxamide. C16H11ClFN7O. 372.1 [M+1]+.
Example 151: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(4-methyl-1H-imidazol-2- yl)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000208_0003
(4-methyl-1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7- carboxylate. A mixture of methyl 2,3-diaminoisonicotinate (0.102 g, 0.610 mmol) and 4-methyl-1H-imidazole-2-carbaldehyde (0.319 g, 2.90 mmol) in DMSO (5 mL) stirred at 100 °C under air atmosphere for 16 h. The mixture was diluted with water and the solid was isolated via filtration. The filter cake was washed with water and then cooled over
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604642.1 Attorney Docket No.: 1115.PF dry ice and dried on the lyophilizer to give the desired product, which was taken on without purification. C12H11N5O2. 258.1 [M+1]+.
Figure imgf000209_0001
rophenyl)-2-(4-methyl-1H-imidazol-2-yl)-1H-imidazo[4,5- b]pyridine-7-carboxamide. To DABAL-Me3 (0.128 g, 0.499 mmol) in THF (2 mL) was added 3-chloro-4-fluoroaniline (0.073 g, 0.499 mmol). The mixture stirred at 40 °C for 1 h. A slurry of methyl 2-(4-methyl-1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7- carboxylate (0.080 g, 0.311 mmol) in THF (2.5 mL) was added and the mixture stirred at 65 °C for 16 h. The mixture was quenched by the addition of 1 N HCl (1 mL) and then was diluted with water/EtOAc. The aqueous layer was extracted 3× with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, concentrated onto silica gel, and purified via column chromatography on silica gel to yield the desired product. C17H12ClFN6O. 371.1 [M+1]+.
Figure imgf000209_0002
rophenyl)-N'-hydroxy-2-(4-methyl-1H-imidazol-2-yl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide. To a mixture of N-(3-chloro-4- fluorophenyl)-2-(4-methyl-1H-imidazol-2-yl)-1H-imidazo[4,5-b]pyridine-7-carboxamide (0.009 g, 0.024 mmol) in DCE (0.5 mL) and phosphoryl chloride (0.5 mL) was added phosphorus pentachloride (0.008 g, 0.036 mmol). The mixture stirred at 90 °C for 4 h. Additional phosphorus pentachloride (0.008 g, 0.036 mmol) was added and the mixture stirred at 90 °C for 72 h. The mixture was cooled to rt and concentrated. The residue was diluted with EtOH (3 mL) and hydroxylamine (0.05 mL of a 50 w/w% solution in water, 0.82 mmol) was added. The mixture was concentrated and the residue was diluted with DMSO/water and purified via preparative HPLC to yield the desired product.
C17H13ClFN7O. 386.0 [M+1]+. 207
604642.1 Attorney Docket No.: 1115.PF Example 152: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(pyrrolidin-2-yl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000210_0001
((2-amino-4-((3-chloro-4-fluorophenyl)carbamoyl)pyridin-3- yl)carbamoyl)pyrrolidine-1-carboxylate. To N-Boc-L-proline (0.429 g, 1.991 mmol) in DCM (20 mL) at 0 °C was added isobutyl chloroformate (0.57 mL, 4.38 mmol) dropwise, followed by TEA (0.69 mL, 4.98 mmol). 2,3-diamino-N-(3-chloro-4- fluorophenyl)isonicotinamide (0.559 g, 1.991 mmol) was added and the mixture was allowed to warm to rt and stirred 16 h. The mixture was diluted with water and the aqueous phase was extracted 3× with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, concentrated onto silica gel, and purified via column chromatography on silica gel to yield the desired product. C22H25ClFN5O4. 478.2
[M+1]+.
Figure imgf000210_0002
hloro-4-fluorophenyl)carbamoyl)-1H-imidazo[4,5- b]pyridin-2-yl)pyrrolidine-1-carboxylate. A solution of (S)-tert-butyl 2-((2-amino-4-((3- chloro-4-fluorophenyl)carbamoyl)pyridin-3-yl)carbamoyl)pyrrolidine-1-carboxylate (0.094 g, 0.197 mmol) in AcOH (4 mL) was heated to 65 °C for 4 h and to 80 °C for 2 h. The mixture was cooled to rt and concentrated. The residue was partitioned between sat. bicarb solution and EtOAc and the aqueous layer was extracted 3× with EtOAc. The combined organic layers were concentrated onto silica gel and purified via column chromatography on silica gel to yield the desired product. C22H23ClFN5O3. 460.1
[M+1]+.
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604642.1 Attorney Docket No.: 1115.PF
Figure imgf000211_0001
hloro-4-fluorophenyl)carbamothioyl)-1H-imidazo[4,5- b]pyridin-2-yl)pyrrolidine-1-carboxylate. A mixture of tert-butyl 2-(7-((3-chloro-4- fluorophenyl)carbamoyl)-1H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylate (0.043 g, 0.093 mmol) and Lawesson’s reagent (0.076 g, 0.187 mmol) in toluene (2 mL) was stirred at 95 °C for 16 h. The mixture was cooled to rt, concentrated onto silica gel, and purified via column chromatography on silica gel to yield the desired product.
C22H23ClFN5O2S. 476.1 [M+1]+.
Figure imgf000211_0002
3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H- imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1-carboxylate. To a mixture of tert-butyl 2-(7- ((3-chloro-4-fluorophenyl)carbamothioyl)-1H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1- carboxylate (0.019 g, 0.040 mmol) in MeOH (2 mL) was added hydroxylamine (0.12 mL of a 50 w/w% solution in water, 2.00 mmol). The mixture was stirred at 70 °C for 45 min. The mixture was cooled to rt and diluted with brine and EtOAc. The aqueous layer was extracted 4× with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to yield the desired product. C22H24ClFN6O3. 475.2 [M+1]+.
Figure imgf000211_0003
orophenyl)-N'-hydroxy-2-(pyrrolidin-2-yl)-1H-imidazo[4,5- b]pyridine-7-carboximidamide. To a solution of tert-butyl 2-(7-(N-(3-chloro-4- fluorophenyl)-N'-hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)pyrrolidine-1- 209
604642.1 Attorney Docket No.: 1115.PF carboxylate (0.018 g, 0.038 mmol) in DCM (1 mL) was added TFA (1 mL). The mixture stirred at rt for 10 min and was then concentrated. The residue was dissolved in DMSO/water and purified via preparative HPLC to yield the desired product.
C17H16ClFN6O. 375.1 [M+1]+.
Example 153: 2-Amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide
Figure imgf000212_0001
4-fluorophenyl)-2-cyanamido-3-nitroisonicotinamide. A mixture of 2-chloro-N-(3-chloro-4-fluorophenyl)-3-nitroisonicotinamide (1.02 g, 3.09 mmol), cyanamide (260 mg, 6.18 mmol), and potassium carbonate (1.28 g, 9.27 mmol) in dimethylformamide (10 mL) was stirred at 80 °C for 2 hr. The reaction mixture was absorbed onto silica gel and purified by silica gel chromatography to give the desired product (1.03 g). C13H7ClFN5O3.336.0 (M+1).
Figure imgf000212_0002
hloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7- carboxamide. A mixture of N-(3-chloro-4-fluorophenyl)-2-cyanamido-3- nitroisonicotinamide (1.07 g, 3.20 mmol) and sodium hydrosulfite (1.96 g, 9.59 mmol) in ethanol (10 mL) and dimethyl sulfoxide (10 mL) was stirred at 70 °C for 24 hr. Water was added and the aqueous layer was washed three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and absorbed onto silica gel and purified by silica gel chromatography to give the desired product. C13H9ClFN5O. 306.1 (M+1).
Figure imgf000212_0003
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604642.1 Attorney Docket No.: 1115.PF [0488] 2-Amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide. Example 153 was made analogously to Example 107 using 2-amino-N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5-b]pyridine-7- carboxamide. C13H10ClFN6O.321.0 (M+1).1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.15– 8.10 (m, 1H), 7.94– 7.89 (m, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.00– 6.92 (m, 1H), 6.91– 6.79 (m, 1H), 6.63– 6.54 (m, 1H).
Example 154: N-(3-Chloro-4-fluorophenyl)-2-(cyclopropylamino)-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000213_0001
fluorophenyl)-2-(cyclopropylamino)-1H-imidazo[4,5- b]pyridine-7-carboxamide. Dissolved 2,3-diamino-N-(3-chloro-4- fluorophenyl)isonicotinamide (0.54g, 0.002 mol) in THF (5 ml), to the solution was added cyclopropyl isothiocyanate (0.23g, 0.002 mmol) and triethylamine (1.95g, 0.02 mol). The reaction mixture was heated at 80oC overnight, then to the reaction mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.44 g, 0.002 mol), heated at 80oC for 1h. The reaction mixture was diluted with EtOAc, and then water was added. Product crashed out to afford 200mg desired product. C16H13ClFN5O. 346.1 (M+1).
Figure imgf000213_0002
luorophenyl)-2-(cyclopropylamino)-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide. Example 154 was made analogously to Example 107 using the general procedure for hydroxyamidine formation. C16H14ClFN6O. 361.1 (M+1).1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.93 (s, 1H), 8.80 (s, 1H), 8.01 (d, J = 6.1 Hz, 1H), 7.13– 7.00 (m, 2H), 6.97 (d, J = 6.1 Hz, 1H), 6.55 (ddd, J 211
604642.1 Attorney Docket No.: 1115.PF = 9.0, 4.0, 2.7 Hz, 1H), 2.81 (dq, J = 6.9, 3.4 Hz, 1H), 0.83 (td, J = 7.1, 5.0 Hz, 2H), 0.59 (p, J = 4.7 Hz, 2H).
Example 155: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(phenylamino)-1H- imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000214_0001
made analogously to Example 154 using phenyl isothiocyanate. C19H14ClFN6O.397.1 (M+1).1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 10.09 (s, 1H), 8.92 (s, 1H), 8.05 (d, J = 6.1 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.39 (t, J = 7.7 Hz, 2H), 7.14– 7.04 (m, 2H), 7.02 (dt, J = 5.6, 2.6 Hz, 2H), 6.60 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H).
Example 156: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(phenethylamino)-1H- imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000214_0002
de analogously to Example 154 using (2- isothiocyanatoethyl)benzene. C21H18ClFN6O.425.1 (M+1).1H NMR (400 MHz, DMSO- d6) δ 11.36 (s, 1H), 8.92 (s, 1H), 7.95 (d, J = 6.3 Hz, 1H), 7.37– 7.16 (m, 6H), 7.13– 7.05 (m, 1H), 7.02 (dd, J = 6.5, 2.8 Hz, 1H), 6.96– 6.85 (m, 1H), 6.57 (ddd, J = 8.9, 4.0, 2.8 Hz, 1H), 3.73– 3.62 (m, 2H), 2.89 (t, J = 7.3 Hz, 2H).
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604642.1 Attorney Docket No.: 1115.PF Example 157: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((2,2,2- trifluoroethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000215_0001
made analogously to Example 154 using 1,1,1-trifluoro-2- isothiocyanatoethane. C15H11ClF4N6O.403.1 (M+1).1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.95 (s, 1H), 8.00 (d, J = 6.2 Hz, 1H), 7.05 (ddd, J = 19.0, 8.5, 4.0 Hz, 3H), 6.95 (d, J = 6.5 Hz, 1H), 6.57 (dt, J = 9.0, 3.3 Hz, 1H), 4.30 (s, 3H).
Example 158: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(methylamino)-1H- imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000215_0002
was made analogously to Example 154 using methyl isothiocyanate. C14H12ClFN6O.335.1 (M+1).1H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 11.37 (s, 1H), 8.96 (s, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.08 (t, J = 9.1 Hz, 1H), 7.03– 6.97 (m, 1H), 6.91 (d, J = 6.2 Hz, 1H), 6.56 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 3.00 (d, J = 4.8 Hz, 3H).
Example 159: Isopropyl (7-(N-(3-chloro-4-fluorophenyl)-N'- hydroxycarbamimidoyl)-1H-imidazo[4,5-b]pyridin-2-yl)carbamate
Figure imgf000215_0003
ro-4-fluorophenyl)carbamoyl)-1H-imidazo[4,5- b]pyridin-2-yl)carbamate. To a mixture of 2-amino-N-(3-chloro-4-fluorophenyl)-1H- imidazo[4,5-b]pyridine-7-carboxamide (30 mg, 0.098mmol) and triethylamine (0.041 mL, 0.29 mmol) in dichloromethane at 0 °C was added solution of isopropyl
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604642.1 Attorney Docket No.: 1115.PF chloroformate (1 M in toluene, 0.118 mL, 0.118 mmol). The reaction was allowed to warm to room temperature and stirred for 1 hr. Saturated sodium bicarbonate was added and the aqueous layer was washed three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was loaded onto a silica gel column and purified by silica gel chromatography to give the desired product mixed with isopropyl 7-((3-chloro-4-fluorophenyl)carbamoyl)-2- ((isopropoxycarbonyl)amino)-1H-imidazo[4,5-b]pyridine-1-carboxylate.
C17H15ClFN5O3.392.2 (M+1).
Figure imgf000216_0001
hloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1H- imidazo[4,5-b]pyridin-2-yl)carbamate. Example 159 was made analogously to Example 107 using isopropyl (7-((3-chloro-4-fluorophenyl)carbamoyl)-1H-imidazo[4,5-b]pyridin- 2-yl)carbamate in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5- b]pyridine-7-carboxamide. C17H16ClFN6O3.407.0 (M+1).1H NMR (400 MHz, DMSO- d6) δ 8.83 (s, 1H), 8.18 (d, J = 5.4 Hz, 1H), 7.13 (t, J = 9.1 Hz, 1H), 7.02– 6.91 (m, 2H), 6.67– 6.57 (m, 1H), 5.00 (dq, J = 6.3, 6.3 Hz, 1H), 1.31 (d, J = 6.2 Hz, 6H).
Example 160: Ethyl (7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)- 1H-imidazo[4,5-b]pyridin-2-yl)carbamate
Figure imgf000216_0002
ade analogously to Example 154 using O-ethyl carbonisothiocyanatidate. C16H14ClFN6O3.393.1 (M+1).1H NMR (400 MHz, DMSO- d6) δ 11.54 (s, 1H), 8.83 (s, 1H), 8.20 (d, J = 5.6 Hz, 1H), 7.11 (t, J = 9.1 Hz, 1H), 7.03 (d, J = 5.6 Hz, 1H), 6.95 (dd, J = 6.5, 2.7 Hz, 1H), 6.62 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H).
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604642.1 Attorney Docket No.: 1115.PF Example 161: N-(3-Chloro-4-fluorophenyl)-2-((cyclopropylmethyl)amino)-N'- hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000217_0001
made analogously to Example 154 using cyclopropyl methyl isothiocyanate. C17H16ClFN6O.375.1 (M+1).1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 8.93 (s, 1H), 7.94 (t, J = 5.3 Hz, 1H), 7.50– 7.25 (m, 1H), 7.14– 6.97 (m, 2H), 6.91 (d, J = 6.3 Hz, 1H), 6.58 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 3.31 (t, J = 6.5 Hz, 2H), 1.11 (d, J = 13.1 Hz, 1H), 0.57– 0.40 (m, 2H), 0.33– 0.19 (m, 2H).
Example 162: N-(3-Chloro-4-fluorophenyl)-2-((3,3-difluorocyclobutyl)amino)-N'- hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000217_0002
made analogously to Example 154 using 1,1-difluoro-3- isothiocyanatocyclobutane. C17H14ClF3N6O.411.0 (M+1).1H NMR (400 MHz, DMSO- d6) δ 11.41 (d, J = 18.8 Hz, 1H), 8.97 (s, 1H), 8.69 (s, 1H), 7.99 (dd, J = 7.9, 6.6 Hz, 1H), 7.09– 6.97 (m, 2H), 6.94 (d, J = 6.2 Hz, 1H), 6.54 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 4.28 (s, 1H), 3.03 (tt, J = 14.3, 7.9 Hz, 2H), 2.77 (d, J = 10.6 Hz, 2H).
Example 163: N-(3-Chloro-4-fluorophenyl)-2-(ethylamino)-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000217_0003
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604642.1 Attorney Docket No.: 1115.PF [0500] N-(3-chloro-4-fluorophenyl)-2-(ethylamino)-1H-imidazo[4,5-b]pyridine-7- carboxamide was made analogously to Example 154 using ethyl isothiocyanate.
C15H13ClFN5O.333.9 (M+1).
Figure imgf000218_0001
uorophenyl)-2-(ethylamino)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide. Example 163 was made analogously to Example 107 using N-(3-chloro-4-fluorophenyl)-2-(ethylamino)-1H-imidazo[4,5-b]pyridine-7- carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H-imidazo[4,5- b]pyridine-7-carboxamide. C15H14ClFN6O.349.1 (M+1).
Example 164: N-(3-Chloro-4-fluorophenyl)-2-(cyclobutylamino)-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide
uorophenyl)-2-(cyclobutylamino)-1H-imidazo[4,5- b]pyridine-7-carboxamide. Example 164 was made analogously to Example 154 using cyclobutyl isothiocyanate. C17H15ClFN5O.360.2 (M+1).
Figure imgf000218_0003
uorophenyl)-2-(cyclobutylamino)-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide. Example 164 was made analogously to Example 107 using N-(3-chloro-4-fluorophenyl)-2-(cyclobutylamino)-1H-imidazo[4,5- b]pyridine-7-carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H- imidazo[4,5-b]pyridine-7-carboxamide. C17H16ClFN6O.375.1 (M+1).1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.98 (s, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.09 (t, J = 9.1
216
604642.1 Attorney Docket No.: 1115.PF Hz, 1H), 7.05 (dd, J = 6.1, 2.5 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 6.62– 6.50 (m, 1H), 4.34 (q, J = 7.2 Hz, 1H), 2.39– 2.24 (m, 2H), 2.15– 1.98 (m, 2H), 1.82– 1.58 (m, 2H).
Example 165: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(isopropylamino)-1H- imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000219_0001
uorophenyl)-2-(isopropylamino)-1H-imidazo[4,5-b]pyridine- 7-carboxamide was made analogously to Example 154 using isopropyl isothiocyanate. C16H15ClFN5O.348.2 (M+1).
Figure imgf000219_0002
uorophenyl)-N'-hydroxy-2-(isopropylamino)-1H- imidazo[4,5-b]pyridine-7-carboximidamide. Example 165 was made analogously to Example 107 using N-(3-chloro-4-fluorophenyl)-2-(isopropylamino)-1H-imidazo[4,5- b]pyridine-7-carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-1H- imidazo[4,5-b]pyridine-7-carboxamide. C16H16ClFN6O.363.1 (M+1).1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.97 (s, 1H), 7.96 (d, J = 6.3 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.05 (dd, J = 6.6, 2.7 Hz, 1H), 6.92 (d, J = 6.3 Hz, 1H), 6.62– 6.56 (m, 1H), 4.06 (sex, J = 6.5 Hz, 1H), 1.25 (d, J = 6.3 Hz, 6H).
Example 166: N-(3-Chlorophenyl)-N'-hydroxy-2-(methylamino)-1H-imidazo[4,5- b]pyridine-7-carboximidamide
Figure imgf000219_0003
217
604642.1 Attorney Docket No.: 1115.PF [0506] Example 166 was made analogously to Example 158 using N-(3-chloro-4- fluorophenyl)-2-(methylamino)-1H-imidazo[4,5-b]pyridine-7-carboxamide.
C14H13ClN6O, 316.3/318.6 (M+1).1H NMR (400 MHz, DMSO-d6) δ 11.42 (br. s, 1H), 8.97 (s, 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.06 (t, J = 8.1 Hz, 1H), 6.99– 6.79 (m, 2H), 6.62 – 6.43 (m, 1H), 3.01 (d, J = 4.8 Hz, 3H).
Example 167: N-(3-Chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-N'- hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000220_0001
, , , was dissolved in methanol (160 mL), H2SO4 (10 mL, 189 mmol, 3.08 equiv) was added, and the reaction was stirred at 80 oC for overnight. The reaction was carefully quenched by the addition of a solution of NaOMe in methanol (80 mL, 13 wt% solution, 189 mmol, 3.08 equiv) at 0 oC. Methanol was subsequently removed in vacuo, the resulting solid was slurried in water and filtered. The solid was dried in a vacuum oven (65 oC) overnight. Methyl 1H-imidazo[4,5-b]pyridine-7-carboxylate was obtained as a brown solid. C8H7N3O2, 178.06 (M+1).
[0508] To a suspension of methyl 1H-imidazo[4,5-b]pyridine-7-carboxylate (7.8 g, 44 mmol, 1 equiv) in a mixture of THF/DMF (70 mL, 6:1 ratio) was added a 60 wt% dispersion of NaH (2.1 g, 53 mmol, 1.2 equiv) in three portions. Once gas evolution ceased, the reaction mixture was cooled to 0 oC and SEM-Cl (9.3 mL, 53 mmol, 1.2 equiv) was added. The ice bath was subsequently removed and the reaction was stirred at room temperature for 3 hours before being quenched with saturated aqueous NH4Cl. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2 over 20 minutes). Methyl 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine-7- carboxylate was isolated as a yellow solid. C14H21N3O3Si.308.01 (M+1).
218
604642.1 Attorney Docket No.: 1115.PF
Figure imgf000221_0001
- - thoxy)methyl)-1H-imidazo[4,5- b]pyridine-7-carboxylate (1.1 g, 4 mmol, 1 equiv) in acetonitrile (23.1 mL) was added NCS (0.72 g, 5 mmol, 1.5 equiv). The reaction mixture was stirred at 100 oC in a sealed vessel for 12 hours. Acetonitrile was subsequently removed in vacuo and the crude product purified by silica gel chromatography (0-5% MeOH/CH2Cl2 over 20 minutes). methyl 2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine-7- carboxylate was obtained as a yellow solid. C14H20ClN3O3Si.341.94/343.93 (M+1).
Figure imgf000221_0002
ound was made analogously to Example 39 using N,N- diethylethane-1,2-diamine in place of N,N-dimethylpropane-1,3-diamine and methyl 2- chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxylate in place of methyl 2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- benzo[d]imidazole-7-carboxylate. The TFA salt of methyl 2-((2- (diethylamino)ethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5- b]pyridine-7-carboxylate was obtained as a yellow oil. C20H35N5O3Si.422.23 (M+1).
Figure imgf000221_0003
was made analogously to Example 39 using methyl 2- ((2-(diethylamino)ethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5- b]pyridine-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5- difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-1H- 219
604642.1 Attorney Docket No.: 1115.PF imidazo[4,5-b]pyridine-7-carboxamide was isolated as a white solid. C19H22ClFN6O. 405.21/407.14 (M+1).
Figure imgf000222_0001
henyl)-2-((2-(diethylamino)ethyl)amino)-N'-hydroxy- 1H-imidazo[4,5-b]pyridine-7-carboximidamide was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-1H-imidazo[4,5- b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5- b]pyridine-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2- (diethylamino)ethyl)amino)-N'-hydroxy-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as a white solid. C19H23ClFN7O.420.16/422.13 (M+1).1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.93 (s, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.99 (dd, J = 6.5, 2.7 Hz, 1H), 6.94 (d, J = 6.0 Hz, 1H), 6.56 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 3.75 (m, 2H), 3.32 (t, J = 6.1 Hz, 2H), 3.23 (q, J = 7.2 Hz, 4H), 1.21 (t, J = 7.2 Hz, 6H).19F NMR (376 MHz, DMSO-d6) δ
-74.40 (9F), -126.69 (1F).
Example 168: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-((2- morpholinoethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000222_0002
d was made analogously to Example 39 using 2- morpholinoethanamine in place of N,N-dimethylpropane-1,3-diamine and methyl 2- chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine-7-carboxylate in place of methyl 2-chloro-4,5-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- benzo[d]imidazole-7-carboxylate. The TFA salt of methyl 2-((2- morpholinoethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5- 220
604642.1 Attorney Docket No.: 1115.PF b]pyridine-7-carboxylate was isolated as a yellow oil. C20H33N5O4Si.436.21 (M+1).
Figure imgf000223_0001
d was made analogously to Example 39 using methyl 2- ((2-morpholinoethyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5- b]pyridine-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5- difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-morpholinoethyl)amino)-1H-imidazo[4,5- b]pyridine-7-carboxamide was isolated as a white solid. C19H20ClFN6O2.419.22/421.14 (M+1).
Figure imgf000223_0002
henyl)-N'-hydroxy-2-((2-morpholinoethyl)amino)-1H- imidazo[4,5-b]pyridine-7-carboximidamide was made analogously to Example 59 using N-(3-chloro-4-fluorophenyl)-2-((2-morpholinoethyl)amino)-1H-imidazo[4,5-b]pyridine- 7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-1H-imidazo[4,5-b]pyridine-7- carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2- morpholinoethyl)amino)-1H-imidazo[4,5-b]pyridine-7-carboximidamide was isolated as a white solid. C19H21ClFN7O2.434.16/436.14 (M+1).1H NMR (400 MHz, DMSO-d6) δ 11.31 (br s, 1H), 10.11 (br s, 1H), 8.94 (s, 1H), 7.98 (d, J = 6.2 Hz, 1H), 7.10 (t, J = 9.1 Hz, 1H), 7.00 (dd, J = 6.6, 2.7 Hz, 1H), 6.94 (d, J = 6.1 Hz, 1H), 6.57 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 3.87– 3.71 (m, 8H), 3.44 - 3.20 (m, 4H).19F NMR (376 MHz, DMSO-d6) δ -74.51 (9F), -126.65 (1F).
221
604642.1 Attorney Docket No.: 1115.PF Example 169: N-(3-Chloro-4-fluorophenyl)-2-(dimethylamino)-N'-hydroxy-1H- imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000224_0001
yl 2-(dimethylamino)-1H-imidazo[4,5-b]pyridine-7-carboxylate.
Dissolved methyl 2,3-diaminoisonicotinate (0.2g, 1 mmol) in DCM (5 mL), to the solution was added phosgeniminium chloride (0.39g, 2 mmol) and triethylamine (0.6g, 6 mmol). The reaction mixture was stirred at 40 degree for 3h. Then the reaction was quenched with NaHCO3 solution, diluted with EtOAc, evaporated organic solvent, the residue was purified with Combi-Flash column to afford the desired product.
C10H12N4O2.221.1 (M+1).
Figure imgf000224_0002
4-fluorophenyl)-2-(dimethylamino)-1H-benzo[d]imidazole-7- carboxamide was made analogously to Example 23 using Methyl 2-(dimethylamino)-1H- imidazo[4,5-b]pyridine-7-carboxylate. C16H14ClFN4O.334.2 (M+1).
Figure imgf000224_0003
4-fluorophenyl)-2-(dimethylamino)-N'-hydroxy-1H-imidazo[4,5- b]pyridine-7-carboximidamide. Example 169 was made analogously to Example 107 using the general procedure for hydroxyamidine formation. C15H14ClFN6O.349.1 (M+1).1H NMR (400 MHz, DMSO-d6) δ 11.36 (d, J = 9.1 Hz, 1H), 10.09 (s, 1H), 9.00 (s, 1H), 7.94 (d, J = 6.3 Hz, 1H), 7.12– 6.98 (m, 2H), 6.90 (d, J = 6.3 Hz, 1H), 6.54 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 3.87 (s, 6H).
222
604642.1 Attorney Docket No.: 1115.PF Example 170: 2-(Chloromethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N'- hydroxy-3H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000225_0001
no-N-(4-fluoro-3-(trifluoromethyl)phenyl)isonicotinamide. To a solution of 3-fluoro-4-trifluromethyl-aniline (0.1 g, 0.65 mmol), 2,3-diaminoisonicotinic acid (0.234 g, 1 mmol) and triethylamine (0.18 mL, 1 mmol) in DMF (2 mL) was added HATU (0.186 g, 0.78 mmol). The reaction stirred for 16 hr at RT. Saturated sodium bicarbonate was added and the aqueous layer was washed three times with AcOEt. The combined organic layers were dried over sodium sulfate, filtered and concentrated onto silica gel and purified by silica gel chromatography (0->100% ethyl acetate in hexanes) to give the desired product as yellow crystals. C13H10F4N4O.315.1 (M+1).
Figure imgf000225_0002
trifluoromethyl)phenyl)-2-(hydroxymethyl)-3H-imidazo[4,5- b]pyridine-7-carboxamide.2,3-diamino-N-(4-fluoro-3- (trifluoromethyl)phenyl)isonicotinamide (0.078 g, 0.25 mmol) and 2-hydroxyacetic acid (0.378 g, 5 mmol) was heated neat in a microwave reactor to 170 C for 20 min. LiOH (0.15 g, 6 mmol) in dioxane/ water (0.6/ 2 mL) was added and stirred for 30 min.
Saturated sodium bicarbonate was added and the aqueous layer was washed three times with AcOEt. The combined organic layers were dried over sodium sulfate, filtered to give the desired product. C15H10F4N4O2.355.1 (M+1).
Figure imgf000225_0003
yl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-3H- imidazo[4,5-b]pyridine-7-carboximidamide. N-(4-fluoro-3-(trifluoromethyl)phenyl)-2- 223
604642.1 Attorney Docket No.: 1115.PF (hydroxymethyl)-3H-imidazo[4,5-b]pyridine-7-carboxamide (0.22 g, 0.62 mmol), POCl3 (0.6 ml, 6 mM) and PCL5 (0.26g, 0.1 mM) was stirred in dioxane (0.6 ml) at RT for 30 min. Volatiles were removed and excess NH2OH in acetonitrile (2 ml, 1/1050% NH2OH in water/ acetonitrile) was added, stirred at RT for 10 min. Volatiles were removed. Purification by preparatory HPLC (5-100% MeCN in water, 0.1% TFA) afforded the desired product. C15H10ClF4N5O.386.1.08 (M-1).
Example 171: N-(4-Fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-2- (hydroxymethyl)-3H-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000226_0001
ethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-3H- imidazo[4,5-b]pyridine-7-carboximidamide. (0.006 g, 0.17 mM), NaI (0.010g, 0.67 mM) and NaOAc (0.010g, 1.7 mM) were stirred in acetone (3 ml) at RT for 30 min. After filtration, volatiles were removed. Purification by preparatory HPLC (5-100% MeCN in water, 0.1% TFA) afforded the desired product. C15H11F4N5O2. Exact Mass: 370.1 (M+1).
Example 172: N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(1-hydroxyethyl)-1H- imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000226_0002
f 2,3-diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide (200 mg, 0.713 mmol) and 2-hydroxypropanoic acid (1.0 mL, 13 mmol) was sparged with argon for 1 min, then sealed and stirred at 180 °C for 1 h in a microwave reactor. The resulting mixture was cooled to room temperature and treated with 1 M lithium hydroxide (20 mL, 20 mmol), then stirred for 30 min. The resulting precipitate was filtered off and rinsed with water to afford N-(3-chloro-4-fluorophenyl)-2-(1- hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide. C15H12ClFN4O2.335.1 (M+1).
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604642.1 Attorney Docket No.: 1115.PF
Figure imgf000227_0001
orophenyl)-2-(1-((triisopropylsilyl)oxy)ethyl)-1H- imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 183 using N- (3-chloro-4-fluorophenyl)-2-(1-hydroxyethyl)-1H-imidazo[4,5-b]pyridine-7- carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)-1H- imidazo[4,5-b]pyridine-7-carboxamide. C24H32ClFN4O2Si.491.2 (M+1).
Figure imgf000227_0002
orophenyl)-2-(1-((triisopropylsilyl)oxy)ethyl)-1H- imidazo[4,5-b]pyridine-7-carbothioamide was made analogously to Example 183 using N-(3-chloro-4-fluorophenyl)-2-(1-((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5- b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2- ((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridine-7-carboxamide.
C24H32ClFN4OSSi.507.2 (M+1).
Figure imgf000227_0003
f N-(3-chloro-4-fluorophenyl)-2-(1- ((triisopropylsilyl)oxy)ethyl)-1H-imidazo[4,5-b]pyridine-7-carbothioamide (30 mg, 0.059 mmol) in methanol (3 mL) was treated with hydrogen chloride (4.0 M solution in dioxane, 0.12 mL, 0.46 mmol). The resulting solution was stirred at 70 °C overnight, then cooled to room temperature, treated with an additional quantity of hydrogen chloride (4.0 M solution in dioxane, 0.12 mL, 0.46 mmol), and stirred at 70 °C for an additional 7 h. The reaction mixture was then cooled to room temperature and
225
604642.1 concentrated under reduced pressure. The resulting residue was taken up in methanol (2.4 mL), treated with hydroxylamine (50% solution in water, 0.370 mL, 6.0 mmol), and stirred at 70 °C for 2 h in a sealed vial. The mixture was then cooled to room
temperature, diluted with dimethyl sulfoxide, and purified by reverse phase preparative HPLC to provide N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(l-hydroxyethyl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide. C15H13CIFN5O2. 350.1 (M+l).
Example 173 : V-(3-Chloro-4-fluorophenyl)- '-hydroxy-2-(hydroxy(phenyl)methyl)- lJff-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000228_0001
[0527] A suspension of 2,3-diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide (400 mg, 1.43 mmol) and 2-hydroxy-2-phenylacetic acid acid (1.74 g, 1 1.4 mmol) in dioxane (3.5 mL) was sparged with argon for 1 min, then sealed and stirred at 180 °C for 1 h in a microwave reactor. The resulting mixture was cooled to room temperature and treated with 1 M lithium hydroxide (14.3 mL, 14.3 mmol), then stirred for 30 min. The resulting precipitate was filtered off and rinsed with water to afford N-(3-chloro-4- fluorophenyl)-2-(hydroxy(phenyl)methyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide. C20H14CIFN4O2. 397.1 (M+l).
Figure imgf000228_0002
[0528] 2-(((tert-butyldimethylsilyl)oxy)(phenyl)methyl)-N-(3-chloro-4- fluorophenyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 183 using N-(3-chloro-4-fluorophenyl)-2-(hydroxy(phenyl)methyl)-lH- imidazo[4,5-b]pyridine-7-carboxamide and fert-butyldimethylsilyl
trifluoromethanesulfonate in place of N-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)- lH-imidazo[4,5-b]pyridine-7-carboxamide and triisopropylsilyl
trifluoromethanesulfonate. C26H28ClFN402Si. 511.2 (M+l).
Figure imgf000229_0001
[0529] 2-(((tert-butyldimethylsilyl)oxy)(phenyl)methyl)-N-(3-chloro-4- fluorophenyl)-lH-imidazo[4,5-b]pyridine-7-carbothioamide was made analogously to Example 183 using 2-(((tert-butyldimethylsilyl)oxy)(phenyl)methyl)-N-(3-chloro-4- fluorophenyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4- fluorophenyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-lH-imidazo[4,5-b]pyridine-7- carboxamide. C26H28ClFN4OSSi. 527.1 (M+l).
Figure imgf000229_0002
[0530] Example 173 was made analogously to Example 172 using 2-(((tert- butyldimethylsilyl)oxy)(phenyl)methyl)-N-(3-chloro-4-fluorophenyl)-lH-imidazo[4,5- b]pyridine-7-carbothioamide in place of N-(3-chloro-4-fluorophenyl)-2-(l- ((triisopropylsilyl)oxy)ethyl)-lH-imidazo[4,5-b]pyridine-7-carbothioamide.
C20H15CIFN5O2. 413.0 (M+l).
Example 174: ^(S-Chloro-^fluorophenylJ-l-icyclopropyl hydroxyJmethyl)-^- hydroxy- lTZ-imidazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000229_0003
[0531] N-(3-chloro-4-fluorophenyl)-2-(cyclopropyl(hydroxy)methyl)-lH- imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 173 using 2- cyclopropyl-2-hydroxyacetic acid in place of 2-hydroxy-2-phenylacetic acid acid. C17H14CIFN4O2. 361.1 (M+l).
Figure imgf000230_0001
[0532] 2-(((tert-butyldimethylsilyl)oxy)(cyclopropyl)methyl)-N-(3-chloro-4- fluorophenyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 183 using N-(3-chloro-4-fluorophenyl)-2-(cyclopropyl(hydroxy)methyl)-lH- imidazo[4,5-b]pyridine-7-carboxamide and fert-butyldimethylsilyl
trifluoromethanesulfonate in place of N-(3-chloro-4-fl uorophenyl)-2-(2 -hydroxy ethyl)- lH-imidazo[4,5-b]pyridine-7-carboxamide and triisopropylsilyl
trifluoromethanesulfonate. C23H28CIFN4O2S1. 475.2 (M+l).
Figure imgf000230_0002
[0533] 2-(((tert-butyldimethylsilyl)oxy)(cyclopropyl)methyl)-N-(3-chloro-4- fluorophenyl)-lH-imidazo[4,5-b]pyridine-7-carbothioamide was made analogously to Example 183 using 2-(((tert-butyldimethylsilyl)oxy)(cyclopropyl)methyl)-N-(3-chloro-4- fluorophenyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4- fluorophenyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-lH-imidazo[4,5-b]pyridine-7- carboxamide. C23H28CIFN4OSS1. 491.2 (M+l).
Figure imgf000230_0003
[0534] Example 175 was made analogously to Example 172 using 2-(((tert- butyldimethylsilyl)oxy)(cyclopropyl)methyl)-N-(3-chloro-4-fluorophenyl)-lH- imidazo[4,5-b]pyridine-7-carbothioamide in place of N-(3-chloro-4-fluorophenyl)-2-(l- ((triisopropylsilyl)oxy)ethyl)-lH-imidazo[4,5-b]pyridine-7-carbothioamide.
C17H15CIFN5O2. 376.1 (M+l).
Example 175: ^^-Chloro-^fluorophenylJ-A'-hydroxy-l-il-hydroxypropan-l-yl)- lJff-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000231_0001
[0535] A suspension of 2,3-diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide (400 mg, 1.43 mmol) and 2-hydroxy-2-methylpropanoic acid (1.19 g, 1 1.4 mmol) in dioxane (2 mL) was sparged with argon for 1 min, then sealed and stirred at 180 °C for 1 h in a microwave reactor. The resulting mixture was cooled to room temperature and treated with 1 M lithium hydroxide (14.3 mL, 14.3 mmol), then stirred for 30 min. The mixture was then filtered, and the resulting filtrate was acidified with 2 M hydrochloric acid to give a precipitate. The solids were filtered off and washed with water to provide N-(3-chloro-4-fluorophenyl)-2-(2-hydroxypropan-2-yl)-lH-imidazo[4,5-b]pyridine-7- carboxamide. Ci6Hi4ClFN402. 349.1 (M+l).
Figure imgf000231_0002
[0536] 2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-N-(3-chloro-4-fluorophenyl)- lH-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 183 using N-(3-chloro-4-fluorophenyl)-2-(2-hydroxypropan-2-yl)-lH-imidazo[4,5-b]pyridine-7- carboxamide and fert-butyldimethylsilyl trifluoromethanesulfonate in place of N-(3- chloro-4-fluorophenyl)-2-(2-hydroxyethyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide and triisopropylsilyl trifluoromethanesulfonate. C22H28CIFN4O2S1. 463.2 (M+l).
Figure imgf000232_0001
[0537] 2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-N-(3-chloro-4-fluorophenyl)- lH-imidazo[4,5-b]pyridine-7-carbothioamide was made analogously to Example 183 using 2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)-N-(3-chloro-4-fluorophenyl)-lH- imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2- ((triisopropylsilyl)oxy)ethyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide.
C22H28CIFN4OSS1. 479.1 (M+l).
Figure imgf000232_0002
[0538] Example 175 was made analogously to Example 172 using 2-(2-((tert- butyldimethylsilyl)oxy)propan-2-yl)-N-(3-chloro-4-fluorophenyl)-lH-imidazo[4,5- b]pyridine-7-carbothioamide in place of N-(3-chloro-4-fluorophenyl)-2-(l - ((triisopropylsilyl)oxy)ethyl)-lH-imidazo[4,5-b]pyridine-7-carbothioamide.
Ci6Hi5ClFN502. 364.1 (M+l).
Example 176: ^(S-Chloro^-fluorophenylJ-^-hydro y-l-l^^-trifluoro-l- hydroxyethylJ-l i-imidazo^^-b] pyridine- 7-carboximidamide
Figure imgf000232_0003
[0539] N-(3-chloro-4-fluorophenyl)-2-(2,2,2-trifluoro-l-hydroxyethyl)-lH- imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 175 using 3,3,3-trifluoro-2-hydroxypropanoic acid in place of 2-hydroxy-2-methylpropanoic acid. C15H9CIF4N4O2. 389.0 (M+l).
Figure imgf000233_0001
[0540] 2-(l-((ter -Bu†yldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-N-(3-chloro-4- fluorophenyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide was made analogously to Example 183 using N-(3-chloro-4-fluorophenyl)-2-(2,2,2-trifluoro-l-hydroxyethyl)-lH- imidazo[4,5-b]pyridine-7-carboxamide and fert-butyldimethylsilyl
trifluoromethanesulfonate in place of N-(3-chloro-4-fl uorophenyl)-2-(2 -hydroxy ethyl)- lH-imidazo[4,5-b]pyridine-7-carboxamide and triisopropylsilyl
trifluoromethanesulfonate. C21H23CIF4N4O2S1. 503.1 (M+l).
Figure imgf000233_0002
[0541] 2-(l-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-N-(3-chloro-4- fluorophenyl)-lH-imidazo[4,5-b]pyridine-7-carbothioamide was made analogously to Example 183 using 2-(l-((tert-butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-N-(3-chloro- 4-fluorophenyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4- fluorophenyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-lH-imidazo[4,5-b]pyridine-7- carboxamide. C21H23CIF4N4OSS1. 519.1 (M+l).
Figure imgf000233_0003
[0542] Example 176 was made analogously to Example 172 using 2-(l-((tert- butyldimethylsilyl)oxy)-2,2,2-trifluoroethyl)-N-(3-chloro-4-fluorophenyl)-lH- imidazo[4,5-b]pyridine-7-carbothioamide in place of N-(3-chloro-4-fluorophenyl)-2-(l- ((triisopropylsilyl)oxy)ethyl)-lH-imidazo[4,5-b]pyridine-7-carbothioamide.
C15H10CIF4N5O2. 404.1 (M+l).
Example 177: ^(S-Chloro^-fluorophenylJ- '-hydroxy-l-ihydroxymethylJ-l.ff- imidazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000234_0001
[0543] A solution of 4-(3-chloro-4-fluorophenyl)-3-(2-(hydroxymethyl)-lH- imidazo[4,5-b]pyridin-7-yl)-l,2,4-oxadiazol-5(4H)-one (20 mg, 0.055 mmol) in tetrahydrofuran (0.75 mL) was treated with water (0.75 mL) followed by 2 M sodium hydroxide (0.75 mL, 1.5 mmol). The mixture was stirred for 20 min, then acidified with acetic acid and purified by reverse phase preparative HPLC to provide the desired product. C14H11CIFN5O2. 336.1 (M+l).
Example 178: V-(3-Chloro-4-fluorophenyl)- '-hydroxy-2-((methylamino)methyl)- lJff-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000234_0002
[0544] Example 178 was made analogously to Example 112 using methylamine (2.0 M solution in THF) in place of morpholine. CI5HI4C1FN60. 349.1 (M+l).
Example 179: 2-(Aminomethyl)- V-(3-chloro-4-fluorophenyl)- '-hydroxy-lJff- imidazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000234_0003
[0545] A solution of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)-l-(methylsulfonyl)-lH-imidazo[4,5-b]pyridin-2-yl)methyl
methanesulfonate (10 mg, 0.019 mmol) in acetonitrile (0.5 mL) was treated with ammonia (0.5 M solution in dioxane, 0.50 mL, 0.25 mmol) and stirred at room temperature overnight. The mixture was then concentrated under reduced pressure. The resulting residue was taken up in tetrahydrofuran (0.50 mL) and treated with water (0.50 mL) followed by 2 M sodium hydroxide (0.20 mL, 0.40 mmol). The resulting mixture was stirred at room temperature for 5 min, then acidified with acetic acid and purified by reverse phase preparative HPLC to provide the desired product. Ci4Hi2ClFN60. 335.1 (M+l).
Example 180: ^(S-Chloro^-fluorophenylJ-^-hydroxy-l- (phenylsulfonamidomethyl)-l ^imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000235_0001
[0546] A solution of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)-l -(methylsulfonyl)-lH-imidazo[4,5-b]pyridin-2-yl)methyl
methanesulfonate (36 mg, 0.069 mmol) in acetonitrile (2 mL) was treated with ammonia (0.5 M solution in dioxane, 1.9 mL, 0.97 mmol) and stirred at room temperature overnight. The mixture was then concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (2 mL) and treated with pyridine (0.054 mL, 0.67 mmol) and divided into two batches of equal volume. One of these batches was then cooled to 0 °C and benzenesulfonyl chloride (0.78 M solution in dichloromethane, 0.130 mL, 0.100 mmol) was added dropwise with stirring. The reaction mixture was then warmed to room temperature and stirred for 10 min, then cooled to 0 °C and treated with water. The mixture was then partially concentrated under reduced pressure, then treated with tetrahydrofuran (1 mL) followed by 2 M sodium hydroxide (1 mL) and stirred for 15 min. The mixture was then acidified with acetic acid, partially concentrated under reduced pressure, diluted with dimethyl sulfoxide (1 mL), and purified by reverse phase preparative HPLC to provide the desired product. C2oHi6ClFN603S. 475.1 (M+l). Example 181: TV- S-Chloro^-fluorophenylJ- '-hydroxy-l- (methylsulfonamidomethyl)-l fimidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000236_0001
[0547] Example 181 was prepared analogously to Example 180 using
methanesulfonyl chloride in place of benzenesulfonyl chloride. C15H14CIFN6O3S. 413.0 (M+l).
Example 182 : V-(3-Chloro-4-fluorophenyl)- '-hydroxy-2-((pyrimidin-2- ylamino)methyl)-lJff-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000236_0002
[0548] A solution of (7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)-l-(methylsulfonyl)-lH-imidazo[4,5-b]pyridin-2-yl)methyl
methanesulfonate (59 mg, 0.114 mmol) in acetonitrile (3 mL) was treated with ammonia (0.5 M solution in dioxane, 1.9 mL, 0.97 mmol) and stirred at room temperature overnight. The solution was then divided into two batches of equal volume. One of the batches was concentrated under reduced pressure and the resulting residue taken up in DMSO (1 mL). The solution was treated with N,N-diisopropylethylamine (0.061 mL, 0.35 mmol) followed by 2-fluoropyrmidine (23 mg, 0.23 mmol) and stirred for at room temperature for 48 h. The mixture was then treated with water (1 mL) and 2 M sodium hydroxide (0.5 mL) and stirred for 15 min, then acidified acetic acid, diluted with dimethyl sulfoxide, and purified by reverse phase preparative HPLC to provide the desired product. Ci8Hi4ClFN80. 413.1 (M+l). Example 183: ^(S-Chloro^-fluorophenylJ- '-hydroxy-l-il-hydroxyethylJ-l.ff- imidazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000237_0001
[0549] Ethyl 2-(7-((3-chloro-4-fluorophenyl)carbamoyl)-lH-imidazo[4,5-b]pyridin- 2-yl)acetate. A suspension of 2,3-diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide (10.9 g, 38.8 mmol) and ethyl 3-ethoxy-3-iminopropanoate hydrochloride (30.4 g, 155 mmol) in ethanol (100 mL) was stirred at 80 °C for 24 h. The mixture was then cooled to room temperature and an additional portion of ethyl 3-ethoxy-3-iminopropanoate hydrochloride (30.4 g, 155 mmol) was added. The suspension was stirred at 80 °C for an additional 24 h. The mixture was then cooled to room temperature and the resulting solid filtered off, rinsed with water, and dried under a stream of air to afford the desired product. C17H14CIFN4O3. 377.1 (M+l).
Figure imgf000237_0002
[0550] N-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)-lH-irnidazo[4,5-b]pyridine- 7-carboxamide. To a stirring suspension of ethyl 2-(7-((3-chloro-4- fluorophenyl)carbamoyl)-lH-imidazo[4,5-b]pyridin-2-yl)acetate (5.55 g, 14.7 mmol) in THF (210 mL) under a positive pressure of nitrogen was added lithium borohydride (3.21 g, 147 mmol) in five equal portions. The resulting mixture was then stirred at 40 °C for 1 h. The mixture was then cooled to 0 °C and water (83 mL) was slowly added, such that the internal temperature was kept below 15 °C. After 30 min of stirring, 1M hydrochloric acid (660 mL) was slowly added, such that the internal temperature was kept below 20 °C. The mixture was then heated to 40 °C and stirred for 2 h. The resulting solution was cooled to room temperature and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the desired product (2.46 g). The aqueous layer contained a yellow precipitate which was filtered off, rinsed with water, and dried under a stream of air to afford an additional quantity of desired product. C15H12CIFN4O2. 335.1 (M+l).
Figure imgf000238_0001
[0551] N-(3-chloro-4-fluorophenyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-lH- imidazo[4,5-b]pyridine-7-carboxamide. To a stirring suspension of N-(3-chloro-4- fluorophenyl)-2-(2-hydroxyethyl)-lH-inddazo[4,5-b]pyridine-7-carboxamide (2.46 g, 7.35 mmol) in dichloromethane (75 mL) under a nitrogen atmosphere was added 2,6- lutidine (10.2 mL, 88.2 mmol). The mixture was then cooled to 0 °C and triisopropylsilyl trifluoromethanesulfonate (1 1.9 mL, 44.1 mmol) was added dropwise with stirring. The mixture was then allowed to warm to room temperature and stirred for an additional 90 min. Water was added with vigorous stirring, then the organic and aqueous layers were separated and the organic layer washed four additional times with water. The organic layer was then adsorbed onto silica gel and purified by flash chromatography (0-100% EtOAc/hexanes). Product-containing fractions were combined and concentrated under reduced pressure, then triturated with acetonitrile to afford the desired product.
C24H32CIFN4O2S1. 491.4 (M+l).
Figure imgf000238_0002
[0552] N-(3-chloro-4-fluorophenyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-lH- imidazo[4,5-b]pyridine-7-carbothioamide. A suspension of N-(3-chloro-4-fluorophenyl)- 2-(2-((triisopropylsilyl)oxy)ethyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide (2.27 g, 4.62 mmol) and 2,4-bis(4-methoxyphenyl)-l ,3,2,4-dithiadiphosphetane 2,4-disulfide (3.74 g, 9.24 mmol) in toluene (92 mL) was stirred at 95 °C for 4 h. The mixture was then cooled to room temperature and filtered, rinsing with dichloromethane. The combined filtrates were adsorbed onto silica gel and purified by flash chromatography (0-75% EtOAc/hexanes) to provide the desired product. C24H32CIFN4OSS1. 507.2 (M+l).
Figure imgf000239_0001
[0553] N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-hydroxyethyl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide. A solution of 4-(3-chloro-4-fluorophenyl)- 3-(2-(2-((triisopropylsilyl)oxy)ethyl)-lH-imidazo[4,5-b]pyridin-7-yl)-l,2,4-oxadiazol- 5(4H)-one (40mg, 0.079mmol) and hydrogen chloride (4.0 M solution in dioxane, 0.158 mL, 0.631 mmol) in methanol (4 mL) was stirred at 70 °C overnight in a sealed screw- top flask. The mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in hydroxylamine (50% solution in water, 0.259 mL, 3.991mmol) in methanol (1.6 mL) was stirred at 70 °C in a sealed screw-top flask for 1 h. The mixture was then cooled to room temperature The mixture was acidified with acetic acid (0.300 mL, 5.24 mmol), diluted with dimethyl sulfoxide (4 mL), and purified by reverse phase preparative HPLC to provide the desired product. C15H13CIFN5O2. 350.10 (M+l).
Example 184 : V-(3-Chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)- '-hydroxy- lJff-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000239_0002
[0554] 4-(3-chloro-4-fluorophenyl)-3-(2-(2-((triisopropylsilyl)oxy)ethyl)-lH- imidazo[4,5-b]pyridin-7-yl)-l,2,4-oxadiazol-5(4H)-one. A suspension of N-(3-chloro-4- fluorophenyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-lH-imidazo[4,5-b]pyridine-7- carbothioamide (1.70 g, 3.33 mmol) and hydroxylamine (50% solution in water, 20.4 mL, 333 mmol) in methanol (135 mL) was stirred at 70 °C in a sealed screw-top flask for 1 h. The mixture was then cooled to room temperature and partially concentrated under reduced pressure to afford a white aqueous suspension. The solids were filtered off and dried under reduced pressure, then taken up in ethyl acetate (135 mL) and treated with Ι,Γ-carbonyldiimidazole (702 mg, 4.33 mmol). The mixture was stirred at 30 °C for 1 h, then adsorbed onto silica gel and purified by flash chromatography (0-100%
EtOAc/hexanes) to provide the desired product. C25H3iClFN503Si. 532.2 (M+l).
Figure imgf000240_0001
[0555] 2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)-l- (methylsulfonyl)-lH-imidazo[4,5-b]pyridin-2-yl)ethyl methanesulfonate. A solution of 4-(3-chloro-4-fluorophenyl)-3-(2-(2-((triisopropylsilyl)oxy)ethyl)-lH-imidazo[4,5- b]pyridin-7-yl)-l,2,4-oxadiazol-5(4H)-one (1.95 g, 3.67 mmol) and hydrogen chloride (4.0 M solution in dioxane, 7.3 mL, 29 mmol) in methanol (180 mL) was stirred at 70 °C overnight in a sealed screw-top flask. The mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in dichloromethane (75 mL), treated with N,N-diisopropylethylamine (6.4 mL, 37 mmol), and cooled to 0 °C under a nitrogen atmosphere. Methanesulfonyl chloride (2.0 mL, 26 mmol) was added drop wise over 5 min with stirring. After 30 min, the mixture was treated with water, the layers were separated, and the organic layer was washed twice more with water. The organic phase was then concentrated under reduced pressure and purified by flash chromatography (0-65% EtOAc/hexanes) to provide the desired product (Note: the connectivity of the methanesulfonyl group on the imidazole ring was assumed to be at N(l) as indicated, though connectivity at N(3) was not rigorously ruled out). CigHisClFNsOvSi. 532.1 (M+l).
Figure imgf000240_0002
[0556] A solution of 2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)-l -(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-2-yl)ethyl
methanesulfonate (20 mg, 0.038 mmol) in acetonitrile (0.2 mL) was treated with dimethylamine (2.0 M solution in tetrahydrofuran, 0.38 mL, 0.75 mmol), and the resulting solution was stirred at room temperature for 1 h. The mixture was then concentrated under reduced pressure. The resulting residue was taken up in
tetrahydrofuran (0.5 mL), treated with water (0.5 mL) followed by 2M sodium hydroxide (0.23 mL, 0.46 mmol), and stirred at room temperature for 15 min. The mixture was acidified with acetic acid (0.064 mL, 1.1 mmol), diluted with dimethyl sulfoxide (3 mL), and purified by reverse phase preparative HPLC to provide the desired product.
CnHigClFNgO. 377.1 (M+1). lH NMR (400 MHz, DMSO-c¾) δ 11.1 1 (s, 1H), 8.91 (s, 1H), 8.31 (d, J = 5.1 Hz, 1H), 7.15 (d, J = 5.1 Hz, 1H), 7.05 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.51 (ddd, J = 9.0, 4.1 , 2.7 Hz, 1H), 3.54 (t, J = 7.3 Hz, 2H), 3.30 (t, J = 7.3 Hz, 2H), 2.86 (s, 6H).
Example 185: V-(3-Chloro-4-fluorophenyl)-2-(2-(diethylamino)ethyl)- '-hydroxy- lJff-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000241_0001
[0557] Example 185 was made analogously to Example 184 using diethylamine in place of dimethylamine. Ci9H22ClFN60. 405.1 (M+1). ¾ NMR (400 MHz, DMSO-c¾) δ 11.08 (s, 1H), 8.91 (s, 1H), 8.30 (d, J = 5.1 Hz, 1H), 7.16 (d, J = 5.2 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.50 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.52 (t, J = 7.5 Hz, 2H), 3.28 (t, J = 7.5 Hz, 2H), 3.21 (q, J = 7.2 Hz, 4H), 1.22 (t, J = 7.2 Hz, 6H).
Example 186: ^-(3-Chloro-4-fluorophenyl)-2-(2- ((cyclopropylmethyl)(methyl)amino)ethyl)- '-hydroxy-lJff-imidazo[4,5-b]pyridine-
7-carboximidamide
Figure imgf000242_0001
[0558] Example 186 was made analogously to Example 184 using 1 -cyclopropyl-N- methylmethanamine in place of dimethylamine. C2oH22ClFN60. 417.1 (M+1). 'H NMR (400 MHz, DMSO-c¾) 5 11.08 (s, 1H), 8.90 (s, 1H), 8.31 (d, J= 5.1 Hz, 1H), 7.17 (d, J = 5.1 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.51 (ddd, J= 9.0, 4.1, 2.7 Hz, 1H), 3.59 (br s, 2H), 3.33 (t, J = 7.4 Hz, 2H), 3.10 (d, J = 7.3 Hz, 2H), 2.88 (s, 3H), 1.18-1.06 (m, 1H), 0.70-0.62 (m, 2H), 0.44-0.38 (m, 2H).
Example 187: ^-(3-Chloro-4-fluorophenyl)-2-(2-((2,2- difluoroethyl)(methyl)amino)ethyl)- '-hydroxy-lJff-imidazo[4,5-b] pyridine- 7- carboximidamide
Figure imgf000242_0002
[0559] A solution of 2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)-l-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-2-yl)ethyl
methanesulfonate (30 mg, 0.056 mmol) in acetonitrile (0.9 mL) was treated with N,N- diisopropylethylamine (0.20 mL, 1.1 mmol) followed by 2,2-difluoro-N- methylethanamine hydrochloride (148 mg, 1.13 mmol). The resulting solution was stirred for 2 h, then treated with dimethylamine (2.0 M solution in tetrahydrofuran, 0.5 mL, 1.0 mmol). After an additional 1 h of stirring, the mixture was treated with isopropylamine (0.2 mL, 2.3 mmol) and stirred for 20 min (in order to cleave the remaining imidazolyl methanesulfonyl group). The solution was then concentrated under reduced pressure and the resulting residue taken up in tetrahydrofuran (0.75 mL). The solution was treated with water (0.75 mL) followed by 2M sodium hydroxide (0.38 mL, 0.76 mmol), and stirred at room temperature for 20 min. An additional amount of 2M sodium hydroxide (0.75 mL, 1.5 mmol) was added, and stirring resumed for 15 min. Finally, the mixture was acidified with acetic acid, partially evaporated under reduced pressure, diluted with dimethyl sulfoxide, and purified by reverse phase preparative HPLC to provide the desired product. CI8HI8C1F3N60. 427.1 (M+l).
Example 188 : V-(3-Chloro-4-fluorophenyl)- '-hydroxy-2-(2-(methylamino)ethyl)- lJff-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000243_0001
[0560] A solution 2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)-l-(methylsulfonyl)-lH-imidazo[4,5-b]pyridin-2-yl)ethyl
methanesulfonate. (20 mg, 0.038mmol) and methylamine (2.0 M solution in tetrahydrofuran, 0.376mL, 0.752mmol) in acetonitrile (1 mL) was stirred for 2hr. The reaction was concentrated. The residue was brought up in tetrahydrofuran (0.5 mL) and water (0.5 mL). To this solution was added 2 N sodium hydroxide (0.22 mL, 0.43 mmol) and the reaction mixture stirred for 10 min. To the mixture was added acetic acid (0.035 mL) and the solution was loaded directly onto a prep HPLC for purification to give the desired product. CI6HI6C1FN60. 363.11(M+1).
Example 189 : 2-(2-Aminoethyl)- V-(3-chloro-4-fluorophenyl)- '-hydroxy- 1H- imidazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000243_0002
[0561] Example 189 was made analogously to Example 188 using ammonia (0.5 M solution in dioxane) in place of dimethylamine (2.0 M solution in tetrahydrofuran). CI5HI4C1FN60. 349.1 (M+l). Example 190: ^(S-Chloro-^fluoropheny -^-hydroxy-l- l- l- methoxyethylJaminoJethylJ-l i-imidazo^^-b] pyridine- 7-carboximidamide
Figure imgf000244_0001
[0562] Example 190 was made analogously to Example 188 using 2- methoxyethanamine in place of dimethylamine (2.0 M solution in tetrahydrofuran). Ci8H2oClFN602. 407.1 (M+1).
Example 191: V-(3-Chloro-4-fluorophenyl)- '-hydroxy-2-(2-morpholinoethyl)-lJff- imidazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000244_0002
[0563] Example 191 was made analogously to Example 188 using morpholine in place of dimethylamine (2.0 M solution in tetrahydrofuran). C19H20CIFN6O2. 419.13 (M+1)
Example 192: >i-(3-Chloro-4-fluorophenyl)- '-hydroxy-2-(2-(piperidin-l-yl)ethyl)- lJff-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000244_0003
[0564] Example 192 was made analogously to Example 184 using piperidine in place of dimethylamine. C20H22ClFN6O. 417.1 (M+1). 'H NMR (400 MHz, DMSO-c/6) δ 11.10 (s, 1H), 8.90 (s, 1H), 8.30 (d, J = 5.1 Hz, 1H), 7.16 (d, J = 5.1 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.52 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 3.69-2.76 (m, 8H), 1.99-1.28 (m, 6H). Example 193: V-(3-Chloro-4-fluorophenyl)- '-hydroxy-2-(2-(pyrrolidin-l-yl)ethyl)- lJff-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000245_0001
[0565] Example 193 was made analogously to Example 184 using pyrrolidine in place of dimethylamine. Ci9H20ClFN6O.403.1 (M+1). ¾NMR (400 MHz, DMSO-c¾) δ 11.10 (s, 1H), 8.89 (s, 1H), 8.31 (d,J=5.1 Hz, 1H), 7.16 (d,J= 5.1 Hz, 1H), 7.04 (t,J = 9.1Hz, 1H), 6.94 (dd,J=6.6, 2.7 Hz, 1H), 6.51 (ddd,J=9.0, 4.1,2.7 Hz, 1H), 3.61 (t,J = 7.4 Hz, 2H), 3.57-2.99 (m, 6H), 1.96 (br s, 4H).
Example 194: V-(3-Chloro-4-fluorophenyl)- '-hydroxy-2-(2-((2- methoxyethyl)(methyl)amino)ethyl)-lJff-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000245_0002
[0566] Example 194 was made analogously to Example 187 using 2-methoxy-N- methylethanamine in place of 2,2-difluoro-N-methylethanamine hydrochloride and N,N- diisopropylethylamine. Ci9H22ClFN602.421.1 (M+1). ¾NMR (400 MHz, DMSO-c¾) δ 11.09 (s, 1H), 8.89 (s, 1H), 8.30 (d, J = 5.1 Hz, 1H), 7.15 (d, J= 5.1 Hz, 1H), 7.04 (t,J = 9.1 Hz, 1H), 6.93 (dd,J=6.5, 2.7 Hz, 1H), 6.52 (ddd,J=9.0, 4.1, 2.8 Hz, 1H), 3.70 (t,J = 5.0 Hz, 2H), 3.60 (t, J= 7.4 Hz, 2H), 3.40 (t, J= 5.1 Hz, 2H), 3.36-3.29 (m, 5H), 2.86 (s, 3H).
Example 195: V-(3-Chloro-4-fluorophenyl)-2-(2-(dimethylamino)-l-hydroxyethyl)- '-hydroxy-lJff-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000245_0003
[0567] N-(3-chloro-4-fluorophenyl)-2-(2,2-dimethyl-l ,3-dioxolan-4-yl)-lH- imidazo[4,5-b]pyridine-7-carboxamide. A solution of 2,3-diamino-N-(3-chloro-4- fluorophenyl)isonicotinamide (3.00 g, 10.7 mmol) and 2,2-dimethyl-l ,3-dioxolane-4- carbaldehyde (50% by weight in dichloromethane, 13.9 g, 53.4 mmol) in dimethyl sulfoxide (110 mL) was stirred vigorously under an air atmosphere at 100 °C overnight. The mixture was cooled to room temperature, diluted with water and brine solution, and extracted with dichloromethane (700 mL). The organic layer was then washed three times with water (500 mL), concentrated under reduced pressure, and adsorbed onto silica gel for purification by flash chromatography (0-70% EtOAc/hexanes) to provide the desired product. Ci8Hi6ClFN403. 391.1 (M+l).
Figure imgf000246_0001
[0568] N-(3-chloro-4-fluorophenyl)-2-(l,2-dihydroxyethyl)-lH-imidazo[4,5- b]pyridine-7-carboxamide. A suspension of N-(3-chloro-4-fluorophenyl)-2-(2,2- dimethyl-l,3-dioxolan-4-yl)-lH-imidazo[4,5-b]pyridine-7-carboxarnide (300 mg, 0.768 mmol) in methanol (38 mL) was treated with hydrogen chloride (4.0 M in dioxane, 1.5 mL, 6.0 mmol) and stirred at 70 °C overnight. The mixture was concentrated under reduced pressure to provide the desired product. C15H12CIFN4O3. 351.1 (M+l).
Figure imgf000246_0002
[0569] N-(3-chloro-4-fluorophenyl)-2-(2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8- disiladecan-5-yl)-lH-imidazo[4,5-b]pyridine-7-carboxamide. A suspension of N-(3- chloro-4-fluorophenyl)-2-(l ,2-dihydroxyethyl)-lH-imidazo[4,5-b]pyridine-7- carboxamide (727 mg, 2.07 mmol) and 2,6-lutidine (3.9 mL, 33 mmol) in
dichloromethane (41 mL) was cooled to 0 °C with stirring under a nitrogen atmosphere. The mixture was then treated with fert-butyldimethylsilyl trifluoromethanesulfonate (3.8 mL, 17 mmol) dropwise and with stirring. The mixture was then warmed to room temperature and stirred for 20 min, then adsorbed onto silica gel for purification by flash chromatography (0-40% EtOAc/hexanes) to provide the desired product.
C27H40CIFN4O3S12. 579.3 (M+l).
Figure imgf000247_0001
[0570] 2-(l-((tert-butyldimethylsilyl)oxy)-2-hydroxyethyl)-N-(3-chloro-4- fluorophenyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide. A suspension of N-(3-chloro- 4-fluorophenyl)-2-(2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)-lH- imidazo[4,5-b]pyridine-7-carboxamide (200 mg, 0.345 mmol) in ethanol (7 mL) was treated with pyridinium / toluenesulfonate (781 mg, 3.11 mmol) and stirred at 80 °C for 90 min. The mixture was then cooled to room temperature, diluted with saturated aqueous sodium bicarbonate, and extracted three times with ethyl acetate. The combined organic layers were adsorbed onto silica gel for purification by flash chromatography (20-55% EtOAc/hexanes) to provide the desired product. C2iH26ClFN403Si. 365.3 (M+l).
Figure imgf000247_0002
[0571] 2-((tert-butyldimethylsilyl)oxy)-2-(7-((3-chloro-4-fluorophenyl)carbamoyl)-
1- (methylsulfonyl)-lH-imidazo[4,5-b]pyridin-2-yl)ethyl methanesulfonate. A solution of
2- (l-((tert-butyldimethylsilyl)oxy)-2-hydroxyethyl)-N-(3-chloro-4-fluorophenyl)-lH- imidazo[4,5-b]pyridine-7-carboxamide (90 mg, 0.19 mmol) and N,N- diisopropylethylamine (0.74 mL, 1.9 mmol) in dichloromethane (3.9 mL) was cooled to 0 °C with stirring under a nitrogen atmosphere. The mixture was treated with methanesulfonyl chloride (0.075 mL, 0.97 mmol) dropwise and with stirring. After 5 min, the mixture was diluted with water, then extracted three times with
dichloromethane. The combined organic layers were loaded onto a silica gel cartridge for purification by flash chromatography (0-100% EtOAc/hexanes) to provide the desired product. C23H3oClFN407S2Si. 621.2 (M+l).
Figure imgf000248_0001
[0572] 2 l-((tert-bu†yldimethylsilyl)oxy)-2 dimethylamino)ethyl)-N-(3-chloro-4- fluorophenyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide. A solution of 2-((tert- butyldimethylsilyl)oxy)-2-(7-((3-chloro-4-fluorophenyl)carbamoyl)-l -(methylsulfonyl)- 3H-imidazo[4,5-b]pyridin-2-yl)ethyl methanesulfonate (90 mg, 0.145 mmol) in acetonitrile (2.9 mL) was treated with dimethylamine (2.0 M in tetrahydrofuran, 2.90 mL, 5.80 mmol) and stirred at 60 °C for for 3 h. Additional dimethylamine (2.0 M in tetrahydrofuran, 1.0 mL, 2.0 mmol) was then added, and stirring at 60 °C resumed for 2 h. The mixture was then cooled to room temperature and concentrated under reduced pressure. Purification of the resulting residue by flash chromatography (0-30%
MeOH/DCM) provided the desired product. C23H31CIFN5O2S1. 492.3 (M+l).
Figure imgf000248_0002
[0573] 2-(l-((tert-butyldimethylsilyl)oxy)-2-(dimethylamino)ethyl)-N-(3-chloro-4- fluorophenyl)-lH-imidazo[4,5-b]pyridine-7-carbothioamide was made analogously to Example 183 using 2-(l-((tert-butyldimethylsilyl)oxy)-2-(dimethylamino)ethyl)-N-(3- chloro-4-fluorophenyl)-lH-imidazo[4,5-b]pyridine-7-carboxarnide in place of N-(3- chloro-4-fluorophenyl)-2-(2-((triisopropylsilyl)oxy)ethyl)-lH-imidazo[4,5-b]pyridine-7- carboxamide. C23H31CIFN5OSS1. 508.2 (M+l).
Figure imgf000248_0003
[0574] N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)-l-hydroxyethyl)-lH- imidazo[4,5-b]pyridine-7-carbothioamide. A solution of 2-(l -((tert- butyldimethylsilyl)oxy)-2-(dimethylamino)ethyl)-N-(3-chloro-4-fluorophenyl)-lH- imidazo[4,5-b]pyridine-7-carbothioamide (59 mg, 0.12 mmol) and hydrogen chloride (4.0 M solution in dioxane, 0.226 mL, 0.906 mmol) in methanol (5.8 mL) was stirred at 80 °C for 24 h. The mixture was then cooled to room temperature, diluted with dimethyl sulfoxide, and purified by reverse phase preparative HPLC to provide the desired product. CivHivClFNsOS. 594.2 (M+l).
Figure imgf000249_0001
[0575] N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)-l-hydroxyethyl)-N'- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide. A solution of N-(3-chloro-4- fluorophenyl)-2-(2-(dimethylamino)-l -hydroxy ethyl)-lH-imidazo[4,5-b]pyridine-7- carbothioamide (5 mg, 0.013 mmol) and hydroxylamine (50% solution in water, 0.156 mL, 2.54 mmol) in methanol (1 mL) was stirred at 70 °C for 10 min. The mixture was then diluted with dimethyl sulfoxide and purified by reverse phase preparative HPLC to provide the desired product. CI7HI8C1FN602. 393.1 (M+l).
Example 196: ^(S-Chloro-^fluorophenylJ- '-hydroxy-l-iiisobutylaminoJmethyl)-
1 H-iniidazo [4,5- b] pyridine-7-carboximidamide
Figure imgf000249_0002
[0576] Example 196 was synthesized analogously to Example 112 using 3-(2- (bromomethyl)-lH-imidazo[4,5- )]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4- oxadiazol-5(4H)-one and 2-methylpropan-l -amine in place of (7-(4-(3-chloro-4- fluorophenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)-l-(methylsulfonyl)-lH- imidazo[4,5-Z>]pyridin-2-yl)methyl methanesulfonate and morpholine, respectively. Ci8H20ClFN6O. 391.1 [M+l]+. Example 197 : ^(S-Chloro-^fluorophenylJ- '-hydroxy-S-methyl-S.ff-imidazo [4,5- b] pyridine- 7-carboximidamide
Figure imgf000250_0001
[0577] N,4-dimethyl-3-nitropyridin-2-amine. A solution of 4-methyl-3-nitro-2- chloropyridine (2.07 g, 12.0 mmol) and methylamine (40% in water, 7.2 mL, 84 mmol) in ethanol (14 mL) was stirred at 80 °C for 1.5 hr. The reaction was concentrated to give the desired product. C7H9N3O2. 168.0 (M+l).
Figure imgf000250_0002
[0578] 2-Methylamino-3-amino-4-methylpyridine. A mixture of N,4-dimethyl-3- nitropyridin-2-amine (2.01 g, 12.0 mmol) and 10% Paladium on Carbon (128 mg, 0.12 mmol) was mixed in a Parr Shaker at 40 psi hydrogen for 2 hr. The reaction mixture was filtered and concentrated to give the desired product. C7H11N3. 138.1 (M+l).
Figure imgf000250_0003
[0579] 3,7-Dimethyl-3H-imidazo[4,5-b]pyridine. A solution of 2-methylamino-3- amino-4-methylpyridine (830 mg, 6.05 mmol) in trimethylorthoformate (20 mL) was stirred at 100 °C for 3 hr and concentrated. The residue was purified by silica gel chromatography to give the desired product. C8H9N3. 148.0 (M+l).
Figure imgf000250_0004
[0580] 3-Methyl-3H-imidazo[4,5-b]pyridine-7-carboxylic acid. To a solution of 3,7- dimethyl-3H-imidazo[4,5-b]pyridine (726 mg, 4.93 mmol) sodium carbonate (523 mg, 4.93 mmol) in water (30 mL) at 100 C was added potassium permanganate (7.8 g, 49.2 mmol) in portions over two days. Na2C03 and water are added to the starting material The reaction mixture is heated until boiled, which caused a homogeneous solution.
KMn04 was added in small portions to the boiling solution. The reaction is stirred for another hour. LCMS shows low conversion. More KMn04 was added in small batches at 100 °C for the next two days. The reaction mixture was filtered hot and the filtrate was acidified with 1 N HC1, concentrated and purified by prep HPLC to give the desired product. C8H7N302. 178.0 (M+l).
Figure imgf000251_0001
[0581] N-(3-chloro-4-fluorophenyl)-3-methyl-3H-imidazo[4,5-b]pyridine-7- carboxamide. A solution of 3-methyl-3H-imidazo[4,5-b]pyridine-7-carboxylic acid (100 mg, 0.564 mmol), hydroxybenzotriazole (173 mg, 1.13 mmol), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (216 mg, 1.13 mmol), and
diisopropylethylamine (0.690 mL, 3.95 mmol) in dimethylformamide (2 mL) was stirred for 18 hr. To the reaction mixture was added saturated sodium bicarbonate Stirred all together overnight. Added saturated aqueous sodium bicarbonate and the resulting solid was filtered, triturated with 10% citric acid, filtered, and dried on high vac.
C14H10CIFN4O. 305.1 (M+l).
Figure imgf000251_0002
[0582] N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3-methyl-3H-imidazo[4,5- b]pyridine-7-carboximidamide. Example 197 was made analogously to Example 107 using N-(3-chloro-4-fluorophenyl)-3-methyl-3H-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-Chloro-4-fluorophenyl)-2-methyl-lH-imidazo[4,5-b]pyridine-7- carboxamide. Ci4HnClFN50. 320.0 (M+l).
[0583] The following compounds were prepared according to the procedures described herein using the appropriate starting materials. Example 198: ^(S-Chloro^-fluoropheny -A'-hydroxy^-P-^- methoxyethylamino)ethyl] -STZ-imidazo [4,5-b] pyridine-7-carboximidamide
Figure imgf000252_0001
Example 199: V-(3-Chloro-4-fluorophenyl)-2- [3-(dimethylamino)propyl]-6,7- difluoro- '-h droxy-3Jff-benzimidazole-4-carboximidamide
Figure imgf000252_0002
Example 200 : V-(3-Chloro-4-fluorophenyl)-7-fluoro- '-hydroxy-2-(3-morpholin-4- lpropylamino)-3Jff-benzimidazole-4-carboximidamide
Figure imgf000252_0003
Example 201 : jV-(3-Chloro-4-fluorophenyl)-2- [2-(dimethylamino)ethylamino] -7- fluoro- '-hydroxy-3Jff-benzimidazole-4-carboximidamide
Figure imgf000252_0004
Example 202 : V-(3-Chloro-4-fluorophenyl)- '-hydroxy-2- [(l-methylpiperidin-2- l)methylamino]-lJff-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000253_0001
Example 203 : V-(3-Chloro-4-fluorophenyl)- '-hydroxy-2- [(l-methylpyrrolidin-3- l)amino]-lJH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000253_0002
Example 204: V-(3-chloro-4-fluorophenyl)-2-(2-(ethylamino)ethyl)- '-hydroxy-3Jff- imidazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000253_0003
[0584] Example 204 was made analogously to Example 188 using ethylamine (2.0 M solution in tetrahydrofuran) in place of dimethylamine. Ci7Hi8ClFN60. 377.1 (M+1).
Example 205: V-(3-chloro-4-fluorophenyl)- '-hydroxy-2-(2- (isopropylamino)ethyl)-3Jff-imidazo[4,5-b]pyridine- 7-carboximidamide
Figure imgf000253_0004
[0585] Example 205 was made analogously to Example 188 using isopropylamine in place of dimethylamine. Ci8H2oClFN60. 391.1 (M+1). Example 206: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-(2-(isobutylamino)ethyl)- zo[4,5-b]pyridine-7-carboximidamide
Figure imgf000254_0001
made analogously to Example 188 using isobutylamine in place of dimethylamine. Ci9H22ClFN60. 405. 1 (M+l).
Example 207: A^-(3-chloro-4-fluorophenyl)-2-(2-(cyclopropylamino)ethyl)-A^- hydroxy-3H-imidazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000254_0002
analogously to Example 188 using cyclopropylamine in place of dimethylamine. CI8HI8C1FN60. 389.1 (M+l).
Example 208: A^-(3-chloro-4-fluorophenyl)-2-(2-((cyclopropylmethyl)amino)ethyl)- iV-hydroxy-3H-imidazo [4,5-b] pyridine-7-carboximidamide
Figure imgf000254_0003
[0588] Example 208 was made analogously to Example 188 using
cyclopropylmethanamine in place of dimethylamine. Ci9H2oClFN60. 403. 1 (M+l).
Example 209: 2-(2-(2-amino-4,5-dihydro-lH-imidazol-l-yl)ethyl)-A^-(3-chloro-4- fluorophenyl)-iV-hydroxy-lH-imidazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000254_0004
[0589] Example 209 was made analogously to Example 188 using 4,5-dihydro-lH- imidazol-2-amine in place of dimethylamine. CisHigClFNgO. 417. 1 (M+l). Example 210: iV-(3-chloro-4-fluorophenyl)-4,5-difluoro-iV-hydroxy-2-(2- (methylsulfonamido)ethyl)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000255_0001
[0590] Example 210 was made analogously to Example 112 using 2-(2-aminoethyl)- N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide in place of 4-(3-chloro-4-fluorophenyl)-3-(2-(hydroxymethyl)-lH- imidazo[4,5-b]pyridin-7-yl)-l,2,4-oxadiazol-5(4H)-one. C17H15CIF3N5O3S. 462.3 (M+1).
Example 211: 2-(2-aminoethyl)-iV-(3-chloro-4-fluorophenyl)-4,5-difluoro-iV'- hydroxy-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000255_0002
[0591] 2-(2-aminoethyl)-4,5-difluoro-lH-benzo[d]imidazole-7-carboxylic acid was made analogously to Example 53 using 3-aminopropanoic acid in place of 3- (dimethylamino)propanoic acid. C10H9F2N3O2. 241.1(M+1).
Figure imgf000255_0003
[0592] To a mixture of 2-(2-aminoethyl)-4,5-difluoro-lH-benzo[d]imidazole-7- carboxylic acid (2g, 8.29 mmol) in THF (30mL) and sat. sodium bicarbonate solution 30mL was added di-tertbutyldicarbonate (7.24g, 33mmol). Stirred for 72 h. Acidified with 4N HC1 and brought the pH to ~1. The reaction mixture was extracted with ethyl acetate (50mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to give 2-(2- ((tert-butoxycarbonyl)amino)ethyl)-4,5-difluoro-lH-benzo[d]imidazole-7-carboxylic acid. Ci5Hi7F2N304. 342.1 (M+1).
Figure imgf000256_0001
[0593] tert-butyl (2-(7-((3-chloro-4-fluorophenyl)carbamoyl)-4,5-difluoro-lH- benzo[d]imidazol-2-yl)ethyl)carbamate was made analogously to Example 53 using 2- (2-((tertbutoxycarbonyl)amino)ethyl)-4,5-difluoro-lH-benzo[d]imidazole-7-carboxylic acid in place of 2-(2-(dimethylamino)ethyl)-6,7-difluoro-lHbenzo[d]imidazole-4- carboxylic. 469.12 (M+l). C21H20CIF3N4O3. 469.12 (M+l).
Figure imgf000256_0002
[0594] 2-(2-aminoethyl)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-lH- benzo[d]imidazole-7-carboximidamide was made analogously to Example 53 using tert- butyl (2-(7-((3-chloro-4-fluorophenyl)carbamoyl)-4,5-difluoro-lH-benzo[d]imidazol-2- yl)ethyl)carbamate in place of N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)- 4,5-difluoro-lH-benzo[d]imidazole-7-carboxamide. C16H13CIF3N5O. 384.2 (M+l).
Example 212: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((2-methoxyethyl)amino)- -imidazo 4 5-b ridine-7-carboximidamide
Figure imgf000256_0003
[0595] A 500mL round bottom flask equipped with a stir bar was charged with 2,3- diamino-N-(3-chloro-4-fluorophenyl)isonicotinamide (34g, 121.1 mmol) and 1 ,1 '- carbonyldiimidazole (CDI) (29.5g, 181.7mmol) followed by THF (300mL). The reaction mixture was stirred at room temperature for 16hr. THF 150mL was removed under reduced pressure. Water 250mL was then slowly added to the reaction mixture.
Reaction mixture was then stirred for 1 hour, and precipitate was isolated via vacuum filtration and washed with water (lOOmL x 3). The solid was dried in a vacuum oven at 40 °C overnight to afford a light red solid (34g, 110.8 mmol) and used in the next step without further purification. Ci3H8ClFN402. 307.2 (M+l).
Figure imgf000257_0001
[0596] N-(3-chloro-4-fluorophenyl)-2-oxo-2,3-dihydro-lH-imidazo[4,5-b]pyridine- 7-carboxamide (5.0g, 16.3 mmol) was dissolved in POCI3 (33 eq., 538 mmol, 82.5 mL) and PCI5 (3 eq., 48.9 mmol, 10.19 g) was added. The reaction was sealed in a glass vessel and heated to 100 °C for 16 hours. The reaction was allowed to cool to room temperature and then transferred to a round bottom flask. The POCI3 was removed under reduced pressure and the residue was taken up in 100 mL of p-dioxane. In a separate round bottom flask, NH2OH (50% in water, 92.8 eq, 1.52 mol, 100 mL) was added to 200 mL p-dioxane and cooled to ~3 °C in an ice bath with continuous stirring. The crude imidoyl chloride in p-dioxane mixture was added very slowly to the
hydroxylamine mixture (over -45 mins, dropwise) while maintaining the
hydroxylamine/dioxane solution ~3 °C. Once the addition was complete, the reaction was allowed to slowly come to room temperature and stirred for 20 mins. The reaction was then diluted with EtOAc (500 mL), sat. sodium bicarbonate solution (300 mL), and brine (150 mL) and allowed to stir for an additional 20 mins. The reaction was extracted and the organic layer was washed once with brine (200 mL), dried over Na2SC>4, filtered, and concentrated to dryness to give crude 2-chloro-N-(3-chloro-4-fluorophenyl)-N'- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide which was used in the next step without further purification. Ci3H8Cl2FN50. 340.1 (M+l).
[0597] Crude 2-chloro-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide from previous step (5.5 g, 16.31 mmol assumed 100% yield from starting N-(3-chloro-4-fluorophenyl)-2-oxo-2,3-dihydro-lH-imidazo[4,5- b]pyridine-7-carboxamide) was dissolved in ethyl acetate (80 mL, C=0.2 M) and 1,1 '- carbonyldiimidazole (CDI) (2 eq, 5.3 g, 32.6 mmol) was added. The reaction was allowed to stir at room temperature (capped but under air) for 1 hour until no SM was seen by LCMS. The reaction was then carefully diluted with water (80 mL, some gas evolution seen) and the reaction was allowed to stir for 10 mins before being poured into a separatory funnel (-15 mL of brine added to help break up emulsions) and the organic layer was extracted. The organic layer was washed once more with water (~50mL with -lOmL brine) and the organic layer was then concentrated. The crude was wet loaded on to silica gel and purified by column chromatography (Rf 0.75 in 100% EtOAc, column run 40-100% EtOAc/hex) to give 3-(2-chloro-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3- chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one as a pale yellow solid.
Ci4H6Cl2FN502. 365.9 (M+l).
Figure imgf000258_0001
[0598] 3-(2-chloro-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)- l,2,4-oxadiazol-5(4H)-one (804 mg, 2.2 mmol) was weighed into a round bottom flask which was then evacuated and purged twice with argon. CH2C12 (30.0 mL, C=0.075 M) was added via syringe and the reaction was cooled to 0 °C in an ice bath. Hunig's base (2.5 eq, 5.49 mmol, 0.956 mL) was added followed by SEM-CI (2.3 eq, 5.051 mmol, 0.894 mL) (added dropwise). The reaction was allowed to stir at 0 °C for 20 mins until no starting material was seen by LCMS. The reaction was then poured into DI water (40 mL) in a separatory funnel and then shaken. The organic layer was removed and concentrated under reduced pressure. The crude was wet loaded on to a silica gel column and purified by normal phase column chromatography (20-80% EtOAc/hex, Rf= 0.42 in 40% EtOAc/hex) to give 3-(2-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one as a pale yellow oil which solidified upon standing.
Figure imgf000258_0002
[0599] 3-(2-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin- 7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one (0.015g, 0.03mmol) was dissolved in DMSO (0.5 ml), and 2-methoxyethanamine (4.54mg, 0.060 mmol) was added to the solution. The reaction mixture was heated at 60°C for 2h. The mixture was cooled to rt and partitioned between sat. bicarb solution (1 mL) and EtOAc (2 mL) and the aqueous layer was extracted 1 χ with EtOAc (1 mL). The combined organic layers were washed with sat. bicarb solution (1 mL). Organic layers were then concentrated and taken up in DCM (1.6mL) and trifluoroacetic acid (0.4 mL). The reaction mixture was stirred for lh and concentrated. The residue was brought up in tetrahydrofuran (0.5 mL). To this solution was added 2 N sodium hydroxide solution (0.22 mL, 0.44 mmol) and the reaction mixture stirred for 30 min. To the mixture was added acetic acid (0.10 mL), DMSO (2 mL) and water (2mL), the solution was loaded directly onto a prep HPLC for purification to give the desired product. Ci6Hi6ClFN602.379.1 (M+l). 'H NMR (400
MHz, DMSO-d6) δ 11.72 (s, 1H), 11.43 (s, 1H), 8.95 (s, 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 6.5, 2.7 Hz, 1H), 6.93 (d, J = 6.3 Hz, 1H), 6.60 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 3.61 (t, J = 5.3 Hz, 2H), 3.53 (t, J = 5.1 Hz, 2H), 3.30 (s,
3H).
Example 213: tert-butyl (2-(7-(^-(3-chloro-4-fluorophenyl)-A^- ixycarbamimidoyl)-4,5-difluoro-lH-benzo[d]imidazol-2-yl)ethyl)carbamate
Figure imgf000259_0001
[0600] Example 213 was made analogously to Example 211 using 2-(2-aminoethyl)- N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide in place of 2-(2-aminoethyl)-4,5-difluoro-lH-benzo[d]imidazole-7- carboxylic acid. C21H21CIF3N5O3. 484.4 (M+l). Example 214: A^-(3-chloro-4-fluorophenyl)-2-((2-(4,4-difluoropiperidin-l- yl)ethyl)amino)-A^-hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide
[0601] Example 214 was made analogously to Example 212 using 2-(4,4- difluoropiperidin-l-yl)ethanamine in place of 2-methoxyethanamine. C20H21CIF3N7O. 468.88 (M+l). XH NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 7.96 (d, J = 5.8 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.98 (s, 1H), 6.91 (d, J = 6.0 Hz, 1H), 6.55 (dt, J = 8.9, 3.5 Hz, 1H), 3.33 (m, 8H), 2.33 - 2.18 (m, 4H).
Example 215: A^-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-A^- hydroxy-lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000260_0002
[0602] Example 215 was made analogously to Example 212 using ΝΙ,ΝΙ- dimethylethane-l,2-diamine in place of 2-methoxyethanamine. C17H19CIFN7O. 392.1 (M+l). 'H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 7.94 (s, 1H), 7.08 (t, J = 9.1 Hz, 1H), 6.96 (s, 1H), 6.89 (d, J = 5.9 Hz, 1H), 6.54 (d, J = 8.6 Hz, 1H), 3.73 (s, 2H), 3.31 (s, 2H), 2.85 (s, 6H).
Example 216: A-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((2- (methylamino)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000260_0003
Example 216 was made analogously to Example 212 using tert-butyl (2- aminoethyl)(methyl)carbamate in place of 2-methoxyethanamine. C16H17CIFN7O. 378.1 (M+l). XH NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.57 (s, 2H), 7.95 (d, J = 6.0 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.97 (s, 1H), 6.90 (d, J = 6.2 Hz, 1H), 6.59 - 6.47 (m, 1H), 3.67 (s, 2H), 3.16 (s, 2H), 2.61 (s, 3H).
Example 217: iV-(3-chloro-4-fluorophenyl)-iV-hydroxy-2-((l-methylazepan-3- yl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000261_0001
[0604] Example 217 was made analogously to Example 212 using 1 -methyl azepan- 3-amine in place of 2-methoxyethanamine. C20H23CIFN7O. 432.2 (M+1). l NMR (400 MHz, DMSO-c¾) δ 8.92 (s, 1H), 7.96 (s, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.97 (s, 1H), 6.90 (d, J = 6.1 Hz, 1H), 6.55 (s, 1H), 4.25 (s, 1H), 3.6 - 3.3 (m, 3H), 3.18 (s, 2H), 2.87 (s, 3H), 2.13 - 1.41 (m, 6H).
Example 218: A^(3-chloro-4-fluorophenyl)-2-((2-(l,l- dioxidothiomorpholino)ethyl)amino)-A^-hydroxy-lH-imidazo[4,5-b] pyridine- 7- carboximidamide
Figure imgf000261_0002
[0605] Example 218 was made analogously to Example 212 using 4-(2- aminoethyl)thiomorpholine 1,1 -dioxide in place of 2-methoxyethanamine.
C19H21CIFN7O3S. 482.1 (M+1). ¾ NMR (400 MHz, DMSO-c¾) δ 11.40 (s, 1H), 8.97 (s, 1H), 7.96 (d, J = 6.4 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 6.91 (d, J = 6.2 Hz, 1H), 6.61 - 6.52 (m, 1H), 3.55 (d, J = 5.9 Hz, 2H), 3.12 (s, 5H), 3.06 (s, 5H), 2.81 (s, 2H). Example 219: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((2-((2- methoxyethyl)(methyl)amino)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000262_0001
[0606] Example 219 was made analogously to Example 212 using Nx-(2- methoxyethy^-N^methylethane-l^-diamine in place of 2-methoxyethanamine.
C19H23CIFN7O2. 427.03 (M+1). 'H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.96 (s, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.98 (d, J = 6.4 Hz, 1H), 6.93 (d, J = 6.2 Hz, 1H), 6.55 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 3.78 (s, 2H), 3.64 (t, J = 5.0 Hz, 2H), 3.37 (s, 4H), 3.24 (s, 3H), 2.86 (s, 3H).
Example 220: A^-(3-chloro-4-fluorophenyl)-2-((2-((2,2- difluoroethyl)(methyl)amino)ethyl)amino)-A^-hydroxy-lH-imidazo[4,5-b]pyridine-
7-carboximidamide
Figure imgf000262_0002
[0607] Example 220 was made analogously to Example 212 using Nx-(2,2- difluoroethy^-N^methylethane-l^-diamine in place of 2-methoxyethanamine.
C18H19CIF3N7O. 442.1 (M+1). 'H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.96 (s, 1H), 7.96 (d, J = 6.3 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.01 (dd, J = 6.5, 2.8 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 6.56 (ddd, J = 8.9, 3.9, 2.7 Hz, 1H), 6.25 (t, J = 55.0 Hz, 1H), 3.62 (d, J = 6.5 Hz, 2H), 3.18 (s, 2H), 2.97 (s, 2H), 2.57 (s, 2H).
Example 221: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((3- morpholinopropyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000262_0003
[0608] Example 221 was made analogously to Example 212 using 3- morpholinylpiOpan-1 -amine in place of 2-methoxyethanamine. C20H23CIFN7O2. 448.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 11.38 (s, IH), 8.96 (s, IH), 7.97 (d, J = 6.2 Hz, IH), 7.09 (t, J = 9.0 Hz, IH), 7.01 (dd, J = 6.5, 2.7 Hz, IH), 6.92 (d, J = 6.2 Hz, IH), 6.60 - 6.52 (m, IH), 4.2-3.55 (m, 8H), 3.49 (d, J = 6.5 Hz, 2H), 3.15 (t, J = 8.0 Hz, 2H), 1.98 (d, J = 8.0 Hz, 2H).
Example 222: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((2-(piperidin-l- yl)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000263_0001
[0609] Example 222 was made analogously to Example 212 using 2-(piperidin-l- yl)ethanamine in place of 2-methoxyethanamine. C20H23CIFN7O.432.2 (M+1). 'H NMR (400 MHz, DMSO-d6) δ 8.94 (s, IH), 7.96 (d, J = 6.2 Hz, IH), 7.09 (t, J = 9.1 Hz, IH), 6.98 (d, J = 6.3 Hz, IH), 6.91 (d, J = 6.0 Hz, IH), 6.60 - 6.51 (m, IH), 3.74 (M, 4H), 3.28 (d, J = 7.0 Hz, 2H), 1.73 (s, 5H), 1.54 (s, 3H).
Example 223: A-(3-chloro-4-fluorophenyl)-2-((2-cyclohexylethyl)amino)-A^- - lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000263_0002
[0610] Example 223 was made analogously to Example 212 using 2-(3- fluoropiperidin-l-yl)ethanamine in place of 2-methoxyethanamine. C21H24CIFN6O. 431.2 (M+1). 'H NMR (400 MHz, DMSO-d6) δ 11.37 (s, IH), 8.94 (s, IH), 7.93 (s, 7.08 (t, J = 9.0 Hz, IH), 7.02 (m, IH), 6.90 (s, IH), 6.56 (d, J = 9.0 Hz, IH), 1.68 (m 6H), 1.46 (d, J = 7.7 Hz, 2H), 1.30 (s, IH), 1.16 (m, 3H), 0.90 m, 3H). Example 224: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((2-(tetrahydro-2H- no)- lH-imidazo [4,5-b] pyridine-7-carboximidamide
Figure imgf000264_0001
[0611] Example 224 was made analogously to Example 212 using 2-(tetrahydro-2H- pyran-4-yl)ethanamine in place of 2-methoxyethanamine. C20H22CIFN6O2. 433.2 (M+l). XH NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.95 (s, 1H), 7.94 (d, J = 6.2 Hz, 1H), 7.08 (t, J = 9.1 Hz, 1H), 7.04 - 6.99 (m, 1H), 6.90 (d, J = 6.1 Hz, 1H), 6.60 - 6.51 (m, 1H), 3.82 (dd, J = 11.0, 4.2 Hz, 2H), 3.26 (d, J = 12.0 Hz, 2H), 1.62 - 1.43 (m, 7H), 1.17 (d, J = 12.6 Hz, 2H).
225: iV-(3-chloro-4-fluorophenyl)-2-((2,2-difluoroethyl)amino)- hydroxy- lH-imidazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000264_0002
[0612] Example 225 was made analogously to Example 212 using 2,2- difluoroethanamine in place of 2-methoxyethanamine. C15H12CIF3N6O. 385.1 (M+H)+. XH NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.98 (s, 1H), 7.08 (t, J = 9.0 Hz, 1H), 7.03 (dd, J = 6.5, 2.7 Hz, 1H), 6.93 (d, J = 6.3 Hz, 1H), 6.62 - 6.52 (m, 1H), 6.22 (t, J = 55.3 Hz, 1H), 3.87 (d, J = 16.8 Hz, 2H).
Example 226: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-(oxetan-3-ylamino)- azo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000264_0003
[0613] Example 226 was made analogously to Example 212 using oxetan-3 -amine in place of 2-methoxyethanamine. CI6HI4C1FN602. 377.1 (M+l). lH NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 7.96 (s, 1H), 7.06 (t, J = 9.1 Hz, 1H), 7.01 (d, J = 5.4 Hz, 1H), 6.96 (d, J = 6.5 Hz, IH), 6.54 (ddd, J = 9.0, 4.1, 2.8 Hz, IH), 4.57 (s, IH), 4.32 (t, J = 9.8 Hz, IH), 4.05 (s, IH), 3.58 (s, 2H).
Example 227: iV-(3-chloro-4-fluorophenyl)-iV-hydroxy-2-((tetrahydrofuran-3- yl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000265_0001
[0614] Example 227 was made analogously to Example 212 using tetrahydrofuran-3- amine in place of 2-methoxyethanamine. Ci7Hi6ClFN602. 391.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.40 (s, IH), 8.94 (s, IH), 8.50 (s, IH), 7.96 (d, J = 6.3 Hz, IH), 7.09 (t, J = 9.0 Hz, IH), 7.02 (dd, J = 6.5, 2.7 Hz, IH), 6.92 (d, J = 6.3 Hz, IH), 6.57 (ddd, J = 8.9, 4.0, 2.8 Hz, IH), 4.44 (q, J = 5.8, 3.7 Hz, IH), 3.93 - 3.78 (m, 2H), 3.74 (td, J = 8.4, 5.3 Hz, IH), 3.69 (d, IH), 2.30 - 2.18 (m, IH), 1.90 (dd, J = 14.8, 7.7 Hz, IH).
Example 228: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((tetrahydro-2H-pyran- 4-yl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000265_0002
[0615] Example 228 was made analogously to Example 212 using tetrahydro-2H- pyran-4-amine in place of 2-methoxyethanamine. CisHigClFNeC . 405.1 (M+1). XH NMR (400 MHz, DMSO-d6) δ 11.43 (s, IH), 8.97 (s, IH), 7.97 (d, J = 6.3 Hz, IH), 7.10 (t, J = 9.1 Hz, IH), 7.06 (dd, J = 6.7, 2.9 Hz, IH), 6.94 (d, J = 6.3 Hz, IH), 6.58 (dt, J = 8.9, 3.4 Hz, IH), 4.04 - 3.86 (m, 3H), 3.41 (td, J = 11.7, 2.1 Hz, 2H), 1.87 (d, J = 12.5 Hz, 2H), 1.70 - 1.48 (m, 2H). Example 229: 3-((7-(A-(3-chloro-4-fluorophenyl)-A^-hydroxycarbamimidoyl)-4,5- difluoro-lH-benzo[d]imidazol-2-yl)amino)propanamide)
Figure imgf000266_0001
[0616] A mixture of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one (0.025 g, 0.047 mmol), 3-aminopropanamide hydrochloride (0.023 g, 0.188 mmol) and DIPEA (0.05 mL, 0.282 mmol) in DMSO (0.5 mL) stirred at 60 °C for 16 h. The mixture was cooled to rt, diluted with water, and extracted 3 * with EtOAc. The combined organic layers were washed with brine, dried Na2S04), filtered and concentrated. The resulting residue was brought up in DCM (0.5 mL) and TFA (0.5 mL) and stirred for 16 h. The reaction solution was concentrated. The resulting residue was brought up in THF (0.5 mL) and water (0.5 mL) and sodium hydroxide (0.76 mL of a 2 N solution, 1.5 mmol). The resulting solution was stirred for 10 min, acidified with AcOH (0.10 mL, 1.8 mmol), and purified by preparative HPLC to give the desired product (0.009 g). Ci7Hi4ClF3N602. 427.0 (M+l).
Example 230: A^(3-chloro-4-fluorophenyl)-2-((2-((2,2- difluoroethyl)amino)ethyl)amino)-A^-hydroxy-lH-imidazo[4,5-b] pyridine- 7- carboximidamide
Figure imgf000266_0002
[0617] Example 230 was made analogously to Example 229 using Nx-(2,2- difluoroethyl)ethane-l,2-diamine hydrochloride in place of 3-aminopropanamide hydrochloride. C17H17CIF3N7O. 428.1 (M+l). 'H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 8.91 (s, 1H), 7.95 (d, J = 6.1 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.97 (dd, J = 6.6, 2.7 Hz, 1H), 6.90 (d, J = 6.1 Hz, 1H), 6.56 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 6.53 - 6.21 (m, 1H), 3.8 - 3.3 (m, 5H) 3.26 (t, J = 5.9 Hz, 2H). Example 231: A^-(3-chloro-4-fluorophenyl)-2-((2- (cyclopropyl(methyl)amino)ethyl)amino)-A^-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000267_0001
[0618] Example 231 was made analogously to Example 212 using N^cyclopropyl- N^methylethane-l^-diamine in place of 2-methoxyethanamine. C19H21CIFN7O. 418.2 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 11.27 (s, 1H), 8.92 (s, 1H), 7.95 (d, J = 6.0 Hz, 1H), 7.83 (s, 1H), 7.08 (t, J = 9.1 Hz, 1H), 6.97 (d, J = 6.4 Hz, 1H), 6.91 (d, J = 6.0 Hz, 1H), 6.55 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 3.76 (s, 3H), 2.90 (s, 3H), 1.02 - 0.66 (m, 5H).
Example 232: A^-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(2- methoxyethyl)amino)ethyl)amino)-A^-hydroxy-lH-imidazo[4,5-b] pyridine- 7- carboximidamide
Figure imgf000267_0002
[0619] Example 232 was made analogously to Example 212 using N^cyclopropyl- N1-(2-methoxyethyl)ethane-l,2-diamine in place of 2-methoxyethanamine.
C2iH25ClFN702. 462.2 (M+l). 'H NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 8.93 (s, 1H), 7.96 (d, J = 6.1 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 7.02 - 6.89 (m, 2H), 6.56 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 3.76 (s, 4H), 3.65 (d, J = 5.1 Hz, 1H), 3.37 (s, 4H), 3.26 (s, 3H), 0.79 (s, 4H).
Example 233: 2-((2-(azetidin-l-yl)ethyl)amino)-A^-(3-chloro-4-fluorophenyl)-A^- hydroxy-lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000268_0001
[0620] Example 233 was made analogously to Example 212 using 22-(azetidin-l- yl)ethanamine in place of 2-methoxyethanamine. CI8HI9C1FN70. 404.2 (M+1). 'H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 9.92 (s, 1H), 8.92 (s, 1H), 7.96 (d, J = 6.1 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 6.98 (dd, J = 6.6, 2.7 Hz, 1H), 6.93 (d, J = 6.1 Hz, 1H), 6.55 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 4.10 (d, J = 8.9 Hz, 4H), 3.38 (s, 4H), 2.32 (d, J = 6.7 Hz, 2H).
Example 234: iV-(3-chloro-4-fluorophenyl)-iV-hydroxy-2-((3- methoxypropyl)amino)- lH-imidazo [4,5-b] pyridine-7-carboximidamide
Figure imgf000268_0002
[0621] Example 234 was made analogously to Example 212 using 3-methoxypropan- 1-amine in place of 2-methoxyethanamine. CnHigClFNeC . 427.03 (M+1). l NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 11.39 (s, 1H), 8.95 (s, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 6.59 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 3.49 (q, J = 6.6 Hz, 2H), 3.41 (t, J = 6.0 Hz, 2H), 3.25 (s, 3H), 1.83 (p, J = 6.5 Hz, 2H).
Example 235: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((2-(2-oxopyrrolidin-l- yl)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000268_0003
[0622] Example 235 was made analogously to Example 212 using l-(2- aminoethyl)pyrrolidin-2-one in place of 2-methoxyethanamine. C19H19CIFN7O2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 11.43 (s, 1H), 8.97 (s, 7.98 (d, J = 6.3 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 6.5, 2.8 Hz, 1H), 6.96 (d, J = 6.3 Hz, 1H), 6.58 (ddd, J = 8.9, 4.0, 2.8 Hz, 1H), 3.59 (q, J = 6.0 Hz, 2H), 3.41 (dt, J = 14.1 , 6.5 Hz, 4H), 2.17 (dd, J = 8.7, 7.5 Hz, 2H), 2.01 - 1.73 (m, 2H).
Example 236: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((2- (morpholinosulfonyl)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000269_0001
[0623] Example 236 was made analogously to Example 212 using 2-
Figure imgf000269_0002
in place of 2-methoxyethanamine. C19H21CIFN7O4S. 498.2 (M+1). 'H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.96 (s, 1H), 7.97 (d, J = 6.4 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 6.93 (d, J = 6.4 Hz, 1H), 6.57 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 3.86 (q, J = 6.5 Hz, 2H), 3.68 - 3.58 (m, 4H), 3.43 (t, J = 6.7 Hz, 2H), 3.21 - 3.09 (m, 4H).
Example 237 : iV-(3-chloro-4-fluorophenyl)-2-((2-(3-fluoropiperidin- 1- yl)ethyl)amino)-A^-hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000269_0003
[0624] Example 237 was made analogously to Example 212 using 2-(3- fluoropiperidin-l-yl)ethanamine TFA salt in place of 2-methoxyethanamine.
C20H22CIF2N7O. 450.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.95 (s, 1H), 7.99 (d, J = 6.1 Hz, 1H), 7.1 1 (t, J = 9.1 Hz, 1H), 7.01 (dd, J = 6.5, 2.8 Hz, 1H), 6.94 (d, J = 6.1 Hz, 1H), 6.58 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 5.09 (d, J = 44.9 Hz, 1H), 3.88 - 3.73 (m, 2H), 3.43 (s, 2H), 3.35 (s, 2H), 3.1 1 (s, 2H), 2.03 - 1.66 (m, 4H). Example 238: A^-(3-bromo-4-fluorophenyl)-A^-hydroxy-2-((2- ino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000270_0001
[0625] Example 238 was made analogously to Example 212 using 4-(3-bromo-4- fluorophenyl)-3-(2-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5- b]pyridin-7-yl)-l,2,4-oxadiazol-5(4H)-one and 2-mo holinoethanamine in place of 3- (2-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-7-yl)-4-(3- chloro-4-fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one and 2-methoxyethanamine, respectively. Ci9H2iBrFN702. 478.1 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.92 (s, 1H), 7.97 (d, J = 6.1 Hz, 1H), 7.12 (dd, J = 6.1, 2.7 Hz, 1H), 7.05 (t, J = 8.7 Hz, 1H), 6.92 (d, J = 6.1 Hz, 1H), 6.58 (ddd, J = 8.9, 4.1, 2.7 Hz, 1H), 3.80 (m, 6H), 3.33
(s, 6H).
Example 239: iV-(3-chloro-4-fluorophenyl)-iV-hydroxy-2-((2-(methyl(tetrahydro- 2H-pyran-4-yl)amino)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000270_0002
[0626] Example 239 was made analogously to Example 212 using N^methyl-N1- (tetrahydro-2H-pyran-4-yl)ethane-l,2-diamine in place of 2-methoxyethanamine.
C21H25CIFN7O2. 462.2 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 7.08 (t, J = 9.1 Hz, 1H), 6.95 (s, 1H), 6.90 (d, J = 6.0 Hz, 1H), 6.54 (dt, J = 9.0, 3.4 Hz, 1H), 3.94 (d, J = 11.8 Hz, 2H), 3.31 (d, J = 12.1 Hz, 3H), 2.82 (s, 3H), 1.87 (d, J = 13.4 Hz, 2H), 1.65 (dd, J = 12.0, 4.6 Hz, 2H). Example 240: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((2- (isopropyl(methyl)amino)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000271_0001
[0627] Example 240 was made analogously to Example 212 using N^isopropyl-N1- methylethane-l,2-diamine in place of 2-methoxyethanamine. C19H23CIFN7O. 420.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 11.28 (s, IH), 8.91 (s, IH), 7.95 (d, J = 5.9 Hz, IH), 7.84 (s, IH), 7.08 (t, J = 9.0 Hz, IH), 6.96 (s, IH), 6.90 (d, J = 6.0 Hz, IH), 6.54 (dt, J = 8.8, 3.5 Hz, IH), 3.74 (s, 2H), 3.69 - 3.59 (m, IH), 3.27 (s, 2H), 2.76 (s, 3H), 1.20 (d, J = 6.6 Hz, 6H).
Example 241: 2-(((l-aminocyclopropyl)methyl)amino)-iV-(3-chloro-4- fluorophenyl)-iV-hydroxy-lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000271_0002
[0628] Example 241 was made analogously to Example 212 using tert-butyl (1- (aminomethyl)cyclopropyl)carbamate in place of 2-methoxyethanamine. C17H17CIFN7O. 390.2 (M+1). 'H NMR (400 MHz, DMSO-d6) δ 11.34 (s, IH), 8.92 (s, IH), 8.34 (s, 3H), 7.95 (d, J = 6.1 Hz, IH), 7.09 (t, J = 9.0 Hz, IH), 6.98 (dd, J = 6.5, 2.7 Hz, IH), 6.91 (d, J = 6.2 Hz, IH), 6.56 (ddd, J = 9.0, 4.0, 2.8 Hz, IH), 3.68 (s, 2H), 0.92 (d, J = 5.5 Hz, 4H).
Example 242: 2-((2-(l-aminocyclopropyl)ethyl)amino)-A^-(3-chloro-4- fluorophenyl)-iV-hydroxy-lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000271_0003
[0629] Example 242 was made analogously to Example 212 using tert-butyl (l-(2- aminoethyl)cyclopropyl)carbamate in place of 2-methoxyethanamine. C18H19CIFN7O. 404.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 11.33 (s, IH), 8.93 (s, IH), 8.20 (s, 3H), 7.95 (d, J = 6.2 Hz, IH), 7.08 (t, J = 9.0 Hz, IH), 6.99 (dd, J = 6.5, 2.7 Hz, IH), 6.93 (d, J = 6.1 Hz, IH), 6.61 - 6.50 (m, IH), 3.57 (t, 2H), 1.89 (t, J = 7.0 Hz, 2H), 0.81 (d, J = 6.9 Hz, 2H), 0.69 (d, J = 5.9 Hz, 2H).
Example 243: 2-((2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethyl)amino)-A^-(3- )-iV -hydroxy- lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000272_0001
[0630] tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethyl)carbamate. A mixture of tert-butyl (2-bromoethyl)carbamate (0.500 g, 3.688 mmol), 2-oxa-5- azabicyclo[4.1.0]heptane hydrochloride (0.826 g, 3.688 mmol) and DIPEA (1.285 mL, 7.375 mmol) in DMSO (4 mL) was stirred at 40 °C for 16 h. The mixture was diluted with sat NaHC03 soln. The aqueous layer was extracted 3* with EtOAc. The combined organic layers were washed with brine, dried Na2S04), filtered and concentrated. The residue was purified via silica gel chromatography to give the desired product (0.440 g). Ci2H22N203. 243.1 (M+1).
Figure imgf000272_0002
[0631] 2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethanamine hydrochloride. To a solution of tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethyl)carbamate (0.08 g, 0.33 mmol) in THF was added HC1 (2.0 mL of a 4 M soln in dioxane, 8 mmol). The mixture stirred at rt for 16 h. The mixture was concentrated to give the desired product as the HC1 salt (0.071 g). C7Hi6N20. 143.1 (M+1).
Figure imgf000272_0003
[0632] Example 243 was made analogously to Example 229 using 3-(2-chloro-l (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 2-(2-oxa-5-azabicyclo[4.1.0]heptan-5 yl)ethanamine hydrochloride in place of 3-(2-chloro-4,5-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-
I, 2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively.
C20H21CIFN7O2. 446.2 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 8.96 (s, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.00 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 6.56 (dt, J = 9.0, 3.4 Hz, 1H), 3.80-3.63 (m, 4H), 3.53 (t, J =
I I.5 Hz, 2H), 3.18 (s, 2H), 2.96 - 2.60 (m, 2H), 0.90 (d, J = 149.8 Hz, 2H).
Example 244: 2-((2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethyl)amino)-A^-(3-chloro-4- fluorophenyl)-iV-hydroxy-lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000273_0001
oc
[0633] tert-butyl (2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethyl)carbamate was prepared analogously to Example 243 using 7-oxa-4-azaspiro[2.5]octane hydrochloride in place of 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride. Ci4Hi6N202. 245.1 (M+l).
Figure imgf000273_0002
[0634] 2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethanamine hydrochloride was prepared analogously to Example 243using tert-butyl (2-(7-oxa-4-azaspiro[2.5]octan-4- yl)ethyl)carbamate in place of tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5- yl)ethyl)carbamate. C8Hi6N20. 157.1 (M+l).
Figure imgf000273_0003
[0635] Example 244 was made analogously to Example 229 using 2-(7-oxa-4- azaspiro[2.5]octan-4-yl)ethanamine in place of 3-aminopropanamide hydrochloride. C21H23CIFN7O2. 460.2 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.96 (s, 1H), 7.97 (d, J = 6.1 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.98 (d, J = 6.0 Hz, 1H), 6.93 (d, J = 6.1 Hz, 1H), 6.56 (dt, J = 8.8, 3.7 Hz, 1H), 4.2-3.00 (m, 10H), 1.20 - 0.34 (m, 4H).
Example 245 : (R)-(3-chloro-4-fluorophenyl)-2-((2-(3-fluoropyrrolidin- 1- yl)ethyl)amino)-A^-hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000274_0001
HBoc
[0636] (R)-tert-butyl (2-(3-fluoropyrrolidin-l-yl)ethyl)carbamate was prepared analogously to Example 242 using (R)-3-fluoropyrrolidine hydrochloride in place of 2- oxa-5-azabicyclo[4.1.0]heptane hydrochloride. C11H21FN2O2. 233.2 (M+l).
Figure imgf000274_0002
[0637] (R)-2-(3-fluoropyrrolidin-l-yl)ethanamine hydrochloride was prepared analogously to Example 242 using (R)-tert-butyl (2-(3-fluoropyrrolidin-l- yl)ethyl)carbamate in place of tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5- yl)ethyl)carbamate. C6Hi3FN2. 133.1 (M+l).
Figure imgf000274_0003
[0638] Example 245 was made analogously to Example 229 using (R)-2-(3- fluoropyrrolidin-l-yl)ethanamine hydrochloride in place of 3-aminopropanamide hydrochloride. C19H20CIF2N7O. 436.2(M+1). lH NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.95 (s, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.98 (dd, J = 6.3, 2.7 Hz, 1H), 6.92 (d, J = 6.1 Hz, 1H), 6.55 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 5.48 (d, J = 53.2 Hz, 1H), 3.90 - 3.35 (m, 8H), 2.43 - 2.09 (m, 2H). Example 246: (S)-(3-chloro-4-fluorophenyl)-2-((2-(3-fluoropyrrolidin-l- yl)ethyl)amino)-A^-hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000275_0001
HBoc
[0639] (S)-tert-butyl (2-(3-fluoropyrrolidin-l-yl)ethyl)carbamate was prepared analogously to Example 243 using (S)-3-fluoropyrrolidine hydrochloride in place of 2- oxa-5-azabicyclo[4.1.0]heptane hydrochloride. C11H21FN2O2. 233.2 (M+1).
Figure imgf000275_0002
[0640] (S)-2-(3-fluoropyrrolidin-l-yl)ethanamine hydrochloride was prepared analogously to Example 242 using (S)-tert-butyl (2-(3-fluoropyrrolidin-l- yl)ethyl)carbamate in place of tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5- yl)ethyl)carbamate. C6Hi3FN2. 133.1 (M+1).
Figure imgf000275_0003
[0641] Example 246 was made analogously to Example 229 using (S)-2-(3- fluoropyrrolidin-l-yl)ethanamine hydrochloride in place of 3-aminopropanamide hydrochloride. C19H20CIF2N7O. 436.2 (M+1) 'H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 8.95 (s, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.99 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 6.55 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 5.48 (d, J = 53.1 Hz, 1H), 3.90 - 3.35 (m, 8H), 2.44 - 2.11 (m, 2H). Example 247: 2-((2-(2-azabicyclo[4.1.0]heptan-2-yl)ethyl)amino)-^-(3-chloro-4- phenyl)-iV-hydroxy-lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000276_0001
[0642] tert-butyl (2-(2-azabicyclo[4.1.0]heptan-2-yl)ethyl)carbamate was prepared analogously to Example 243 using (2-azabicyclo[4.1.0]heptane in place of 2-oxa-5- azabicyclo[4.1.0]heptane hydrochloride. C13H24N2O2. 241.3 (M+l).
Figure imgf000276_0002
[0643] 2-(2-azabicyclo[4.1.0]heptan-2-yl)ethanamine hydrochloride was prepared analogously to Example 243 using tert-butyl (2-(2-azabicyclo[4.1.0]heptan-2- yl)ethyl)carbamate in place of tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5- yl)ethyl)carbamate. C8Hi6N2. 141.3 (M+l).
Figure imgf000276_0003
[0644] Example 247 was made analogously to Example 229 using 2-(2- azabicyclo[4.1.0]heptan-2-yl)ethanamine hydrochloride in place of 3- aminopropanamide hydrochloride. C21H23CIFN7O. 444.2 (M+l). XH NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.96 (s, 1H), 8.08 (s, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.99 (dd, J = 6.5, 2.7 Hz, 1H), 6.93 (d, J = 6.2 Hz, 1H), 6.55 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 3.90 - 3.30 (m, 5H), 3.12 (s, 1H), 3.01 (s, 1H), 2.90 (d, J = 19.4 Hz, 1H), 1.98 (d, J = 10.9 Hz, 1H), 1.54 (s, 2H), 1.43 - 1.28 (m, 1H), 1.00 - 0.91 (m, 1H), 0.91 - 0.81 (m, 1H). Example 248: 2-((2-(4-azaspiro[2.5]octan-4-yl)ethyl)amino)-A-(3-chloro-4- phenyl)-/V-hydroxy-lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000277_0001
[0645] Example 248 was prepared analogously to Example 243 using 4- azaspiro[2.5]octane hydrochloride in place of 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride. C14H26N2O2. 255.3 (M+l).
Figure imgf000277_0002
[0646] 2-(4-azaspiro[2.5]octan-4-yl)ethanamine hydrochloride was prepared analogously to Example 243 using tert-butyl (2-(4-azaspiro[2.5]octan-4- yl)ethyl)carbamate in place of tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5- yl)ethyl)carbamate. C9Hi8N2. 155.3 (M+l).
Figure imgf000277_0003
[0647] Example 248 was made analogously to Example 229 using 2-(4- azaspiro[2.5]octan-4-yl)ethanamine hydrochloride in place of 3-aminopropanamide hydrochloride. C22H25CIFN7O. 458.2 (M+l). XH NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.95 (s, 1H), 7.97 (d, J = 6.0 Hz, 1H), 7.78 (s, 1H), 7.08 (t, J = 9.0 Hz, 1H), 6.96 (s, 1H), 6.92 (d, J = 6.0 Hz, 1H), 6.54 (dt, J = 9.0, 3.5 Hz, 1H), 3.8-3.3 (m, 8H), 1.80 (s, 2H), 1.65 (s, 2H), 1.04 (s, 2H), 0.76 (s, 2H).
Example 249: A^-(3-chloro-4-fluorophenyl)-2-((2-(3-fluoroazetidin-l- )ethyl)amino)-A^-hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000277_0004
HBoc [0648] tert-butyl (2-(3-fluoroazetidin-l-yl)ethyl)carbamate was prepared analogously to Example 243 using 3-fluoroazetidine hydrochloride in place of 2-oxa-5- azabicyclo[4.1.0]heptane hydrochloride. C10H26FN2O2. 218.2 (M+l).
Figure imgf000278_0001
[0649] 2-(3-fluoroazetidin-l-yl)ethanamine hydrochloride was prepared analogously to Example 243 using tert-butyl (2-(3-fluoroazetidin-l-yl)ethyl)carbamate in place of tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethyl)carbamate. C9H18N2. 119.1 (M+l).
Figure imgf000278_0002
[0650] Example 249 was made analogously to Example 229 using 2-(3- fluoroazetidin-l-yl)ethanamine hydrochloride in place of 3-aminopropanamide hydrochloride. Ci8Hi8ClF2N70. 422.2 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 11.34 (s, 1H), 8.94 (s, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 6.98 (dd, J = 6.4, 2.7 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 6.55 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 5.45 - 5.30 (m, 1H), 4.52 (dd, J = 20.6, 12.4, 5.9 Hz, 2H), 4.33 (dd, J = 22.1, 12.2 Hz, 2H), 3.63 (s, 2H), 3.48 (s, 2H).
Example 250: A^-(3-chloro-4-fluorophenyl)-2-((2-(3,3-difluoroazetidin-l- yl)ethyl)amino)-A^-hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000278_0003
HBoc [0651] tert-butyl (2-(3,3-difluoroazetidin-l-yl)ethyl)carbamate was prepared analogously to Example 243 using 3,3-difluoroazetidine hydrochloride in place of 2-oxa- 5-azabicyclo[4.1.0]heptane hydrochloride. CioHigFjNjCh. 237.2 (M+1).
Figure imgf000279_0001
[0652] 2-(3,3-difluoroazetidin-l-yl)ethanamine hydrochloride was prepared analogously to Example 243 using tert-butyl (2-(3,3-difluoroazetidin-l - yl)ethyl)carbamate in place of tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5- yl)ethyl)carbamate. C5H10 F2N2. 137.1 (M+1).
Figure imgf000279_0002
[0653] Example 250 was made analogously to Example 229 using 2-(3,3- difluoroazetidin-l-yl)ethanamine hydrochloride in place of 3-aminopropanamide hydrochloride. C18H17CIF3N7O. 440.2 (M+1). XH NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.96 (s, 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.01 (dd, J = 6.5, 2.7 Hz, 1H), 6.93 (d, J = 6.3 Hz, 1H), 6.56 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 4.09 (s, 4H), 3.54 (s, 2H), 3.07 (s, 2H).
Example 251: 2-((2-(4-azaspiro[2.4]heptan-4-yl)ethyl)amino)-A^-(3-chloro-4- fluorophenyl)-iV-hydroxy-lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000279_0003
oc
[0654] tert-butyl (2-(4-azaspiro[2.4]heptan-4-yl)ethyl)carbamate was prepared analogously to Example 244 using 4-azaspiro[2.4]heptane hydrochloride in place of 2- oxa-5-azabicyclo[4.1.0]heptane hydrochloride. C13H24N2O2. 241.2 (M+1).
Figure imgf000280_0001
[0655] 2-(4-azaspiro[2.4]heptan-4-yl)ethanamine hydrochloride was prepared analogously to Example 243 using tert-butyl (2-(4-azaspiro[2.4]heptan-4- yl)ethyl)carbamate in place of tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5- yl)ethyl)carbamate. C8Hi6N2. 141.1 (M+1).
Figure imgf000280_0002
[0656] Example 251 was made analogously to Example 229 using 2-(4- azaspiro[2.4]heptan-4-yl)ethanamine hydrochloride in place of 3-aminopropanamide hydrochloride. C21H23CIFN7O. 444.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.95 (s, 1H), 7.97 (d, J = 6.1 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 6.98 (d, J = 6.4 Hz, 1H), 6.93 (d, J = 6.1 Hz, 1H), 6.55 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 3.65 -3.75 (m, 4H), 3.17 (t, J = 6.0 Hz, 2H), 2.17 - 1.92 (m, 4H), 1.22 (t, 2H), 0.84 (t, 2H).
Example 252: A^-(3-chloro-4-fluorophenyl)-2-((3-(3-fluoropiperidin-l- yl)propyl)amino)-A^-hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000280_0003
[0657] tert-butyl (3-(3-fluoropiperidin-l-yl)propyl)carbamate was prepared analogously to Example 243 using 3-fluoropiperidine hydrochloride in place of 2- azabicyclo[4.1.0]heptane hydrochloride. C13H25FN2O2. 261.2 (M+1).
Figure imgf000280_0004
[0658] 3-(3-fluoropiperidin-l-yl)propan-l-amine hydrochloride was prepared analogously to Example 243 using tert-butyl (3-(3-fluoropiperidin-l-yl)propyl)carbamate in place of tert-butyl (2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethyl)carbamate.
C8Hi7FN2. 161.1 (M+1).
Figure imgf000281_0001
[0659] Example 252 was made analogously to Example 229 using 3-(3- fluoropiperidin-l-yl)propan-l -amine hydrochloride in place of 3-aminopropanamide hydrochloride. C21H24CIF2N7O.464.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 11.38 (s, 1H), 8.96 (s, 1H), 8.22 (d, J = 58.7 Hz, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.01 (dd, J = 6.5, 2.7 Hz, 1H), 6.93 (d, J = 6.2 Hz, 1H), 6.56 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 5.08 (d, J = 45.5 Hz, 1H), 3.47 (d, J = 6.4 Hz, 1H), 3.35 (s, 3H), 3.12 (q, J = 7.4 Hz, 2H), 3.02 (s, 2H), 2.08 - 1.84 (m, 4H), 1.75 (d, J = 14.5 Hz, 2H).
Example 253: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((2- iylamino)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000281_0002
[0660] Example 253 was made analogously to Example 212 using N -phenylethane-
1,2-diamine in place of 2-methoxyethanamine. C21H19CIFN7O. 440.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.96 (s, 1H), 7.95 (d, J = 6.3 Hz, 1H), 7.14 - 7.04 (m, 4H), 7.02 (dd, J = 6.5, 2.8 Hz, 1H), 6.90 (d, J = 6.3 Hz, 1H), 6.65 - 6.50 (m, 4H), 3.62 (d, J = 6.0 Hz, 2H), 3.28 (t, J = 6.3 Hz, 2H). Example 254: iV-(3-chloro-4-fluorophenyl)-iV-hydroxy-2-((2- amino)- IH-imidazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000282_0001
[0661] Example 254 was made analogously to Example 212 using N1 -methyl -N1- phenylethane-l,2-diamine in place of 2-methoxyethanamine. C22H21CIFN7O. 454.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 11.95 (s, IH), 11.42 (s, IH), 8.97 (s, IH), 7.95 (d, J = 6.4 Hz, IH), 7.19 - 7.12 (m, 2H), 7.09 (t, J = 9.0 Hz, IH), 7.03 (dd, J = 6.5, 2.7 Hz, IH), 6.92 (d, J = 6.3 Hz, IH), 6.75 (d, J = 8.1 Hz, 2H), 6.61 (tt, J = 7.3, 1.0 Hz, IH), 6.56 (ddd, J = 9.0, 4.0, 2.8 Hz, IH), 3.64 (M, 4H), 2.89 (s, 3H).
Example 255: iV-(3-chloro-4-fluorophenyl)-2-(((l,l-dioxidotetrahydro-2H- thiopyran-3-yl)methyl)amino)-iV-hydroxy-lH-imidazo [4,5-b] pyridine-7- carboximidamide
Figure imgf000282_0002
[0662] Example 255 was made analogously to Example 212 using 3- (aminomethyl)tetrahydro-2H-thiopyran 1,1 -dioxide in place of 2-methoxyethanamine. Ci9H2oClFN603S. 467.2 (M+1). 'H NMR (400 MHz, DMSO-d6) δ 11.41 (s, IH), 8.96 (s, IH), 7.95 (d, J = 6.3 Hz, IH), 7.09 (t, J = 9.0 Hz, IH), 7.03 (dd, J = 6.5, 2.7 Hz, IH), 6.92 (d, J = 6.3 Hz, IH), 6.57 (ddd, J = 9.0, 4.0, 2.8 Hz, IH), 3.06 (m, 2H), 3.00 - 2.87 (m, IH), 2.31 (m, 2H), 2.06 (dd, J = 10.3, 3.9 Hz, 2H), 1.76 (d, J = 13.6 Hz, 2H), 1.24 (q, J = 12.4 Hz, 2H).
Example 256: iV-(3-chloro-4-fluorophenyl)-2-((2-ethoxycyclopropyl)amino)-iV'- - IH-imidazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000282_0003
[0663] Example 256 was made analogously to Example 212 using 2- methoxycyclopropanamine in place of 2-methoxyethanamine. CigHigClFNeC . 405.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.95 (s, 1H), 7.98 (d, J = 6.3 Hz, 1H), 7.07 (t, J = 9.1 Hz, 1H), 7.02 (d, J = 5.5 Hz, 1H), 6.94 (d, J = 6.2 Hz, 1H), 6.55 (ddd, J = 8.9, 4.0, 2.8 Hz, 1H), 3.67 - 3.51 (m, 2H), 2.88 (s, 1H), 1.13 (t, J = 7.0 Hz, 3H), 1.11 - 1.04 (m, 2H), 0.83 (s, 1H).
Example 257: iV-(3-bromo-4-fluorophenyl)-iV-hydroxy-2-(methylamino)-lH- dazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000283_0001
[0664] Example 257 was made analogously to Example 212 using 4-(3-bromo-4- fluorophenyl)-3-(2-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5- b]pyridin-7-yl)-l,2,4-oxadiazol-5(4H)-one and methylamine (2.0 M solution in tetrahydrofuran) in place of 3-(2-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 2-methoxyethanamine, respectively. Ci4Hi2BrFN60. 379.1 (M+1). l NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 11.38 (s, 1H), 8.95 (s, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.16 (dd, J = 6.1, 2.7 Hz, 1H), 7.04 (t, J = 8.8 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 6.58 (ddd, J = 8.9, 4.1, 2.7 Hz, 1H), 3.00 (d, J = 4.7 Hz, 3H).
Example 258: 2-(2-(azepan-l-yl)ethyl)-A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-lH- imidazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000283_0002
[0665] Example 258 was made analogously to Example 184 using
hexamethyleneimine in place of dimethylamine. C2iH24ClFN60. 431.2 (M+1). l NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.90 (s, 1H), 8.30 (d, J = 5.1 Hz, 1H), 7.16 (d, J = 5.1 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.51 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 3.58 (t, J = 7.5 Hz, 2H), 3.45 - 3.22 (m, 6H), 1.90 - 1.74 (m, 4H), 1.69 - 1.57 (m, 4H).
Example 259: 2-(2-(azetidin-l-yl)ethyl)-A^-(3-chloro-4-fluorophenyl)-A^-hydroxy- lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000284_0001
[0666] Example 259 was made analogously to Example 184 using azetidine hydrochloride and Ν,Ν-diisopropylethylamine in place of dimethylamine.
Ci8H18ClFN60. 389.1 (M+l).
Example 260: (R)-A^-(3-chloro-4-fluorophenyl)-^'-hydroxy-2-(2-(3- hydroxypyrrolidin-l-yl)ethyl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000284_0002
[0667] Example 260 was made analogously to Example 184 using (R)-pyrrolidin-3- ol in place of dimethylamine. Ci9H2oClFN602. 419.1 (M+l).
Example 261: (S)-^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-(2-(3- hydroxypyrrolidin-l-yl)ethyl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000284_0003
[0668] Example 261 was made analogously to Example 184 using (S)-pyrrolidin-3- ol hydrochloride and Ν,Ν-diisopropylethylamine in place of dimethylamine.
Ci9H2oClFN602. 419.1 (M+l). Example 262 : iV-(3-chloro-4-fluorophenyl)-iV-hydroxy-2-(2-(4-hydroxypiperidin- -lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000285_0001
[0669] Example 262 was made analogously to Example 184 using 4- hydroxypiperidine in place of dimethylamine. C20H22CIFN6O2. 433.1 (M+l).
Example 263: iV-(3-bromo-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-iV'- lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000285_0002
[0670] Ethyl 2-(7-((3-bromo-4-fluorophenyl)carbamoyl)-lH-imidazo[4,5-b]pyridin- 2-yl)acetate was made analogously to Example 183 using 2,3-diamino-N-(3-bromo-4- fluorophenyl)isonicotinamide in place of 2,3-diamino-N-(3-chloro-4- fluorophenyl)isonicotinamide. C17H14B1-FN4O3. 421.2, 423.1 (M+l).
Figure imgf000285_0003
[0671] N-(3-bromo-4-fluorophenyl)-2-(2-hydroxyethyl)-lH-imidazo[4,5-b]pyridine- 7-carboxamide was made analogously to Example 184 using ethyl 2-(7-((3-bromo-4- fluorophenyl)carbamoyl)-lH-imidazo[4,5-b]pyridin-2-yl)acetate in place of ethyl 2-(7- ((3-chloro-4-fluorophenyl)carbamoyl)-lH-imidazo[4,5-b]pyridin-2-yl)acetate.
Ci5Hi2BrFN402. 379.0, 381.0 (M+l).
Figure imgf000285_0004
[0672] N-(3-bromo-4-fluorophenyl)-2-(2-(dime lamino)ethyl)-lH-imidazo[4,5- b]pyridine-7-carboxamide was made analogously to Example 184 using N-(3-bromo-4- fluorophenyl)-2-(2-hydroxyethyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-hydroxyethyl)-lH-imidazo[4,5-b]pyridine-7- carboxamide. Ci7Hi7BrFN50. 406.1 , 408.1 (M+1).
Figure imgf000286_0001
[0673] N-(3-bromo-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-N'-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide. Example XX was made analogously to Example 184 using N-(3-bromo-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-lH- imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2- (dimethylamino)ethyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide. Ci7Hi8BrFN60. 421.0, 423.0 (M+1). XH NMR (400 MHz, DMSO-d6) δ 10.99 (s, IH), 8.86 (s, IH), 8.27 (dd, J = 5.0, 0.5 Hz, IH), 7.13 (d, J = 5.1 Hz, IH), 7.07 (dd, J = 6.1, 2.7 Hz, IH), 6.99 (t, J = 8.8 Hz, IH), 6.53 (ddd, J = 9.0, 4.1, 2.8 Hz, IH), 3.38 - 3.18 (m, 4H), 2.69 (s, 6H).
Example 264: iV-(3-chlorophenyl)-2-(2-(dimethylamino)ethyl)-iV -hydroxy- 1H- imidazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000286_0002
[0674] Ethyl 2-(7-((3-chlorophenyl)carbamoyl)-lH-imidazo[4,5-b]pyridin-2- yl)acetate was made analogously to Example 183 using 2,3-diamino-N-(3- chlorophenyl)isonicotinamide in place of 2,3-diamino-N-(3-chloro-4- fluorophenyl)isonicotinamide. C17H15CIN4O3. 359.3 (M+1).
Figure imgf000287_0001
[0675] N-(3-chlorophenyl)-2-(2-hydroxyethyl)-lH-imidazo[4,5-b]pyridine-7- carboxamide was made analogously to Example 184 using ethyl 2-(7-((3- chlorophenyl)carbamoyl)-lH-imidazo[4,5-b]pyridin-2-yl)acetate in place of ethyl 2-(7- ((3-chloro-4-fluorophenyl)carbamoyl)-lH-imidazo[4,5-b]pyridin-2-yl)acetate.
C15H13CIN4O2. 317.1 (M+1).
Figure imgf000287_0002
[0676] N-(3-chlorophenyl)-2-(2-(dimethylamino)ethyl)-lH-imidazo[4,5-b]pyridine- 7-carboxamide was made analogously to Example 184 using N-(3-chl orophenyl)-2-(2- hydroxyethyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4- fluorophenyl)-2-(2-hydroxyethyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide.
CivHigClNsO. 344.3 (M+1).
Figure imgf000287_0003
[0677] N-(3-chlorophenyl)-2-(2-(dimethylamino)ethyl)-N'-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide was made analogously to Example 184 using N-(3- chlorophenyl)-2-(2-(dimethylamino)ethyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-lH-imidazo[4,5- b]pyridine-7-carboxamide. Ci7Hi9ClN60. 359.1 (M+1). 'H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 11.10 (s, 1H), 8.86 (s, 1H), 8.22 (d, J = 5.2 Hz, 1H), 7.08 (d, J = 5.0 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H), 6.83 (t, J = 2.1 Hz, 1H), 6.77 (dd, J = 7.8, 1.9 Hz, 1H), 6.44 (dd, J = 8.1 , 2.1 Hz, 1H), 2.93 (t, J = 7.3 Hz, 2H), 2.61 (t, J = 7.3 Hz, 2H), 2.16 (s, 6H). Example 265: A^-(3-bromophenyl)-2-(2-(dimethylamino)ethyl)-A^-hydroxy-lH- imidazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000288_0001
[0678] Ethyl 2-(7-((3-bromophenyl)carbamoyl)-lH-imidazo[4,5-b]pyridin-2- yl)acetate was made analogously to Example using 2,3-diamino-N-(3- bromophenyl)isonicotinamide in place of 2,3-diamino-N-(3-chloro-4- fluorophenyl)isonicotinamide. Ci7Hi5BrN403. 403.3, 405.2 (M+l).
Figure imgf000288_0002
[0679] N-(3-bromophenyl)-2-(2-hydroxyethyl)-lH-imidazo[4,5-b]pyridine-7- carboxamide was made analogously to Example 184 using ethyl 2-(7-((3- bromophenyl)carbamoyl)-lH-imidazo[4,5-b]pyridin-2-yl)acetate in place of ethyl 2-(7- ((3-chloro-4-fluorophenyl)carbamoyl)-lH-imidazo[4,5-b]pyridin-2-yl)acetate.
Ci5Hi3BrN402. 361.0, 363.0 (M+l).
Figure imgf000288_0003
[0680] N-(3-bromophenyl)-2-(2-(dimethylamino)ethyl)-lH-imidazo[4,5-b]pyridine- 7-carboxamide was made analogously to Example 184 using N-(3-bromophenyl)-2-(2- hydroxyethyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4- fluorophenyl)-2-(2-hydroxyethyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide.
Ci7Hi8BrN50. 388.2, 390.2 (M+l).
Figure imgf000289_0001
[0681] N-(3-bromophenyl)-2-(2-(dimethylamino)ethyl)-N'-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide. Example 266 was made analogously to Example 184 using N-(3-bromophenyl)-2-(2-(dimethylamino)ethyl)-lH-imidazo[4,5-b]pyridine-7- carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-lH- imidazo[4,5-b]pyridine-7-carboxamide. Ci7Hi9BrN60. 403.0, 405.0 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 1 1.05 (s, 1H), 8.85 (s, 1H), 8.23 (dd, J = 5.1 , 0.5 Hz, 1H), 7.09 (d, J = 5.1 Hz, 1H), 7.00 - 6.97 (m, 1H), 6.93 - 6.87 (m, 2H), 6.50 - 6.45 (m, 1H), 2.95 (t, J = 7.3 Hz, 2H), 2.69 - 2.62 (m, 2H), 2.19 (s, 6H).
Example 266: A-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-(2- o[4,5-b] pyridine- 7-carboximidamide
Figure imgf000289_0002
[0682] N-(2-(7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)-l -(methylsulfonyl)-lH-imidazo[4,5-b]pyridin-2-yl)ethyl)-N-(2,4- dimethoxybenzyl)methanesulfonamide. A solution of 4-(3-chloro-4-fluorophenyl)-3-(2- (2-((2,4-dimethoxybenzyl)amino)ethyl)-lH-imidazo[4,5-b]pyridin-7-yl)-l,2,4-oxadiazol- 5(4H)-one (15 mg, 0.029 mmol) and pyridine (0.046 mL, 0.57 mmol) in
dichloromethane (1.0 mL) was cooled in an ice bath with stirring and treated with methanesulfonyl chloride (0.022 mL, 0.29 mmol). The reaction mixture was then allowed to warm to room temperature. After 35 min, another portion of methanesulfonyl chloride (0.022 mL, 0.29 mmol) was added, followed 15 min later by further treatment with pyridine (0.023 mL, 0.29 mmol). After another 15 min, the reaction appeared to have stalled (based on LCMS analysis), with added reagents having no effect, so N,N- diisopropylethylamine (0.10 mL, 0.57 mmol) was added, resulting in complete conversion within 15 min. The reaction mixture was concentrated under reduced pressure, and loaded directly onto a silica gel cartridge for purification by flash chromatography (0-20% methanol/dichloromethane) to afford the desired product (20 mg) C27H26C1FN608S2. 681.0 (M+l).
Figure imgf000290_0001
[0683] N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(methylsulfonamido)ethyl)- lH-imidazo[4,5-b]pyridine-7-carboximidamide. A solution of N-(2-(7-(4-(3-chloro-4- fluorophenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)-l -(methylsulfonyl)-lH- imidazo[4,5-b]pyridin-2-yl)ethyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide (20 mg, 0.029 mmol) and triethylsilane (0.023 mL, 0.15 mmol) in dichloromethane (1 mL) was treated with trifluoroacetic acid (1 mL), and the reaction mixture was stirred overnight at room temperature. The mixture was then concentrated under reduced pressure and taken up in tetrahydrofuran (0.75 mL) and water (0.75 mL), and treated with a 2M aqueous solution of sodium hydroxide (0.75 mL, 1.5 mmol). After 15 min of stirring at room temperature, the reaction mixture was acidified with acetic acid, diluted with dimethyl sulfoxide, and purified by reverse phase preparative HPLC to provide the desired product (7 mg). Ci6H16ClFN603S. 427.0 (M+l).
Example 267: A-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-(2- (sulfamoylamino)ethyl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000290_0002
[0684] A suspension of 4-(3-chloro-4-fluorophenyl)-3-(2-(2-((2,4- dimethoxybenzyl)amino)ethyl)-lH-imidazo[4,5-b]pyridin-7-yl)-l ,2,4-oxadiazol-5(4H)- one (15 mg, 0.029 mmol) and sulfamide (27 mg, 0.29 mmol) in pyridine (1 mL) was stirred at 120 °C for 20 min. The mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was suspended in dichloromethane (0.5 mL) and treated with triethylsilane (0.022 mL, 0.14 mmol) followed by trifluoroacetic acid (0.5 mL). After stirring at room temperature for 1 h, the reaction mixture was concentrated under reduced pressure and taken up in
tetrahydrofuran (0.75 mL) and water (0.75 mL), and treated with a 2M aqueous solution of sodium hydroxide (0.75 mL, 1.5 mmol). After 15 min, another portion of 2M sodium hydroxide (1 mL, 2 mmol) was added, and the reaction was stirred for an additional 15 min. The mixture was then acidified with acetic acid, diluted with dimethyl sulfoxide, and purified by reverse phase preparative HPLC to provide the desired product (7 mg). C15H15CIFN7O3S. 428.0 (M+1).
Example 268: A^-(3-chlorophenyl)-A^-hydroxy-2-(2-(pyrrolidin-l-yl)ethyl)-lH- imidazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000291_0001
[0685] N-(3-chlorophenyl)-2-(2-(pyrrolidin-l -yl)ethyl)-lH-imidazo[4,5-b]pyridine- 7-carboxamide was made analogously to Example 184 using N-(3-chl orophenyl)-2-(2- hydroxyethyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4- fluorophenyl)-2-(2-hydroxyethyl)-lH-inddazo[4,5-b]pyridine-7-carboxamide and pyrrolidine in place of dimethylamine. C19H20CIN5O. 370.1 (M+1).
Figure imgf000291_0002
[0686] N-(3-chlorophenyl)-N'-hydroxy-2-(2-(pyrrolidin-l -yl)ethyl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide was made analogously to Example using N-(3- chlorophenyl)-2-(2-(pyrrolidin-l -yl)ethyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-lH-imidazo[4,5- b]pyridine-7-carboxamide. Ci9H2iClN60. 385.1 (M+1). 'H NMR (400 MHz, DMSO-d6) δ 1 1.08 (s, 1H), 8.90 (s, 1H), 8.26 (dd, J = 5.1 , 0.6 Hz, 1H), 7.11 (d, J = 5.0 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.84 - 6.76 (m, 2H), 6.46 (dd, J = 8.1 , 2.1 Hz, 1H), 3.50 - 2.84 (m, 8H), 1.87 (s, 4H).
Example 269: A^-(3-bromophenyl)-A^-hydroxy-2-(2-(pyrrolidin-l-yl)ethyl)-lH- imidazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000292_0001
[0687] N-(3 -bromophenyl)-2-(2-(py rrolidin- 1 -yl)ethyl)- 1 H-imidazo [4,5 -b]pyridine- 7-carboxamide was made analogously to Example 184 using N-(3-bromophenyl)-2-(2- hydroxyethyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4- fluorophenyl)-2-(2-hydroxyethyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide and pyrrolidine in place of dimethylamine. Ci9H2oBrN50. 414.1, 416.1 (M+l).
Figure imgf000292_0002
[0688] N-(3-bromophenyl)-N'-hydroxy-2-(2-(pyrrolidin-l -yl)ethyl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide. To a suspension of N-(3-bromophenyl)-2-(2-(pyrrolidin- l-yl)ethyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide (54 mg, 0.13 mmol) in 1,2- dichloroethane (1.0 mL) and phosphorus oxy chloride (1.0 mL) was added phosphorus pentachloride (33 mg, 0.16 mmol). The mixture was stirred at 90 °C for 1 h. Another portion of phosphorus pentachloride (33 mg, 0.16 mmol) was then added, and stirring resumed for an additional 45 min at 90 °C. A third portion of phosphorus pentachloride (33 mg, 0.16 mmol) was then added, and stirring resumed for an additional 1 h at 90 °C. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was treated with hydroxylamine (50 wt. % in water, 1.0 mL, 16 mmol) in ethanol (1.0 mL) with vigorous stirring. The mixture was stirred for 15 min, then diluted with saturated aqueous sodium chloride and
dichloromethane/isopropanol (2: 1). The layers were then separated, and the organic phase was concentrated under reduced pressure. The resulting crude residue was suspended in 30% methanol in dichloromethane, filtered to remove salts, and loaded directly onto a silica gel cartridge for purification by flash chromatography (0-50% methanol/dichloromethane). Product-containing fractions were pooled and concentrated under reduced pressure, then taken up in 5% methanol in dichloromethane and filtered through celite to remove silica gel that may have eluted from the column with the material. The filtrate was concentrated under reduced pressure, coevaporated with methanol (3x) to remove residual dichloromethane, dissolved in methanol/water, frozen, and lyophilized to afford the product as an off-white solid (30 mg). Ci9H2iBrN60. 429.1, 431.1 (M+l). ΧΗ ΝΜΚ (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.90 (s, 1H), 8.27 (d, J = 5.1 Hz, 1H), 7.15 - 7.09 (m, 1H), 7.01 - 6.96 (m, 1H), 6.95 - 6.88 (m, 2H), 6.51 - 6.47 (m, 1H), 3.71 - 2.85 (m, 8H), 1.89 (s, 4H).
Example 270: A^-(2-(7-(N-(3-chloro-4-fluorophenyl)-A^-hydroxycarbamimidoyl)-lH- imidazo [4,5-b] pyridin-2-yl)ethyl)acetamide
Figure imgf000293_0001
[0689] A solution of 4-(3-chloro-4-fluorophenyl)-3-(2-(2-((2,4- dimethoxybenzyl)amino)ethyl)-lH-imidazo[4,5-b]pyridin-7-yl)-l,2,4-oxadiazol-5(4H)- one (15 mg, 0.029 mmol) and 4-(dimethylamino)pyridine (1 flake) in dichloromethane (1 mL) was treated with acetic anhydride (0.027 mL, 0.29 mmol) and stirred at room temperature for 10 min. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (0.5 mL) and treated with triethylsilane (0.022 mL, 0.14 mmol) followed by trifluoroacetic acid (0.5 mL). The reaction solution was stirred at room temperature overnight, then concentrated under reduced pressure, taken up in tetrahydrofuran (1 mL) and water (1 mL), and treated with a 2M aqueous solution of sodium hydroxide (1 mL, 2 mmol). After stirring for 15 min, the mixture was acidified with acetic acid, diluted with dimethyl sulfoxide, and purified by reverse phase preparative HPLC to provide the desired product (9 mg).
CI7HI6C1FN602. 391.1 (M+l). Example 271: iV-(3-chlorophenyl)-iV-hydroxy-2-(2-(piperidin-l-yl)ethyl)-lH- -b] pyridine- 7-carboximidamide
Figure imgf000294_0001
[0690] N-(3-chlorophenyl)-2-(2-(piperidin-l-yl)ethyl)-lH-imidazo[4,5-b]pyridine-7- carboxamide was made analogously to Example 184 using N-(3-chloropheny l)-2-(2- hydroxyethyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4- fluorophenyl)-2-(2-hydroxyethyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide and piperidine in place of dimethylamine. C20H22CIN5O. 384.3 (M+1).
Figure imgf000294_0002
[0691] N-(3-chlorophenyl)-N'-hydroxy-2-(2-(piperidin-l-yl)ethyl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide was made analogously to Example 184 using N-(3- chlorophenyl)-2-(2-(piperidin-l -yl)ethyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-lH-imidazo[4,5- b]pyridine-7-carboxamide. C2oH23ClN60. 399.2 (M+1). 'H NMR (400 MHz, DMSO-d6) δ 1 1.08 (s, 1H), 8.91 (s, 1H), 8.27 (dd, J = 5.0, 0.7 Hz, 1H), 7.11 (d, J = 5.0 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.84 - 6.76 (m, 2H), 6.46 (dd, J = 8.2, 2.1 Hz, 1H), 3.67 - 2.70 (m, 8H), 1.73 (s, 4H), 1.53 (s, 2H).
Example 272: iV-(3-bromophenyl)-iV-hydroxy-2-(2-(piperidin-l-yl)ethyl)-lH- -b] pyridine- 7-carboximidamide
Figure imgf000294_0003
[0692] N-(3-bromophenyl)-2-(2-(piperidin-l -yl)ethyl)-lH-imidazo[4,5-b]pyridine-7- carboxamide was made analogously to Example 184 using N-(3-bromophenyl)-2-(2- hydroxyethyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4- fluorophenyl)-2-(2-hydroxyethyl)-lH-iniidazo[4,5-b]pyridine-7-carboxamide and piperidine in place of dimethylamine. C20H22B1-N5C). 428.3, 430.3 (M+l).
Figure imgf000295_0001
[0693] N-(3-bromophenyl)-N'-hydroxy-2-(2-(piperidin-l-yl)ethyl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide was made analogously to Example 184 using N-(3- bromophenyl)-2-(2-(piperidin-l-yl)ethyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-lH-imidazo[4,5- b]pyridine-7-carboxamide. C2oH23BrN60. 443.1, 445.1 (M+l). XH NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.90 (s, 1H), 8.27 (dd, J = 5.1, 0.8 Hz, 1H), 7.12 (d, J = 4.5 Hz, 1H), 6.98 - 6.96 (m, 1H), 6.95 - 6.89 (m, 2H), 6.52 - 6.47 (m, 1H), 3.63 - 2.72 (m, 8H), 1.88 - 1.35 (m, 6H).
Example 273: Methyl (2-(7-(iV-(3-chloro-4-fluorophenyl)-iV'- imidazo[4,5-b]pyridin-2-yl)ethyl)carbamate
Figure imgf000295_0002
[0694] A solution of 4-(3-chloro-4-fluorophenyl)-3-(2-(2-((2,4- dimethoxybenzyl)amino)ethyl)-lH-imidazo[4,5-b]pyridin-7-yl)-l,2,4-oxadiazol-5(4H)- one (30 mg, 0.057 mmol) and N,N-diisopropylethylamine (0.20 mL, 1.2 mmol) in dichloromethane (1 mL) was treated with methyl chloroformate (0.044 mL, 0.57 mmol) dropwise and with stirring. After 1 h, another portion of methyl chloroformate (0.044 mL, 0.57 mmol) was added, and the reaction mixture was stirred for an additional 5 min. The mixture was the concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (0.5 mL) and treated with triethylsilane (0.046 mL, 0.29 mmol) followed by trifluoroacetic acid (0.5 mL). The reaction solution was stirred at room temperature overnight, then concentrated under reduced pressure, taken up in tetrahydrofuran (0.75 mL) and water (0.75 mL), and treated with a 2M aqueous solution of sodium hydroxide (1.5 mL, 3 mmol). After stirring for 5 min, the mixture was acidified with acetic acid, diluted with dimethyl sulfoxide, and purified by reverse phase preparative HPLC to provide the desired product. CI7HI6C1FN603. 407. 1 (M+l).
Example 274: A^-(3-chloro-4-fluorophenyl)-2-(2-((2,4- dimethoxybenzyl)amino)ethyl)-A^-hydroxy-lH-imidazo[4,5-b]pyridine-7- idamide
Figure imgf000296_0001
[0695] 4-(3-chloro-4-fluorophenyl)-3-(2-(2-((2,4-dimethoxybenzyl)amino)ethyl)-lH- imidazo[4,5-b]pyridin-7-yl)-l,2,4-oxadiazol-5(4H)-one. A solution of 2-(7-(4-(3-chloro- 4-fluorophenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)-l-(methylsulfonyl)-3H- imidazo[4,5-b]pyridin-2-yl)ethyl methanesulfonate (60 mg, 0. 1 1 mmol) in acetonitrile (2.2 mL) was treated with 2,4-dimethoxybenzylamine (0.34 mL, 2.2 mmol). The resulting solution was stirred for 2.5 h at room temperature. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was taken up in dichloromethane (1 mL) and treated with trifluoroacetic acid (1 mL). The solution was stirred overnight at room temperature, then concentrated under reduced pressure. The crude material was dissolved in dichloromethane and washed with saturated aqueous potassium carbonate. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were loaded onto a silica gel cartridge for purification by flash chromatography (0-20% methanol/dichloromethane) to provide the desired product. C25H22C1FN604. 525.2 (M+l).
Figure imgf000297_0001
[0696] N-(3-chloro-4-fluorophenyl)-2-(2-((2,4-dimethoxybenzyl)amino)ethyl)-N'- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide was made analogously to Example 177 using 4-(3-chloro-4-fluoropheny l)-3-(2-(2-((2,4- dimethoxybenzyl)amino)ethyl)-lH-imidazo[4,5-b]295yridine-7-yl)-l,2,4-oxadiazol- 5(4H)-one in place of 4-(3-chloro-4-fluorophenyl)-3-(2-(hydroxymethyl)-lH- imidazo[4,5-b]295yridine-7-yl)-l,2,4-oxadiazol-5(4H)-one. C24H24C1FN603. 499.2
(M+1).
Example 275: 2-(2-(4-benzylpiperidin-l-yl)ethyl)-A^-(3-chloro-4-fluorophenyl)-A^- hydroxy- lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000297_0002
[0697] Example 275 was made analogously to Example 184 using 4- benzylpiperidine in place of dimethylamine. C27H28C1FN60. 507.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) 5 11.08 (s, 1H), 8.91 (s, 1H), 8.29 (d, J = 5.1 Hz, 1H), 7.34 - 7.25 (m, 2H), 7.24 - 7.12 (m, 4H), 7.03 (t, J = 9.1 Hz, 1H), 6.92 (dd, J = 6.4, 2.7 Hz, 1H), 6.55 - 6.46 (m, 1H), 3.51 (s, 4H), 3.29 (t, J = 7.4 Hz, 2H), 2.96 (s, 2H), 2.62 - 2.48 (m, 2H), 1.78 (d, J = 14.5 Hz, 3H), 1.41 (s, 2H).
Example 276: 2-(2-(3-azabicyclo [3.3.1] nonan-3-yl)ethyl)-iV-(3-chloro-4- fluorophenyl)-iV-hydroxy-lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000297_0003
[0698] Example 276 was made analogously to Example 184 using 3- azabicyclo[3.3. l]nonane hydrochloride and Ν,Ν-diisopropylethylamine in place of dimethylamine. C23H26C1FN60. 457.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 11.07 (s, IH), 8.93 (s, IH), 8.32 (dd, J = 5.0, 3.2 Hz, IH), 7.14 (dd, J = 5.0, 3.0 Hz, IH), 7.05 (td, J = 9.1, 3.0 Hz, IH), 6.93 - 6.88 (m, IH), 6.50 (ddd, J = 8.7, 6.2, 2.6 Hz, IH), 3.69 (d, J = 12.4 Hz, 2H), 3.54 - 3.47 (m, 2H), 3.41 - 3.34 (m, 2H), 3.25 (d, J = 12.3 Hz, 2H), 2.14 (s, 3H), 1.89 - 1.57 (m, 7H).
Example 277 : 2-(2-(3-azabicyclo [3.2.1] octan-3-yl)ethyl)-iV-(3-chloro-4- imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000298_0001
[0699] Example 277 was made analogously to Example 184 using 3- azabicyclo[3.2. l]octane hydrochloride and Ν,Ν-diisopropylethylamine in place of dimethylamine. C22H24C1FN60. 443.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 11.07 (s, IH), 8.92 (s, IH), 8.31 (d, J = 5.1 Hz, IH), 7.15 (d, J = 5.1 Hz, IH), 7.05 (t, J = 9.0 Hz, IH), 6.92 (dd, J = 6.5, 2.6 Hz, IH), 6.53 - 6.46 (m, IH), 3.50 (t, J = 6.9 Hz, 2H), 3.42 (d, J = 11.7 Hz, 2H), 3.30 (t, J = 7.2 Hz, 2H), 3.08 (d, J = 11.6 Hz, 2H), 2.40 (s, 2H), 1.80 (s, 4H), 1.70 (d, J = 11.2 Hz, IH), 1.49 (d, J = 10.0 Hz, IH).
Example 278: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((l-methylpiperidin-3- -lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000298_0002
[0700] Example 278 was made analogously to Example 212 using 1- methylpiperidin-3-amine in place of 2-methoxyethanamine. C19H21CIFN7O. 418.2 (M+1). 'H NMR (400 MHz, DMSO-d6) δ 11.36 (s, IH), 9.79 (s, IH), 8.95 (s, IH), 7.98 (d, J = 5.1 Hz, 1H), 7.10 (t, J = 9.1 Hz, 1H), 7.05 - 6.90 (m, 2H), 6.61 - 6.55 (m, 1H), 4.18 - 4.01 (m, 1H), 2.97 - 2.72 (m, 6H), 2.1 1 - 1.62 (m, 4H), 1.57 - 1.41 (m, 1H).
Examples 279 and 280: (S)-^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((2-(3- hydroxypyrrolidin-l-yl)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7- carboximidamide and (S)-A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-(3- hydroxypyrrolidin- 1-yl)- lH-imidazo [4,5-b] pyridine-7-carboximidamide
Figure imgf000299_0001
[0701] A solution of 3-(2-chloro-l -((2-(trimethylsilyl)ethoxy)methyl)-lH- imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one (25 mg, 0.050 mmol) in DMSO (0.5 mL) was treated with (S)-l -(2-aminoethyl)pyrrolidin-3- ol (13 mg, 0.10 mmol). The solution was stirred at 60 °C overnight, then cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium chloride (3 x). The organic layer was dried over sodium sulfate, filtered, and
concentrated under reduced pressure. The resulting residue was dissolved in
dichloromethane (0.5 mL) and treated with trifluoroacetic acid (0.5 mL). The solution was stirred at room temperature for 1 h, then concentrated under reduced pressure, taken up in tetrahydrofuran (0.5 mL) and water (0.5 mL) and treated with 2M aqueous sodium hydroxide (0.99 mL, 2.0 mmol). After stirring for 10 min, the mixture was acidified with acetic acid, diluted with dimethyl sulfoxide, and purified by reverse phase preparative HPLC to provide (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(3- hydroxypyrrolidin-l -yl)ethyl)ariiino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide (10 mg) and (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(3-hydroxypyrrolidin-l-yl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide (4 mg).
Figure imgf000300_0001
[0702] (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(3-hydroxypyrrolidin-l- yl)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide. C19H21CIFN7O2. 434.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 11.40 (s, IH), 8.99 (s, IH), 7.99 (d, J = 6.2 Hz, IH), 7.15 - 7.07 (m, IH), 7.04 - 6.98 (m, IH), 6.98 - 6.93 (m, IH), 6.61 - 6.54 (m, IH), 4.45 (s, IH), 4.16 - 2.91 (m, 8H), 2.14 (s, IH), 1.94 - 1.82 (m, IH).
Figure imgf000300_0002
[0703] (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(3-hydroxypyrrolidin-l-yl)- lH-imidazo[4,5-b]pyridine-7-carboximidamide. Ci7Hi6ClFN602. 391.1 (M+i). 'H NMR (400 MHz, DMSO-c/g) δ 11.38 (s, IH), 9.03 (s, IH), 8.02 - 7.94 (m, IH), 7.11 - 7.03 (m, 2H), 6.91 (d, J= 6.0 Hz, IH), 6.60 - 6.53 (m, IH), 4.46 (s, IH), 3.79 - 3.50 (m, 4H), 2.14 - 2.02 (m, IH), 1.98 (s, IH).
Example 281: iV-(3-chloro-4-fluorophenyl)-iV-hydroxy-2-((l-(2- methoxyethyl)pyrrolidin-3-yl)amino)- lH-imidazo [4,5-b] pyridine-7- carboximidamide
Figure imgf000300_0003
[0704] Example 281 was made analogously to Example 212 using l-(2- methoxyethyl)pyrrolidin-3-amine in place of 2-methoxyethanamine. C20H23CIFN7O2. 448.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 11.32 (s, IH), 9.98 (s, IH), 8.95 (s, IH), 7.99 (d, J = 4.3 Hz, IH), 7.09 (t, J = 9.1 Hz, IH), 7.04 - 6.92 (d, J = 17.3 Hz, 3H), 6.57 (ddd, J = 8.3, 5.8, 2.4 Hz, IH), 4.70 - 4.49 (m, 2H), 4.00 - 3.09 (m, 10H), 2.08 (s, IH), 1.97 (s, IH).
Example 282: A/-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-(((4-methylmorpholin-3- yl)methyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000301_0001
[0705] Example 282 was made analogously to Example 212 using (4- methylmo holin-3-yl)methanamine in place of 2-methoxyethanamine. C19H21CIFN7O2. 434.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 11.40 (s, IH), 8.97 (s, IH), 7.99 (d, J = 6.3 Hz, IH), 7.10 (t, J = 9.0 Hz, IH), 7.01 (dd, J = 6.6, 2.6 Hz, IH), 6.96 (d, J = 6.2 Hz, IH), 6.57 (ddd, J = 9.0, 4.0, 2.7 Hz, IH), 4.12 - 3.75 (m, 6H), 3.28 - 3.14 (m, 3H), 3.01 (s, 3H).
Example 283: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((2-(pyrrolidin-l- yl)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000301_0002
[0706] Example 283 was made analogously to Example 212 using 2-(pyrrolidin-l- yl)ethan-l -amine in place of 2-methoxyethanamine. C19H21CIFN7O. 418.2 (M+1). XH NMR (400 MHz, DMSO-d6) δ 11.35 (s, IH), 8.97 (s, IH), 7.98 (d, J = 6.2 Hz, IH), 7.10 (t, J = 9.0 Hz, IH), 7.03 - 6.98 (m, IH), 6.94 (d, J = 6.1 Hz, IH), 6.57 (ddd, J = 9.1, 4.1, 2.8 Hz, IH), 3.82 - 3.35 (m, 8H), 1.94 (s, 4H). Example 284: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-(((4- sulfonyl)methyl)tetrahydro-2H-pyran-4-yl)methyl)amino)-lH-imidazo[4,5 b] pyridine- 7-carboximidamide
Figure imgf000302_0001
[0707] Example 284 was prepared analogously to Example 333 using 3-(2-chloro-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one, 2H-pyran-4-methanamine, tetrahydro-4- [(methylsulfonyl)methyl]- hydrochloride, and N,N-diisopropylethylamine in place of 3- (2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)- 4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and tert-butyl (2- aminoethyl)carbamate (bis-TFA salt, white solid). C2iH24ClFN604S. 511.4 (M+l). l NMR (400 MHz, DMSO- ) δ 11.45 (s, 1H), 8.96 (s, 1H), 7.95 (d, J = 6.4 Hz, 1H), 7.12 (t, J= 9.0 Hz, 1H), 7.04 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.4 Hz, 1H), 6.60 (ddd, J = 8.9, 4.0, 2.8 Hz, 1H), 3.85 (d, J = 6.6 Hz, 4H), 3.81 - 3.45 (m, 4H), 3.10 (s, 3H), 1.77 - 1.65 (m, 2H), 1.61 (dd, J = 8.5, 4.6 Hz, 2H). 19F NMR (377 MHz, DMSO-c¾) δ -74.67 (6F), -126.62 (IF).
Example 285: A-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((2- (methylsulfonyl)benzyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000302_0002
[0708] Example 285 was prepared analogously to Example 333 using 3-(2-chloro-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one, (2-methylsulfonylphenyl)methanamine hydrochloride, and N,N-diisopropylethylamine in place of 3-(2-chloro-4,5-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)- l,2,4-oxadiazol-5(4H)-one and fert-butyl (2-aminoethyl)carbamate (bis-TFA salt, white solid). C2IHI8C1FN603S. 489.4 (M+l). ¾ NMR (400 MHz, OMSO-d6) δ 11.88 (br s, 1H), 11.43 (s, 1H), 8.95 (s, 1H), 8.31 (br s, 1H), 8.03 - 7.91 (m, 2H), 7.75 - 7.67 (m, 1H), 7.66 - 7.56 (m, 2H), 7.09 (t, J = 9.0 Hz, 1H), 7.03 (d, J = 6.3 Hz, 1H), 6.93 (d, J = 6.3 Hz, 1H), 6.59 (dt, J = 8.9, 3.5 Hz, 1H), 5.06 (d, J = 6.2 Hz, 2H), 3.39 (s, 3H). 19F NMR (376 MHz, DMSO-c¾) δ -74.4 (6F), -126.6 (IF).
Example 286: 2-((l-acetylpiperidin-3-yl)amino)-A-(3-chloro-4-fluorophenyl)-A^- hydroxy-lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000303_0001
[0709] Example 286 was prepared analogously to Example 333 using 3-(2-chloro-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and l-(3-aminopiperidin-l-yl)ethanone in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7- yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and fert-butyl (2- aminoethyl)carbamate, respectively (bis-TFA salt, off-white solid). C20H21CIFN7O2. 446.4 (M+l). ¾ NMR (400 MHz, OMSO-d6) δ 11.46 (s, 1H), 8.98 (s, 1H), 8.17 (br s, 1H), 7.98 (t, J = 6.6 Hz, 1H), 7.11 (td, J = 9.0, 4.1 Hz, 1H), 7.04 (td, J = 6.7, 2.6 Hz, 1H), 6.92 (dd, J = 8.6, 6.3 Hz, 1H), 6.66 - 6.51 (m, 1H), 4.06 - 3.70 (m, 3H), 3.30 - 3.20 (m, 3H), 2.01 (d, J = 27.2 Hz, 3H), 1.98 - 1.95 (m, 1H) 1.80 - 1.60 (m, 2H), 1.59 - 1.41 (m, 1H). 19F NMR (376 MHz, OMSO-d6) δ -74.53 (6F), -126.59 (IF).
Example 287: iV-(3-chloro-4-fluorophenyl)-2-((ethylamino)methyl)-4-fluoro-iV'- roxy- lH-benzo[d]imidazole- 7-carboximidamide
Figure imgf000303_0002
[0710] Methyl 4-fluoro-2-(methoxymethyl)-lH-benzo[d]imidazole-7-carboxylate was prepared analogously to Example 45, using methyl 2,3-diamino-4-fluorobenzoate in place of methyl 2,3-diamino-4,5-difluorobenzoate. C11H11FN2O3. 239.0 (M+l).
Figure imgf000304_0001
[0711] N-(3-chloro-4-fluorophenyl)-4-fluoro-2-(methoxymethyl)-lH- benzo[d]imidazole-7-carboxamide was prepared analogously to Example 45, using methyl 4-fluoro-2-(methoxymethyl)-lH-benzo[d]imidazole-7-carboxylate in place of methyl 4,5-difluoro-2-(methoxymethyl)-lH-benzo[d]imidazole-7-carboxylate.
Ci6Hi2ClF2N302. 352.0 (M+l).
Figure imgf000304_0002
[0712] 4-(3-chloro-4-fluorophenyl)-3-(4-fluoro-2-(methoxymethyl)-lH- benzo[d]imidazol-7-yl)-l,2,4-oxadiazol-5(4H)-one was prepared analogously to
Example 45, using N-(3-chloro-4-fluorophenyl)-4-fluoro-2-(methoxymethyl)-lH- benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-4,5-difluoro- 2-(methoxymethyl)-lH-benzo[d]imidazole-7-carboxamide. C17H11CIF2N4O3. 393.0 (M+l).
Figure imgf000304_0003
[0713] 3-(2-(bromomethyl)-4-fluoro- 1 H-benzo [d] imidazol-7-yl)-4-(3 -chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one was prepared analogously to Example 45, using 4-(3-chloro-4-fluorophenyl)-3-(4-fluoro-2-(methoxymethyl)-lH-benzo[d]imidazol- 7-yl)-l,2,4-oxadiazol-5(4H)-one in place of 4-(3-chloro-4-fluorophenyl)-3-(4,5-difluoro- 2-(methoxymethyl)-lH-benzo[d]imidazol-7-yl)-l,2,4-oxadiazol-5(4H)-one.
Ci6H8BrClF2N402. 440.9/442.9 (M+l).
Figure imgf000305_0001
[0714] N-(3-chloro-4-fluorophenyl)-2-((ethylamino)methyl)-4-fluoro-N'-hydroxy- lH-benzo[d]imidazole-7-carboximidamide. Example 287 was prepared analogously to Example 45 using 3-(2-(bromomethyl)-4-fluoro-lH-benzo[d]imidazol-7-yl)-4-(3-chloro- 4-fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one and ethylamine (2 M in THF) in place of 3- (2-(bromomethyl)-4,5-difluoro-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)- l,2,4-oxadiazol-5(4H)-one and 3 -methoxy propyl amine, respectively. Ci7Hi6ClF2N50. 360.1 (M+l).
Example 288 : /V-(3-chloro-4-fluorophenyl)-2-((dimethylamino)methyl)-4-fluoro-iV- hydroxy-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000305_0002
[0715] Example 288 was prepared analogously to Example 45 using 3-(2- (bromomethyl)-4-fluoro-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l ,2,4- oxadiazol-5(4H)-one and dimethylamine (2 M in THF) in place of 3-(2-(bromomethyl)- 4,5-difluoro-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol- 5(4H)-one and 3-methoxypropylamine, respectively. Ci7Hi6ClF2N50. 380.0 (M+l). Example 289: A^-(3-chloro-4-fluorophenyl)-4-fluoro-A^-hydroxy-2- l)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000306_0001
[0716] Example 289 was prepared analogously to Example 45 using 3-(2- (bromomethyl)-4-fluoro-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4- oxadiazol-5(4H)-one and isopropylamine in place of 3-(2-(bromomethyl)-4,5-difluoro- lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3-methoxypropylamine, respectively. Ci8Hi8ClF2N50. 394.1 (M+l).
Example 290: A^-(3-chloro-4-fluorophenyl)-4-fluoro-A^-hydroxy-2- ((methylamino)methyl)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000306_0002
[0717] Example 290 was prepared analogously to Example 45 using 3-(2- (bromomethyl)-4-fluoro-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4- oxadiazol-5(4H)-one and methylamine (2 M in THF) in place of 3-(2-(bromomethyl)- 4,5-difluoro-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol- 5(4H)-one and 3-methoxypropylamine, respectively. Ci6Hi4ClF2N50. 366.0 (M+l).
Example 291: 2-(aminomethyl)-A^-(3-chloro-4-fluorophenyl)-4-fluoro-A^-hydroxy- lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000306_0003
[0718] Example 291 was prepared analogously to Example 45 using 3-(2- (bromomethyl)-4-fluoro-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4- oxadiazol-5(4H)-one and ammonia (0.5 M in dioxane) in place of 3-(2-(bromomethyl)- 4,5-difluoro-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol- 5(4H)-one and 3-methoxypropylamine, respectively. C15H12CIF2N5O. 352.0 (M+l).
Example 292: iV-(3-chloro-4-fluorophenyl)-4,5-difluoro-iV-hydroxy-2-((2-hydroxy- 2-methylpropyl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000307_0001
[0719] Example 292 was prepared analogously to Example 333 using l-amino-2- methylpropan-2-ol in place of fert-butyl (2-aminoethyl)carbamate. C18H17CIF3N5O2. 428.1 (M+l).
Example 293 : A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-((2- hydroxypropyl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000307_0002
[0720] Example 293 was prepared analogously to Example 333 using 1- aminopropan-2-ol in place of fert-butyl (2-aminoethyl)carbamate. C17H15CIF3N5O2. 414.1 (M+l).
Example 294: 2-((7-(iV-(3-chloro-4-fluorophenyl)-iV-hydroxycarbamimidoyl)-4,5- difluoro-lH-benzo[d]imidazol-2-yl)amino)acetamide
Figure imgf000307_0003
[0721] Example 294 was prepared analogously to Example 333 using 2- aminoacetamide in place of fert-butyl (2-aminoethyl)carbamate. Ci6Hi2ClF3N602. 413.3 (M+l).
Example 295 : A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-((2- -lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000308_0001
[0722] Example 295 was prepared analogously to Example 333 using 2-aminoethan- l-ol in place of teri-butyl (2-aminoethyl)carbamate. C16H13CIF3N5O2. 400.1 (M+l).
Example 296 : A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-((3- no)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000308_0002
[0723] Example 296 was prepared analogously to Example 333 using 3- aminocyclobutanol in place of fert-butyl (2-aminoethyl)carbamate. C18H15CIF3N5O2. 426.3 (M+l).
Example 297 : A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-((3-(pyridin- -ylamino)propyl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000308_0003
[0724] Example 297 was prepared analogously to Example 333 using N-(3- aminopropyl)pyridine-2-amine in place of tert-butyl (2-aminoethyl)carbamate.
C22H19CIF3N7O. 490.3 (M+l).
Example 298: 7Y-(3-chloro-4-fluorophenyl)-4,5-difluoro-iV-hydroxy-2-((2- benzo[d]imidazole-7-carboximidamide
Figure imgf000309_0001
[0725] Example 298 was prepared analogously to Example 333 using 2- aminoethanesulfonamide in place of tert-butyl (2-aminoethyl)carbamate.
Ci6Hi4ClF3N603S. 463.1 (M+l).
Example 299: A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-(((l-methyl- -pyrazol-5-yl)methyl)amino)- IH-benzo [d] imidazole-7-carboximidamide
Figure imgf000309_0002
[0726] Example 299 was prepared analogously to Example 333 using (1-methyl-lH- pyrazol-5-yl)methanamine in place of tert-butyl (2-aminoethyl)carbamate.
C19H15CIF3N7O. 450.1 (M+l).
Example 300 : 2-((2-(lH-pyrazol- l-yl)ethyl)amino)-A^-(3-chloro-4-fluorophenyl)-4,5- -Λ^ -hydroxy- lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000309_0003
[0727] Example 300 was prepared analogously to Example 333 using 2-(lH-pyrazol- l-yl)ethan-l -amine in place of tert-butyl (2-aminoethyl)carbamate. C19H15CIF3N7O. 450.1 (M+l).
Example 301: 2-((7-(A-(3-chloro-4-fluorophenyl)-A^-hydroxycarbamimidoyl)-4,5- -lH-benzo[d]imidazol-2-yl)amino)-A V-dimethylacetamide
Figure imgf000310_0001
[0728] Example 301 was prepared analogously to Example 333 using glycine dimethylamide in place of tert-butyl (2-aminoethyl)carbamate. Ci8Hi6ClF3N602. 441.1 (M+l).
Example 302: iV-(3-chloro-4-fluorophenyl)-4,5-difluoro-iV-hydroxy-2-(2-hydroxy-2- opyl)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000310_0002
[0729] 4,5-difluoro-2-(2-hydroxy-2-methylpropyl)-lH-benzo[d]imidazole-7- carboxylic acid. A mixture of 3-hydroxy-3-methylbutyric acid (1.6 mL, 15.1 mmol) and methyl 2,3-diamino-4,5-difluorobenzoate (1.529 g, 7.56 mmol) in HCl (7.5 mL of a 6 M aqueous soln) stirred at 120 °C in a sealed tube for 16 h. The mixture was cooled to rt and concentrated to remove HCl. The remaining solution was frozen and lyophilized to give the crude desired product. C12H12F2N2O3. 271.1 (M+l).
Figure imgf000310_0003
[0730] N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(2-hydroxy-2-methylpropyl)-lH- benzo[d]imidazole-7-carboxamide was prepared analogously to Example 80 using 4,5- difluoro-2-(2-hydroxy-2-methylpropyl)-lH-benzo[d]imidazole-7-carboxylic acid and 3- chloro-4-fluoroaniline in place of lHimidazo[4,5-Z>]pyridine-7-carboxylic acid and 3- bromoaniline, respectively. C18H15CIF3N3O2. 420.1 (M+23).
Figure imgf000311_0001
[0731] 2-(2-((teri-butyldimethylsilyl)oxy)-2-methylpropyl)-N-(3-chloro-4- fluorophenyl)-4,5-difluoro-lH-benzo[d]imidazole-7-carboxamide. To a solution of N- (3-chloro-4-fluorophenyl)-4,5-difluoro-2-(2-hydroxy-2-methylpropyl)-lH- benzo[d]imidazole-7-carboxamide (0.145 g, 0.365 mmol) and 2,6-lutidine (0.34 mL, 2.9 mmol) in DCM (7 mL) at 0 °C was added fert-butyldimethylsilyl
trifluoromethanesulfonate (0.17 mL, 0.740 mmol). The mixture warmed to rt and stirred 48 h. 2,6-Lutidine (0.34 mL, 2.9 mmol) and fert-butyldimethylsilyl
trifluoromethanesulfonate (0.34 mL, 1.48 mmol) were added. After 4 h, 2,6-lutidine (0.34 mL, 2.9 mmol) and fert-butyldimethylsilyl trifluoromethanesulfonate (0.34 mL, 1.48 mmol) were added and the mixture stirred 4 h. The mixture was concentrated onto silica gel and purified via silica gel chromatography to give the desired product.
C24H29CIF3N3O2S1. 512.2 (M+l).
Figure imgf000311_0002
[0732] 2-(2-((teri-butyldimethylsilyl)oxy)-2-methylpropyl)-N-(3-chloro-4- fluorophenyl)-4,5-difluoro-lH-benzo[d]imidazole-7-carbothioamide was prepared analogously to Example 13, using 2-(2-((fer^butyldimethylsilyl)oxy)-2-methylpropyl)- N-(3-chloro-4-fluorophenyl)-4,5-difluoro-lH-benzo[d]imidazole-7-carboxamide in place of 2-amino-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-lH-benzo[d]imidazole-7- carboxamide. C24H29CIF3N3OSS1. 528.3 (M+l).
Figure imgf000312_0001
[0733] 2-(2-((teri-butyldimethylsilyl)oxy)-2-methylpropyl)-N-(3-chloro-4- fluorophenyl)-4,5-difluoro-N'-hydroxy-lH-benzo[d]imidazole-7-carboximidamide was prepared analogously to Example 13, using 2-(2-((teri-butyldimethylsilyl)oxy)-2- methylpropyl)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-lH-benzo[d]imidazole-7- carbothioamide in place of 2-amino-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-lH- benzo[d]imidazole-7-carbothioamide. C24H30CIF3N4O2S1. 527.3 (M+l).
Figure imgf000312_0002
[0734] N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(2-hydroxy-2- methylpropyl)-lH-benzo[d]imidazole-7-carboximidamide. To a soln of 2-(2-((ieri- butyldimethylsilyl)oxy)-2-methylpropyl)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- hydroxy-lH-benzo[d]imidazole-7-carboximidamide (0.007 g, 0.013 mmol) in THF (1 mL) at 0 °C was added HF-pyridine (0.02 mL, 0.664 mmol). Mixture warmed to rt and stirred 16 h. HF-pyridine (0.04 mL, 1.32 mmol) was added and mixture stirred an additional 24 h. The mixture was diluted with EtOAc and washed with sat NaHCC soln. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and concentrated. The residue was purified by silica gel chromatography to give the desired product (0.001 g).
Figure imgf000312_0003
413.1 (M+H). Example 303: A^-(3-chloro-4-fluorophenyl)-2-((4-(dimethylamino)butyl)amino)-4,5- difluoro-iV -hydroxy- lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000313_0001
[0735] Example 303 was prepared analogously to Example 333 using 4- dimethylaminobutan-1 -amine in place of fert-butyl (2-aminoethyl)carbamate.
C2oH22ClF3N60. 455.2 (M+H).
Example 304 : A/-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-((piperidin-3- ylmethyl)amino)- lH-benzo [d] imidazole-7-carboximidamide
Figure imgf000313_0002
[0736] Example 304 was prepared analogously to Example 333 using l -Boc-3- (aminomethyl)piperidine in place of fert-butyl (2-aminoethyl)carbamate.
C2oH2oClF3N60. 453.2 (M+H).
Example 305: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((l-methylpiperidin-2- yl)methyl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000313_0003
[0737] 2-((l -methylpiperidin-2-yl)methyl)-lH-imidazo[4,5-b]pyridine-7-carboxylic acid. A suspension of 2,3-diaminoisonicotinic acid hydrochloride (200 mg, 0.106 mmol) and 2-(l -methylpiperidin-2-yl)acetic acid (498 mg, 0.317 mmol) in sulfuric acid (1.5 mL) was stirred at room temperature for 5 min and, then, was sealed in a vial and stirred at 160 °C for 3 hours. Once the mixture had cooled, water (2 mL) was added and the solution was purified by preparative HPLC to give the desired product. C14H18N4O2. 275.1 (M+l).
Figure imgf000314_0001
[0738] N-(3-chloro-4-fluorophenyl)-2-((l-methylpiperidin-2-yl)methyl)-lH- imidazo[4,5-b]pyridine-7-carboxamide. A solution of 2-((l-methylpiperidin-2- yl)methyl)-lH-imidazo[4,5-b]pyridine-7-carboxylic acid (75 mg, 0.273 mmol), 4-fluoro- 3-chloroaniline (60 mg, 0.410 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (139 mg, 0.547 mmol) and N,N-diisopropylethylamine (0.240 ml, 1.37 mmol) in
dichloromethane (1.5 mL) was stirred for 3 hours. The reaction mixture was concentrated and purified by preparative HPLC. The resulting lyophilized material was mixed with saturated aqueous sodium bicarbonate (5 mL), filtered, washed with water and dried on high vacuum to give the desired product. C20H21CIFN5O. 402.1 (M+l).
Figure imgf000314_0002
[0739] N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((l -methylpiperidin-2-yl)methyl)- lH-imidazo[4,5-b]pyridine-7-carboximidamide. To a mixture of N-(3-chloro-4- fluorophenyl)-2-((l -methylpiperidin-2-yl)methyl)-lH-imidazo[4,5-b]pyridine-7- carboxamide (1 1 mg, 0.027 mmol) and potassium carbonate (26 mg, 0.192 mmol) in dichloromethane (0.5 ml) was added phosphorous pentachloride (11 mg, 0.055 mmol). The reaction mixture stirred for 2 hours and was concentrated. The residue was brought up in ethanol (0.5 ml) and hydroxylamine (0.07 mL, 50% in water, 1.08 mmol) and stirred for 1 hour. The reaction mixture was concentrated and purified by preparative HPLC to give the desired product. C2oH22ClFN60. 417.1 (M+l). Example 306: A^-(3-bromophenyl)-A^-hydroxy-2-((2-morpholinoethyl)amino)-lH- ] pyridine- 7-carboximidamide
Figure imgf000315_0001
[0740] Example 306 was prepared analogously to Example 333 using 4-(3- bromophenyl)-3-(2-chloro-l -((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5- b]pyridin-7-yl)-l ,2,4-oxadiazol-5(4H)-one and 2-morpholinoethan-l -amine in place of 3-(2-chloro-4,5-difluoro-l -((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7- yl)-4-(3-chloro-4-fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one and fert-butyl (2- aminoethyl)carbamate, respectively. CifeBrNyC . 460.2/462.1 (M+H). ¾ NMR (400 MHz, DMSO-d6) δ 1 1.35 (s, 1H), 8.94 (s, 1H), 7.98 (d, J = 6.1 Hz, 1H), 7.09 - 6.95 (m, 3H), 6.93 (d, J = 5.9 Hz, 1H), 6.61 - 6.50 (m, 1H), 3.95 - 3.20 (m, 12H).
Example 307: /V-(3-chloro-4-fluorophenyl)-5-fluoro-iV-hydroxy-4-methoxy-lH- benzo[d]imidazole-7-carboximidamide
Figure imgf000315_0002
[0741] N-(3-chloro-4-fluorophenyl)-4,5-difluoro-l-((2-
(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxamide. To a solution of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-lH-benzo[d]imidazole-7-carboxamide (1.92 g, 5.89 mmol) and TEA (3.3 mL, 23.6 mmol) in DCM (60 mL) was added SEMCl (2.6 mL, 14.7 mmol). After 45 min, TEA (1.1 mL, 7.9 mmol) and SEMCl (0.9 mL, 4.9 mmol) were added. After 20 min, the mixture was diluted with EtOAc, concentrated onto silica gel, and purified via silica gel chromatography to give the desired product.
C2oH2iClF3N302Si. 456.2 (M+l).
Figure imgf000316_0001
[0742] N-(3-chloro-4-fluorophenyl)-5-fluoro-4-methoxy-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxamide. A mixture of N- (3-chloro-4-fluorophenyl)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazole-7-carboxamide (0.250 g, 0.548 mmol) and sodium methoxide (0.50 mL of a 25% soln in MeOH, 2.19 mmol) in MeOH (1 mL) was stirred at 65 °C for 8 h. Mixture was cooled to rt and diluted with sat. NH4C1 soln. The aqueous layer was extracted 3 χ with EtOAc. The combined organic layers were washed with brine, dried (Na2S04), filtered and concentrated to give the desired product. C2iH24ClF2N303Si. 468.3 (M+l).
Figure imgf000316_0002
[0743] N-(3-chloro-4-fluorophenyl)-5-fluoro-N'-hydroxy-4-methoxy-lH- benzo[d]imidazole-7-carboxirnidamide was prepared analogously to Example 305 using N-(3-chloro-4-fluorophenyl)-5-fluoro-4-methoxy-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-((l- methylpiperidin-2-yl)methyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide.
C15H11CIF2N4O2. 353.1 (M+H).
Example 308: iV-(3-chloro-4-fluorophenyl)-iV-hydroxy-2-((pyridin-2- dazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000316_0003
[0744] Example 308 was prepared analogously to Example 333 using 3-(2-chloro-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one and 2-picolylamine in place of 3-(2-chloro-4,5- difluoro-l -((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4- fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one and tert-bu yl (2-aminoethyl)carbamate, respectively. C19H15CIFN7O. 412.2 (M+H). XH NMR (400 MHz, DMSO-d6) δ 1 1.48 (s, 1H), 8.99 (s, 1H), 8.59 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 7.98 (d, J = 6.4 Hz, 1H), 7.84 (td, J = 7.7, 1.8 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.36 (ddd, J = 7.4, 5.0, 1.1 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.05 (dd, J = 6.5, 2.7 Hz, 1H), 6.95 (d, J = 6.3 Hz, 1H), 6.60 (ddd, J = 9.0, 3.9, 3.0 Hz, 1H), 4.80 (d, J = 5.7 Hz, 2H).
Example 309: 2-((2-(lH-pyrazol-l-yl)ethyl)amino)-A^-(3-chloro-4-fluorophenyl)-A^- -lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000317_0001
[0745] Example 309 was prepared analogously to Example 333 using 3-(2-chloro-l - ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one and 2-(lH-pyrazol-l -yl)ethan-l-amine in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7- yl)-4-(3-chloro-4-fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one and tert-butyl (2- aminoethyl)carbamate, respectively. C I8HI6C1FN80. 415.2 (M+H).
Example 310: A-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-(((l-methyl-lH-pyrazol-3- yl)methyl)amino)-lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000317_0002
[0746] Example 310 was prepared analogously to Example 333 using 3-(2-chloro-l - ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one and (1 -methyl- lH-pyrazol-3-yl)methanamine in place of 3-(2-chloro-4,5-difluoro-l -((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and tert- butyl (2-aminoethyl)carbamate, respectively. CI8HI6C1FN80. 415.2 (M+H).
Example 311: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((4,4,4- trifluorobutyl)amino)-lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000318_0001
[0747] Example 311 was prepared analogously to Example 333 using 3-(2-chloro-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 4,4,4-trifluorobutylamine in place of 3-(2- chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4- (3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and fert-butyl (2- aminoethyl)carbamate, respectively. CI7HI5C1F4N60. 431.1 (M+H).
Example 312: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((3,3,3- trifluoropropyl)amino)- lH-imidazo [4,5-b] pyridine-7-carboximidamide
Figure imgf000318_0002
[0748] Example 312 was prepared analogously to Example 333 using 3-(2-chloro-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3,3,3-trifluoropropylamine in place of 3- (2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)- 4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and fert-butyl (2- aminoethyl)carbamate, respectively. CI6HI3C1F4N60. 417.1 (M+H). ^ NMR ^OO MHz, DMSO-d6) 5 11.42 (s, 1H), 8.98 (s, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.03 (dd, J = 6.3, 2.4 Hz, 1H), 6.94 (d, J = 6.3 Hz, 1H), 6.58 (ddd, J = 9.0, 4.0, 3.0 Hz, 1H), 3.78 - 3.63 (m, 2H), 2.76 - 2.56 (m, 2H). Example 313: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((2-(2- methoxyethoxy)ethyl)amino)-lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000319_0001
[0749] Example 313 was prepared analogously to Example 333 using 3-(2-chloro-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 2-(2-methoxyethoxy)ethanamine in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7- yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and tert-bu yl (2- aminoethyl)carbamate, respectively. Ci8H2oClFN603. 423.2 (M+H).
Example 314: A^-(3-chloro-4-fluorophenyl)-2-((3- (cyclopropyl(methyl)amino)propyl)amino)-A^-hydroxy-lH-imidazo[4,5-b]pyridine-
7-carboximidamide
Figure imgf000319_0002
[0750] 2-(3-(cyclopropyl(methyl)amino)propyl)isoindoline-l,3-dione. A solution of 2-(3-bromopropyl)isoindoline-l,3-dione (1.89 g, 7.03 mmol), cyclopropylmethylamine (0.59 mL, 7.03 mmol), and potassium carbonate (1.94 g, 14 mmol) in
dimethylformamide (7 mL) was stirred at 40 °C for 6 hr. Water was added and the aqueous layer was washed three times with diethyl ether. The combined organic layers were washed with brine and dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to give the desired product (1.8 g). Ci5Hi8N202. 259.2 (M+l).
Figure imgf000319_0003
[0751] N-(3-chloro-4-fluorophenyl)-2-((3-
(cyclopropyl(methyl)amino)propyl)amino)-N'-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide. A solution of 2-(3-(cyclopropyl(methyl)amino)propyl)isoindoline-l,3- dione (63 mg, 0.24 mmol) and hydrazine (0.006 mL, 0.2 mmol) in ethanol (1 mL) was stirred at 80 °C for one hour. The reaction was cooled to room temperature, filtered and concentrated. To the resulting residue was added 3-(2-chloro-4,5-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-
I, 2,4-oxadiazol-5(4H)-one (24 mg, 0.024 mmol), and dimethylsulfoxide (0.25 mL). The resulting solution was stirred at 65 °C for one hour. The reaction mixture was cooled and diluted with ethyl acetate and washed three times with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was brought up in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) and stirred for 3 hours. The reaction solution was concentrated. The resulting residue was brought up in tetrahydrofuran (0.2 mL) and methanol (0.2 mL) and to this solution was added 2 N sodium hydroxide (0.24 mL, 0.48 mmol). The resulting solution was stirred for 30 min and concentrated and purified by preparative HPLC to give the desired product (9 mg). C2oH23ClFN70. 432.2 (M+1). l NMR (400 MHz, DMSO-d6) δ
I I .34 (s, 1H), 8.95 (s, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.00 (d, J = 5.6 Hz, 1H), 6.92 (d, J = 6.1 Hz, 1H), 6.61 - 6.53 (m, 1H), 3.54 - 3.42 (m, 2H), 3.30 - 3.19 (m, 3H), 2.92 - 2.77 (m, 5H), 2.05 - 1.92 (m, 3H), 0.96 - 0.78 (m, 6H).
Example 315 : A-(3-chloro-4-fluorophenyl)-2-((3-(cyclopropylamino)propyl)amino)- ^-hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000320_0001
[0752] 2-(3-(cyclopropylamino)propyl)isoindoline-l,3-dione was prepared analogously to Example 314 using cyclopropylamine in place of
cyclopropylmethylamine. Ci4Hi6N202. 245.1 (M+1).
Figure imgf000321_0001
[0753] N-(3-chloro-4-fluorophenyl)-2-((3-(cyclopropylamino)propyl)amino)-N'- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide was prepared analogously to Example 314 using 2-(3-(cyclopropylamino)propyl)isoindoline-l,3-dione in place of 2- (3-(cyclopropyl(methyl)amino)propyl)isoindoline-l,3-dione. C19H21CIFN7O. 418.2 (M+H).
Example 316: A^-(3-chloro-4-fluorophenyl)-2-((3- (cyclopropyl(ethyl)amino)propyl)amino)-A^-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000321_0002
[0754] 2-(3-(cyclopropyl(ethyl)amino)propyl)isoindoline-l,3-dione was prepared analogously to Example 314 using N-ethylcyclopropylamine in place of
cyclopropylmethylamine. C16H20N2O2. 273.2 (M+l).
Figure imgf000321_0003
[0755] N-(3-chloro-4-fluorophenyl)-2-((3-(cyclopropyl(ethyl)ainino)propyl)arnino)- N'-hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide was prepared analogously to Example 314 using 2-(3-(cyclopropyl(ethyl)amino)propyl)isoindoline-l,3-dione in place of 2-(3-(cyclopropyl(methyl)amino)propyl)isoindoline-l,3-dione. C21H25CIFN7O. 446.2 (M+H). 'H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.96 (s, 1H), 7.97 (d, J = 6.1 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.05 - 6.98 (m, 1H), 6.97 - 6.89 (m, 1H), 6.58 (dt, J = 8.9, 3.5 Hz, 1H), 3.51 (s, 2H), 3.35 - 3.18 (m, 4H), 2.94 - 2.73 (m, 1H), 2.15 - 1.92 (m, 2H), 1.26 (t, J = 7.3 Hz, 3H), 1.02 - 0.78 (m, 4H).
Example 317: iV-(3-chloro-4-fluorophenyl)-2-((2-(4-fluoropiperidin- 1- yl)ethyl)amino)-A^-hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000322_0001
[0756] Example 317 was prepared analogously to Example 333 using 3-(2-chloro-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 2-(4-fluoropiperidin-l-yl)ethan-l -amine in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and tert- butyl (2-aminoethyl)carbamate, respectively. C20H22CIF2N7O. 450.2 (M+H). ¾ NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.94 (s, 1H), 7.98 (d, J = 5.6 Hz, 1H), 7.10 (t, J = 9.1 Hz, 1H), 6.99 (d, J = 5.7 Hz, 1H), 6.96 - 6.85 (m, 1H), 6.64 - 6.45 (m, 1H), 5.10 - 4.80 (m, 1H), 3.86 - 3.70 (m, 2H), 3.50 - 3.20 (m, 6H), 2.23 - 1.93 (m, 4H).
Example 318: A^-(3-chloro-4-fluorophenyl)-^'-hydroxy-2-((2-(2,2,2- trifluoroethoxy)ethyl)amino)-lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000322_0002
[0757] Example 318 was prepared analogously to Example 229 using 3-(2-chloro-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 2-(2,2,2-trifluoroethoxy)ethan-l -amine hydrochloride in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. C17H15CIF4N6O2. 447.1 (M+H).
Example 319: iV-(3-chloro-4-fluorophenyl)-iV-hydroxy-2-((3-(2,2,2- trifluoroethoxy)propyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000323_0001
[0758] Example 319 was prepared analogously to Example 229 using 3-(2-chloro-l - ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one and 3-(2,2,2-trifluoroethoxy)propan-l -amine hydrochloride in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. C18H17CIF4N6O2. 461.2 (M+H). XH NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.94 (s, 1H), 7.94 (d, J = 6.2 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 7.01 (dd, J = 6.5, 2.3 Hz, 1H), 6.89 (d, J = 6.3 Hz, 1H), 6.56 (ddd, J = 8.9, 3.9, 2.8 Hz, 2H), 4.04 (q, J = 9.5 Hz, 2H), 3.65 (t, J = 6.1 Hz, 2H), 3.52 - 3.42 (m, 2H), 1.85 (p, J = 6.9 Hz, 2H).
Example 320: A/-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((2-(3-methoxypiperidin- l)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000323_0002
[0759] tert-Bu yl (2-(3-methoxypiperidin-l-yl)ethyl)carbamate. A mixture of tert- butyl (2-bromoethyl)carbamate (0.147 g, 0.656 mmol), 3-methoxypiperidine hydrochloride (0.099 g, 0.656 mmol) and DIPEA (0.25 mL, 1.44 mmol) in DMSO (1.5 mL) was stirred at 40 °C for 16 h. The mixture was diluted with sat NaHC03 soln. The aqueous layer was extracted 3 * with EtOAc. The combined organic layers were washed with brine, dried Na2S04), filtered and concentrated. The residue was purified via silica gel chromatography to give the desired product (0.047 g). C13H26N2O3. 259.2 (M+l).
Figure imgf000324_0001
[0760] 2-(3-Methoxypiperidin-l -yl)ethan-l -amine. To a solution of fert-butyl (2-(3- methoxypiperidin-l-yl)ethyl)carbamate (0.047 g, 0.182 mmol) in THF was added HC1 (2.3 mL of a 4 M soln in dioxane, 9.1 mmol). The mixture stirred at rt for 16 h. The mixture was concentrated to give the desired product as the HC1 salt (0.042 g).
Figure imgf000324_0002
[0761] N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(3-methoxypiperidin-l - yl)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboxirnidamide was prepared analogously to Example 229 using 3-(2-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 2-(3-methoxypiperidin-l -yl)ethan-l -amine hydrochloride in place of 3-(2-chloro-4,5- difluoro-l -((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4- fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. C21H25CIFN7O2. 462.2 (M+H). ¾ NMR (400 MHz, DMSO-c¾) δ 1 1.30 (s, 1H), 8.93 (s, 1H), 7.97 (d, J = 5.6 Hz, OH), 7.09 (t, J = 9.1 Hz, 1H), 7.03 - 6.75 (m, 2H), 6.55 (ddd, J = 9.0, 3.9, 2.7 Hz, 1H), 3.88 - 3.02 (m, 14H), 2.00 - 1.54 (m, 2H).
Example 321 : A^-(3-chloro-4-fluorophenyl)-2-((3-(difluoromethoxy)propyl)amino)-
A^-hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000324_0003
[0762] Example 321 was prepared analogously to Example 333 using 3-(2-chloro-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3-(difluoromethoxy)propan-l -amine in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and tert- butyl (2-aminoethyl)carbamate, respectively. c17Hle,ciF3N6o2. 429.1 (M+H). 1H NMR (400 MHz, DMSO-c4) 5 11.38 (s, 1H), 8.94 (s, 1H), 7.94 (d, J = 6.2 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 7.05 - 6.96 (m, 1H), 6.93 - 6.80 (m, 1H), 6.66 (t, J= 76.1 Hz, 1H), 6.56 (ddd, J = 8.8, 4.2, 2.8 Hz, 1H), 3.90 (t, J = 6.2 Hz, 2H), 3.55 - 3.45 (m, 2H), 1.96 - 1.83 (m, 2H).
Example 322 : (R)-A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-(((tetrahydrofuran-2- yl)methyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000325_0001
[0763] Example 322 was prepared analogously to Example 333 using 3-(2-chloro-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and (i?)-(-)-tetrahydrofurfurylamine in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7- yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and fert-butyl (2- aminoethyl)carbamate, respectively. CigHigClFNeCh. 405.2 (M+l).
Example 323: (S)-A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-(((tetrahydrofuran-2- yl)methyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000325_0002
[0764] Example 323 was prepared analogously to Example 333 using 3-(2-chloro-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and (5 -(+)-tetrahydrofurfurylamine in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7- yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and fert-butyl (2- aminoethyl)carbamate, respectively. CI8HI8C1FN602. 405.2 (M+H). ^NMR^OO MHz, DMS0-i¾)511.45 (s, 1H), 8.97 (s, 1H), 7.98 (d,J=6.3Hz, 1H), 7.11 (t,J=9.0 Hz, 1H), 7.04 (dd,J=6.5, 2.8 Hz, 1H), 6.93 (d,J=6.3 Hz, 1H), 6.60 (ddd,J=8.9, 4.0, 3.0 Hz, 1H), 4.09 - 3.98 (m, 1H), 3.80 (dt, J= 8.2, 6.7 Hz, 1H), 3.68 (dt, J= 8.1, 6.8 Hz, 1H), 3.63 - 3.52 (m, 1H), 3.51 - 3.38 (m, 1H), 2.03 - 1.76 (m, 3H), 1.66 - 1.49 (m, 1H).
Example 324: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((2-(tetrahydrofuran-2- -lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000326_0001
[0765] Example 324 was prepared analogously to Example 333 using 3-(2-chloro-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 2-(oxolan-2-yl)ethan-l -amine in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7- yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and fert-butyl (2- aminoethyl)carbamate, respectively. Ci9H2oClFN602. 419.2 (M+H). ^NMR^OO MHz, DMSO-i¾)511.38 (s, 1H), 8.96 (s, 1H), 7.95 (d,J=6.1 Hz, 1H), 7.10 (t,J=9.0 Hz, 1H), 7.03 (dd,J=6.5, 2.7 Hz, 1H), 6.91 (d,J=6.2Hz, 1H), 6.58 (ddd, J= 9.0, 4.1, 3.0 Hz, 1H), 3.89 - 3.75 (m, 2H), 3.62 (td, J= 7.9, 6.4 Hz, 1H), 3.54 - 3.47 (m, 2H), 2.03 - 1.67 (m, 5H), 1.52 - 1.37 (m, 1H).
Example 325: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-(piperidin-2-ylmethyl)- lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000326_0002
[0766] 2-(piperidin-2-ylmethyl)-lH-imidazo[4,5-b]pyridine-7-carboxylic acid. A suspension of 2,3-diaminoisonicotinic acid hydrochloride (200 mg, 0.106 mmol) and 2- (piperidin-2-yl)acetic acid (453 mg, 0.317 mmol) in sulfuric acid (1.5 mL) was stirred at room temperature for 5 min and, then, was sealed in a vial and stirred at 160 °C for 3 hours. Once the mixture had cooled, water (2 mL) was added and the solution was purified by preparative HPLC to give the desired product. C13H16N4O2. 261.1 (M+l).
Figure imgf000327_0001
[0767] 2-((l-(tert-butoxycarbonyl)piperidin-2-yl)methyl)-lH-imidazo[4,5- b]pyridine-7-carboxylic acid. A solution of 2-(piperidin-2-ylmethyl)-lH-imidazo[4,5- b]pyridine-7-carboxylic acid (205 mg, 0.788 mmol), di-tert-butyl dicarbonate (189 mg, 0.866 mmol), and triethylamine (0.440 ml, 3.15 mmol) in dichloromethane (8 mL) was stirred for 3 hr and concentrated to give the desired product. C18H24N4O4. 361.1 (M+l).
Figure imgf000327_0002
[0768] tert-butyl 2-((7-((3-chloro-4-fluorophenyl)carbamoyl)-lH-imidazo[4,5- b]pyridin-2-yl)methyl)piperidine-l-carboxylate. A solution of 2-((l-(tert- butoxycarbonyl)piperidin-2-yl)methyl)-lH-imidazo[4,5-b]pyridine-7-carboxylic acid (283 mg, 0.785 mmol), 4-fluoro-3-chloroaniline (171 mg, 1.18 mmol), 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid
hexafluorophosphate (388 mg, 1.02 mmol) and N,N-diisopropylethylamine (0.684 ml, 3.93 mmol) in dimethylformamide (1.5 mL) was stirred for 3 hours. The reaction mixture was concentrated and purified by preparative HPLC. The resulting lyophilized material was mixed with saturated aqueous sodium bicarbonate (5 mL), filtered, washed with water and dried on high vacuum to give the desired product. C24H27CIFN5O3. 488.1 (M+l).
Figure imgf000328_0001
[0769] N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(piperidin-2-ylmethyl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide. To a mixture of tert-butyl 2-((7-((3-chloro- 4-fluorophenyl)carbamoyl)-lH-imidazo[4,5-b]pyridin-2-yl)methyl)piperidine-l- carboxylate (100 mg, 0.205 mmol) and potassium carbonate (198 mg, 1.43 mmol) in dichloromethane (2 ml) was added phosphorous pentachloride (85 mg, 0.409 mmol). The reaction mixture stirred for 2 hours and was concentrated. The residue was brought up in ethanol (2 ml) and hydroxylamine (0.50 mL, 50% in water, 8 mmol) and stirred for 1 hour. The reaction mixture was concentrated and purified by preparative HPLC to give the desired product. Ci9H20ClFN6O. 403.1 (M+l).
Example 326: A^-(3-chloro-4-fluorophenyl)-2-(l-(dimethylamino)propan-2-yl)-A^- hydroxy-lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000328_0002
[0770] Example 326 was prepared analogously to Example 305 using 3- (dimethylamino)-2-methylpropanoic acid in place of 2-(l -methylpiperidin-2-yl)acetic acid. Ci8H20ClFN6O. 391.1 (M+l).
Example 327: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-(2-(methylamino)propyl)- lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000328_0003
[0771] Example 327 was prepared analogously to Example 325 using 3- (methylamino)butanoic acid in place of 2-(piperidin-2-yl)acetic acid. Ci7Hi8ClFN60. 377. 1 (M+l).
Example 328 : iV-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)propyl)-iV'- hydroxy-lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000329_0001
[0772] Example 328 was prepared analogously to Example 305 using 3- (dimethylamino)butanoic acid in place of 2-(l-methylpiperidin-2-yl)acetic acid.
Ci8H20ClFN6O. 391. 1 (M+l).
Example 329: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-(pyrrolidin-2-ylmethyl)- lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000329_0002
[0773] Example 329 was prepared analogously to Example 325 using 2-(pyrrolidin- 2-yl)acetic acid in place of 2-(piperidin-2-yl)acetic acid. CI8HI8C1FN60. 389. 1 (M+l).
Example 330: A^-(3-chlorophenyl)-4,5-difluoro-A^-hydroxy-2-((2-(pyrrolidin-l- -benzo[d]imidazole-7-carboximidamide
Figure imgf000329_0003
[0774] Example 330 was prepared analogously to Example 39 using 2-(pyrrolidin-l- yl)ethanamine in place of N,N-dimethylpropane-l,3-diamine and 3-chloroaniline in place of 3-chloro-4-fluoroaniline. C2oH2iClF2N60. 435.1 (M+1). 1H NMR (400 MHz, DMSO- d6) δ 11.02 - 10.85 (m, 1H), 10.79 (s, 1H), 9.83 - 9.63 (m, 1H), 8.68 (s, 1H), 7.03 (t, J = 8.0 Hz, 1H), 6.89 - 6.73 (m, 2H), 6.55 - 6.44 (m, 1H), 3.74 - 3.60 (m, 2H), 3.44 - 3.32 (m, 2H), 2.05 - 1.83 (m, 4H).
Example 331: A-(3-bromophenyl)-4,5-difluoro-A^-hydroxy-2-((2-(pyrrolidin-l- yl)ethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000330_0001
[0775] Example 331 was prepared analogously to Example 39 using 2-(pyrrolidin-l- yl)ethanamine in place of N,N-dimethylpropane-l,3-diamine and 3-bromoaniline in place of 3-chloro-4-fluoroaniline. C2oH2iBrF2N60. 479.1 (M+1). NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.83 - 9.67 (m, 1H), 8.67 (s, 1H), 7.01 - 6.73 (m, 6H), 6.52 (dt, J = 7.7, 1.8 Hz, 1H), 3.71 - 3.59 (m, 2H), 3.42 - 3.32 (m, 2H), 1.93 (s, 4H).
Example 332: iV-(3-bromo-4-fluorophenyl)-4,5-difluoro-iV-hydroxy-2-((2- (pyrrolidin-l-yl)ethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000330_0002
[0776] Example 332 was prepared analogously to Example 39 using 2-(pyrrolidin-l- yl)ethanamine in place of N,N-dimethylpropane-l,3-diamine and 3-bromo-4- fluoroaniline in place of N,N-dimethylpropane-l,3-diamine. C2oH2oBrF3N60. 497.1 (M+l).
Example 333: 2-((2-aminoethyl)amino)-A^-(3-chloro-4-fluorophenyl)-4,5-difluoro- -hydroxy- LH-benzo[d] imidazole- 7-carboximidamide
Figure imgf000331_0001
[0777] Methyl 6,7-difluoro-2-oxo-2,3-dihydro-lH-benzo[d]imidazole-4-carboxylate. A solution of methyl 2,3-diamino-4,5-difluorobenzoate (10 g, 50 mmol) and
carbonyldiimidazole (12 g, 75 mmol) in THF (100 mL) was stirred ovemight. Diethyl ether was added to the reaction mixture and the precipitate was filtered and dried on high vacuum to give the desired product. C9H6F2N2O3. 229.5 (M+l).
Figure imgf000331_0002
[0778] Methyl 2-chloro-4,5-difluoro-lH-benzo[d]imidazole-7-carboxylate. A mixture of methyl 6,7-difluoro-2-oxo-2,3-dihydro-lH-benzo[d]imidazole-4-carboxylate (9.98 g, 43.7 mmol) in phosphoryl chloride (80 mL) was stirred ovemight at 120 °C. The solution was cooled and concentrated. To the solid residue cooled in an ice bath was cautiously added a saturated aqueous sodium bicarbonate solution. The slurry was filtered and the filtrate was washed with water and dried on high vacuum to give the desired product. C9H5CIF2N2O2. 247.2 (M+l).
Figure imgf000331_0003
[0779] 2-chloro-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-lH-benzo[d]imidazole-7- carboxamide. To a solution of the 3-chloro-4-fluoroaniline (4.43 g, 30 mmol) in dichloroethane (50 niL) at 0 °C was added a solution of trimethylaluminum (30.4 niL, 2 M in heptane, 61 mmol) drop wise over 5 min. The ice bath was removed and the mixture stirred for 30 minutes. The solution was cooled back down with and ice bath and methyl 2-chloro-4,5-difluoro-lH-benzo[d]imidazole-7-carboxylate (5 g, 20 mmol) was added to this solution as a solid. The reaction stirred at 60 °C for 6 hours. The reaction was cooled in an ice bath and to this cooled mixture was added 10% citric acid (30 mL). To this solution was added 2N sodium hydroxide and the aqueous layer was washed three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the desired product. C14H6CI2F3N3O. 360.5 (M+l).
Figure imgf000332_0001
[0780] 3-(2-chloro-4,5-difluoro-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one. A mixture of 2-chloro-N-(3-chloro-4- fluorophenyl)-4,5-difluoro-lH-benzo[d]imidazole-7-carboxarnide (6.56 g, 18.2 mmol) and potassium carbonate (17.6 g, 127 mmol) in dichloromethane (100 mL) was stirred together for 5 min. To this mixture was added phosphorus pentachloride (7.58 g, 36 mmol) and the mixture stirred for two hours. More phosphorus penetachloride was added (7.58 g, 36 mmol) and the mixture stirred for another three hours. The reaction mixture was concentrated and placed in an ice bath. To the cooled residue was added a solution of hydroxyamine (44.5 mL, 50% in water, 728 mmol) and ethanol (100 mL) over 20 min. The ice bath was removed and the reaction stirred for 30 min. The reaction mixture was concentrated and brought up in water and washed three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to about 50 ml. To this solution was added carbonyldiimidazole (5.9 g, 36 mmol). The reaction solution stirred for 30 min and was diluted with ethyl acetate and washed twice with 1 N hydrochloric acid and once with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated to give the desired product. C15H5CI2F3N4O2. 401.0 (M+l).
Figure imgf000333_0001
[0781] 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one. To a solution of 3-(2-chloro-4,5-difluoro-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one (7.3 g, 18 mmol) and triethylamine (15 niL, 109 mmol) in dichloromethane (200 mL) was added (2-
(chloromethoxy)ethyl)trimethylsilanel (8 mL, 46 mmol). Reaction was stirred for 2 hr, and was adsorbed onto silica gel and purified by silica gel chromatography to give the desired product.
Figure imgf000333_0002
554.9 (M+23).
Figure imgf000333_0003
[0782] 3-(2-((2-aminoethyl)amino)-4,5-difluoro-lH-benzo[d]imidazol-7-yl)-4-(3- chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one. A solution of 3-(2-chloro-4,5- difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one (390 mg, 0.734 mmol), and tert-butyl (2- aminoethyl)carbamate (141 mg, 0.881 mmol) in dimethylsulfoxide (3.5 mL) was stirred at 65 °C overnight. The reaction mixture was cooled and diluted with ethyl acetate and washed three times with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was brought up in dichloromethane (3 mL) and trifiuoroacetic acid (3 mL) and stirred for 3 hours. The reaction solution was concentrated and brought up in saturated aqueous sodium bicarbonate and washed three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the desired product (312 mg). Ci7Hi2ClF3N602. 425.2 (M+l).
Figure imgf000334_0001
[0783] 2-((2-aminoethyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- hydroxy-lH-benzo[d]imidazole-7-carboximidamide. A solution of 3-(2-chloro-4,5- difluoro-l -((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4- fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one (29 mg, 0.056 mmol), and tert-butyl (2- aminoethyl)carbamate (44 mg, 0.27 mmol) in dimethylsulfoxide (0.2 mL) was stirred at 65 °C overnight. The reaction mixture was cooled and diluted with ethyl acetate and washed three times with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was brought up in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) and stirred for 3 hours. The reaction solution was concentrated. The resulting residue was brought up in
tetrahydrofuran (0.2 mL) and methanol (0.2 mL) and to this solution was added 2 N sodium hydroxide (0.27 mL, 0.54 mmol). The resulting solution was stirred for 30 min and concentrated and purified by preparative HPLC to give the desired product.
Ci6H14ClF3N60. 399.1 (M+l).
Example 334: A-(2-((7-(A^-(3-chloro-4-fluorophenyl)-A^-hydroxycarbamimidoyl)- 4,5-difluoro- lH-benzo [d] imidazol-2-yl)amino)ethyl)acetamide
Figure imgf000334_0002
[0784] To a solution of 3-(2-((2-aminoethyl)amino)-4,5-difluoro-lH- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one (29 mg, 0.068 mmol) and triethylamine (0.048 mL, 0.34 mmol) in tetrahydrofuran (0.5 mL) was added acetyl chloride (0.007 mL, 0.10 mmol). The resulting solution stirred for one hour and was concentrated. The resulting residue was brought up in tetrahydrofuran (0.4 mL) and methanol (0.4 niL) and to this solution was added 2 N sodium hydroxide (0.34 mL, 0.68 mmol). The resulting solution was stirred for one hour, concentrated and purified by preparative HPLC to give the desired product (11 mg). Ci8Hi6ClF3N602. 441.1 (M+1).
Example 335: A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-((2- )-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000335_0001
[0785] Example 335 was prepared analogously to Example 334 using
methanesulfonyl chloride in place of acetyl chloride. C17H16CIF3N6O3S. 477.1 (M+1).
Example 336: A^-(3-chloro-4-fluorophenyl)-2-((2- (cyclopropanesulfonamido)ethyl)amino)-4,5-difluoro-A^ -hydroxy- 1H- benzo[d]imidazole-7-carboximidamide
Figure imgf000335_0002
[0786] Example 336 was prepared analogously to Example 334 using
cyclopropylsulfonyl chloride in place of acetyl chloride. Ci9Hi8ClF3N603S. 503.1 (M+1).
Example 337: Methyl (2-((7-(^-(3-chloro-4-fluorophenyl)-A^- hydroxycarbamimidoyl)-4,5-difluoro-lH-benzo[d]imidazol-2- o)ethyl)carbamate
Figure imgf000335_0003
[0787] Example 337 was prepared analogously to Example 334 using methyl chloroformate in place of acetyl chloride. Ci8Hi6ClF3N603. 457.1 (M+1).
Examples 338: A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-((2- (sulfamoylamino)ethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000336_0001
[0788] A solution of 3-(2-((2-aminoethyl)amino)-4,5-difluoro-lH-benzo[d]imidazol- 7-yl)-4-(3-chloro-4-fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one (33 mg, 0.078 mmol) and sulfamide (75 mg, 0.78 mmol) was stirred at 1 10 °C for 20 min and was concentrated. The resulting residue was brought up in tetrahydrofuran (0.4 mL) and methanol (0.4 mL) and to this solution was added 2 N sodium hydroxide (0.38 mL, 0.76 mmol). The resulting solution was stirred for one hour, concentrated and purified by preparative HPLC to give the desired product. CieHisClFsNyOsS. 478.1 (M+1).
Examples 339: A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-((2- (phenylsulfonamido)ethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000336_0002
[0789] Example 339 was prepared analogously to Example 334 using
benzenesulfonyl chloride in place of acetyl chloride. C22H18CIF3N6O3S. 539.1 (M+1). Examples 340: iV-(3-chloro-4-fluorophenyl)-2-((2-cyanoethyl)amino)-4,5-difluoro- zo[d] imidazole- 7-carboximidamide
Figure imgf000337_0001
[0790] Example 340 was prepared analogously to Example 333 using 3- aminopropanenitrile in place of tert-butyl (2-aminoethyl)carbamate. Ci7Hi2ClF3N60. 409.4 (M+l). es 341 : iV-(3-chloro-4-fluorophenyl)-2-((2-(3-ethylureido)ethyl)amino)- difluoro-Λ^ -hydroxy- lH-benzo[d]imidazole- 7-carboximidamide
Figure imgf000337_0002
[0791] Example 341 was prepared analogously to Example 334 using ethyl isocyanate in place of acetyl chloride. C19H19CIF3N7O2. 470.0 (M+l).
Examples 342 : iV-(3-chloro-4-fluorophenyl)-4,5-difluoro-iV-hydroxy-2-((pyridin-2- ylmethyl)amino)- lH-benzo [d] imidazole-7-carboximidamide
Figure imgf000337_0003
[0792] Example 342 was prepared analogously to Example 333 using 2-picolylamine in place of tert-butyl (2-aminoethyl)carbamate. C2oHi4ClF3N60. 447.2 (M+l). 343: A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-((pyridin-3- ylmethyl)amino)- lH-benzo [d] imidazole-7-carboximidamide
Figure imgf000338_0001
[0793] Example 343 was prepared analogously to Example 333 using 2-picolylamine in place of tert-butyl (2-aminoethyl)carbamate. C2oHi4ClF3N60. 447.3 (M+l).
Example 344: A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-((pyridin-3- -benzo [d] imidazole-7-carboximidamide
Figure imgf000338_0002
[0794] N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((pyridin-3- ylmethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide. Example 344 was prepared analogously to Example 333 using 2-(l-methyl-lH-imidazol-2-yl)ethanamine in place of tert-butyl (2-aminoethyl)carbamate. C20H17CIF3N7O. 464.3 (M+l).
Examples 345 and 346: 2-(((lH-imidazol-2-yl)methyl)amino)-A^-(3-chloro-4- fluorophenyl)-4,5-difluoro-A^-hydroxy-lH-benzo[d]imidazole-7-carboximidamide and 2-chloro-A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-lH- benzo [d] imidazole-7-carboximidamide
Figure imgf000338_0003
[0795] Example 345 was prepared analogously to Example 333 using (lH-imidazol- 2-yl)methanamine dihydrochloride and diisopropylethylamine in place of tert-butyl (2- aminoethyl)carbamate. C18H13CIF3N7O. 436.3 (M+l). Unreacted 2-((2- aminoethyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-lH- benzo[d]imidazole-7-carboximidamide through this sequence gave Example 346 (2- chloro-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide). Ci4H7Cl2F3N40. 375.1 (M+l).
Example 347: 2-((2-aminobenzyl)amino)-iV-(3-chloro-4-fluorophenyl)-4,5-difluoro- J P -hydroxy- lH-benzo[d] imidazole- 7-carboximidamide
Figure imgf000339_0001
[0796] Example 347 was prepared analogously to Example 333 using 2- (aminomethyl)aniline in place of tert-butyl (2-aminoethyl)carbamate. C2iHi6ClF3N60. 461.1 (M+l).
Example 348 : iV-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)benzyl)amino)- 4,5-difluoro-iV -hydroxy- lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000339_0002
[0797] Example 348 was prepared analogously to Example 333 using 2- (aminomethyl)-N,N-dimethylaniline in place of tert-butyl (2-aminoethyl)carbamate. C23H2oClF3N60. 489.2 (M+l). Example 349: A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-(((l-methyl- lH-imidazol-2-yl)methyl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000340_0001
[0798] Example 349 was prepared analogously to Example 333 using ( 1 -methyl- 1Η- imidazol-2-yl)methanamine in place of tert-butyl (2-aminoethyl)carbamate.
C19H15CIF3N7O. 450.1 (M+l).
Example 350 : A/-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-((pyrimidin- 2-ylmethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000340_0002
[0799] Example 350 was prepared analogously to Example 333 using pyrimidin-2- ylmethanamine hydrochloride and diisopropylethylamine in place of tert-butyl (2- aminoethyl)carbamate. C19H13CIF3N7O. 448.1 (M+l).
Example 351 : A^-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)-2,2- dimethylpropyl)amino)-4,5-difluoro-A^-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
Figure imgf000340_0003
[0800] Example 351 was prepared analogously to Example 333 using N^N1^^- tetramethylpropane- 1,3 -diamine in place of tert-butyl (2-aminoethyl)carbamate.
C2iH24ClF3N60. 469.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 10.80 (s, IH), 8.71 (s, IH), 7.08 (t, J = 9.1 Hz, IH), 6.91 (dd, J = 6.5, 2.7 Hz, IH), 6.89 - 6.80 (m, IH), 6.52 (ddd, J = 9.0, 4.0, 2.7 Hz, IH), 3.33 (s, 2H), 2.98 (s, 2H), 2.85 (s, 6H), 1.03 (s, 6H).
Example 352: iV-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)-2- methylpropyl)amino)-4,5-difluoro-iV -hydroxy- lH-benzo[d]imidazole-7- oximidamide
Figure imgf000341_0001
[0801] Example 352 was prepared analogously to Example 333 using N^N1^- trimethylpropane- 1,3 -diamine in place of tert-butyl (2-aminoethyl)carbamate.
C2oH22ClF3N60. 455.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 10.80 (s, IH), 8.74 (s, IH), 7.07 (t, J = 9.1 Hz, IH), 6.97 - 6.80 (m, 2H), 6.52 (dt, J = 8.2, 3.5 Hz, IH), 3.38 - 3.25 (m, 2H), 3.02 - 2.61 (m, 8H), 2.31 - 2.16 (m, IH), 1.01 - 0.89 (m, 3H).
Example 353: A^-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)butyl)amino)-4,5- difluoro-iV -hydroxy- lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000341_0002
[0802] Example 353 was prepared analogously to Example 333 using N3,N3- dimethylbutane-l,3-diamine in place of tert-butyl (2-aminoethyl)carbamate.
C2oH22ClF3N60. 455.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 10.78 (s, IH), 8.71 (s, IH), 7.07 (t, J = 9.1 Hz, IH), 6.91 (dd, J = 6.6, 2.7 Hz, IH), 6.89 - 6.79 (m, IH), 6.52 (dt, J = 9.0, 3.4 Hz, IH), 3.49 - 3.28 (m, 3H), 2.69 (d, J = 4.4 Hz, 6H), 2.01 (d, J = 11.7 Hz, IH), 1.71 (dt, J = 14.1 , 7.5 Hz, IH), 1.22 (d, J = 6.5 Hz, 3H).
Example 354: A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-((2-(l- methylpyrrolidin-2-yl)ethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000342_0001
[0803] Example 354 was prepared analogously to Example 333 using 2-(l- methylpyrrolidin-2-yl)ethanamine in place of tert-butyl (2-aminoethyl)carbamate.
C2iH22ClF3N60. 467.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 10.79 (s, IH), 9.55 (s, IH), 8.70 (s, IH), 7.07 (t, J = 9.1 Hz, IH), 6.92 (dd, J = 6.5, 2.7 Hz, IH), 6.89 - 6.81 (m, IH), 6.51 (ddd, J = 9.0, 4.1 , 2.8 Hz, IH), 3.62 - 3.47 (m, IH), 3.47 - 3.32 (m, 2H), 3.32 - 3.18 (m, IH), 3.1 1 - 2.98 (m, IH), 2.81 (d, J = 4.6 Hz, 3H), 2.34 - 2.09 (m, 2H), 2.05 - 1.69 (m, 3H), 1.68 - 1.57 (m, IH).
Example 355: A-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-((2-(l- methylpiperidin-2-yl)ethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000342_0002
[0804] Example 355 was prepared analogously to Example 333 using 2-(l- methylpiperidin-2-yl)ethanamine in place of tert-butyl (2-aminoethyl)carbamate.
C22H24C1F3N60. 481.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 10.75 (s, IH), 9.13 (s, lh), 8.67 (s, IH), 7.07 (t, J = 8.9 Hz, IH), 6.93 - 6.88 (m, IH), 6.80-6.74 (m, IH), 6.55 - 6.49 (m, 1H), 2.85 - 2.81 (m, 2H), 2.80-2.75, (m, 2H), 2.56-2.6 (m, 1H), 2.52 (s, 3H), 1.83 - 1.35 (m, 8H).
Example 356: A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-(((4- methylmorpholin-2-yl)methyl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000343_0001
[0805] Example 356 was prepared analogously to Example 333 using (4- methylmo holin-2-yl)methanamine in place of tert-butyl (2-aminoethyl)carbamate. C2oH2oClF3N602. 469.2 (M+1). XH NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.89 (s, 1H), 8.67 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.5, 2.8 Hz, 1H), 6.81 (dd, J = 12.3, 6.9 Hz, 1H), 6.53 (ddd, J = 8.9, 4.1, 2.7 Hz, 1H), 4.07 (d, J = 12.7 Hz, 1H), 3.96 - 3.83 (m, 1H), 3.66 (t, J = 12.4 Hz, 1H), 3.59 - 3.32 (m, 4H), 3.10 - 2.95 (m, 1H), 2.90 - 2.80 (m, 4H).
Example 357: iV-(3-chloro-4-fluorophenyl)-iV-hydroxy-2-(((4-methylmorpholin-2- yl)methyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000343_0002
[0806] Example 357 was prepared analogously to Example 333 using 3-(2-chloro-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)- l,2,4-oxadiazol-5(4H)-one and
Figure imgf000343_0003
in place of tert- butyl (2-aminoethyl)carbamate. C19H21CIFN7O2. 434.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 10.18 (s, 1H), 8.93 (s, 1H), 7.96 (d, J = 6.2 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 6.99 (dd, J = 6.5, 2.8 Hz, 1H), 6.91 (d, J = 6.2 Hz, 1H), 6.58 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 4.07 (d, J = 12.8 Hz, 1H), 3.90 (s, 1H), 3.73 - 3.34 (m, 5H), 3.08 - 2.94 (m, 1H), 2.92 - 2.77 (m, 4H).
Example 358: A-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-(((l-methyl-lH-pyrazol-5- yl)methyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000344_0001
[0807] Example 358 was prepared analogously to Example 333 using 3-(2-chloro-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)- l,2,4-oxadiazol-5(4H)-one and (l-methyl-lH-pyrazol-5-yl)methanamine in place of tert- butyl (2-aminoethyl)carbamate. CI8HI6C1FN80. 415.1 (M+l). 'H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.98 (s, 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.32 (d, J = 1.9 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 6.5, 2.7 Hz, 1H), 6.93 (d, J = 6.4 Hz, 1H), 6.61 - 6.53 (m, 1H), 6.18 (d, J = 1.9 Hz, 1H), 4.71 (d, J = 5.9 Hz, 2H), 3.83 (s, 3H).
Example 359: 2-((7-(A-(3-chloro-4-fluorophenyl)-A^-hydroxycarbamimidoyl)-lH- imidazo[4,5-b]pyridin-2-yl)amino)-A V-dimethylacetamide
Figure imgf000344_0002
[0808] Example 359 was prepared analogously to Example 333 using 3-(2-chloro-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)- l,2,4-oxadiazol-5(4H)-one and (4-methylmo holin-2-yl)methanamine in place of tert- butyl (2-aminoethyl)carbamate. C17H17CIFN7O2. 406.2 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 8.95 (s, 1H), 7.98 (d, J = 6.2 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 6.58 (ddd, J = 8.9, 3.9, 2.7 Hz, 1H), 4.30 (d, J = 4.9 Hz, 2H), 2.98 (s, 3H), 2.89 (s, 3H).
Examples 360 and 361: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-(3- (hydroxymethyl)azetidin-l-yl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide and A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((oxetan-3-ylmethyl)amino)-lH- imidazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000345_0001
[0809] Examples 360 and 361 were prepared analogously to Example 333 using 3- (2-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3- chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro- l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and oxetan-3-ylmethanamine in place of tert- butyl (2-aminoethyl)carbamate. CI7HI6C1FN602. 391.1 (M+l). XH NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 11.22 (s, 1H), 8.92 (s, 1H), 8.09 (s, 1H), 7.08 (t, J = 9.0 Hz, 1H), 7.03 (d, J = 5.4 Hz, 1H), 6.99 (dd, J = 6.4, 2.7 Hz, 1H), 6.53 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 4.98 (s, 1H), 4.23 (dd, J = 12.4, 4.9 Hz, 1H), 3.78 (dd, J = 12.3, 8.6 Hz, 1H), 3.35 - 3.23 (m, 1H). CI7HI6C1FN602. 391.1 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.44 - 9.28 (m, 1H), 9.09 (s, 1H), 7.97 - 7.85 (m, 1H), 7.09 (dd, J = 6.5, 2.7 Hz, 1H), 7.04 (t, J = 9.0 Hz, 1H), 6.83 (s, 1H), 6.59 (dt, J = 8.9, 3.6 Hz, 1H), 4.26 (dd, J = 12.3, 4.8 Hz, 1H), 3.91 - 3.81 (m, 1H), 3.25 (t, J = 10.9 Hz, 1H). Example 362: iV-(3-chloro-4-fluorophenyl)-iV-hydroxy-2-((2-(l-methyl-lH- imidazol-2-yl)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000346_0001
[0810] Example 362 was prepared analogously to Example 333 using 3-(2-chloro-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)- l,2,4-oxadiazol-5(4H)-one and 2-(l -methyl- lH-imidazol-2-yl)ethanamine in place of tert-butyl (2-aminoethyl)carbamate. Ci9Hi8ClFN80.429.2 (M+1). 'H NMR (400 MHz, DMSO-d6) 5 11.36 (s, 1H), 8.96 (s, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 6.99 (dd, J = 6.5, 2.7 Hz, 1H), 6.94 (d, J = 6.2 Hz, 1H), 6.60 - 6.50 (m, 1H), 3.83 - 3.68 (m, 5H), 3.31 - 3.21 (m, 2H).
Example 363: iV-(3-chloro-4-fluorophenyl)-iV-hydroxy-2-((3-(pyridin-2- ylamino)propyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000346_0002
[0811] Example 363 was prepared analogously to Example 333 using 3-(2-chloro-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)- l,2,4-oxadiazol-5(4H)-one and N1-(pyridin-2-yl)propane-l,3-diamine in place of tert- butyl (2-aminoethyl)carbamate. C2iH20ClFN8O.455.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.95 (s, 1H), 7.95 (d, J = 6.2 Hz, 1H), 7.92 (d, J = 6.2 Hz, 1H), 7.85 - 7.74 (m, 1H), 7.08 (t, J = 9.0 Hz, 1H), 7.01 (dd, J = 6.5, 2.7 Hz, 1H), 6.91 (d, J = 6.2 Hz, 1H), 6.84 - 6.72 (m, 1H), 6.56 (dt, J = 9.0, 4.0, 3.0 Hz, 1H), 3.56 - 3.44 (m, 2H), 3.42 - 3.31 (m, 2H), 1.96 - 1.83 (m, 2H). Example 364 : iV-(3-chloro-4-fluorophenyl)-iV-hydroxy-2-(neopenrylamino)- 1H- imidazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000347_0001
[0812] Example 364 was prepared analogously to Example 333 using 3-(2-chloro-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-
I, 2,4-oxadiazol-5(4H)-one and isopentylamine in place of tert-butyl (2- aminoethyl)carbamate. Ci8H20ClFN6O. 391.2 (M+1). 'H NMR (400 MHz, DMSO-d6) δ
I I .41 (s, 1H), 8.95 (s, 1H), 7.95 (d, J = 6.3 Hz, 1H), 7.09 (t, J = 8.9 Hz, 1H), 7.03 (dd, J = 6.6, 2.7 Hz, 1H), 6.91 (d, J = 6.2 Hz, 1H), 6.62 - 6.53 (m, 1H), 3.27 (d, J = 6.3 Hz, 2H), 0.92 (s, 9H).
Example 365: iV-(3-chloro-4-fluorophenyl)-iV-hydroxy-2-(isoburylamino)- imidazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000347_0002
[0813] Example 365 was prepared analogously to Example 333 using 3-(2-chloro-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one in place of S-^-chloro^S-difluoro-l-^- rimethylsily ethoxy^ethy^-lH-benzofdlimidazol-^^
I, 2,4-oxadiazol-5(4H)-one and isobutylamine in place of tert-butyl (2- aminoethyl)carbamate. CnHi8ClFN60. 377.2 (M+1). 'H NMR (400 MHz, DMSO-d6) δ
I I.38 (s, 1H), 8.95 (s, 1H), 7.95 (d, J = 6.2 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 7.03 (dd, J = 6.6, 2.7 Hz, 1H), 6.91 (d, J = 6.2 Hz, 1H), 6.61 - 6.51 (m, 1H), 3.29 - 3.18 (m, 2H), 1.95 - 1.78 (m, 1H), 0.90 (d, J = 6.7 Hz, 6H).
Example 366: iV-(3-chloro-4-fluorophenyl)-iV-hydroxy-2-(((tetrahydro-2H-pyran-2- yl)methyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000348_0001
[0814] Example 366 was prepared analogously to Example 333 using 3-(2-chloro-l - ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-l -((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)- l,2,4-oxadiazol-5(4H)-one and (tetrahydro-2H-pyran-2-yl)methanamine in place of tert- butyl (2-aminoethyl)carbamate. Ci9H2oClFN602. 419.2 (M+l). XH NMR (400 MHz, DMSO-d6) δ 1 1.43 (s, 1H), 8.95 (s, 1H), 7.95 (d, J = 6.4 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 6.90 (d, J = 6.3 Hz, 1H), 6.62 - 6.54 (m, 1H), 3.91 (d, J = 11.2 Hz, 1H), 3.57 - 3.43 (m, 2H), 3.44 - 3.30 (m, 2H), 1.84 - 1.71 (m, 1H), 1.58 (d, J = 12.7 Hz, 1H), 1.54 - 1.38 (m, 3H), 1.30 - 1.14 (m, 1H).
Example 367: iV-(3-chloro-4-fluorophenyl)-iV-hydroxy-2-(((tetrahydrofuran-3- yl)methyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000348_0002
[0815] Example 367 was prepared analogously to Example 333 using 3-(2-chloro-l - ((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-l -((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)- l,2,4-oxadiazol-5(4H)-one and (tetrahydrofuran-3-yl)methanamine in place of tert-butyl (2-aminoethyl)carbamate. CI8HI8C1FN602. 405.2 (M+l). ¾ NMR (400 MHz, DMSO- d6) δ 11.38 (s, 1H), 8.96 (s, 1H), 7.95 (d, J = 6.3 Hz, 1H), 7.08 (t, J = 9.0 Hz, 1H), 7.03 (dd, J = 6.5, 2.7 Hz, 1H), 6.91 (d, J = 6.2 Hz, 1H), 6.59 - 6.53 (m, 1H), 3.75 (td, J = 8.1, 5.6 Hz, 1H), 3.68 (dd, J = 8.6, 7.0 Hz, 1H), 3.62 (td, J = 8.0, 6.7 Hz, 1H), 3.47 (dd, J = 8.7, 5.1 Hz, 1H), 3.43 - 3.36 (m, 2H), 2.00 - 1.90 (m, 1H), 1.58 (dq, J = 12.8, 6.4, 6.3 Hz, 1H).
Example 368: A^-(3-chloro-4-fluorophenyl)-4-fluoro-A^-hydroxy-2-((2-
Figure imgf000349_0001
[0816] Methyl 2,3-diamino-4-fluorobenzoate (0.150 g, 0.814 mmol) was dissolved in THF (4.0 mL) and 4-(2-isothiocyanatoethyl)mo holine (5.0 mmol) and triethylamine (7.0 mmol) was added. The reaction was sealed in a vial and heated to 66 °C for 12 hours. l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.0 mmol) was added in one portion and the reaction was allowed to heat an additional 1 hour at 66 °C. The reaction was cooled to rt and quenched with saturated sodium bicarbonate solution (4 mL). The reaction mixture was extracted with EtOAc (3 x 3 mL) and the combined organic layers were washed once with water, concentrated, and purified by silica gel column chromatography (0-15% MeOH/CH2Cl2, Rf= 0.33 in 10% MeOH/ CH2C12) to give methyl 4-fluoro-2-((2-morpholinoethyl)amino)-lH-benzo[d]imidazole-7- carboxylate.
[0817] Methyl 4-fluoro-2-((2-mo holinoethyl)amino)-lH-benzo[d]imidazole-7- carboxylate (0.208g, 0.645 mmol) and 3-chloro-4-fluoroaniline (3.0 mmol) were dissolved in DCE (6.0 mL) under inert conditions. Trimethylaluminium (5.0 mmol, 2.26 mL) was added at 0 C and the reaction was then heated to 60 C overnight. The reaction was allowed to cool to rt, quenched with water (3 mL) and extracted with EtOAc (4 x 3 mL). The combined organic layers were washed once with water, concentrated, and purified by silica gel chromatography (Rf= 0.37 10% MeOH/DCM) to give the desired product.
Figure imgf000350_0001
[0818] N-(3-chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy-2-((2- mo holinoethyl)amino)-lH-benzo[d]imidazole-7-carboxilτddamide was made analogously to Example 10 using the procedure for hydroxy ami dine formation.
C20H2iClF2N6O2. 451.8 (M+l).
Example 369: /V-(3-chloro-4-fluorophenyl)-/V-hydroxy-/V-methyl-lH-imidazo[4,5- b] pyridine- 7-carboximidamide
Figure imgf000350_0002
[0819] lH-imidazo[4,5-b]pyridine-7-carboxylic acid (0.20 g, 1.22 mmol) and 3- chloro-4-fluoro-N-methylaniline hydrochloride (1.02 mmol) were dissolved in DMF (3.0 mL) and HATU (1.2 mmol) and DIPEA (2.78 mmol) were added and the reaction was allowed to stir overnight at rt. The reaction was quenched with sat/ sodium bicarbonate solution (3.0 mL) and the reaction was extracted with EtOAc (3 2 mL). Combined organic layers were washed with water (lx 4 mL) and the crude was purified by silica gel chromatography (Rf=0.25 50% EtO Ac/hex) to give N-(3-chloro-4-fluorophenyl)-N- methyl-lH-imidazo[4,5-b]pyridine-7-carboxamide. [0820] N-(3-chloro-4-fluorophenyl)-N-methyl-lH-imidazo[4,5-b]pyridine-7- carboxamide (0.05g, 0.164 mmol) was dissolved in toluene (3.0 mL) and Lawesson's reagent (0.656 mmol) was added. The reaction was sealed in a vial and heated overnig at 100 C. The reaction was then cooled to rt and solids were removed by vacuum filtration. The filtrate was concentrated and purified by silica gel chromatography to give N-(3-chloro-4-fluorophenyl)-N-methyl-lH-imidazo[4,5-b]pyridine-7- carbothioamide.
Figure imgf000351_0001
[0821] N-(3-chloro-4-fluorophenyl)-N-methyl-lH-imidazo[4,5-b]pyridine-7- carbothioamide (0.014 g, 0.0455 mmol) was dissolved in ethanol (3.0 mL) and hydroxylamine (50% solution in water) (0.455 mmol) was added and the reaction was allowed to stir at rt overnight. The reaction was concentrated to dryness then purified by RP HPLC to give N-(3-chloro-4-fluorophenyl)-N'-hydroxy-N-methyl-lH-imidazo[4,5- b]pyridine-7-carboximidamide (3.1 mg, 21%). Ci4HnClFN50. 320.7 (M+l).
Example 370: 2-amino-A^-(3-chloro-4-fluorophenyl)-5-fluoro-A^-hydroxy-lH- -7-carboximidamide
Figure imgf000351_0002
[0822] 2,3-diamino-5-fluorobenzoic acid (5.0 g, 29 mmol) was dissolved in sulfuric acid (5.0 mL) and MeOH (40.0 mL) and heated to 71 C overnight. The reaction was allowed to cool to rt then concentrated to approximately half the volume. The reaction was neutralized to pH=7 with saturated sodium carbonate solution then extracted with EtOAc (5 x 20 mL). Combined organic layers were washed once with water and concentrated to dryness to give methyl 2,3-diamino-5-fluorobenzoate. [0823] Methyl 2,3-diamino-5-fluorobenzoate (2.0 g, 11.0 mmol) and cyanogen bromide (1 1.0 mmol) were dissolved in methanol (45 mL) and water (20 mL) and heated to 70 C for 30 mins. The reaction was cooled to rt and diluted with water (5 mL) and EtOAc (20 mL). The water layer was separated and neutralized to pH=7 with saturated sodium carbonate solution then extracted with EtOAc (4 x 10 mL). The combined organic layers were washed once with water then concentrated to give methyl 2-amino-5- fluoro-lH-benzo[d]imidazole-7-carboxylate.
[0824] Methyl 2-amino-5-fluoro-lH-benzo[d]imidazole-7-carboxylate (0.2g, 0.956 mmol) and 3-chloro-4-fluoroaniline (4.0 mmol) were dissolved in DCE (3.0 mL) and cooled to 0 C under an inert atmosphere. Trimethylaluminium (7.0 mmol, 3.34 mL) was added and the reaction was slowly heated to 65 C overnight. The reaction was cooled to rt, quenched with water (3 mL) and extracted with EtOAc (3 x 5 mL). Combined organic layers were washed once with water and purified by silica gel chromatography (Rf 100% EtOAc = 0.32) to give 2-amino-N-(3-chloro-4-fluorophenyl)-5-fluoro-lH- benzo[d]imidazole-7-carboxamide.
Figure imgf000352_0001
[0825] 2-amino-N-(3-chloro-4-fluorophenyl)-5-fluoro-lH-benzo[d]imidazole-7- carboxamide and Lawesson's reagent (3.0 mmol) were dissolved in toluene and heated overnight at 100 C. The reaction was allowed to cool to rt and the solids were removed by filtration. The filtrate was concentrated and used directly in the next reaction with no further purification.
[0826] 2-amino-N-(3-chloro-4-fluorophenyl)-5-fluoro-lH-benzo[d]imidazole-7- carbothioamide (0.267 g, 0.788 mmol) was dissolved in ethanol (3 mL) and
hydroxylamine (50% solution in water) (0.5 mL) was added and the reaction was allowed to stir overnight at rt. The reaction was concentrated and purified by RP HPLC to give 2-amino-N-(3-chloro-4-fluorophenyl)-5-fluoro-N'-hydroxy-lH- benzo[d]imidazole-7-carboximidamide. C14H10CIF2N5O. 338.1 (M+l). Example 371: 2-amino-iV-(3-chlorophenyl)-5-fluoro-iV' -hydroxy- LH- zo[d]imidazole-7-carboximidamide
Figure imgf000353_0001
[0827] Example 371 was made analogously to Example 370 using 3-chloroaniline in place of 3 -chloro-4-fluoroaniline. Ci4HnClFN50. 320.7 (M+1). IH NMR (400 MHz, DMSO-d6) δ 12.05 (s, IH), 11.10 (s, IH), 8.83 (s, IH), 8.26 (s, 2H), 7.26 (dd, J = 8.3, 2.4 Hz, IH), 7.06 (t, J = 8.3 Hz, IH), 6.91 (dd, J = 10.5, 2.4 Hz, IH), 6.88 - 6.83 (m, 2H), 6.57 - 6.48 (m, IH).
Example 372: 2-amino-iV-(3-bromophenyl)-5-fluoro-iV' -hydroxy- 1H- o[d]imidazole-7-carboximidamide
Figure imgf000353_0002
[0828] Example 372 was made analogously to Example 370 using 3-bromoaniline in place of 3 -chloro-4-fluoroaniline. Ci4HnBrFN50. 365.2 (M+1). IH NMR (400 MHz, DMSO-d6) δ 12.05 (s, IH), 11.10 (s, IH), 8.82 (s, IH), 8.27 (s, 2H), 7.26 (dd, J = 8.3, 2.4 Hz, IH), 7.04 - 6.95 (m, 3H), 6.91 (dd, J = 10.5, 2.4 Hz, IH), 6.60 - 6.51 (m, IH).
Example 373: 2-amino-iV-(3-bromo-4-fluorophenyl)-5-fluoro-iV' -hydroxy- 1H- o[d]imidazole-7-carboximidamide
Figure imgf000353_0003
[0829] Example 373 was made analogously to Example 370 using 3-bromo-4- fluoroaniline in place of 3-chloro-4-fluoroaniline. Ci4HioBrF2N50. 383.2 (M+1). IH NMR (400 MHz, DMSO-d6) δ 12.11 (s, IH), 11.03 (s, IH), 8.79 (s, IH), 8.36 - 8.23 (m, 2H), 7.26 (dd, J = 8.3, 2.4 Hz, 1H), 7.13 - 7.04 (m, 2H), 6.92 (dd, J = 10.5, 2.4 Hz, 1H), 6.60 (ddd, J = 8.9, 4.2, 2.8 Hz, 1H).
Example 374: A^-(3-chloro-4-fluorophenyl)-2-((2-(l,l- dioxidothiomorpholino)ethyl)amino)-4,5-difluoro-A^-hydroxy-lH- benzo[d]imidazole-7-carboximidamide
Figure imgf000354_0001
[0830] Example 374 was made analogously to Example 32 using 4-(2- aminoethyl)thiomorpholine 1 , 1-dioxide. C2oH2oClF3N603S. 517.9 (M+l).
Example 375: A^-(3-chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-4- fluoro-iV-hydroxy-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000354_0002
[0831] N^N^diethylethane-l ^-diamine (0.50 g, 4.0 mmol) and sodium bicarbonate (86 mmol) were dissolved in DCM (12.0 mL) under argon. Thiophosgene (17.0 mmol) was added dropwise and the reaction was allowed to stir at rt for 2 hours. DCM (10 mL) and water (10 mL) were added and the water layer was extracted with DCM (2 x 8 mL). Combined organic layers were washed with water (1 x 20 mL) and concentrated to a volume of 5 mL to give N,N-diethyl-2-isothiocyanatoethan-l -amine which was used without further purification.
[0832] N-(3-chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-4-fluoro-N'- hydroxy-lH-benzo[d]imidazole-7-carboximidamide was made analogously to Example 23 using N,N-diethyl-2-isothiocyanatoethan-l -amine, methyl 2,3-diamino-4- fluorobenzoate, and 3-chloro-4-fluoroaniline. C2oH22ClF3N60. 437.9 (M+l).
Example 376: A^-(3-chloro-4-fluorophenyl)-4-fluoro-A^-hydroxy-2-((2-(pyrrolidin-l- yl)ethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000355_0001
[0833] Example 376 was made analogously to Example 375 using 2-(pyrrolidin-l- yl)ethan-l -amine in place of N^N^diethylethane-l ^-diamine. C20H2iClF2N6O. 435.8 (M+l).
Example 377 : A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-((2- morpholinopropyl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000355_0002
[0834] Example 377 was made analogously to Example 32 using 2- morpholinopropan-1 -amine. C2iH22ClF3N602. 483.9 (M+l). 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.71 (s, 1H), 7.17 (s, 1H), 7.09 (td, J = 9.1 , 2.4 Hz, 2H), 6.94 (dd, J = 6.5, 2.7 Hz, 1H), 6.88 (dd, J = 12.2, 6.9 Hz, 1H), 6.78 (d, J = 6.4 Hz, 1H), 6.60 (d, J = 9.1 Hz, 1H), 6.54 (ddd, J = 9.0, 4.1 , 2.7 Hz, 1H), 3.89 (s, 4H), 3.72 (s, 1H), 3.69 - 3.55 (m, 2H), 3.37 (s, 4H), 1.29 (d, J = 6.6 Hz, 3H). Example 378: iV-(3-chloro-4-fluorophenyl)-2-((l-(dimethylamino)propan-2- yl)amino)-4,5-difluoro-iV -hydroxy- IH-benzo [d] imidazole-7-carboximidamide
Figure imgf000356_0001
[0835] Exampl 378 was made analogously to Example 23 using N^N1- dimethylpropane-l,2-diamine. Ci9H2oClF3N60. 441.8 (M+l).
Example 379 : A^-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-5- fluoro-iV-hydroxy-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000356_0002
[0836] Example 379 was made analogously to Example 23 using methyl 2,3- diamino-5-fluorobenzoate and 2-isothiocyanato-N,N-dimethylethan-l -amine.
CI8HI9C1F2N60. 409.8 (M+l). 1H NMR (400 MHz, Methanol-d4) 5 7.19 (dd, J = 8.1, 2.4 Hz, 1H), 6.97 (t, J = 8.9 Hz, 1H), 6.94 - 6.89 (m, 2H), 6.69 (dt, J = 8.8, 3.4 Hz, 1H), 3.85 (d, J = 5.8 Hz, 3H), 3.46 (dd, J = 12.2, 6.4 Hz, 3H), 2.99 (s, 6H).
Example 380: A^-(3-chloro-4-fluorophenyl)-5-fluoro-A^-hydroxy-2-((2-(pyrrolidin-l- -lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000356_0003
[0837] Example 380 was made analogously to Example 375 using l-(2- isothiocyanatoethyl)pyrrolidine. C2oH2iClF2N60. 435.8 (M+l). Example 381 : A^-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)-2,2- dimethylpropyl)amino)-4-fluoro-A^-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
Figure imgf000357_0001
[0838] Example 381 was made analogously to Example 23 using methyl 2,3- diamino-4-fluorobenzoate and 3-isothiocyanato-N,N,2,2-tetramethylpropan- 1 -amine (made from
Figure imgf000357_0002
C2iH25ClF2N60. 451.9 (M+1).
Example 382: A^-(3-bromo-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4- fluoro-iV-hydroxy-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000357_0003
[0839] Example 382 was made analogously to Example 23 using methyl 2,3- diamino-4-fluorobenzoate, 2-isothiocyanato-N,N-dimethylethan-l -amine, and 3-bromo- 4-fluoroaniline. Ci8Hi9BrF2N60. 454.3 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.41 (dd, J = 6.0, 2.4 Hz, 1H), 7.36 (dd, J = 8.7, 4.4 Hz, 1H), 7.16 (dd, J = 9.9, 8.7 Hz, 1H), 7.09 - 7.01 (m, 2H), 3.94 (t, J = 5.9 Hz, 2H), 3.52 (t, J = 6.0 Hz, 2H), 3.01 (s, 6H).
Example 383 : A^-(3-bromophenyl)-2-((2-(dimethylamino)ethyl)amino)-4-fluoro-A^- hydroxy- lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000357_0004
[0840] Example 383 was made analogously to Example 23 using methyl 2,3- diamino-4-fluorobenzoate, 2-isothiocyanato-N,N-dimethylethan-l -amine, and 3- bromoaniline. Ci8H20BrFN6O. 436.3 (M+1). IH NMR (400 MHz, Methanol-d4) δ 7.33 (dd, J = 8.8, 4.5 Hz, IH), 7.26 (d, J = 8.4 Hz, 2H), 7.19 - 7.06 (m, 2H), 6.93 (d, J = 8.6 Hz, IH), 3.92 (t, J = 6.0 Hz, 2H), 3.51 (t, J = 6.0 Hz, 2H), 3.01 (s, 6H).
Example 384 : iV-(3-chlorophenyl)-2-((2-(dimethylamino)ethyl)amino)
- lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000358_0001
[0841] Example 384 was made analogously to Example 23 using methyl 2,3- diamino-4-fluorobenzoate, 2-isothiocyanato-N,N-dimethylethan-l -amine, and 3- chloroaniline. Ci8H20ClFN6O. 391.8 (M+1). IH NMR (400 MHz, Methanol-d4) δ 7.39 (dd, J = 8.7, 4.4 Hz, IH), 7.22 - 7.01 (m, 5H), 6.94 (dq, J = 7.1, 2.3 Hz, IH), 3.94 (t, J = 6.0 Hz, 2H), 3.52 (t, J = 6.1 Hz, 3H), 3.00 (s, 6H).
Example 385 : iV-(3-chlorophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5- -iV -hydroxy- lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000358_0002
[0842] Example 385 was made analogously to Example 32 using methyl 2-chloro- 4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate, Nl,Nl-dimethylpropane-l,3-diamine, and 3 -chloroaniline. C19H21CIF2N5O. 423.9 (M+1). IH NMR (400 MHz, DMSO-d6) δ 10.88 (s, IH), 9.69 (s, IH), 8.74 (s, IH), 7.05 (t, J = 8.3 Hz, IH), 6.95 - 6.78 (m, 3H), 6.52 (dt, J = 8.3, 1.6 Hz, IH), 3.42 (d, J = 6.4 Hz, 2H), 3.09 (d, J = 10.5 Hz, 2H), 2.80 (d, J = 4.4 Hz, 6H), 1.94 (p, J = 6.8 Hz, 2H). Example 386: iV-(3-bromophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5- difluoro-iV -hydroxy- lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000359_0001
[0843] Example 386 was made analogously to Example 32 using methyl 2-chloro- 4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate, Nl,Nl-dimethylpropane-l,3-diamine, and 3-bromoaniline. Ci9H2iBrF2NeO. 468.3 (M+l). 1H NMR (400 MHz, Methanol-d4) δ 7.37 - 7.27 (m, 1H), 7.10 - 6.99 (m, 3H), 6.69 (ddd, J = 8.0, 2.2, 1.1 Hz, 1H), 3.57 (t, J = 6.6 Hz, 2H), 3.28 - 3.21 (m, 2H), 2.93 (s, 6H), 2.18 - 2.08 (m, 2H).
Example 387: iV-(3-bromo-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)- -difluoro-iV -hydroxy- lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000359_0002
[0844] Example 387 was made analogously to Example 32 using methyl 2-chloro- 4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate, Nl,Nl-dimethylpropane-l,3-diamine, and 3-bromo-4-fluoroaniline. Ci9H2oBrF3N60. 486.3 (M+l). 1H NMR (400 MHz, Methanol-d4) δ 7.14 - 7.04 (m, 2H), 6.96 (t, J = 8.6 Hz, 1H), 6.74 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 3.56 (t, J = 6.6 Hz, 2H), 3.28 - 3.21 (m, 2H), 2.93 (s, 6H), 2.17 - 2.09 (m, 2H). Example 388 : A-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-4- -iV-hydroxy-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000360_0001
[0845] Example 388 was made analogously to Example 23 using methyl 2,3- diamino-4-fluorobenzoate and 3-isothiocy anato-N,N-dimethylpropan- 1 -amine.
C I9H2IC1F2N60. 423.8 (M+l) 1H NMR (400 MHz, Methanol-d4) δ 7.44 (dd, J = 8.8, 4.3 Hz, 1H), 7.39 (dd, J = 6.4, 2.3 Hz, 1H), 7.23 (dd, J = 9.8, 8.8 Hz, 1H), 7.15 - 7.05 (m, 2H), 3.62 (t, J = 6.8 Hz, 2H), 3.34 - 3.30 (m, 2H), 2.17 (t, J = 8.0 Hz, 2H).
Example 389 : A-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-5- -iV-hydroxy-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000360_0002
[0846] Example 389 was made analogously to Example 23 using methyl 2,3- diamino-5-fluorobenzoate, 3-isothiocyanato-N,N-dimethylpropan-l -amine, and 3- chloro-4-fluoroaniline. CI9H2IC1F2N60. 423.8 (M+l).
Example 390: 2-((2-(benzyl(methyl)amino)ethyl)amino)-iV-(3-chloro-4- fluorophenyl)-4,5-difluoro-iV -hydroxy- LH-benzo[d] imidazole- 7-carboximidamide
Figure imgf000360_0003
[0847] Example 390 was made analogously to Example 32 using N^benzyl-N1- methylethane-l,2-diamine. C24H22C1F3N60. 503.9 (M+l).
Example 391: A^-(3-chloro-4-fluorophenyl)-2-(2- ((cyclohexylmethyl)(methyl)amino)ethyl)-A^-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000361_0001
[0848] Example 391 was made analogously to Example 184 using N-(3-chloro-4- fluorophenyl)-2-(2-hydroxyethyl)-lH-imidazo[4,5-b]pyridine-7-carboxamide and 1- cyclohexyl-N-methylmethanamine. C23H28C1FN60. 459.9 (M+l).
Example 392: A-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-(2- thyl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000361_0002
[0849] Example 392 was made analogously to Example 184 using N,2,2- trimethylpropan-1 -amine hydrochloride. C2iH26ClFN60. 434.1 (M+l).
Example 393 : iV-(3-chloro-4-fluorophenyl)-2-(2-(cyclohexyl(methyl)amino)i
iV-hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000361_0003
[0850] Example 393 was made analogously to Example 184 using N- methylcyclohexanamine. C22H26C1FN60. 445.9 (M+l). Example 394: A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-((2- (methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)amino)-lH- benzo[d]imidazole-7-carboximidamide
Figure imgf000362_0001
[0851] Methyl 2-chloro-4,5-difluoro-l -((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazole-7-carboxylate (1.39 g, 4.0 mmol) and tert-butyl (2- aminoethyl)(methyl)carbamate (6.0 mmol) were dissolved in DMSO (5.0 mL) and heated overnight at 60 C. The reaction was allowed to cool to rt and quenched with water (3 mL). The reaction was extracted with EtOAc (5 x 3mL) and combined organic layers were washed once with water and purified by silica gel column chromatography to give methyl 2-((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)amino)-4,5-difluoro-l -((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate .
[0852] Methyl 2-((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)amino)-4,5- difluoro-l -((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate (1.14 g, 2.0 mmol) and 3-chloro-4-fluoroaniline (9.0 mmol) were dissolved in DCE (15.0 mL) under an inert atmosphere. Triemthylaluminium (9.0 mmol, 4.430 mL) was added at 0 C and the reaction was allowed to come to rt and stir overnight. The reaction was quenched with water (5 mL) and extracted with DCM (3 x 6 mL). Combined organic layers were washed with water (1 x 8 mL) and concentrated to dryness. The crude was dissolved in DCM (8 mL) and TFA (4 mL) was added and the reaction was allowed to stir at rt for 1 hour. The reaction was concentrated and purified by silica gel chromatography to give N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((2- (methylamino)ethyl)amino)-lH-benzo[d]imidazole-7-carboxamide.
Figure imgf000363_0001
[0853] N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((2-(methylamino)ethyl)amino)- lH-benzo[d]imidazole-7-carboxamide (0.053 g, 0.132 mmol) and tetrahydro-2H-pyran- 4-carbaldehyde (0.126 mmol) were dissolved in DCE (2.0 mL) under inert conditions. Sodium triacetoxyborohydride (STAB) (0.176 mmol) was added and the reaction was allowed to stir for 2 hours at rt. The reaction was quenched with water (3 mL) and then extracted with DCM (3 x 4 mL). Combined organic layers were washed once with water, dried over Mg2S04, filtered, and concentrated to give N-(3-chloro-4- fluorophenyl)-4,5-difluoro-2-((2-(methyl((tetrahydro-2H-pyran-4- yl)methyl)amino)ethyl)amino)-lH-benzo[d]imidazole-7-carboxamide, which was then converted to N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2- (methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)ethyl)amino)-lH-benzo[d]imidazole- 7-carboximidamide using hydroxyamidine formation conditions described herein. C23H26C1F3N602. 512.0 (M+l). 1H NMR (400 MHz, Methanol-d4) δ 7.45 (s, 1H), 6.95 (t, J = 8.9 Hz, 1H), 6.86 (td, J = 7.4, 4.9 Hz, 2H), 6.66 - 6.60 (m, 1H), 3.90 - 3.81 (m, 2H), 3.75 (t, J = 5.1 Hz, 2H), 3.43 (d, J = 5.9 Hz, 2H), 3.41 - 3.35 (m, 2H), 3.14 (d, J = 7.1 Hz, 2H), 3.00 (s, 3H), 1.71 (d, J = 13.0 Hz, 2H), 1.43 - 1.26 (m, 3H).
Example 395 : iV-(3-chloro-4-fluorophenyl)-4,5-difluoro-iV-hydroxy-2-((2- (methylamino)ethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000363_0002
[0854] 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one (0.03 g, 0.0565 mmol) and tert-butyl (2-aminoethyl)(methyl)carbamate (0.0847 mmol) were dissolved in DMS (0.6 mL) and heated overnight at 60 C. The reaction was cooled to rt, diluted with water, and extracted with DCM (3 x 1 mL). Combined organic layers were washed once with water and concentrated to give tert-butyl (2-((7-(4-(3-chloro-4- fluorophenyl)-5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)-4,5-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-2- yl)amino)ethyl)(methyl)carbamate which was used without further purification.
[0855] Tert-butyl (2-((7-(4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol- 2-yl)amino)ethyl)(methyl)carbamate (0.057 mmol) was dissolved in DCM (2 mL) and TFA (1.0 mL) was added and the reaction was allowed to stir at rt for 2 hours before being concentrated to dryness. The residue was then dissolved in MeOH (2.0 mL) and 1M NaOH (0.5 mL) was added and the reaction was allowed to stir at rt for 30 mins. The reaction was then concentrated and purified by RP HPLC to N-(3-chloro-4- fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(methylamino)ethyl)amino)-lH- benzo[d]imidazole-7-carboximidamide. CI7HI6C1F3N60. 413.8 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.65 (s, 1H), 8.50 (s, 2H), 6.98 (t, J = 9.1 Hz, 1H), 6.85 - 6.80 (m, 1H), 6.76 (s, 1H), 6.42 (dt, J = 8.9, 3.4 Hz, 1H), 3.52 (d, J = 5.8 Hz, 2H), 3.04 (t, J = 5.9 Hz, 2H), 2.50 (t, J = 5.3 Hz, 3H).
Example 396: 2-(2-(benzyl(methyl)amino)ethyl)-A^-(3-chloro-4-fluorophenyl)-A^- hydroxy- lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000364_0001
[0856] Example 396 was made analogously to Example 184 using N-(3-chloro-4- fluorophenyl)-2-(2-hydroxyethyl)-lH-inddazo[4,5-b]pyridine-7-carboxamide and N- methyl-l-phenylmethanamine. C23H22C1FN60. 454.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.90 (s, 1H), 8.30 (d, J = 5.0 Hz, 1H), 7.56 (dd, J = 6.4, 3.3 Hz, 2H), 7.50 (dt, J = 4.5, 2.9 Hz, 3H), 7.15 (d, J = 5.1 Hz, 1H), 7.03 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.51 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 4.44 (s, 2H), 3.57 (t, J = 7.5 Hz, 2H), 3.36 (t, J = 7.4 Hz, 2H), 2.76 (s, 3H).
Example 397: A^-(3-chloro-4-fluorophenyl)-2-((2-((2- ethylbutyl)(methyl)amino)ethyl)amino)-4,5-difluoro-A^-hydroxy-lH- idazole-7-carboximidamide
Figure imgf000365_0001
[0857] Example 397 was made analogously to Example 395 using 2-ethylbutanal for the reductive amination. C23H28C1F3N60. 498.1 (M+1).
Example 398: A^(3-chloro-4-fluorophenyl)-2-((2- ((cyclopropylmethyl)(methyl)amino)ethyl)amino)-4,5-difluoro-A^ -hydroxy- 1H- midazole-7-carboximidamide
Figure imgf000365_0002
[0858] Example 398 was made analogously to Example 394 using
cyclopropanecarbaldehyde for the reductive amination. C2iH22ClF3N60. 468.1 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 6.95 (t, J = 8.9 Hz, 1H), 6.92 - 6.86 (m, 2H), 6.66 (ddd, J = 8.9, 3.9, 2.8 Hz, 1H), 3.77 (t, J = 5.3 Hz, 2H), 3.46 (d, J = 8.4 Hz, 2H), 3.14 (d, J = 7.2 Hz, 2H), 3.02 (s, 3H), 1.16 (ddd, J = 7.7, 4.7, 2.9 Hz, 1H), 0.71 (dd, J = 8.1, 1.5 Hz, 2H), 0.40 (dd, J = 4.7, 1.3 Hz, 2H). Example 399: iV-(3-chloro-4-fluorophenyl)-iV-hydroxy-2-(2-(methyl((tetrahydro- -pyran-4-yl)methyl)amino)ethyl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000366_0001
[0859] Example 399 was made analogously to Example 184 using N-methyl-1- (tetrahydro-2H-pyran-4-yl)methanamine. C22H26C1FN602. 461.9 (M+l).
Example 400: 2-(2-(((l,4-dioxan-2-yl)methyl)(methyl)amino)ethyl)-A^-(3-chloro-4- fluorophenyl)-iV-hydroxy-lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000366_0002
[0860] Example 400 was made analogously to Example 184 using l-(l,4-dioxan-2- yl)-N-methylmethanamine hydrochloride. C2iH24ClFN603. 463.9 (M+l). 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.89 (s, 1H), 8.31 (d, J = 5.1 Hz, 1H), 7.16 (d, J = 5.1 Hz, 1H), 7.05 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.52 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 4.10 - 4.01 (m, 1H), 3.83 - 3.20 (m, 13H), 2.89 (s, 3H).
Example 401: iV-(3-chloro-4-fluorophenyl)-iV-hydroxy-2-(2-(methyl(2-(tetrahydro- 2H-pyran-4-yl)ethyl)amino)ethyl)- IH-imidazo [4,5-b] pyridine- 7-carboximidamide
Figure imgf000367_0001
[0861] Example 401 was made analogously to Example 184 using N-methyl-2- (tetrahydro-2H-pyran-4-yl)ethan-l -amine. C23H28C1FN602. 476.0 (M+1). IH NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.91 (s, 1H), 8.30 (d, J = 5.1 Hz, 1H), 7.16 (d, J = 5.1 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.55 - 6.48 (m, 1H),
3.83 (dd, J = 11.2, 4.3 Hz, 2H), 3.55 (s, 1H), 3.35 - 3.23 (m, 4H), 3.23 - 3.15 (m, 2H),
2.84 (s, 3H), 1.59 (dd, J = 15.6, 10.5 Hz, 6H), 1.20 (d, J = 11.8 Hz, 2H).
Example 402 : A^-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropylamino)ethyl)amino)- iV-hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000367_0002
[0862] Example 402 was made analogously to Example 395 using 3-(2-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)- l,2,4-oxadiazol-5(4H)-one and tert-butyl (2-aminoethyl)(cyclopropyl)carbamate.
C18H19CIFN7O. 404.8 (M+1). IH NMR (400 MHz, DMSO-d6) δ 11.39 (s, 1H), 8.97 (s, 3H), 7.99 (d, J = 6.3 Hz, 1H), 7.11 (t, J = 9.1 Hz, 1H), 7.01 (dd, J = 6.5, 2.7 Hz, 1H), 6.95 (d, J = 6.3 Hz, 1H), 6.58 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 3.75 (s, 2H), 3.31 (s, 2H), 2.80 (s, 1H), 0.87 - 0.75 (m, 4H). Example 403: A^-(3-chloro-4-fluorophenyl)-2-((2- (cyclopropyl(ethyl)amino)ethyl)amino)-A^-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000368_0001
[0863] Example 403 was made analogously to Example 402 using N^cyclopropyl- N1-e lethane-l,2-diamine. C20H23CIFN7O. 432.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 7.97 (d, J = 6.1 Hz, 1H), 7.10 (t, J = 9.1 Hz, 1H), 6.99 (s, 1H), 6.93 (d, J = 6.0 Hz, 1H), 6.61 - 6.53 (m, 1H), 3.80 (s, 2H), 3.45 (s, 2H), 3.33 (s, 2H), 2.86 (s, 1H), 1.27 (t, J = 7.2 Hz, 3H), 1.00 - 0.78 (m, 4H).
Example 404: iV-(2-((7-(N-(3-chloro-4-fluorophenyl)-iV-hydroxycarbamimidoyl)- lH-imidazo [4,5-b] pyridin-2-yl)amino)ethyl)acetamide
Figure imgf000368_0002
[0864] Example 404 was made analogously to Example 402 using N-(2- aminoethyl)acetamide. C17H17CIFN7O2. 406.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.97 (s, 1H), 8.03 (s, 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.3 Hz, 1H), 6.63 - 6.55 (m, 1H), 3.50 (d, J = 6.0 Hz, 2H), 3.30 (d, J = 6.0 Hz, 2H), 1.82 (s, 3H). Example 405: iV-(3-chloro-4-fluorophenyl)-iV-hydroxy-2-((2- (methylsulfonamido)ethyl)amino)-lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000369_0001
[0865] Example 405 was made analogously to Example 402 using N-(2- aminoethyl)methanesulfonamide. CieHnClFNyOsS. 442.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H), 8.97 (s, 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.25 (d, J = 5.8 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.03 (s, 1H), 6.92 (d, J = 6.4 Hz, 1H), 6.59 (dt, J = 8.9, 3.4 Hz, 1H), 3.57 (d, J = 6.2 Hz, 2H), 3.21 (d, J = 6.1 Hz, 2H), 2.94 (s, 3H).
Example 406: A^-(3-chloro-4-fluorophenyl)-2-((2- (cyclopropyl(isopropyl)amino)ethyl)amino)-A^-hydroxy-lH-imidazo[4,5-b]pyridine- -carboximidamide
Figure imgf000369_0002
[0866] Example 406 was made analogously to Example 402 using N^cyclopropyl- N^isopropylethane-l^-diamine. C21H25CIFN7O. 446.4 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.94 (s, 1H), 7.97 (s, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.03 - 6.94 (m, 1H), 6.92 (d, J = 6.0 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 3.80 (s, 3H), 3.42 (s, 2H), 2.86 (s, 1H), 1.30 (d, J = 6.7 Hz, 6H), 1.01 (s, 2H), 0.89 (s, 2H). Example 407: A^-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(2- hydroxyethyl)amino)ethyl)amino)-A^-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide
Figure imgf000370_0001
[0867] Example 407 was made analogously to Example 402 using 2-((2- aminoethyl)(cyclopropyl)amino)ethan-l-ol dihydrochloride and Hunig's base.
C20H23CIFN7O2. 448.2 (M+l). 1H NMR (400 MHz, Methanol-d4) δ 7.89 (d, J = 6.5 Hz, 1H), 7.05 (d, J = 6.5 Hz, 1H), 7.03 - 6.95 (m, 2H), 6.67 (ddd, J = 8.9, 4.0, 2.8 Hz, 1H), 4.06 (t, J = 6.3 Hz, 2H), 4.01 - 3.95 (m, 2H), 3.71 (t, J = 6.3 Hz, 2H), 3.59 - 3.52 (m, 2H), 2.98 (dt, J = 7.3, 3.5 Hz, 1H), 1.19 - 1.12 (m, 2H), 1.07 - 1.01 (m, 2H).
Example 408: 2-((2-aminoethyl)amino)-A^-(3-chloro-4-fluorophenyl)-A^-hydroxy- lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000370_0002
[0868] Example 408 was made analogously to Example 402 using tert-butyl (2- aminoethyl)carbamate. CI5HI5C1FN70. 364.9 (M+l).
Example 409: A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-(((5-oxopyrrolidin-3- azo[4,5-b]pyridine-7-carboximidamide
Figure imgf000370_0003
[0869] Example 409 was made analogously to Example 402 using 4- (aminomethyl)pyrrolidin-2-one. CigHnClFNyC . 418.4 (M+l). Example 410: 2-(((lH-pyrazol-5-yl)methyl)amino)-iV-(3-chloro-4-fluorophi
- lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000371_0001
[0870] Example 410 was made analogously to Example 402 using (lH-pyrazol-5- yl)methanamine. CI7HI4C1FN80. 401. 1 (M+l).
Examples 411 and 412: iV-(3-((7-(N-(3-chloro-4-fluorophenyl)-iV'- hydroxycarbamimidoyl)-lH-imidazo[4,5-b]pyridin-2-yl)amino)propyl)acetamide and 2-((3-aminopropyl)amino)-A^-(3-chloro-4-fluorophenyl)-A^-hydroxy-lH- -b] pyridine- 7-carboximidamide
Figure imgf000371_0002
[0871] 3-(2-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin- 7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one (0.06 g, 0.121 mmol) and tert-butyl (3-aminopropyl)carbamate (0.181 mmol) were dissolved in DMSO (2.80 mL) and heated overnight at 60 C. The reaction was cooled to rt, diluted with water (3 mL) and extracted with EtOAc (3 x 2mL). Combined organic layers were washed with water (1 x 5 mL) and concentrated. The crude was dissolved in DCM (2 mL) and TFA (1.0 mL) was added and the reaction was allowed to stir at rt for 2 hours before being concentrated to dryness to give 3-(2-((3-aminopropyl)amino)-lH-imidazo[4,5-b]pyridin- 7-yl)-4-(3 -chloro-4-fluorophenyl)- 1 ,2,4-oxadiazol-5 (4H)-one.
Figure imgf000372_0001
[0872] 3-(2-((3-aminopropyl)amino)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one (0.015 g, 0.0317 mmol) was dissolved in THF (1.0 iriL) and triethylamine (0.186 mmol) was added. Acetyl chloride (0.0557 mmol) was added slowly and the reaction was allowed to stir at rt for 1 hour before being concentrated to dryness. The residue was dissolved in THF (0.4 mL), MeOH (0.4 mL) and 1M NaOH (0.6 mL) and stirred at rt for 1 hour. The reaction was concentrated and purified by RP HPLC to give two products: N-(3-((7-(N-(3-chloro-4-fluorophenyl)-N'- hydroxycarbandmidoyl)-lH-imidazo[4,5-b]pyridin-2-yl)amino)propyl)acetamide (2.8 mg, 18%) and 2-((3-aminopropyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide.
[0873] N-(3-((7-(N-(3-chloro-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-lH- imidazo[4,5-b]pyridin-2-yl)amino)propyl)acetamide: CigHigClFNyC . 420.2 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.84 (d, J = 6.5 Hz, 1H), 7.04 - 6.96 (m, 3H), 6.67 (ddd, J = 8.9, 4.0, 2.8 Hz, 1H), 3.58 (t, J = 6.7 Hz, 2H), 3.28 (d, J = 6.7 Hz, 2H), 1.96 (s, 3H), 1.87 (t, J = 6.7 Hz, 2H).
[0874] 2-((3-aminopropyl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide: CI6HI7C1FN70. 378.3 (M+1). IH NMR (400 MHz, Methanol-d4) δ 7.85 (d, J = 6.6 Hz, 1H), 7.04 - 6.95 (m, 3H), 6.68 (ddd, J = 8.9, 3.9, 2.8 Hz, 1H), 3.68 (t, J = 6.6 Hz, 2H), 3.11 - 3.03 (m, 2H), 2.12 - 2.02 (m, 2H).
Example 413: A-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((2- (sulfamoylamino)ethyl)amino)-lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000372_0002
[0875] Example 413 was made analogously to Example 411 using 3-(2-((2- aminoethyl)amino)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4- oxadiazol-5(4H)-one, sulfamide, and pyridine. CI5HI6C1FN803S. 443.1 (M+l). 1H NMR (400 MHz, Methanol-d4) δ 7.84 (d, J = 6.5 Hz, 1H), 7.04 - 6.95 (m, 3H), 6.67 (ddd, J = 8.8, 4.0, 2.7 Hz, 1H), 3.73 (td, J = 6.1, 5.6, 0.9 Hz, 3H), 1.87 (ddt, J = 6.6, 4.6, 2.4 Hz, 1H).
Example 414: A-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((2- (phenylsulfonamido)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000373_0001
[0876] Example 414 was made analogously to Example 411 using 3-(2-((2- aminoethyl)amino)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4- oxadiazol-5(4H)-one, benzenesulfonyl chloride, and triethylamine. C21H19CIFN7O3S. 504.1 (M+l).
Example 415: Methyl (2-((7-(iV-(3-chloro-4-fluorophenyl)-iV'- hydroxycarbamimidoyl)-lH-imidazo[4,5-b]pyridin-2-yl)amino)ethyl)carbamate
Figure imgf000373_0002
[0877] Example 415 was made analogously to Example 411 using 3-(2-((2- aminoethyl)amino)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4- oxadiazol-5(4H)-one, methyl chloroformate, and triethylamine. C17H17CIFN7O3. 422.1 (M+l). 1H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 8.96 (s, 1H), 7.97 (d, J = 6.4 Hz, 1H), 7.28 (s, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 6.5, 2.8 Hz, 1H), 6.93 (d, J = 6.3 Hz, 1H), 6.59 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 3.53 (d, J = 3.9 Hz, 5H), 3.25 (d, J = 6.0 Hz, 2H). Example 416: A^-(3-chloro-4-fluorophenyl)-2-((2- (cyclopropanesulfonamido)ethyl)amino)-A^-hydroxy-lH-imidazo[4,5-b]pyridine-7- rboximidamide
Figure imgf000374_0001
[0878] Example 416 was made analogously to Example 41 1 using 3-(2-((2- aminoethyl)amino)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-l ,2,4- oxadiazol-5(4H)-one, cyclopropanesulfonyl chloride, and triethylamine.
C18H19CIFN7O3S. 468.9 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.84 (d, J = 6.5 Hz, 1H), 7.04 - 6.96 (m, 3H), 6.67 (ddd, J = 8.9, 3.9, 2.8 Hz, 1H), 3.70 (dd, J = 6.5, 5.3 Hz, 2H), 3.42 (dd, J = 6.6, 5.3 Hz, 2H), 2.56 (ddd, J = 7.9, 5.5, 2.9 Hz, 1H), 1.10 - 0.97 (m, 4H).
Example 417: A-(3-chloro-4-fluorophenyl)-A^-hydroxy-2-((2- ((trifluoromethyl)sulfonamido)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7- rboximidamide
Figure imgf000374_0002
[0879] Example 417 was made analogously to Example 41 1 using 3-(2-((2- aminoethyl)amino)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4-fluorophenyl)-l ,2,4- oxadiazol-5(4H)-one, trifluoromethanesulfonyl chloride, and triethylamine.
Ci6Hi4ClF4N703S. 496.3 (M+1). Example 418: 2-(((lH-imidazol-2-yl)methyl)amino)-A^-(3-chloro-4-fluorophenyl)-A^- hydroxy-lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000375_0001
[0880] Example 418 was made analogously to Example 402 using (lH-imidazol-2- yl)methanamine dihydrochloride and Hunig's base. CI7HI4C1FN80. 401.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 7.97 (d, J = 5.9 Hz, 1H), 7.60 (s, 2H), 7.10 (t, J = 9.0 Hz, 1H), 6.94 (d, J = 15.7 Hz, 2H), 6.60 - 6.53 (m, 1H), 4.92 (s, 2H).
Example 419: 2-(((lH-imidazol-5-yl)methyl)amino)-A^-(3-chloro-4-fluorophenyl)-A^- -lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000375_0002
[0881] Example 419 was made analogously to Example 402 using (lH-imidazol-5- yl)methanamine dihydrochloride and Hunig's base. CI7HI4C1FN80. 401.2 (M+1).
Example 420 : iV-(3-chloro-4-fluorophenyl)-iV-hydroxy-2-(((3-methyl- 1,2,4- oxadiazol-5-yl)methyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000375_0003
[0882] Example 420 was made analogously to Example 402 using (3-methyl- 1,2,4- oxadiazol-5-yl)methanamine. CI7HI4C1FN802. 417.2 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.50 (d, J = 12.2 Hz, 1H), 7.99 (d, J = 6.4 Hz, 1H), 7.11 (d, J = 9.1 Hz, 1H), 7.08 - 7.03 (m, 1H), 6.96 (d, J = 6.4 Hz, 1H), 6.60 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 4.97 (d, J = 6.0 Hz, 2H), 2.32 (s, 3H). Example 421: A^-(3-bromophenyl)-A^-hydroxy-2-(methylamino)-lH-imidazo[4,5- b] pyridine- 7-carboximidamide
Figure imgf000376_0001
[0883] Example 421 was made analogously to Example 402 using 4-(3- bromophenyl)-3-(2-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5- b]pyridin-7-yl)-l,2,4-oxadiazol-5(4H)-one and methylamine (2.0 M in MeOH).
Ci4Hi3BrN60. 361.2 (M+1). IH NMR (400 MHz, DMSO-d6) δ 8.97 (s, IH), 7.97 (d, J = 6.2 Hz, IH), 7.07 (d, J = 2.0 Hz, IH), 7.02 - 6.92 (m, 3H), 6.57 (dt, J = 7.0, 2.1 Hz, IH), 3.02 (d, J = 4.7 Hz, 3H).
Example 422: Methyl (3-((7-(iV-(3-chloro-4-fluorophenyl)-iV'- hydroxycarbamimidoyl)-lH-imidazo[4,5-b]pyridin-2-yl)amino)propyl)carbamate
Figure imgf000376_0002
[0884] Example 422 was made analogously to Example 411 using 3-(2-((3- aminopropyl)amino)- 1 H-imidazo[4,5 -b] pyridin-7-yl)-4-(3 -chloro-4-fluorophenyl)- 1 ,2,4- oxadiazol-5(4H)-one, methyl chloroformate, and triethylamine. C18H19CIFN7O3. 436.2 (M+1). IH NMR (400 MHz, DMSO-d6) δ 8.94 (s, IH), 7.96 (d, J = 6.2 Hz, IH), 7.19 (d, J = 5.6 Hz, IH), 7.10 (t, J = 9.0 Hz, IH), 7.04 (dd, J = 6.6, 2.7 Hz, IH), 6.91 (d, J = 6.2 Hz, IH), 6.59 (ddd, J = 8.9, 4.0, 2.8 Hz, IH), 3.53 (s, 3H), 3.44 (d, J = 6.5 Hz, 2H), 3.07 (d, J = 6.3 Hz, 2H), 1.79 - 1.64 (m, 2H). Example 423: /y-(3-bromophenyl)-/V-hydroxy-2-methoxy-lH-imidazo[4,5- b] pyridine- 7-carboximidamide
Figure imgf000377_0001
[0885] Example 423 was made analogously to Example 402 using 4-(3- bromophenyl)-3-(2-chloro-l -((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5- b]pyridin-7-yl)-l ,2,4-oxadiazol-5(4H)-one and sodium hydride in MeOH to generate sodium methoxide in situ. C^H^BrNsO^ 362.0 (M+l).
Example 424: /y-(3-bromophenyl)-/V-hydroxy-2-((2-(methylsulfonyl)ethyl)amino)- lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000377_0002
[0886] Example 424 was made analogously to Example 402 using 4-(3- bromophenyl)-3-(2-chloro-l -((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5- b]pyridin-7-yl)-l ,2,4-oxadiazol-5(4H)-one, 2-(methylsulfonyl)ethan-l -amine hydrochloride, and Hunig's base. Ci6Hi7BrN603S. 453.2 (M+l).
Example 425: iV-(3-bromophenyl)-iV-hydroxy-2-((2- (methylsulfonamido)ethyl)amino)-lH-imidazo[4,5-b] pyridine- 7-carboximidamide
Figure imgf000377_0003
[0887] Example 425 was made analogously to Example 424 using N-(2- aminoethyl)methanesulfonamide. Ci6Hi8BrN703S. 468.2 (M+l). Example 426: A-(3-bromophenyl)-A^-hydroxy-2-((2-sulfamoylethyl)amino)-lH- -b] pyridine- 7-carboximidamide
Figure imgf000378_0001
[0888] Example 426 was made analogously to Example 424 using 4-(3- bromophenyl)-3-(2-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5- b]pyridin-7-yl)-l,2,4-oxadiazol-5(4H)-one and 2-aminoethane-l -sulfonamide.
Ci5Hi6BrN703S. 454.2 (M+l).
Example 427: iV-(3-chloro-4-fluorophenyl)-iV-hydroxy-2-(((5-methyl-l^,4- o)-lH-imidazo[4,5-b]pyridine-7-carboximidamide
Figure imgf000378_0002
[0889] Example 427 was made analogously to Example 402 using (5-methyl- 1,3,4- oxadiazol-2-yl)methanamine oxalate and Hunig's base.
Figure imgf000378_0003
417.2 (M+l).
Example 428: A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-(((l- methylpiperidin-2-yl)methyl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000378_0004
[0890] Methyl 4,5-difluoro-2-(((l-methylpiperidin-2-yl)methyl)amino)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using (l-methylpiperidin-2-yl)methanamine in place of N,N- dimethylpropane- 1,3 -diamine. The TFA salt of methyl 4,5-difluoro-2-(((l- methylpiperidin-2-yl)methyl)amino)- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1H- benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C22H34F2N4O3SL 469.2 (M+l).
Figure imgf000379_0001
[0891] N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(((l -methylpiperidin-2- yl)methyl)amino)-lH-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-(((l-methylpiperidin-2-yl)methyl)amino)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-benzo[cf|imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5- difluoro-2-(((l-methylpiperidin-2-yl)methyl)amino)-lH-benzo[d]imidazole-7- carboxamide was isolated as a white solid. C21H21CIF3N5O. 452.2/454.1 (M+l).
Figure imgf000379_0002
[0892] Example 428 was made analogously to Example 59 using N-(3-chloro-4- fluorophenyl)-4,5-difluoro-2-(((l -methylpiperidin-2-yl)methyl)amino)-lH- benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-lH- imidazo[4,5-b]pyridine-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)- 4,5-difluoro-N'-hydroxy-2-(((l -methylpiperidin-2-yl)methyl)amino)-lH- benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid.
C2iH22ClF3N60.467.2/469.1 (M+l). ΧΗ ΝΜΚ (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.25 (s, 1H), 8.69 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 7.00 (s, 1H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.83 (dd, J = 12.2, 6.8 Hz, 1H), 6.53 (ddd, J = 9.0, 4.1 , 2.7 Hz, 1H), 3.79 (m, 1H), 3.68 (m, 1H), 3.41 (m, 1H), 3.24 (m, 1H), 3.04 (m, 1H), 2.97 (s, 3H), 2.83 (m, 1H), 1.94 (m, 1H), 1.85 - 1.70 (m, 2H), 1.65 - 1.40 (m, 2H).19F NMR (377 MHz, DMSO) δ -75.02 (9F), -127.46 (IF), -150.44 (IF), -157.01 (IF). Example 429: /V-(3-chloro-4-fluorophenyl)-4,5-difluoro-iV-hydroxy-2-(((4- methylmorpholin-3-yl)methyl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000380_0001
[0893] Example 429 was made analogously to Example 39 using (4- methylmo holin-3-yl)methanamine in place of N,N-dimethylpropane-l,3-diamine. The TFA salt of methyl 4,5-difluoro-2-(((4-methylmorpholin-3-yl)methyl)amino)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C21H32F2N4O4S1. 471.2 (M+l).
Figure imgf000380_0002
[0894] N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(((4-methylmo holin-3- yl)methyl)amino)-lH-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-(((4-methylmo holin-3-yl)methyl)amino)-l - ((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-l-((2-
(trimethylsilyl)ethoxy)methyl)-lH-benzo[cf]imidazole-7-carboxylate. The TFA salt of N- (3-chloro-4-fluorophenyl)-4,5-difluoro-2-(((4-methylmo holin-3-yl)methyl)amino)-lΗ- benzo[d]imidazole-7-carboxamide was isolated as a white solid. C20H19CIF3N5O2.
454.2/456.1 (M+l).
Figure imgf000380_0003
[0895] Example 429 was made analogously to Example 59 using N-(3-chloro-4- fluorophenyl)-4,5-difluoro-2-(((4-methylmoφholin-3-yl)methyl)amino)-lH- benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-lH- imidazo[4,5-b]pyridine-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)- 4,5-difluoro-N'-hydroxy-2-(((4-methylmorpholin-3-yl)methyl)amino)-lH- benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid.
C20H20CIF3N6O2.469.1/471.1 (M+l). ΧΗ ΝΜΚ (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.68 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 6.92 (dd, J = 6.5, 2.8 Hz, 2H), 6.83 (dd, J = 12.2, 6.8 Hz, 1H), 6.53 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 4.10 - 3.84 (m, 4H), 3.80 - 3.65 (m, 2H), 3.58 - 3.34 (m, 2H), 3.26 (m, 1H), 3.03 (s, 3H).19F NMR (377 MHz, DMSO-d6) δ - 74.98 (9F), -127.43 (IF), -150.47 (dd, J = 21.1 , 12.8 Hz, IF), -157.02 (IF).
Example 430 : iV-(3-bromophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro- xy- lH-benzo[d] imidazole- 7-carboximidamide
Figure imgf000381_0001
[0896] N-(3-bromophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-lH- benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 2- ((2-(dimethylamino)ethyl)amino)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-
(dimethylamino)propyl)amino)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[cf|imidazole-7-carboxylate. The TFA salt of N-(3-bromophenyl)-2-((2- (dimethylamino)ethyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7-carboxamide was isolated as a white solid. Ci8Hi8BrF2N50. 438.1/440.1 (M+l).
Figure imgf000381_0002
[0897] Example 430 was made analogously to Example 59 using N-(3- bromophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-lH-benzo[d]imidazole- 7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-lH-imidazo[4,5-b]pyridine-7- carboxamide. The TFA salt of N-(3-bromophenyl)-2-((2-(dimethylamino)ethyl)amino)- 4,5-difluoro-N'-hydroxy-lH-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. Ci8Hi9BrF2N60.455.1/456.1 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.68 (s, 1H), 7.04 - 6.93 (m, 3H), 6.89 (s, 1H), 6.81 (dd, J = 12.2, 6.9 Hz, 1H), 6.54 (dt, J = 7.7, 1.7 Hz, 1H), 3.70 (m, 2H), 3.32 (m, 2H), 2.86 (s, 6H).19F NMR (377 MHz, DMSO) δ -74.85 (9F), -150.52 (IF), -157.05 (IF).
Example 431 : iV-(3-chlorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro- xy- LH-benzo[d] imidazole- 7-carboximidamide
Figure imgf000382_0001
[0898] N-(3-chlorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-lH- benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 2- ((2-(dimethylamino)ethyl)amino)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-
(dimethylamino)propyl)amino)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[cf|imidazole-7-carboxylate. The TFA salt of N-(3-chlorophenyl)-2-((2- (dimethylamino)ethyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7-carboxamide was isolated as a white solid. CI8HI8C1F2N50. 394. 1/396.2 (M+ 1).
Figure imgf000382_0002
[0899] Example 431 was made analogously to Example 59 using N-(3- chlorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-lH-benzo[d]imidazole- 7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-lH-imidazo[4,5-b]pyridine-7- carboxamide. The TFA salt of N-(3-chlorophenyl)-2-((2-(dimethylamino)ethyl)amino)- 4,5-difluoro-N'-hydroxy-lH-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid . Ci8Hi9ClF2N6O.409.1/41 1.1 (M+1)). 'H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.68 (s, 1H), 7.05 (t, J = 8.0 Hz, 1H), 6.86 - 6.72 (m, 3H), 6.54 - 6.46 (m, 1H), 3.69 (s, 3H), 3.32 (s, 4H), 2.86 (s, 6H). F NMR (376 MHz, DMSO-d6) δ -74.52, - 150.61 , -157.17.
Example 432: /V-(3-bromo-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5- difluoro-/V -hydroxy- lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000383_0001
[0900] N-(3-bromo-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5- difluoro-lH-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-l -((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-benzo[cf]imidazole-7-carboxylate and 3-bromo-4-fluoroaniline in place of 3-chloro- 4-fluoroaniline. The TFA salt of N-(3-bromo-4-fluorophenyl)-2-((2- (dimethylamino)ethyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7-carboxamide was isolated as a white solid. CigHnBrFsNsO. 456.1/458.1 (M+1).
Figure imgf000383_0002
[0901] Example 432 was made analogously to Example 59 using N-(3-bromo-4- fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7- carboxamide in place of N-(3-chloro-4-fluorophenyl)-lH-imidazo[4,5-b]pyridine-7- carboxamide. The TFA salt of N-(3-bromo-4-fluorophenyl)-2-((2- (dimethylamino)ethyl)amino)-4,5-difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide was isolated as an off-white solid. Ci8Hi8BrF3N60.471.2/474.1 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.64 (s, 1H), 7.08 - 7.01 (m, 2H), 6.79 (s, 2H), 6.54 (ddd, J = 9.0, 4.2, 2.7 Hz, 1H), 3.66 (s, 2H), 3.30 (s, 2H), 2.84 (s, 6H). Example 433: N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((3- morpholinopropyl)amino)-lH-benzo[d]imidazole-7-carboxamide
Figure imgf000384_0001
[0902] Methyl 4,5-difluoro-2-((3-morpholinopropyl)amino)-l -((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using 3^ο ηο1ίηορΓορ3η-1 ^ιηιη6 in place of N,N- dimethylpropane- 1 ,3 -diamine. The TFA salt of methyl 4,5-difluoro-2-((3- mo holinopropyl)amino)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole- 7-carboxylate was isolated as a yellow oil. C22H34F2N4O4SL 485.1 (M+l).
Figure imgf000384_0002
lH-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-((3-moφholinopropyl)amino)-l-((2-
(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-benzo[cf]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5- difluoro-2-((3-moφholinopropyl)amino)-lΗ-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C21H21CIF3N5O2. 468.2/470.1 (M+l).
Figure imgf000384_0003
[0904] Example 433 was made analogously to Example 432 using N-(3-chloro-4- fluorophenyl)-4,5-difluoro-2-((3-moφholinopropyl)amino)-lH-benzo[d]imidazole-7- carboxamide in place of N-(3-bromo-4-fluorophenyl)-2-((2-
(dimethylamino)ethyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7-carboxamide. The TFA salt ofN-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((3- mo holinopropyl)amino)-lH-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C2iH22ClF3N602.483.1/485.1 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.66 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.82 (s, 2H), 6.54 (dq, J = 9.0, 3.1 Hz, 1H), 3.82 (m, 2H), 3.42 (m, 2H), 3.27 (m, 2H), 3.17 (t, J = 7.9 Hz, 2H), 1.97 (t, J = 7.8 Hz, 2H).
Example 434 : /V-(3-chloro-4-fluorophenyl)-4,5-difluoro-iV-hydroxy-2-((3- (pyrrolidin-l-yl)propyl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000385_0001
[0905] Methyl 4,5-difluoro-2-((3-(pyrrolidin-l-yl)propyl)amino)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using 3-(pyrrolidin-l-yl)propan-l -amine in place of NN- dimethylpropane- 1,3 -diamine. The TFA salt of methyl 4,5-difluoro-2-((3-(pyrrolidin-l- yl)propyl)amino)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7- carboxylate was isolated as a yellow oil. C22H34F2N4O3S1. 469.2 (M+1).
Figure imgf000385_0002
[0906] N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((3-(pyrrolidin-l- yl)propyl)amino)-lH-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-((3-(pyrrolidin-l-yl)propyl)amino)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-benzo[cf]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5- difluoro-2-((3-(pyrrolidin-l-yl)propyl)amino)-lH-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C21H21CIF3N5O. 452.0/454.1 (M+1).
Figure imgf000386_0001
[0907] Example 434 was made analogously to Example 432 using N-(3-chloro-4- fluorophenyl)-4,5-difluoro-2-((3-(pyrrolidin-l -yl)propyl)amino)-lH-benzo[d]imidazole- 7-carboxamide in place of N-(3-bromo-4-fluorophenyl)-2-((2-
(dimethylamino)ethyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((3-(pyrrolidin-l- yl)propyl)amino)-lH-benzo[d]imidazole-7-carboximidamide was isolated as an off- white solid. C2iH22ClF3N60.467.2/469.1 (M+l). 'H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.68 (s, 1H), 8.66 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.90-6.75 (m, 2H), 6.54 (ddd, J = 9.0, 4. 1 , 2.8 Hz, 1H), 3.55 - 3.34 (m, 8H), 3.17 (m, 2H), 1.93 (m, 6H).19F NMR (377 MHz, DMSO) δ -74.57, -127.43, -150.48, - 157.56.
Example 435: 2-(((3R)-4-amino-l-methylpyrrolidin-3-yl)amino)-N-(3-chloro-4- fluorophenyl)-4,5-difluoro-N'-hydroxy- IH-benzo [d] imidazole-7-carboximidamide
Figure imgf000386_0002
[0908] Methyl (5 -4,5-difluoro-2-((l-methylpyrrolidin-3-yl)amino)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using (,S)-l -methylpyrrolidin-3 -amine in place of N,N- dimethylpropane- 1 ,3 -diamine. The TFA salt of methyl (S)-4,5-difluoro-2-((l - methylpyrrolidin-3-yl)amino)-l -((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C21H32F2N4O3SL 441.0 (M+l).
Figure imgf000387_0001
[0909] (5 -N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((l-methylpyrrolidin-3- yl)amino)-lH-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl (5 -4,5-difluoro-2-((l-methylpyrrolidin-3-yl)amino)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-benzo[cf]imidazole-7-carboxylate. The TFA salt of (<S)-N-(3-chloro-4-fluorophenyl)- 4,5-difluoro-2-((l -methylpyrrolidin-3-yl)amino)-lH-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C19H17CIF3N5O. 424.1/426.1 (M+l).
Figure imgf000387_0002
[0910] Example 435 was made analogously to Example 432 using (5)-N-(3-chloro-4- fluorophenyl)-4,5-difluoro-2-((l -methylpyrrolidin-3-yl)amino)-lH-benzo[d]imidazole-7- carboxamide in place of N-(3-bromo-4-fluorophenyl)-2-((2-
(dimethylamino)ethyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7-carboxamide. The TFA salt of 2-(((3i?)-4-amino-l -methylpyrrolidin-3-yl)amino)-N-(3-chloro-4- fluorophenyl)-4,5-difluoro-N'-hydroxy-lH-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid (15.8 mg, 67%). Ci9Hi9ClF3N70.454.1/456.1 (M+l). l NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.67 (s, 1H), 7.10 (t, J = 9.2 Hz, 1H), 7.08 (br s, 1H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.83 (dd, J = 12.2, 7.0 Hz, 1H), 6.54 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 6.10 (s, 2H), 4.77 (s, 1H), 4.00 (dq, J = 8.3, 7.0 Hz, 1H), 3.90 (dd, J = 12.5, 8.1 Hz, 1H), 3.82 (t, J = 9.9 Hz, 1H), 3.67 (d, J = 12.7 Hz, 1H), 3.58 (td, J = 11.2, 8.1 Hz, 1H), 3.38 (s, 3H), 2.76 - 2.64 (m, 1H), 2.25 - 2.12 (m, 1H).19F NMR (376 MHz, DMSO) δ -74.87, -127.5, -150.4, -156.9. Example 436: iV-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)-2- phenylethyl)amino)-4,5-difluoro-/V' -hydroxy- lH-benzo[d]imidazole- 7- carboximidamide
Figure imgf000388_0001
[0911] Methyl 2-((2-(dimethylamino)-2-phenylethyl)amino)-4,5-difluoro-l -((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using N^^dimethyl-l -phenylethane-l ^-diamine in place of N^V-dimethylpropane-l,3-diamine. The TFA salt of methyl 2-((2-(dimethylamino)-2- phenylethyl)amino)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C25H34F2N4O3SL 505.1 (M+l).
Figure imgf000388_0002
[0912] N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)-2-phenylethyl)amino)- 4,5-difluoro-lH-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 2-((2-(dimethylamino)-2-phenylethyl)amino)-4,5-difluoro-l -((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-benzo[cf]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2- ((2-(dimethylamino)-2-phenylethyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7- carboxamide was isolated as a white solid. C24H21CIF3N5O. 488.1/490.1 (M+l).
Figure imgf000389_0001
[0913] Example 436 was made analogously to Example 432 using N-(3-chloro-4- fluorophenyl)-2-((2-(dimethylamino)-2-phenylethyl)amino)-4,5-difluoro-lH- benzo[d]imidazole-7-carboxamide in place of N-(3-bromo-4-fluorophenyl)-2-((2- (dimethylamino)ethyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7-carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)-2-phenylethyl)amino)- 4,5-difluoro-N'-hydroxy-lH-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C24H22ClF3N6O.503.1/505.1 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 10.68 (s, 1H), 8.66 (s, 1H), 7.62 - 7.55 (m, 1H), 7.53 (d, J = 3.3 Hz, 3H), 7.09 (t, J = 8.9 Hz, 1H), 6.89 (dd, J = 6.5, 2.7 Hz, 1H), 6.85 - 6.74 (m, 1H), 6.67 - 6.58 (m, 1H), 6.54 - 6.46 (m, 1H), 4.69 (m, 1H), 4.26 (m, 1H), 3.97 (m, 1H), 2.75 (s, 6H). 19F NMR (377 MHz, DMSO-d6) δ -74.37 (9F), -127.54 (IF), -150.55 (IF), -156.90 (IF).
Example 437: 7V-(3-chloro-4-fluorophenyl)-2-(((7i?,2i?)-2-
(dimethylamino)cyclohexyl)amino)-4,5-difluoro-/V-hydroxy-lH-benzo[d]imidazole-
7-carboximidamide
Figure imgf000389_0002
[0914] Methyl 2-(((7i?,2i?)-2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-l -((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using (7i?,2i?)-N1,N1-dimethylcyclohexane-l ,2-diamine in place of N,N-dimethylpropane-l ,3-diamine. The TFA salt of methyl 2-(((lR,2R)-2- (dimethylamino)cyclohexyl)amino)-4,5-difluoro-l -((2-(trimethylsilyl)ethoxy)methyl)- lH-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C23H36F2N4O3SL 483.2 (M+1).
Figure imgf000390_0001
[0915] N-(3-chloro-4-fluorophenyl)-2-(((lR,2R)-2-
(dimethylamino)cyclohexyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7-carboxamid^ was made analogously to Example 39 using methyl 2-(((7i?,2i?)-2- (dimethylamino)cy clohexyl)amino)-4,5 -difluoro- l -((2-(trimethylsilyl)ethoxy)methyl)- lH-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-
(dimethylamino)propyl)amino)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[cf|imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2- ((( 1 R,2R)-2-(dimethylamino)cyclohexyl)amino)-4,5 -difluoro- 1 H-benzo [d] imidazole-7- carboxamide was isolated as a white solid. C22H23CIF3N5O. 466.2/468.1 (M+1).
Figure imgf000390_0002
[0916] Example 437 was made analogously to Example 402 using N-(3-chloro-4- fluorophenyl)-2-(((lR,2R)-2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-lH- benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(((l- (dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7- carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((7i?,2i?)-2- (dimethylamino)cyclohexyl)amino)-4,5-difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide was isolated as an off-white solid. C22H24C1F3N60.481.2/483.1 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.91 (s, 1H), 8.67 (s, 1H), 7.11 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.84 (dd, J = 12.3, 7.0 Hz, 1H), 6.79 (d, J = 9.7 Hz, 1H), 6.53 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 4.02 (m, 1H), 3.33 (m, 1H), 2.77 (s, 3H), 2.78 (s, 3H), 2.07 (m, 1H), 1.93 (app. d, J = 9.9 Hz, 1H), 1.83 (app. d, J = 11.8 Hz, 1H), 1.70 (app. d, J = 9.5 Hz, 1H), 1.63 - 1.48 (m, 1H), 1.36 (dq, J = 27.4, 13.2, 12.3 Hz, 3H).19F NMR (377 MHz, DMSO-d6) δ -75.02 (9F), -127.56 (IF), -150.41 (IF), -156.89 (IF). Example 438: A^-(3-chloro-4-fluorophenyl)-2-(((l- (dimethylamino)cyclopentyl)methyl)amino)-4,5-difluoro-A^ -hydroxy- 1H- benzo[d]imidazole-7-carboximidamide
Figure imgf000391_0001
[0917] Methyl 2-(((l-(dimethylamino)cyclopentyl)methyl)amino)-4,5-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using l-(aminomethyl)-N,N-dimethylcyclopentan-l -amine in place of N,N-dimethylpropane-l,3-diamine. The TFA salt of methyl 2-(((l- (dimethylamino)cyclopentyl)methyl)amino)-4,5-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C23H36F2N4O3S1. 483.2 (M+l).
Figure imgf000391_0002
[0918] N-(3-chloro-4-fluorophenyl)-2-(((l-
(dimethylamino)cyclopentyl)methyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7- carboxamide was made analogously to Example 39 using methyl 2-(((l- (dimethylamino)cyclopentyl)methyl)amino)-4,5-difluoro-l-((2-
(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-benzo[cf]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2- (((l-(dimethylamino)cyclopentyl)methyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7- carboxamide was isolated as a white solid. C22H23CIF3N5O. 466.2/468.1 (M+l).
Figure imgf000392_0001
[0919] Example 438 was made analogously to Example 402 using N-(3-chloro-4- fluorophenyl)-2-(((l-(dimethylamino)cyclopentyl)methyl)amino)-4,5-difluoro-lH- benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(((l- (dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7- carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((l- (dimethylamino)cyclopentyl)methyl)amino)-4,5-difluoro-N'-hydroxy-lH- benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid.
C22H24C1F3N60.481.2/483.1 (M+l). ΧΗ ΝΜΚ (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.68 (s, 1H), 8.70 (s, 1H), 7.15 - 7.01 (m, 2H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.85 (dd, J = 12.2, 6.9 Hz, 1H), 6.52 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 3.74 (d, J = 6.6 Hz, 2H), 2.84 (s, 3H), 2.83 (s, 3H), 1.96 - 1.79 (m, 4H), 1.71 (t, J = 5.6 Hz, 4H).19F NMR (377 MHz, DMSO) δ -74.89 (9F), -127.51 (IF), -150.42 (IF), -157.09 (IF).
Example 439: iV^3-chloro-4-fluorophenyl)-2 ((½V?S)-3-
(dimethylamino)cyclohexyl)amino)-4,5-difluoro-A^-hydroxy-lH-benzo[d]imidazole-
7-carboximidamide
Figure imgf000392_0002
[0920] Methyl 2-((3-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using N^^dimethylcyclohexane-l^-diamine in place of N,N-dimethylpropane-l,3-diamine. The TFA salt of methyl 2-((3- (dimethylamino)cyclohexyl)amino)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C23H36F2N4O3S1. 483.1 (M+l).
Figure imgf000393_0001
[0921] N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)cyclohexyl)amino)-4,5- difluoro-lH-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 2-((3-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-benzo[cf|imidazole-7-carboxylate. The TFA salt of N-^-chloro^-fluorophenyl^- ^^dimethylamino^yclohexy amino^S-difluoro-l^
carboxamide was isolated as a white solid. C22H23CIF3N5O. 466.2 (M+1).
Figure imgf000393_0002
[0922] Example 439 was made analogously to Example 402 using N-(3-chloro-4- fluorophenyl)-2-((3-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-lH- benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(((l- (dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7- carboxamide. The two diastereomers were separated by reverse phase HPLC and the TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((75',35)-3-
(dimethylamino)cyclohexyl)amino)-4,5-difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide was isolated as an off-white solid. (C22H24CIF3N6O. 481.1/483.1 (M+1). 'H NMR (400 MHz, DMSO-d6) δ 10.81 (s, IH), 9.45 (s, IH), 8.69 (s, IH), 7.10 (t, J = 9.1 Hz, IH), 6.92 (dd, J = 6.5, 2.7 Hz, IH), 6.81 (t, J = 9.8 Hz, IH), 6.54 (ddd, J = 9.0, 4.0, 2.7 Hz, IH), 3.33 (m, IH), 2.76 (d, J = 5.0 Hz, 3H), 2.74 (d, J = 4.9 Hz, 3H), 2.39 (d, J = 11.9 Hz, IH), 1.93 (dd, J = 27.6, 11.7 Hz, 4H), 1.48 - 1.30 (m, 4H), 1.21 (d, J = 13.5 Hz, IH). 19F NMR (377 MHz, DMSO-d6) δ -74.82, -127.48, -149.43, -156.88. Example 440: A^-(3-chloro-4-fluorophenyl)-2-(((lS,3R)-3- (dimethylamino)cyclohexyl)amino)-4,5-difluoro-A^-hydroxy-lH-benzo[d]imidazole-
7-carboximidamide
Figure imgf000394_0001
[0923] The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((75',3i?)-3- (dimethylamino)cyclohexyl)amino)-4,5-difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide was isolated from the sequence described in Example 439 as an off- white solid. C22H24C1F3N60. 481.1/483.0 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.27 (s, 1H), 8.65 (s, 1H), 7.11 (t, J = 9.1 Hz, 1H), 7.00 (s, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.79 (dd, J = 12.0, 7.5 Hz, 1H), 6.54 (dt, J = 9.1, 3.5 Hz, 1H), 5.06 (q, J = 9.0 Hz, 1H), 4.21 (m, 1H), 3.29 (m, 1H), 2.77 (d, J = 4.6 Hz, 3H), 2.72 (d, J = 4.7 Hz, 3H), 2.29 (d, J = 14.9 Hz, 1H), 1.98 (m, 1H), 1.77 (m, 3H), 1.56 (m, 3H).
Example 441: iV-(3-chloro-4-fluorophenyl)-2-(((l- (dimethylamino)cyclobutyl)methyl)amino)-4,5-difluoro-iV-hydroxy-lH- benzo[d]imidazole-7-carboximidamide
Figure imgf000394_0002
[0924] Methyl 2-(((l-(dimethylamino)cyclobutyl)methyl)amino)-4,5-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using l-(aminomethyl)-N,N-dimethylcyclobutan-l -amine in place of N,N-dimethylpropane-l,3-diamine. The TFA salt of methyl 2-(((l- (dimethylamino)cyclobutyl)methyl)amino)-4,5-difluoro-l-((2-
(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C22H34F2N4O3S1. 469.2 (M+l).
Figure imgf000395_0001
[0925] N-(3-chloro-4-fluorophenyl)-2-(((l-
(dimethylamino)cyclobufyl)methyl)anTino)-4,5-difluoro-lH-benzo[d]imidazole-7- carboxamide was made analogously to Example 39 using methyl 2-(((l- (dimethylamino)cyclobutyl)methyl)amino)-4,5-difluoro-l-((2-
(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-benzo[cf|imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2- (((l-(dimethylamino)cyclobufyl)methyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7- carboxamide was isolated as a white solid. C2iH2iClF3N50. 452.2/545.1 (M+1).
Figure imgf000395_0002
[0926] Example 441 was made analogously to Example 402 using N-(3-chloro-4- fluorophenyl)-2-(((l-(dimethylamino)cyclobutyl)methyl)amino)-4,5-difluoro-lH- benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(((l- (dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7- carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((l- (dimethylamino)cyclobutyl)methyl)amino)-4,5-difluoro-N'-hydroxy-lH- benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid.
C2iH22ClF3N60. 467.2/469.1 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.70 (s, 1H), 7.17 (t, J = 6.6 Hz, 1H), 7.08 (t, J = 9.1 Hz, 1H), 6.94 (dd, J = 6.5, 2.7 Hz, 1H), 6.87 (dd, J = 12.2, 6.9 Hz, 1H), 6.54 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 6.06 (s, 1H), 4.06 (d, J = 6.6 Hz, 2H), 3.20 (s, 6H), 2.74 (dt, J = 14.1, 10.0 Hz, 2H), 2.12 - 1.99 (m, 2H), 1.85 - 1.70 (m, 2H).19F NMR (376 MHz, DMSO-d6) δ -75.09, -127.43, -150.31, - 156.83. Example 442: A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-((l- in-4-yl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000396_0001
[0927] Methyl 4,5-difluoro-2-((l -methylpiperidin-4-yl)amino)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using 1 -methylpiperidin-4-amine in place of N,N- dimethylpropane- 1 ,3 -diamine. The TFA salt of methyl 4,5-difluoro-2-((l - methylpiperidin-4-yl)amino)-l -((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C21H32F2N4O3S1. 455.1 (M+l).
Figure imgf000396_0002
[0928] N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((l-methylpiperidin-4-yl)amino)- lH-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-((l-methylpiperidin-4-yl)amino)-l-((2-
(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-benzo[cf]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5- difluoro-2-((l-methylpiperidin-4-yl)amino)-lH-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C20H19CIF3N5O. 438.2/440.3 (M+l).
Figure imgf000396_0003
[0929] Example 442 was made analogously to Example 402 using N-(3-chloro-4- fluorophenyl)-4,5-difluoro-2-((l-methylpiperidin-4-yl)amino)-lH-benzo[d]imidazole-7- carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(((l- (dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7- carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2- ((l-methylpiperidin-4-yl)amino)-lH-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C2oH2oClF3N60. 453.1/455.1 (M+1). 'H NMR (400 MHz, DMSO- d6) δ 10.78 (s, 1H), 9.26 (s, 1H), 8.68 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 6.92 (m, 1H), 6.82 (m, 1H), 6.53 (ddd, J = 8.9, 4.1, 2.7 Hz, 1H), 4.31 - 4.17 (m, 1H), 3.09 (q, J = 11.6 Hz, 4H), 2.80 (d, J = 4.7 Hz, 3H), 2.17 (d, J = 13.6 Hz, 2H), 1.64 (q, J = 13.0, 11.7 Hz, 2H).
Example 443: /V-(3-chloro-4-fluorophenyl)-4,5-difluoro-iV-hydroxy-2-((l- 3-yl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000397_0001
[0930] Methyl 4,5-difluoro-2-((l-methylpiperidin-3-yl)amino)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using l-methylpiperidin-3-amine in place of N,N- dimethylpropane- 1,3 -diamine. The TFA salt of methyl 4,5-difluoro-2-((l- methylpiperidin-3-yl)amino)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C21H32F2N4O3SL 455.2 (M+1).
Figure imgf000397_0002
[0931] N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((l-methylpiperidin-3-yl)amino)- lH-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-((l-methylpiperidin-3-yl)amino)-l-((2-
(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)m lH-benzo[cf]imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5- difluoro-2-((l-methylpiperidin-3-yl)amino)-lH-benzo[d]imidazole-7-carboxamide was isolated as a white solid. C20H19CIF3N5O. 438.2/440.1 (M+1).
Figure imgf000398_0001
[0932] Example 443 was made analogously to Example 402 using N-(3-chloro-4- fluorophenyl)-4,5-difluoro-2-((l-methylpiperidin-3-yl)amino)-lH-benzo[d]imidazole-7- carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(((l- (dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7- carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2- ((l-methylpiperidin-3-yl)amino)-lH-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C2oH2oClF3N60. 453.2/455.1 (M+1). ¾ NMR (400 MHz, DMSO- d6) δ 10.80 (s, 1H), 9.63 (s, 1H), 8.68 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 6.92 (dd, J = 6.5, 2.8 Hz, 1H), 6.82 (dd, J = 12.3, 6.9 Hz, 1H), 6.54 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 4.03 (m, 1H), 3.65 (m, 1H), 3.42 (m, 1H), 2.88 (d, J = 4.7 Hz, 1H), 2.83 (d, J = 4.6 Hz, 3H), 2.78 (d, J = 8.7 Hz, 1H), 2.06 - 1.65 (m, 3H), 1.53 - 1.38 (m, 1H).19F NMR (377 MHz, DMSO-d6) δ -74.95 (9F), -127.50 (IF), -150.55 (IF), -156.90 (IF).
Example 444: ^-(S-chloro^-fluoropheny -l-iiii^S)-!- (dimethylamino)cyclohexyl)amino)-4,5-difluoro-A^-hydroxy-lH-benzo[d]imidazole-
7-carboximidamide
Figure imgf000398_0002
[0933] Methyl 2-(((75',25 -2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-l -((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using (ii'^^-N^N^dimethylcyclohexane-l^-diamine in place of N,N-dimethylpropane-l,3-diamine. The TFA salt of methyl 2-(((lS,2S)-2- (dimethylamino)cyclohexyl)amino)-4,5-difluoro-l -((2-(trimethylsilyl)ethoxy)methyl)- lH-benzo[d]imidazole-7-carboxylate was isolated as a yellow oil. C23H36F2N4O3SL 483.2/484.1 (M+l).
Figure imgf000399_0001
[0934] N^-chloro^-fluorophenyl)^-^^^-
(dimethylamino)cyclohexyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 2-(((75',25 -2- (dimethylamino)cyclohexyl)amino)-4,5-difluoro-l -((2-(trimethylsilyl)ethoxy)methyl)- 7H-benzo[cf|imidazole-7-carboxylate in place of methyl 2-((3-
(dimethylamino)propyl)amino)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-7H- benzo[cf|imidazole-7-carboxylate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2- (((75,,25 -2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7- carboxamide was isolated as a white solid. C22H23CIF3N5O. 466.2/468.1 (M+l).
Figure imgf000399_0002
[0935] Example 444 was made analogously to Example 402 using N-(3-chloro-4- fluorophenyl)-2-(((75',25 -2-(dimethylamino)cyclohexyl)amino)-4,5-difluoro-lH- benzo[d]imidazole-7-carboxamide in place of N-(3-chloro-4-fluorophenyl)-2-(((l- (dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7- carboxamide. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((75',25)-2- (dimethylamino)cyclohexyl)amino)-4,5-difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide was isolated as an off-white solid. C22H24CIF3N6O. 481.2/483.1 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 10.92 - 10.67 (m, 1H), 8.92 (s, 1H), 8.67 (s, 1H), 7.1 1 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.88 - 6.75 (m, 2H), 6.53 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 4.04 (m, 1H), 3.33 (td, J = 1 1.6, 3.5 Hz, 1H), 2.77 (d, J = 4.3 Hz, 6H), 2.13 - 2.03 (m, 1H), 1.94 (app. d, J = 10.7 Hz, 1H), 1.83 (app. d, J = 11.9 Hz, 1H), 1.70 (app. d, J = 9.4 Hz, 1H), 1.53 (app. dd, J = 13.6, 10.1 Hz, 1H), 1.37 (m, 3H). 19F NMR (376 MHz, DMSO-d6) δ -75.01 (9F), -127.56 (IF), -150.41 (IF), -156.9 (d, J = 22.3 Hz, IF).
Example 445: (.S)-A/-(3-chloro-4-fluorophenyl)-4,5-difluoro-A/'-hydroxy-2- (piperidin-3-ylamino)-iH-benzo[i/]imidazole-7-carboximidamide
Figure imgf000400_0001
[0936] Example 445 was made analogously to Example 333 using tert-butyl (5 -3- aminopiperidine-l-carboxylate in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of (5 -N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(piperidin-3- ylamino)-7H-benzo[cf]imidazole-7-carboximidamide was isolated as an off-white solid. CI9HI8C1F3N60. 439.2/441.1 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.69-8.50 (m, 3H), 7.10 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.86 (m, 1H), 6.79 (m, 1H), 6.55 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 4.00 (m, 1H), 3.47 (app. d, J = 11.9 Hz, 1H), 3.21 (app. d, J = 12.3 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.00 (m, 1H), 1.89 (m, 1H), 1.80 - 1.63 (m, 1H), 1.57 (m, 1H).19F NMR (376 MHz, DMSO) δ -74.92, -127.48, - 150.57, -156.96.
Example 446: (i?)-iV-(3-chloro-4-fluorophenyl)-4,5-difluoro-iV'-hydroxy-2- (piperidin-3-ylamino)-iH-benzo[i/]imidazole-7-carboximidamide
Figure imgf000400_0002
[0937] Example 446 was made analogously to Example 333 using /er/-butyl (R)-3- aminopiperidine-l-carboxylate in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of (i?)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(piperidin-3- ylamino)-7H-benzo[cf|imidazole-7-carboximidamide was isolated as an off-white solid. CI9HI8C1F3N60. 439.2/441.1 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.78 - 8.51 (m, 3H), 7.10 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.86 (d, J = 6.6 Hz, 1H), 6.81 (dd, J = 12.1, 6.8 Hz, 1H), 6.54 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 4.02 (m, 1H), 3.47 (app. d, J = 12.2 Hz, 1H), 3.21 (app. d, J = 12.4 Hz, 1H), 2.93 - 2.80 (m, 2H), 2.00 (app. d, J = 12.2 Hz, 1H), 1.89 (m, 1H), 1.71 (m, 1H), 1.56 (m, 1H).19F NMR (377 MHz, DMSO-d6) δ -74.88 (9F), -127.50 (IF), -150.58 (IF), -156.99 (IF).
Example 447: (.S)-iV-(3-chloro-4-fluorophenyl)-4,5-difluoro-iV'-hydroxy-2-((l- methylpyrrolidin-3-yl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000401_0001
[0938] Example 447 was made analogously to Example 333 using (S)-l- methylpyrrolidin-3 -amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of (5 -N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((l-methylpyrrolidin-3- yl)amino)-lH-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. Ci9Hi8ClF3N60.439.2/441.1 (M+l). ΧΗ ΝΜΚ (400 MHz, DMSO-d6) δ 10.76 (br. s, 1H), 9.75 (br. s, 1H), 8.67 (d, J = 3.5 Hz, 1H), 7.09 (td, J = 9.1, 3.4 Hz, 1H), 6.98 (m, 1H), 6.92 (dt, J = 6.5, 2.4 Hz, 1H), 6.85 (m, 1H), 6.53 (dt, J = 8.9, 3.5 Hz, 1H), 4.49 (m, 1H), 3.94 (m, 1H), 3.36 (m, 1H), 3.23 (m, 1H), 3.06 (m, 1H), 2.89 (app. dd, J = 9.0, 4.8 Hz, 3H), 2.06 (m, 1H), 1.90 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ -74.77, -127.47, - 150.47, -156.78.
Example 448 : A^-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)-2- hydroxypropyl)amino)-4,5-difluoro-A^'-hydroxy-iH-benzo[i/]imidazole-7- carboximidamide
Figure imgf000402_0001
[0939] Example 448 was made analogously to Example 333 using l-amino-3- (dimethylamino)propan-2-ol in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)-2-hydroxypropyl)amino)-4,5- difluoro-N'-hydroxy-7H-benzo[cf|imidazole-7-carboximidamide was isolated as an off- white solid. Ci9H2oClF3N602.457.2/459.1 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 10.86 (br. s, 1H), 9.38 (br. s, 1H), 8.73 (s, 1H), 7.30 (m, 1H), 7.10 (t, J = 9.1 Hz, 1H), 6.94 (dd, J = 6.5, 2.7 Hz, 1H), 6.88 (dd, J = 12.2, 6.9 Hz, 1H), 6.54 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 4.11 (dq, J = 9.7, 5.0 Hz, 1H), 3.47 (dt, J = 13.9, 5.5 Hz, 1H), 3.39 (m, 1H), 3.16 (app. d, J = 12.8 Hz, 1H), 3.06 (dd, J = 12.9, 10.1 Hz, 1H), 2.81 (s, 6H).19F NMR (377 MHz, DMSO-d6) δ -75.02, -127.32, -149.66, -156.59.
Example 449: A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^'-hydroxy-2-((2-(4- methyl-3-oxopiperazin-l-yl)ethyl)amino)-7H-benzo[i/]imidazole-7-carboximidamide
Figure imgf000402_0002
[0940] Example 449 was made analogously to Example 333 using 4-(2-aminoethyl)- l-methylpiperazin-2-one in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(4-methyl-3-oxopiperazin-l- yl)ethyl)amino)-7H-benzo[(i]imidazole-7-carboximidamide was isolated as an off-white solid. C21H21CIF3N7O2.496.2/498.I (M+l). XH NMR (400 MHz, DMSO-d6) δ 10.81 (br. s, 1H), 8.71 (s, 1H), 7.14 (br. s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 6.94 (dd, J = 6.5, 2.7 Hz, 1H), 6.87 (dd, J = 12.2, 6.9 Hz, 1H), 6.53 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 3.90 (s, 2H), 3.71 (m, 2H), 3.65 - 3.50 (m, 4H), 3.35 (m, 2H), 2.89 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -75.14, -127.23, -149.86, -156.94.
Example 450: ZV-(3-chloro-4-fluorophenyl)-2-(((l-
(dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-A^'-hydroxy-iH- benzo[</]imidazole-7-carboximidamide
Figure imgf000403_0001
[0941] Methyl 4,5-difluoro-2-((l-methylpiperidin-3-yl)amino)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using l-(aminomethyl)-N,N-dimethylcyclohexan-l -amine in place of N,N-dimethylpropane-l,3-diamine. The TFA salt of methyl 2-(((l- (dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro- 1 -((2- (trimethylsilyl)ethoxy)methyl)-7H-benzo[cf|imidazole-7-carboxylate was isolated as a yellow oil. C21H32F2N4O3S1. 497.3 (M+l).
Figure imgf000403_0002
[0942] N-(3-chloro-4-fluorophenyl)-2-(((l-
(dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7- carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-((l- methylpiperidin-3-yl)amino)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazole-7-carboxylate in place of methyl 2-((3-
(dimethylamino)propyl)amino)-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[cf]imidazole-7-carboxylate. N-(3-chloro-4-fluorophenyl)-2-(((l- (dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7- carboxamide was isolated as a white solid. C23H25CIF3N5O. 480.2/482.1 (M+l).
Figure imgf000404_0001
[0943] The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((l- (dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-lH-benzo[d]imidazole-7- carboxamide (103 mg, 0.15 mmol, 1 equiv) was dissolved in EtOAc, saturated aqueous NaHC03 was added and the mixture was extracted twice with EtOAc. The combined organics were dried over MgSC>4, filtered and concentrated in vacuo. The resulting residue was dissolved in CH2CI2 (1 mL) and potassium carbonate (148 mg, 01.05 mmol, 7 equiv) and PCI5 (95 mg, 0.46 mmol, 3 equiv) were added. The reaction was stirred at room temperature for 3 hours before being concentrated in vacuo. A solution of
TMSONH2 (0.185 mL, 1.5 mmol, 10 equiv) in trifluoroethanol (1.5 mL) was added at 0 °C. The reaction was slowly warmed to room temperature and stirred for 1 hour before being concentrated in vacuo. A solution of 2N HCl was added and the resulting mixture was stirred for 30 minutes before diluting with DMF/H20 and purification by reverse phase HPLC. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((l- (dimethylamino)cyclohexyl)methyl)amino)-4,5-difluoro-N'-hydroxy-7H- benzo[(i|imidazole-7-carboximidamide was isolated as an off-white solid.
C23H26C1F3N60.495.2/497.1 (M+l). ΧΗ ΝΜΚ (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.49 (br. s, 1H), 8.68 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 7.03 (br. s, 1H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.85 (dd, J = 12.2, 6.9 Hz, 1H), 6.53 (dt, J = 8.9, 3.5 Hz, 1H), 4.31 (m, 1H), 3.86 (d, J = 6.5 Hz, 1H), 2.81 (s, 3H), 2.80 (s, 3H), 1.83-1.93 (m, 2H), 1.74 - 1.43 (m, 7H), 1.20 (m, 1H).19F NMR (376 MHz, DMSO) δ -75.00, -127.52, -150.3, -156.97.
Example 451: A-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^'-hydroxy-2-((l- methylazepan-3-yl)amino)-7H-benzo[i/]imidazole-7-carboximidamide
Figure imgf000405_0001
[0944] Example 451 was made analogously to Example 333 using 1 -methyl azepan- 3-amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4- fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((l-methylazepan-3-yl)amino)-7H- benzo[(i|imidazole-7-carboxirnidamide was isolated as an off-white solid.
C2iH22ClF3N60.467.2/469.1 (M+l). *H MR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 9.68 (br. s, 1H), 8.66 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.83 (m, 1H), 6.54 (m, 1H), 4.19 (m, 1H), 3.37 (m, 2H), 3.20 (m, 2H), 2.87 (s, 3H), 2.03 (m, 1H), 1.97 - 1.54 (m, 5H).19F NMR (376 MHz, DMSO-d6) δ -74.83, -127.52, -150.54, - 156.65.
Example 452: (1S)-A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-^'-hydroxy-2-((2-(3- hydroxypyrrolidin-l-yl)ethyl)amino)-iH-benzo[</[ imidazole- 7-carboximidamide
Figure imgf000405_0002
[0945] Example 452 was made analogously to Example 333 using (S)-l-(2- aminoethyl)pyrrolidin-3-ol in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of (5)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(3-hydroxypyrrolidin- l-yl)ethyl)amino)-7H-benzo[(i]imidazole-7-carboximidamide was isolated as an off- white solid. C2oH2oClF3N602.469.2/471.1 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.04 (br. s, 1H), 8.68 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 6.97-6.90 (m, 2H), 6.83 (dd, J = 12.2, 6.9 Hz, 1H), 6.53 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 4.43 (m, 1H), 3.68 (m, 6H), 3.41 (m, 2H), 2.15 (m, 1H), 1.88 (m, 1H). F NMR (376 MHz, DMSO) δ - 74.97, -127.34, -150.40, -156.84.
Example 453: A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^'-hydroxy-2-((l-(2- methoxyethyl)piperidin-3-yl)amino)-iH-benzo[i/|imidazole-7-carboximidamide
Figure imgf000406_0001
[0946] Example 453 was made analogously to Example 333 using l -(2- methoxyethyl)piperidin-3-amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((l -(2- methoxyethyl)piperidin-3-yl)amino)-7H-benzo[(i]imidazole-7-carboximidamide was isolated as an off-white solid. C22H24C1F3N602.497.2/499.1 (M+1). ¾ NMR (400 MHz, DMSO-d6) 5 10.81 (s, 1H), 9.63 (br. s, 1H), 8.68 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 6.96- 6.88 (m, 2H), 6.81 (dd, J = 12.2, 6.9 Hz, 1H), 6.55 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 3.72 (m, 1H), 3.67 (app. t, J = 4.9 Hz, 2H), 3.50 (m, 1H), 3.35 (m, 2H), 3.32 (s, 3H), 3.25 (m, 1H), 2.95-2.70 (m, 2H), 2.05-1.75 (m, 3H), 1.48 (m, 1H). 19F NMR (377 MHz, DMSO- d6) δ -75.0 (9F), -127.5 (IF), -150.6 (IF), -157.0 (IF).
Example 454: A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-((l-(2- methoxyethyl)pyrrolidin-3-yl)amino)-lH-benzo[d]imidazole-7-carboximidamide
[0947] Example 454 was made analogously to Example 333 using l -(2- methoxyethyl)pyrrolidin-3-amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt ofN-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((l -(2- methoxyethyl)pyrrolidin-3-yl)amino)-lH-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C2iH22ClF3N602.483.3/485.1 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.19 (br. s, 1H), 8.72 (s, 1H), 7.26 (d, J = 10.0 Hz, 1H), 7.13 - 7.05 (m, 2H), 6.93 (dd, J = 6.5, 2.6 Hz, 1H), 6.87 (dt, J = 12.0, 4.8 Hz, 1H), 6.53 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 4.65 - 4.45 (m, 1H), 3.98 - 3.70 (m, 1H), 3.67 - 3.56 (m, 3H), 3.50 - 3.37 (m, 3H), 3.32 (d, J = 7.0 Hz, 3H), 3.11 (m, 1H), 2.37 - 2.25 (m, 1H), 2.07 - 1.84 (m, 1H).19F NMR (377 MHz, DMSO-d6) δ -75.04 (9F), -127.36 (IF), - 150.26 (IF), -156.63 (IF).
Example 455: A-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^'-hydroxy-2-((l- isopropylpiperidin-3-yl)amino)-7H-benzo[i/|imidazole-7-carboximidamide
Figure imgf000407_0001
[0948] Example 455 was made analogously to Example 333 using 1- isopropylpiperidin-3-amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((l-isopropylpiperidin-3- yl)amino)-7H-benzo[cf|imidazole-7-carboximidamide was isolated as an off-white solid. C22H24C1F3N60.481.3/483.1 (M+1). ΧΗ ΝΜΚ (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.26 (s, 1H), 8.67 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.85 - 6.75 (m, 2H), 6.54 (m, 1H), 4.16 (m, 1H), 3.59 - 3.51 (m, 2H), 3.36 (m, 1H), 2.94 - 2.77 (m, 2H), 2.00 (m, 2H), 1.77 (m, 1H), 1.54 (m, 1H), 1.26 (t, J = 6.2 Hz, 6H). 19F NMR (377 MHz, DMSO-d6) δ -74.90 (9F), -127.52 (IF), -150.59 (IF), -157.02 (IF).
Example 456: iV-(3-chloro-4-fluorophenyl)-4,5-difluoro-iV'-hydroxy-2-((2-(3- methoxyazetidin-l-yl)ethyl)amino)-7H-benzo[i/]imidazole-7-carboximidamide
Figure imgf000407_0002
[0949] Example 456 was made analogously to Example 333 using 2-(3- methoxyazetidin-l-yl)ethan-l-amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt ofN-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(3- methoxyazetidin-l-yl)ethyl)amino)-7H-benzo[cf]imidazole-7-carboximidamide was isolated as an off-white solid. C2oH2oClF3N602.469.2/471.1 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.94 (br. s, 1H), 8.72 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 6.97 - 6.90 (m, 2H), 6.85 (dd, J = 12.2, 6.9 Hz, 1H), 6.53 (ddd, J = 8.9, 4.0, 2.8 Hz, 1H), 4.30 - 4.15 (m, 3H), 4.03 (m, 2H), 3.55 (m, 2H), 3.41 (m, 2H), 3.25 (s, 3H).19F NMR (377 MHz, DMSO-d6) δ -75.03 (9F), -127.30 (IF), -150.32 (IF), -157.00 (IF).
Example 457: (i?)-7V-(3-chloro-4-fluorophenyl)-4,5-difluoro-7V'-hydroxy-2-((l- methylpyrrolidin-3-yl)amino)-iH-benzo[</[ imidazole- 7-carboximidamide
Figure imgf000408_0001
[0950] Example 457 was made analogously to Example 333 using (R)-l- methylpyrrolidin-3 -amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of (i?)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((l-methylpyrrolidin-3- yl)amino)-7H-benzo[(i]imidazole-7-carboxirnidamide was isolated as an off-white solid. Ci9Hi8ClF3N60.439.2/441.1 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.11 (br. s, 0.5H), 9.85 (br. s, 0.5H), 8.71 (s, 1H), 7.28 (d, J = 9.3 Hz, 0.5H), 7.15 - 7.01 (m, 1.5H), 6.93 (dt, J = 6.3, 2.8 Hz, 1H), 6.87 (dd, J = 12.2, 6.9 Hz, 1H), 6.53 (m, 1H), 4.53 (m, 0.5H), 4.45 (m, 0.5H), 3.71 (m, 0.5H), 3.62 (m, 0.5H), 3.35 (m, 1H), 3.23 (m, 0.5H), 3.16 - 2.97 (m, 1.5H), 2.90 (d, J = 5.0 Hz, 1.5H), 2.88 (d, J = 4.6 Hz, 1.5H), 2.56 (m, 0.5H), 2.31 (m, 0.5H), 2.06 (m, 0.5H), 1.91 (m, 0.5H).19F NMR (377 MHz, DMSO- d6) δ -75.00, -127.38, -150.33, -156.70. Example 458: A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^'-hydroxy-2-(((3i?,4i?)-4- methoxy-l-methylpyrrolidin-3-yl)amino)-7H-benzo[i/] imidazole- 7- carboximidamide
Figure imgf000409_0001
[0951] Example 458 was made analogously to Example 333 using (3R,4R)-4- methoxy-l-methylpyrrolidin-3 -amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((3i?,4i?)-4- methoxy-l-methylpyrrolidin-3-yl)amino)-7H-benzo[(i]imidazole-7-carboximidamide was isolated as an off-white solid. C2oH2oClF3N602.469.2/471.1 (M+1). l NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 10.13 (br. s, 1H), 8.70 (s, 1H), 7.20 (m, 1H), 7.09 (td, J = 9.1, 3.0 Hz, 1H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.86 (m, 1H), 6.53 (dt, J = 8.9, 3.4 Hz, 1H), 4.41 (m, 1H), 4.09 (m, 1H), 3.95 (m, 1H), 3.71 (m, 1H), 3.37 (m, 3H), 3.21 (m, 1H), 3.10 (m, 1H), 2.90 (m, 3H).19F NMR (377 MHz, DMSO-d6) δ -74.80, -127.49, - 150.49, -157.01.
Example 459: (,S)-7V-(3-chlorophenyl)-4,5-difluoro-7V-hydroxy-2-((l- methylpiperidin-3-yl)amino)-iH-benzo[i/|imidazole-7-carboximidamide
Figure imgf000409_0002
[0952] Example 459 was made analogously to Example 460 using (5 -N-(3- chlorophenyl)-4,5-difluoro-2-((l-methylpiperidin-3-yl)amino)-l-((2- (trimethylsilyl)ethoxy)methyl)-7H-benzo[cf]imidazole-7-carboxylate. The TFA salt of (5,*)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((l-methylpiperidin-3-yl)amino)- 7H-benzo[cf]imidazole-7-carboximidamide was isolated as an off-white solid.
C2oH2iClF2N60.435.2/437.1 (M+l);435.2/437.1 (M+1). XH NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.66 (br. s, 1H), 8.67 (s, 1H), 7.06 (t, J = 8.1 Hz, 1H), 6.95 (m, 1H), 6.82 (dd, J = 8.0, 2.2 Hz, 1H), 6.79 (t, J = 2.2 Hz, 1H), 6.53 (dd, J = 8.2, 2.1 Hz, 1H), 4.06 (m, 1H), 3.67 (m, 1H), 3.42 (m, 1H), 2.83 (d, J = 4.4 Hz, 3H), 2.82 - 2.73 (m, 2H), 2.00 (m, 2H), 1.75 (m, 1H), 1.45 (m, 1H).;1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.63 (br. s, 1H), 8.69 (s, 1H), 7.06 (t, J = 8.0 Hz, 1H), 6.92 (m, 1H), 6.83 (m, 2H), 6.79 (t, J = 2.2 Hz, 1H), 6.52 (dd, J = 8.1, 2.2 Hz, 1H), 4.06 (m, 1H), 3.65 (m, 1H), 3.42 (m, 1H), 2.83 (d, J = 4.6 Hz, 3H), 2.81 - 2.75 (m, 2H), 1.99 (m, 2H), 1.72 (m, 1H), 1.45 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ -74.95, -150.50, -156.86.
Example 460: (i?)-^-(3-chlorophenyl)-4,5-difluoro-A^'-hydroxy-2-((l- n-3-yl)amino)-iH-benzo[i/]imidazole-7-carboximidamide
Figure imgf000410_0001
[0953] Methyl 4,5-difluoro-2-((l-methylpiperidin-3-yl)amino)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxylate was made analogously to Example 39 using l-methylpiperidin-3-amine in place of N,N- dimethylpropane- 1,3 -diamine. The TFA salt of methyl 4,5-difluoro-2-((l- methylpiperidin-3-yl)amino)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[cf|imidazole-7-carboxylate was isolated as an amorphous yellow oil.
C21H32F2N4O3S1. 455.2 (M+l).
Figure imgf000410_0002
[0954] N-(3-chlorophenyl)-4,5-difluoro-2-((l-methylpiperidin-3-yl)amino)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole-7-carboxamide was made analogously to Example 39 using methyl 4,5-difluoro-2-((l-methylpiperidin-3- yl)amino)-l-((2-(trimethylsilyl)ethoxy)methyl)-7H-benzo[(i]imidazole-7-carboxylate in place of methyl 2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[cf]imidazole-7-carboxylate and 3-chloroaniline in place of 3-chloro-4-fluoroaniline. N-(3-chlorophenyl)-4,5-difluoro-2-((l- methylpiperidin-3-yl)aniino)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazole-7- carboxamide was purified by silica gel chromatography (0-16% MeOH/CH2Cl2 w/ 0.5% NEt3) isolated as a white solid. C21H32F2N4O3S1. 455.2 (M+1). Each enantiomer was isolated using chiral SFC (AD-H, 15% iPrOH, 60 mL/min, 100 bar). C26H34ClF2N502Si. 550.3/552.1 (M+1).
Figure imgf000411_0001
[0955] (i?)-N-(3-chlorophenyl)-4,5-difluoro-2-((l-methylpiperidin-3-yl)amino)-l- ((2-(trimethylsilyl)ethoxy)methyl)-7H-benzo[(i]imidazole-7-carboxamide (60 mg, 0.11 mmol, 1 equiv) was dissolved in CH2CI2 (2 mL) and TFA (2 mL) was added. The SEM- deprotection was stirred overnight before being concentrated in vacuo. The crude product was dissolved in EtOAc, saturated aqueous NaHCC was added and the mixture was extracted twice with EtOAc. The combined organics were dried over MgSC>4, filtered and concentrated in vacuo. The resulting residue was dissolved in CH2CI2 (1 mL) and potassium carbonate (106 mg, 0.76 mmol, 7 equiv) and PC15 (68 mg, 0.33 mmol, 3 equiv) were added. The reaction was stirred at room temperature for 3 hours before being concentrated in vacuo. A solution of TMSONH2 (0.132 mL, 1.1 mmol, 10 equiv) in trifluoroethanol (1.5 mL) was added at 0 °C. The reaction was slowly warmed to room temperature and stirred for 1 hour before being concentrated in vacuo. A solution of 2N HC1 was added and the resulting mixture was stirred for 30 minutes before diluting with DMF/H2O and purification by reverse phase HPLC. The TFA salt of (R)-N-(3- chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((l-methylpiperidin-3-yl)amino)-lH- benzo[d]imidazole-7-carboxirnidamide was isolated as an off-white solid.
C2oH2iClF2N60.435.2/437.1 (M+l);435.2/437.1 (M+1). XH NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.66 (br. s, 1H), 8.67 (s, 1H), 7.06 (t, J = 8.1 Hz, 1H), 6.95 (m, 1H), 6.82 (dd, J = 8.0, 2.2 Hz, 1H), 6.79 (t, J = 2.2 Hz, 1H), 6.53 (dd, J = 8.2, 2.1 Hz, 1H), 4.06 (m, 1H), 3.67 (m, 1H), 3.42 (m, 1H), 2.83 (d, J = 4.4 Hz, 3H), 2.82 - 2.73 (m, 2H), 2.00 (m, 2H), 1.75 (m, 1H), 1.45 (m, 1H).; 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.63 (br. s, 1H), 8.69 (s, 1H), 7.06 (t, J = 8.0 Hz, 1H), 6.92 (m, 1H), 6.83 (m, 2H), 6.79 (t, J = 2.2 Hz, 1H), 6.52 (dd, J = 8.1, 2.2 Hz, 1H), 4.06 (m, 1H), 3.65 (m, 1H), 3.42 (m, 1H), 2.83 (d, J = 4.6 Hz, 3H), 2.81 - 2.75 (m, 2H), 1.99 (m, 2H), 1.72 (m, 1H), 1.45 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ -74.95, -150.50, -156.86.
Example 461: A-(3-chloro-4-fluorophenyl)-2-((2- (dimethylamino)cyclopentyl)amino)-4,5-difluoro-A^'-hydroxy-iH- benzo [d\ imidazole-7-carboximidamide
Figure imgf000412_0001
[0956] Example 461 was made analogously to Example 333 using Nl,Nl- dimethylcyclopentane-l,2-diamine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)cyclopentyl)amino)-4,5- difluoro-N'-hydroxy-7H-benzo[cf|imidazole-7-carboximidamide was isolated as an off- white solid. C2iH22ClF3N60.467.3/469.1 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.69 (s, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.83 (m, 1H), 6.52 (m, 1H), 4.34 (m, 1H), 3.63 (m, 1H), 2.85 (s, 6H), 2.15 - 2.00 (m, 2H), 1.87 (m, 1H), 1.79 - 1.63 (m, 3H).
Example 462 : (S)-2-(azepan-3-ylamino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro- N'-hydroxy- lH-benzo [d] imidazole- 7-carboximidamide
Figure imgf000412_0002
[0957] Example 462 was made analogously to Example 333 using tert-butyl (5 -3- aminoazepane-l-carboxylate in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of (5 -2-(azepan-3-ylamino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy- 7H-benzo[(¾iinidazole-7-carboximidamide was isolated as an off-white solid.
C2oH2oClF3N60.453.3 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.77 (br. s, 2H), 8.66 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.86 (d, J = 6.9 Hz, 1H), 6.82 (dd, J = 12.3, 6.9 Hz, 1H), 6.58 - 6.51 (m, 1H), 4.15 (m, 1H), 3.42 (m, 1H), 3.26 (m, 1H), 3.21 - 3.11 (m, 2H), 2.04 (m, 1H), 1.92 - 1.54 (m, 5H).19F NMR (376 MHz, DMSO-d6) δ -74.9, -127.5, -150.5, -156.8.
Example 463: (i?)-2-(azepan-3-ylamino)-A^-(3-chloro-4-fluorophenyl)-4,5-difluoro- iV-hydroxy-7H-benzo[d]imidazole-7-carboximidamide
Figure imgf000413_0001
[0958] Example 463 was made analogously to Example 333 using tert-butyl (R)-3- aminoazepane-l-carboxylate in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of (i?)-2-(azepan-3-ylamino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy- 7H-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid.
C2oH2oClF3N60.453.2/455.1 (M+l). 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.76 (br. s, 2H), 8.66 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.83 (d, J = 6.8 Hz, 1H), 6.80 (d, J = 6.7 Hz, 1H), 6.54 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 4.15 (m, 1H), 3.42 (m, 1H), 3.26 (m, 1H), 3.20 - 3.07 (m, 2H), 2.05 (m, 1H), 1.91 - 1.54 (m, 5H).19F NMR (376 MHz, DMSO-d6) δ -74.8, -127.5, -150.5, -156.8.
Example 464: A/-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^'-hydroxy-2-(pyrrolidin-
3-ylamino)-iH-benzo[</[ imidazole- 7-carboximidamide
Figure imgf000413_0002
[0959] Example 464 was made analogously to Example 333 using tert-butyl 3- aminopyrrolidine-l-carboxylate in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(pyrrolidin-3-ylamino)- 7H-benzo[cf]imidazole-7-carboximidamide was isolated as an off-white solid.
Ci8Hi6ClF3N60.425.2/427.1 (M+1). *H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.89 (br. s, 1H), 8.79 (br. s, 1H), 8.70 (s, 1H), 7.12 - 7.05 (m, 2H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.85 (dd, J = 12.3, 6.9 Hz, 1H), 6.53 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 4.44 (m, 1H), 3.47 (m, 1H), 3.27 (m, 2H), 2.27 (m, 1H), 1.94 (m, 1H).19F NMR (377 MHz, DMSO-d6) δ -74.9 (9F), -127.4 (IF), -150.44 (IF), -156.81 (IF).
Example 465: (i?)-7V-(3-chloro-4-fluorophenyl)-4,5-difluoro-7V'-hydroxy-2-((l- (oxetan-3-yl)piperidin-3-yl)amino)-7H-benzo[i/|imidazole-7-carboximidamide
Figure imgf000414_0001
[0960] Example 465 was made analogously to Example 333 using (i?)-l-(oxetan-3- yl)piperidin-3-amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of (i?)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((l-(oxetan-3-yl)piperidin-3- yl)amino)-7H-benzo[cf|imidazole-7-carboximidamide was isolated as an off-white solid. C22H22C1F3N602.495.3/497.1 (M+1). ΧΗ ΝΜΚ (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 10.61 br. (s, 1H), 8.70 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 7.04 (m, 1H), 6.92 (dd, J = 6.6, 2.7 Hz, 1H), 6.84 (dd, J = 12.3, 6.9 Hz, 1H), 6.54 (dt, J = 8.9, 3.4 Hz, 1H), 4.80 - 4.65 (m, 4H), 4.40 (m, 1H), 4.14 (m, 1H), 3.53 (m, 1H), 3.38 (m, 1H), 2.84 - 2.65 (m, 2H), 2.1 - 1.90 (m, 2H), 1.77 (m, 1H), 1.53 (m, 1H).19F NMR (377 MHz, DMSO-d6) δ -74.8 (9F), -127.3 (IF), -150.3 (IF), -156.7 (IF).
Example 466: A^-(3-chloro-4-fluorophenyl)-2-(((l,4-dimethylpiperidin-2- yl)methyl)amino)-4,5-difluoro-A^'-hydroxy-iH-benzo[i/]imidazole-7- carboximidamide
Figure imgf000415_0001
[0961] Example 466 was made analogously to Example 333 using (1,4- dimethylpiperidin-2-yl)methanamine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((l,4-dimethylpiperidin-2-yl)methyl)amino)- 4,5-difluoro-N'-hydroxy-7H-benzo[cf|imidazole-7-carboximidamide was isolated as an off-white solid. C22H24CIF3N6O.481.3/483.2 (M+l). 'H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.20 (br. s, 1H), 8.69 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 7.02 (m, 1H), 6.92 (dd, J = 6.5, 2.7 Hz, 1H), 6.84 (dd, J = 12.2, 6.9 Hz, 1H), 6.54 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.81 (m, 1H), 3.66 (m , 1H), 3.40 (m, 1H), 3.27 (m, 1H), 3.08 (m, 1H), 2.99 (s, 3H), 1.93 (m, 1H), 1.84 - 1.60 (m, 2H), 1.25 (m, 1H), 0.93 (d, J = 6.4 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -75.1 , -127.4 , -150.4, -157.0.
Example 467 : iV-(3-chloro-4-fluorophenyl)-4,5-difluoro-iV'-hydroxy-2-((morpholin- 3-ylmethyl)amino)-iH-benzo [d] imidazole-7-carboximidamide
Figure imgf000415_0002
[0962] Example 467 was made analogously to Example 333 using /er/-butyl 3- (aminomethyl)morpholine-4-carboxylate in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((mo holin-3- ylmethyl)arnino)-7H-benzo[cf]imidazole-7-carboximidamide was isolated as an off-white solid. Ci9Hi8ClF3N602.455.2/457.1 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.06 (br. s, 2H), 8.71 (s, 1H), 7.10 (t, J = 9.1 Hz, 1H), 7.02 (m, 1H), 6.92 (dd, J = 6.6, 2.7 Hz, 1H), 6.83 (dd, J = 12.3, 6.9 Hz, 1H), 6.53 (dt, J = 9.0, 3.4 Hz, 1H), 3.95 (m, 1H), 3.88 (m, 1H), 3.67 (m, 1H), 3.62 - 3.50 (m, 4H), 3.30 (m, 1H), 3.09 (m, 1H).19F NMR (377 MHz, DMSO-d6) δ -74.9 (9F), -127.2 (IF), -150.2 (IF), -156.4 (IF).
Example 468: A^-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^'-hydroxy-2-(((3i?,4S)-4- hydroxypyrrolidin-3-yl)amino)-lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000416_0001
[0963] Example 468 was made analogously to Example 333 using tert-butyl (3R,4S)- 3-amino-4-hydroxypyrrolidine-l-carboxylate in place of tert-butyl (2- aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- hydroxy-2-(((3i?,4^-4-hydroxypyirolidin-3-yl)amino)-lH-benzo[d]imidazole-7- carboximidamide was isolated as an off-white solid. Ci8Hi6ClF3N602.441.2/443.1
(M+l). ¾ NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.18 (br. s, 1H), 8.81 (br. s, 1H), 8.69 (s, 1H), 7.11 (t, J = 9.1 Hz, 1H), 6.95 - 6.90 (m, 2H), 6.82 (dd, J = 12.3, 6.8 Hz, 1H), 6.53 (dt, J = 8.8, 3.4 Hz, 1H), 6.13 (br. s, 1H), 4.49 (m, 1H), 4.36 (m, 1H), 3.56 (m, 1H), 3.42 (m, 1H), 3.17 (m, 1H), 3.01 (m, 1H).19F NMR (377 MHz, DMSO-d6) δ -74.7 (9F), -127.4 (IF), -150.3 (IF), -156.8 (IF).
Example 469: iV-(3-chloro-4-fluorophenyl)-4,5-difluoro-iV'-hydroxy-2-(((li?,5i?)-8- methyl-8-azabicyclo [3.2.1] octan-2-yl)amino)-iH-benzo [d\ imidazole- 7- carboximidamide
Figure imgf000416_0002
[0964] Example 469 was made analogously to Example 333 using (li?,5i?)-8-methyl- 8-azabicyclo[3.2.1]octan-2-amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt ofN-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((li?,5i?)-8-methyl- 8-azabicyclo[3.2.1]octan-2-yl)amino)-/H-benzo[cf]imidazole-7-carboximidamide was isolated as an off-white solid. C22H22C1F3N60. 479.3/481.1 (M+1). XH NMR (400 MHz, DMSO-d6, 2: 1 mixture of diastereomers) δ 10.82 (br. s, 1H), 9.72 (s, 1H), 8.69 (d, J = 7.8 Hz, 1H), 7.17 - 7.03 (m, 2H), 6.90 (td, J = 6.5, 2.8 Hz, 1H), 6.81 (dd, J = 12.3, 7.0 Hz, 1H), 6.55 (ddd, J = 8.9, 4.6, 3.1 Hz, 1H), 4.29 (m, 1H), 4.05 - 3.70 (m, 2H), 2.75 (d, J = 4.9 Hz, '2H'), 2.63 (d, J = 4.8 Hz, ΊΗ), 2.23 (m, 1H), 2.14 - 1.80 (m, 5H), 1.73 (m, 1H), 1.54 (m, 1H).19F NMR (377 MHz, DMSO) δ -75.02, Major: -127.83, -150.68, - 156.90, Minor: -127.66, -150.46, -156.51
Example 470: (,S)-iV-(3-chloro-4-fluorophenyl)-4,5-difluoro-iV'-hydroxy-2-((2-(2- (trifluoromethyl)pyrrolidin-l-yl)ethyl)amino)-iH-benzo[i/]imidazole-7- carboximidamide
Figure imgf000417_0001
[0965] Example 470 was made analogously to Example 333 using (S)-2-(2- (trifluoromethyl)pyrrolidin-l-yl)ethan-l -amine in place of tert-butyl (2- aminoethyl)carbamate. The TFA salt of (<S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- hydroxy-2-((2-(2-(trifluoromethyl)pyrrolidin^
7-carboximidamide was isolated as an off-white solid. C2iHi9ClF6N60. 521.3/523.1 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 10.99 (br. s, 1H), 8.82 (s, 1H), 7.95 (br. s, 1H), 7.13 - 7.03 (m, 2H), 6.97 (dd, J = 6.5, 2.7 Hz, 1H), 6.54 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 3.59 - 3.40 (m, 3H), 3.19 (m, 1H), 3.03 (dt, J = 13.6, 7.1 Hz, 1H), 2.82 (dt, J = 12.7, 5.2 Hz, 1H), 2.46 (m, 1H), 2.04 (m, 1H), 1.87 - 1.64 (m, 3H).19F NMR (377 MHz,
DMSO-d6) δ -75.31 (9F), -75.43 (d, J = 8.2 Hz, 3F), -126.82 (IF), -147.12 (IF), -155.04 (IF). Example 471 : iV-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(((hexahydro- 1H- pyrrolizin-7a-yl)methyl)amino)-/V-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
Figure imgf000418_0001
[0966] Example 471 was made analogously to Example 333 using (tetrahydro-lH- pyrrolizin-7a(5H)-yl)methanamine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(((hexahydro-lH-pyrrolizin-7a- yl)methyl)amino)-N'-hydroxy-lH-benzo[d]imidazole-7-carboximidamide was isolated as an off-white solid. C22H22C1F3N60. 479.4/481.1 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 10.75 (br. s, 1H), 8.74 (s, 1H), 7.08 (t, J = 9.1 Hz, 1H), 6.93 (dd, J = 6.5, 2.7 Hz, 1H), 6.87 (dd, J = 12.2, 7.1 Hz, 1H), 6.50 (dq, J = 9.0, 3.0 Hz, 1H), 3.69 (app. d, J = 5.9 Hz, 2H), 3.46 (dq, J = 12.0, 6.1 Hz, 2H), 3.20 (m, 2H), 2.14 - 1.96 (m, 4H), 1.95 - 1.80 (m, 4H).19F NMR (377 MHz, DMSO-d6) δ -75.1 (9F), -127.3 (IF), -149.9 (dd, J = 22.6, 12.3 Hz, IF), -156.8 (IF).
Example 472 : iV-(3-chloro-4-fluorophenyl)-2-(((3,3-dimethylazetidin-2- yl)methyl)amino)-4,5-difluoro-iV'-hydroxy-iH-benzo[i/]imidazole-7- carboximidamide
Figure imgf000418_0002
[0967] Example 472 was made analogously to Example 333 using tert-butyl 2- (aminomethyl)-3,3-dimethylazetidine-l -carboxylate in place of tert-butyl (2- aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((3,3- dimethylazetidin-2-yl)methyl)amino)-4,5-difluoro-N'-hydroxy-7H-benzo[cf]imidazole-7- carboximidamide was isolated as an off-white solid. C2oH2oClF3N60. 453.2/455.1 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.97 (br. s, 1H), 8.75 - 8.65 (m, 2H), 7.09 (t, J = 9.1 Hz, 1H), 6.97 - 6.78 (m, 3H), 6.53 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 4.24 (m, 1H), 3.80 - 3.59 (m, 3H), 3.49 (m, 1H), 1.27 (s, 3H), 1.22 (s, 3H).19F NMR (377 MHz, DMSO-d6) δ -75.0 (9F), -127.3 (IF), -150.3 (IF), -156.7 (d, J = 23.0 Hz, IF).
Example 473: A-(3-chloro-4-fluorophenyl)-4,5-difluoro-A^-hydroxy-2-((4- (pyrrolidin-l-yl)tetrahydro-2H-pyran-3-yl)amino)-lH-benzo[d]imidazole-7- carboximidamide
Figure imgf000419_0001
[0968] Example 473 was made analogously to Example 333 using 4-(pyrrolidin-l- yl)tetrahydro-2H-pyran-3 -amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((4-(pyrrolidin-l- yl)tetrahydro-2H-pyran-3-yl)amino)-7H-benzo[cf]imidazole-7-carboximidamide was isolated as an off-white solid. C23H24C1F3N602. 509.3/511.1 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.65 (br. s, 1H), 8.68 (s, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.11 (t, J = 9.1 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.84 (dd, J = 12.3, 6.8 Hz, 1H), 6.54 (ddd, J = 9.0, 4.0, 2.8 Hz, 1H), 4.35 (s, 1H), 4.04 (dd, J = 12.5, 3.2 Hz, 1H), 3.83 - 3.73 (m, 2H), 3.66 (m, 1H), 3.55 - 3.40 (m, 5H), 2.13 (m, 1H), 2.00 - 1.85 (m, 4H), 1.71 (m, 1H).19F NMR (377 MHz, DMSO-d6) δ -74.93 (9F), -127.54 (IF), -150.41 (IF), -156.80
(IF).
Example 474: 2-(((l.S',2i?)-2-aminocyclohexyl)amino)-iV-(3-chloro-4-fluorophenyl)- 4,5-difluoro-iV'-hydroxy-iH-benzo[i/]imidazole-7-carboximidamide
Figure imgf000419_0002
[0969] Example 474 was made analogously to Example 333. The TFA salt of 2- (((15,,2i?)-2-aminocyclohexyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- hydroxy-/H-benzo[cf]imidazole-7-carboximidamide was isolated as an off-white solid. C2oH2oClF3N60. 453.2/455.1 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.64 (s, 1H), 7.78 (br. s, 3H), 7.12 (t, J = 9.1 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 6.88 (dd, J = 6.5, 2.7 Hz, 1H), 6.76 (dd, J = 12.3, 6.8 Hz, 1H), 6.53 (ddd, J = 9.0, 3.9, 2.6 Hz, 1H), 4.27 (m, 1H), 3.45 (m, 1H), 1.81 - 1.60 (m, 4H), 1.58 - 1.31 (m, 4H).19F NMR (376 MHz, DMSO-d6) δ -74.8, -127.66 , -150.5 , -156.8.
Example 475 : iV-(3-chloro-4-fluorophenyl)-4,5-difluoro-iV'-hydroxy-2-((2-methyl- 1,2,3,4- tetrahydroisoquinolin-4-yl)amino)-lH-benzo[i/]imidazole-7- carboximidamide
Figure imgf000420_0001
[0970] Example 475 was made analogously to Example 333 using 2-methyl-l, 2,3,4- tetrahydroisoquinolin-4-amine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt ofN-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-methyl-l,2,3,4- tetrahydroisoquinolin-4-yl)amino)-lH-benzo[cf]imidazole-7-carboximidamide was isolated as an off-white solid. C24H2oClF3N60. 501.3/503.1 (M+1). 'H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 10.32 (br. s, 1H), 8.69 (s, 1H), 7.49 (m, 1H), 7.45 - 7.34 (m, 2H), 7.30 - 7.20 (m, 2H), 7.07 (m, 1H), 6.95 - 6.80 (m, 2H), 6.51 (m, 1H), 5.62 (m, 1H), 5.16 (m, 1H), 4.61 (m, 1H), 4.37 (m, 1H), 3.40 (m, 1H), 3.03 (s, 3H).19F NMR (376 MHz, DMSO-d6) δ -74.8, -127.4, -150.0 -156.9. Example 476: /V-CS-chloro-^fluorophenylJ-l-CCCS^S)^- (diethylamino)tetrahydrofuran-3-yl)amino)-4,5-difluoro-/V'-hydroxy-lH- benzo[</]imidazole-7-carboximidamide
Figure imgf000421_0001
[0971] Example 476 was made analogously to Example 333 using (3S,4S)-N ,N3- diethyltetrahydrofuran-3,4-diamine. The TFA salt of N-(3-chloro-4-fluorophenyl)-2- (((3S*,4£*)-4-(diethylamino)teTjah^
benzo[cf|imidazole-7-carboximidamide was isolated as an off-white solid.
C22H24C1F3N602. 497.3/499.1 (M+1). 'H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 10.18 (br. s, 1H), 8.69 (s, 1H), 7.38 (s, 1H), 7.08 (t, J = 9.1 Hz, 1H), 6.97 - 6.81 (m, 2H), 6.53 (dt, J = 9.0, 3.4 Hz, 1H), 4.63 (m, 1H), 4.21 (m, 1H), 4.15 - 4.03 (m, 2H), 3.59 (m, 2H), 3.40 - 3.20 (m, 4H), 1.23 (t, J = 7.2 Hz, 6H).19F NMR (376 MHz, DMSO-d6) δ - 74.9, -127.4, -150.1 , -157.2.
Example 477: 2-((l,4-oxazepan-6-yl)amino)-iV-(3-chloro-4-fluorophenyl)-4,5- difluoro-iV'-hydroxy-lH-benzo[i/]imidazole-7-carboximidamide
Figure imgf000421_0002
[0972] Example 477 was made analogously to Example 333 using tert-butyl 6- amino-l ,4-oxazepane-4-carboxylate in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of 2-((l,4-oxazepan-6-yl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- hydroxy-lH-benzo[cf]imidazole-7-carboximidamide was isolated as an off-white solid. Ci9Hi8ClF3N602. 455.2/457.1 (M+1). 'H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.01 (br. s, 2H), 8.69 (s, 1H), 7.11 (t, J = 9.1 Hz, 1H), 6.97 (d, J = 7.3 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.82 (dd, J = 12.3, 6.9 Hz, 1H), 6.53 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 4.33 (m, 1H), 3.99 - 3.74 (m, 4H), 3.54 (m, 1H), 3.46 (m, 1H), 3.32 (m, 1H).19F NMR (377 MHz, DMSO-d6) δ -74.9 (9F), -127.5 (IF), -150.5 (IF), -156.8 (IF).
Example 478: ^-(S-chloro^-fluoropheny -l-iil-^l^ ?)-!^- dimethylmorpholino)ethyl)amino)-A^'-hydroxy-iH-imidazo[4,5-Z>]pyridine-7- carboximidamide
Figure imgf000422_0001
[0973] Example 478 was made analogously to Example 229 using 3-(2-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one and 2-((2,$',6Λ)-2,6^™6^^ο 1ιο1ίηο)6ΐ]ΐ3η- 1-amine in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3- aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4- fluorophenyl)-2-((2-((25',6 ?)-2,6-dimethylmo holino)ethyl)amino)-N'-hydroxy-7H- imidazo[4,5-Z>]pyridine-7-carboximidamide was isolated as an off-white solid.
C21H25CIFN7O2. 462.3/464.2 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 11.40 (br. s, 1H), 8.98 (s, 1H), 8.20 (br. s, 1H), 8.00 (d, J = 6.2 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 6.95 (d, J = 6.2 Hz, 1H), 6.57 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 3.88 - 3.78 (m, 4H), 3.63 - 3.53 (m, 2H), 3.40 - 3.31 (m, 2H), 2.77 - 2.61 (m, 2H), 1.15 (d, J = 6.3 Hz, 6H).19F NMR (377 MHz, DMSO-d6) δ -74.60 (9F), -126.59 (IF).
Example 479: iV-(3-chloro-4-fluorophenyl)-/V'-hydroxy-2-(((3i?,4i?)-4-methoxy-l- methylpyrrolidin-3-yl)amino)-iH-imidazo[4,5-Z>]pyridine-7-carboximidamide
Figure imgf000423_0001
[0974] Example 479 was made analogously to Example 333 using (3R,4R)-4- methoxy-l-methylpyrrolidin-3 -amine in place of 3-(2-chloro-4,5-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)- l,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt ofN-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((3i?,4i?)-4-methoxy-l- methylpyrrolidin-3-yl)amino)-/H-imidazo[4,5-/)]pyridine-7-carboximidamide was isolated as an off-white solid. C19H21CIFN7O2. 434.2/436.1 (M+1). XH NMR (400 MHz, DMSO-d6) δ 11.25 (br. s, 1H), 10.23 (br. s, 1H), 8.92 (s, 1H), 7.98 (s, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.03 - 6.90 (m, 2H), 6.67 (m, 1H), 4.49 (m, 1H), 4.11 (m, 1H), 3.97 (m, 1H), 3.72 (m, 1H), 3.36 (s, 3H), 3.30 - 3.04 (m, 2H), 2.90 (s, 3H).19F NMR (377 MHz, DMSO-d6) δ -74.4, -126.7.
Example 480: iV-(3-chloro-4-fluorophenyl)-2-(((3i?,4i?)-4- (diethylamino)tetrahydrofuran-3-yl)amino)-/V'-hydroxy-iH-imidazo[4,5-Z»]pyridine-
7-carboximidamide
Figure imgf000423_0002
[0975] Example 480 was made analogously to Example 229 using 3-(2-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one and (3i?,4i?)-N3,N3-diethyltetrahydrofuran-3,4- diamine in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3- aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4- fluorophenyl)-2-(((3i?,4i?)-4-(diethylamino)tetrahydrofuran-3-yl)amino)-N'-hydroxy-7H- imidazo[4,5- >]pyridine-7-carboximidamide was isolated as an off-white solid.
C21H25CIFN7O2. 462.2/464.2 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 11.20 (br. s, 1H), 8.86 (s, 1H), 7.96 (s, 2H), 7.07 (s, 1H), 7.00 - 6.85 (m, 1H), 6.53 (s, 1H), 4.65 (m, 1H), 4.21 (m, 1H), 4.16 - 4.05 (m, 2H), 3.36 - 3.22 (m, 4H), 1.24 (t, J = 7.2 Hz, 6H).
Example 481: (,S)-iV-(3-chloro-4-fluorophenyl)-iV'-hydroxy-2-((2-(2- (trifluoromethyl)pyrrolidin- l-yl)ethyl)amino)-iH-imidazo [4,5-Z>] pyridine-7- carboximidamide
Figure imgf000424_0001
[0976] Example 481 was made analogously to Example 229 using 3-(2-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and (5)-2-(2-(trifluoromethyl)pyrrolidin-l- yl)ethan-l -amine in place of 3-(2-chloro-4,5-difluoro-l-((2-
(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)- l,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of (5 -N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(2- (trifluoromethyl)pyrrolidin-l-yl)ethyl)amino)-7H-imidazo[4,5-/)]pyridine-7- carboximidamide was isolated as an off-white solid. C20H20CIF4N7O. 486.3/488.1 (M+l). 'H NMR (400 MHz, DMSO-d6) δ 11.41 (br. s, 1H), 8.95 (s, 1H), 7.97 (d, J = 6.4 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 6.94 (d, J = 6.3 Hz, 1H), 6.59 (dt, J = 9.0, 3.5 Hz, 1H), 3.60 - 3.50 (m, 2H), 3.18 (m, 1H), 3.06 (m, 1H), 2.81 (dt, J = 11.6, 5.4 Hz, 1H), 2.45 (m, 1H), 2.02 (m, 1H), 1.87 - 1.64 (m, 4H).19F NMR (376 MHz, DMSO-d6) δ -74.5 , -75.5, -126.5. Example 482: (i?)-/V-(3-chloro-4-fluorophenyl)-/V'-hydroxy-2-(((4- methylmorpholin-3-yl)methyl)amino)-iH-imidazo[4,5-Z>]pyridine-7- carboximidamide
Figure imgf000425_0001
[0977] Example 482 was made analogously to Example 229 using 3-(2-chloro-l -((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one and (i?)-(4-methylmorpholin-3- yl)methanamine in place of 3-(2-chloro-4,5-difluoro-l -((2-
(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)- l ,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of (i?)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((4-methylmorpholin-3- yl)methyl)amino)-/H-imidazo[4,5-/)]pyridine-7-carboximidamide was isolated as an off- white solid. C19H21CIFN7O2. 434.2/436.1 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 8.87 (br. s, 1H), 7.95 (s, 1H), 7.09 (t, J = 8.9 Hz, 1H), 7.05 - 6.8 (m, 2H), 6.57 (dt, J = 9.0, 3.4 Hz, 1H), 4.09 - 3.88 (m, 2H), 3.69 - 3.40 (m, 7H), 2.98 (s, 3H).
Example 483: iV-(3-chloro-4-fluorophenyl)-2-((2-(2,6- dimethylmorpholino)propyl)amino)-/V'-hydroxy-iH-imidazo[4,5-Z»]pyridine-7- carboximidamide
Figure imgf000425_0002
[0978] Example 483 was made analogously to Example 229 using 3-(2-chl
(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)- 1 ,2,4-oxadiazol-5(4H)-one and
Figure imgf000426_0001
amine in place of 3-(2-chloro-4,5-difluoro-l -((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3- aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4- fluorophenyl)-2-((2-(2,6-dimethylmo holino)propyl)arrlino)-N'-hydroxy-/H- imidazo[4,5- >]pyridine-7-carboximidamide was isolated as an off-white solid.
C22H27C1FN702. 476.3/478.2 (M+1). 'H NMR (400 MHz, DMSO-d6) δ 1 1.80 (br. s, 1H), 11.31 (br. s, 1H), 8.95 (s, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.00 (dd, J = 6.6, 2.7 Hz, 1H), 6.93 (d, J = 6.0 Hz, 1H), 6.57 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 3.98 - 3.66 (m, 7H), 2.83 - 2.65 (m, 2H), 1.28 (d, J = 6.6 Hz, 3H), 1.17 (d, J = 4.3 Hz, 3H), 1.15 (d, J = 4.2 Hz, 3H).19F NMR (377 MHz, DMSO-d6) δ -74.5 (9H), -126.8 (1H).
Example 484: iV-(3-chloro-4-fluorophenyl)-2-((2-(2,6-dimethylmorpholino)-2- methylpropyl)amino)-/V'-hydroxy-iH-imidazo[4,5-Z»]pyridine-7-carboximidamide
Figure imgf000426_0002
[0979] Example 484 was made analogously to Example 229 using 3-(2-chloro-l -((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one and 2-(2,6-dimethylmorpholino)-2- methylpropan-1 -amine in place of 3-(2-chloro-4,5-difluoro-l -((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)- l ,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt ofN-(3-chloro-4-fluorophenyl)-2-((2-(2,6-dimethylmo holino)-2- methylpropyl)amino)-N'-hydroxy-7H-imidazo[4,5-/)]pyridine-7-carboxirnidamide was isolated as an off-white solid. C23H29CIFN7O2. 490.2/492.1 (M+1). XH NMR (400 MHz, DMSO-d6) δ 1 1.60 (br. s, 1H), 11.27 (br. s, 1H), 8.89 (s, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.00 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.0 Hz, 1H), 6.57 (ddd, J = 8.9, 3.9, 2.7 Hz, 1H), 4.00 - 3.85 (m, 2H), 3.78 - 3.50 (m, 4H), 2.70 (m, 2H), 1.32 (s, 6H), 1.19 (s, 3H), 1.17 (s, 3H). F NMR (376 MHz, DMSO-d6) δ -74.51 (9F), - 126.81 (IF).
Example 485: A^-(3-chloro-4-fluorophenyl)-2-((2-(2,5- dimethylmorpholino)ethyl)amino)-A^'-hydroxy-iH-imidazo[4,5-Z>]pyridine-7- carboximidamide
Figure imgf000427_0001
[0980] Example 485 was made analogously to Example 229 using 3-(2-chloro-l -((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one and 2-(2,5-ά^6^^οφηο1ϊηο)6Ϊτΐ£ΐη-1 -amine in place of 3-(2-chloro-4,5-difluoro-l -((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3- aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4- fluorophenyl)-2-((2-(2,5-dimethylmo holino)ethyl)amino)-N'-hydroxy-7H-imidazo[4,5-)]pyridine-7-carboximidamide was isolated as an off-white solid. C21H25CIFN7O2.
462.3/464.2 (M+l). 'H NMR (400 MHz, DMSO-d6) δ 1 1.28 (br. s, 1H), 8.92 (m, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 6.99 (d, J = 6.3 Hz, 1H), 6.93 (t, J = 6.8 Hz, 1H), 6.58 (ddd, J = 9.3, 4.4, 2.9 Hz, 1H), 4.00 - 3.75 (m, 6H), 3.37 - 3.17 (m, 2H), 2.93 (m, 2H), 1.33 (d, J = 6.8 Hz, 2H), 1.16 (d, J = 6.2 Hz, 4H).19F NMR (376 MHz, DMSO-d6) δ -74.5, -126.6.
Example 486: A^-(3-chloro-4-fluorophenyl)-2-(((li?,2i?)-2- (dimethylamino)cyclopentyl)amino)-4,5-difluoro-A^'-hydroxy-iH- benzo [d\ imidazole-7-carboximidamide
Figure imgf000428_0001
[0981] Example 486 was made analogously to Example 333 using (li?,2i?)-Nl ^Vl- dimethylcyclopentane-l,2-diamine in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((li?,2i?)-2-
(dimethylamino)cyclopentyl)amino)-4,5-difluoro-N'-hydroxy-7H-benzo[cf]imidazole-7- carboximidamide was isolated as an off-white solid. C2iH22ClF3N60. 467.3/469.1 (M+l). 'H NMR (400 MHz, DMSO-d6) δ 10.74 (br. s, 1H), 8.69 (s, 1H), 7.09 (t, J = 9.0 Hz, 1H), 6.91 (dd, J = 6.5, 2.7 Hz, 1H), 6.84 (m, 1H), 6.52 (m, 1H), 4.34 (m, 1H), 3.61 (m, 1H), 2.85 (s, 6H), 2.17 - 1.96 (m, 2H), 1.89 (m, 1H), 1.80 - 1.59 (m, 3H).19F NMR (376 MHz, DMSO-d6) δ -74.8, -127.4, -150.3, -157.2.
Example 487: iV-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)thio)-iV'- hydroxy-iH-imidazo [4,5-Z>] pyridine-7-carboximidamide
Figure imgf000428_0002
[0982] To a solution of 2-(dimethylamino)ethane-l -thiol (0.01 mL, 0.096 mmol, 1.9 equiv) in 0.5 mL THF at -78 °C was added 0.04 mL of «-BuLi (0.06 mmol, 1.6 equiv). The mixture was stirred for 10 minutes before the addition of 3-(2-chloro-l -((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one (25 mg, 0.05 mmol, 1 equiv) in 0.5 mL of THF. The reaction was slowly warmed to room temperature and stirred for 3 hours before being quenched with saturated aqueous NH4C1. The reaction mixture was extracted twice with EtOAc, the combined organic layers were dried over MgSC>4, filtered and concentrated in vacuo. The crude product was dissolved in 0.75 mL CH2CI2 and 0.75 mL of TFA was added. The reaction was stirred at room temperature for 3 hours before being concentrated in vacuo. The crude product was then dissolved in 0.4 mL THF, 0.4 mL MeOH and 0.9 mL of 2N aqueous NaOH was added. The reaction was stirred at room temperature for 30 minutes before being neutralized with 0.9 mL of 2N aqueous HC1, diluted with DMF and purified by reverse phase HPLC. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)thio)-N'-hydroxy-7H- imidazo[4,5- )]pyridine-7-carboximidamide was isolated as an off-white solid.
CnHigClFNgOS. 409.3/411.0 (M+l). 'H NMR (400 MHz, DMSO-d6) δ 10.99 (br. s, 1H), 8.87 (s, 1H), 8.21 (d, J = 5.2 Hz, 1H), 7.15 - 7.00 (m, 2H), 6.93 (dd, J = 6.6, 2.7 Hz, 1H), 6.50 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 3.70 - 3.55 (m, 2H), 3.55 - 3.45 (m, 2H), 2.89 (s, 6H).19F NMR (376 MHz, DMSO-d6) δ -74.69 (9F), -127.08 (IF).
Example 488: iV-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)thio)-4,5- difluoro-ZV -hydroxy- lH-benzo[d]imidazole-7-carboximidamide
Figure imgf000429_0001
[0983] Example 488 was made analogously to Example 212 using 3-(2-chloro-4,5- difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-7H-benzo[cf|imidazol-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one. The TFA salt of N-(3-chloro-4-fluorophenyl)- 2-((2-(dimethylamino)ethyl)thio)-4,5-difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide was isolated as an off-white solid. C18H17CIF3N5OS. 444.3/446.0 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 12.91 (br. s, 1H), 10.83 (br. s, 1H), 9.65 (s, 1H), 8.76 (s, 1H), 7.18 - 7.00 (m, 2H), 6.96 (dd, J = 6.6, 2.7 Hz, 1H), 6.49 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.61 - 3.44 (m, 4H), 2.87 (d, J = 3.0 Hz, 6H).19F NMR (377 MHz, DMSO-d6) δ -74.5 (6F), -127.0 (IF), -149.5 (IF), -154.15 (IF). Example 489: 7V-(3-chloro-4-fluorophenyl)-4,5-difluoro-7V'-hydroxy-2-((2-(2- (hydroxymethyl)piperidin-l-yl)ethyl)amino)-iH-benzo[i/]imidazole-7- carboximidamide
Figure imgf000430_0001
[0984] Example 489 was made analogously to Example 333 using (l-(2- aminoethyl)piperidin-2-yl)methanol in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt ofN-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(2- (hydroxymethyl)piperidin-l-yl)ethyl)anTino)-7H-benzo[(i|imidazole-7-carboximidamide was isolated as an off-white solid. C22H24C1F3N602. 497.3/499.1 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.56 (br. s, 1H), 8.72 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 6.98 (s, 1H), 6.94 (dd, J = 6.5, 2.7 Hz, 1H), 6.85 (dd, J = 12.2, 6.9 Hz, 1H), 6.52 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.88 (m, 1H), 3.80 - 3.65 (m, 2H), 3.60 - 3.40 (m, 3H), 3.35 - 3.20 (m, 2H), 3.13 (m, 1H), 1.90 - 1.65 (m, 5H), 1.50 (m, 1H).19F NMR (377 MHz, DMSO-d6) δ -75.1 (9F), -127.3 (IF), -150.2 (IF), -156.9 (IF).
Example 490: iV-(3-chloro-4-fluorophenyl)-4,5-difluoro-iV-hydroxy-2-((2-(2- (hydroxymethyl)pyrrolidin-l-yl)ethyl)amino)-iH-benzo[i/]imidazole-7- carboximidamide
Figure imgf000430_0002
[0985] Example 490 was made analogously to Example 333 using (l-(2- aminoethyl)pyrrolidin-2-yl)methanol in place of tert-butyl (2-aminoethyl)carbamate. The TFA salt ofN-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(2- (hydroxymethyl)pyrrolidin-l-yl)ethyl)amino)-7H-benzo[(i]imidazole-7-carboximidamide was isolated as an off-white solid. C2iH22ClF3N602. 483.3/485.1 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 10.79 (br. s, 1H), 9.82 (br. s, 1H), 8.70 (s, 1H), 7.09 (t, J = 9.1 Hz, 1H), 7.02 (s, 1H), 6.94 (dd, J = 6.6, 2.7 Hz, 1H), 6.85 (dd, J = 12.2, 6.9 Hz, 1H), 6.53 (ddd, J = 9.0, 4.1, 2.7 Hz, 1H), 3.78 - 3.64 (m, 4H), 3.63 - 3.50 (m, 3H), 3.35 (m, 1H), 3.19 (m, 1H), 2.14 - 1.95 (m, 2H), 1.90 (m, 1H), 1.75 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ -75.1 , -127.3, -150.2, -156.9.
Example 491: iV-(3-chloro-4-fluorophenyl)-2-((2-(3,3-difluoropyrrolidin-l- yl)ethyl)amino)-/V'-hydroxy-iH-imidazo[4,5-Z>]pyridine-7-carboximidamide
Figure imgf000431_0001
[0986] Example 491 was made analogously to Example 229 using 3-(2-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 2-(3,3-difluoropyrrolidin-l-yl)ethan-l- amine in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3- aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4- fluorophenyl)-2-((2-(3,3-difluoropyrrolidin-l-yl)ethyl)amino)-N'-hydroxy-7H- imidazo[4,5- >]pyridine-7-carboximidamide was isolated as an off-white solid.
C19H19CIF3N7O. 454.3/456.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 11.40 (br. s, 1H), 8.97 (s, 1H), 7.98 (d, J = 6.2 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.03 (dd, J = 6.5, 2.7 Hz, 1H), 6.94 (d, J = 6.2 Hz, 1H), 6.59 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 3.62 (m, 2H), 3.34 (m, 2H), 3.18 - 2.89 (m, 4H), 2.45 - 2.28 (m, 2H).19F NMR (377 MHz, DMSO-d6) δ - 74.7 (9F), -92.1 (2F), -126.6 (IF). Example 492: A^-(3-chloro-4-fluorophenyl)-A^'-hydroxy-2-((2- sulfamoylethyl)amino)-iH-imidazo[4,5-Z>]pyridine-7-carboximidamide
Figure imgf000432_0001
[0987] Example 492 was made analogously to Example 229 using 3-(2-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 2-aminoethane-l -sulfonamide in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7- yl)-4-(3-chloro-4-fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2- ((2-sulfamoylethyl)amino)-7H-imidazo[4,5- )]pyridine-7-carboximidamide was isolated as an off-white solid. C15H15CIFN7O3S. 428.1/430.1 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 12.00 (br. s, 1H), 11.47 (br. s, 1H), 8.99 (s, 1H), 7.97 (d, J = 6.4 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.06 (s, 2H), 7.04 (dd, J = 6.8, 3.0 Hz, 1H), 6.92 (d, J = 6.4 Hz, 1H), 6.59 (ddd, J = 8.9, 4.0, 2.8 Hz, 1H), 3.87 (q, J = 6.5 Hz, 2H), 3.35 (t, J = 6.6 Hz, 2H).19F NMR (377 MHz, DMSO-d6) δ -74.6 (6F), -126.5 (IF).
Example 493: iV-(3-chloro-4-fluorophenyl)-iV'-hydroxy-2-((2- (methylsulfonyl)ethyl)amino)-iH-imidazo[4,5-Z>]pyridine-7-carboximidamide
Figure imgf000432_0002
[0988] Example 493 was made analogously to Example 229 using 3-(2-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 2-(methylsulfonyl)ethan-l -amine in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7- yl)-4-(3-chloro-4-fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2- ((2-(methylsulfonyl)ethyl)amino)-/H-imidazo[4,5-/)]pyridine-7-carboximidami was isolated as an off-white solid. CI6HI6C1FN603S. 427.1/429.0 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 11.46 (br. s, 1H), 8.97 (s, 1H), 7.99 (d, J = 6.3 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 6.5, 2.7 Hz, 1H), 6.95 (d, J = 6.3 Hz, 1H), 6.59 (dq, J = 8.8, 3.0 Hz, 1H), 3.91 (q, J = 6.4 Hz, 2H), 3.51 (d, J = 6.4 Hz, 2H), 3.07 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -74.6 (6F), -126.5 (IF).
Example 494 : /V-(3-chloro-4-fluorophenyl)-iV'-hydroxy-2-((pyrimidin-2- ylmethyl)amino)-iH-imidazo [4,5-Z>] pyridine-7-carboximidamide
Figure imgf000433_0001
[0989] Example 494 was made analogously to Example 229 using 3-(2-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and pyrimidin-2-ylmethanamine in place of 3- (2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)- 4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2- ((pyrimidin-2-ylmethyl)amino)-7H-imidazo[4,5-/)]pyridine-7-carboxirnidamide was isolated as an off-white solid. CI8HI4C1FN80. 413.2/415.1 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 11.49 (br. s, 1H), 9.00 (s, 1H), 8.83 (d, J = 4.9 Hz, 2H), 7.99 (d, J = 6.3 Hz, 1H), 7.48 (t, J = 4.9 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.05 (dd, J = 6.5, 2.7 Hz, 1H), 6.95 (d, J = 6.3 Hz, 1H), 6.60 (dt, J = 8.9, 3.3 Hz, 1H), 4.91 (d, J = 5.9 Hz, 2H).19F NMR (377 MHz, DMSO-d6) δ -74.7 (6F), -126.6 (IF). Example 495: (i?)-^-(3-chlorophenyl)-4,5-difluoro-A^'-hydroxy-2-((l-(2- methoxyethyl)pyrrolidin-3-yl)amino)-iH-benzo[i/]imidazole-7-carboximidamide
Figure imgf000434_0001
[0990] Example 495 was made analogously to Example 333 using (i?)-l-(2- methoxyethyl)pyrrolidin-3-amine dihydrochloride and N-ethyl-N-isopropylpropan-2- amine in place of tert-butyl (2-aminoethyl)carbamate and 3-(2-chloro-4,5-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chlorophenyl)-l,2,4- oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-l-((2-
(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)- l,2,4-oxadiazol-5(4H)-one. The TFA salt of (i?)-N-(3-chlorophenyl)-4,5-difluoro-N'- hydroxy-2-((l-(2-methoxyethyl)pyrrolidin-3-yl)amino)-7H-benzo[cf|imidazole-7- carboximidamide was isolated as an off-white solid. C2iH23ClF2N602. 465.2/467.1 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 10.20 (br. s, 1H), 8.74 (s, 1H), 7.26 (m, 1H), 7.04 (m, 1H), 6.82 (m, 2H), 6.50 (m, 1H), 4.65 - 4.40 (m, 1H), 3.98 - 3.70 (m, 1H), 3.68 - 3.55 (m, 3H), 3.51 - 3.36 (m, 2H), 3.33 (m, 3H), 3.13 (m, 2H), 2.10 - 1.85 (m, 2H).19F NMR (377 MHz, DMSO-d6) δ -75.0 (9F), -150.3 (IF), -156.7 (IF).
Example 496: (i?)-/V-(3-bromophenyl)-4,5-difluoro-iV'-hydroxy-2-((l-(2- methoxyethyl)pyrrolidin-3-yl)amino)-7H-benzo[i/]imidazole-7-carboximidamide
Figure imgf000434_0002
[0991] Example 496 was made analogously to Example 333 using (i?)-l-(2- methoxyethyl)pyrrolidin-3-amine dihydrochloride and N-ethyl-N-isopropylpropan-2- amine in place of tert-butyl (2-aminoethyl)carbamate and 4-(3-bromophenyl)-3-(2- chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)- l,2,4-oxadiazol-5(4H)-one in place of 3-(2-chloro-4,5-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)- l,2,4-oxadiazol-5(4H)-one. The TFA salt of (i?)-N-(3-bromophenyl)-4,5-difluoro-N'- hydroxy-2-((l-(2-methoxyethyl)pyrrolidin-3-yl)amino)-7H-benzo[cf]imidazole-7- carboximidamide was isolated as an off-white solid. C2iH23BrF2N602. 509.2/511.1 (M+l). 'H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 10.18 (br. s, 1H), 8.69 (d, J = 2.6 Hz, 1H), 7.17 (m, 1H), 7.05 (m, 1H), 7.00 - 6.91 (m, 3H), 6.84 (dd, J = 12.3, 6.9 Hz, 1H), 6.55 (dt, J = 7.7, 1.7 Hz, 1H), 4.65 - 4.35 (m, 1H), 4.00 - 3.70 (m, 1H), 3.65 - 3.55 (m, 3H), 3.51 - 3.36 (m, 2H), 3.32 (m, 3H), 3.12 (m, 2H), 2.11 - 1.85 (m, 2H).19F NMR (376 MHz, DMSO-d6) δ -75.0 (9F), -150.4 (9F), -156.7 (9F).
Example 497 : (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((l-(oxetan-3- yl)piperidin-3-yl)amino)-iH-imidazo[4,5-Z>]pyridine-7-carboximidamide
Figure imgf000435_0001
[0992] Example 497 was made analogously to Example 229 using 3-(2-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and (<S)-l-(oxetan-3-yl)piperidin-3-amine in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3- aminopropanamide hydrochloride, respectively. The TFA salt of (5)-N-(3-chloro-4- fluorophenyl)-N'-hydroxy-2-((l-(oxetan-3-yl)piperidin-3-yl)amino)-7H-imidazo[4,5- &]pyridine-7-carboximidamide was isolated as an off-white solid. C21H23CIFN7O2. 460.2/462.2 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 11.39 (br. s, 1H), 8.95 (s, 1H), 8.16 (br. s, 1H), 7.98 (d, J = 6.2 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 6.94 (d, J = 6.2 Hz, 1H), 6.59 (dt, J = 8.9, 3.5 Hz, 1H), 4.75 - 4.65 (m, 4H), 4.20 - 4.05 (m, 2H), 3.80 - 3.55 (m, 2H), 2.85 - 2.60 (m, 2H), 2.05 - 1.85 (m, 2H), 1.81 - 1.45 (m, 2H).19F NMR (376 MHz, DMSO-d6) δ -74.6, -126.7. Example 498: 7Y-(3-chloro-4-fluorophenyl)-/Y'-hydroxy-2-((l-(2- methoxyethyl)piperidin-3-yl)amino)-iH-imidazo[4,5-Z>]pyridine-7-carboximidamide
Figure imgf000436_0001
[0993] Example 498 was made analogously to Example 229 using 3-(2-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and l-(2-methoxyethyl)piperidin-3 -amine in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3- aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4- fluorophenyl)-N'-hydroxy-2-((l-(2-methoxyethyl)piperidin-3-yl)amino)-7H-imidazo[4,5- Z>]pyridine-7-carboximidamide was isolated as an off-white solid. C21H25CIFN7O2.
462.1/464.1 (M+l). 'H NMR (400 MHz, DMSO-d6) δ 9.70 (br. s, 1H), 8.89 (br. s, 1H), 7.96 (s, 1H), 7.10 (t, J = 9.0 Hz, 1H), 6.98 (m, 1H), 6.90 (m, 1H), 6.58 (dt, J = 8.9, 3.5 Hz, 1H), 4.20 (m, 1H), 3.75 - 3.60 (m, 2H), 3.50 - 3.25 (m, 4H), 3.32 (s, 3H), 2.95 - 2.80 (m, 2H), 2.09 - 1.73 (m, 3H), 1.51 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ - 74.31, -126.85.
Example 499 : N-(3-chloro-4-fluorophenyl)-2-((l-cyclopropylpyrrolidin-3- yl)amino)-/V'-hydroxy-iH-imidazo[4,5-Z»]pyridine-7-carboximidamide
Figure imgf000436_0002
[0994] Example 499 was made analogously to Example 229 using 3-(2-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and l-cyclopropylpyrrolidin-3-amine trifluoroacetic acid salt (1 :2) and N-ethyl-N-isopropylpropan-2-amine in place of 3-(2- chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4- (3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-((l- cyclopropylpyrrolidin-3-yl)amino)-N'-hydroxy-/H-imidazo[4,5-/)]pyridine-7- carboximidamide was isolated as an off-white solid. C2oH2iClFN70. 430.1/432.1 (M+1). 'H NMR (400 MHz, DMSO-d6) δ 11.21 (br. s, 1H), 8.89 (s, 1H), 7.96 (m, 1H), 7.08 (t, J = 9.1 Hz, 1H), 7.05 - 6.80 (m, 2H), 6.57 (dt, J = 8.9, 3.5 Hz, 1H), 4.60 - 4.45 (m, 2H), 3.95 - 3.45 (m, 4H), 3.05 - 2.90 (m, 2H), 1.00 - 0.75 (m, 4H).
Example 500: (i?)-iV-(3-chloro-4-fluorophenyl)-iV'-hydroxy-2-((l-(oxetan-3- yl)piperidin-3-yl)amino)-iH-imidazo[4,5-Z>]pyridine-7-carboximidamide
Figure imgf000437_0001
[0995] Example 500 was made analogously to Example 229 using 3-(2-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and (i?)-l-(oxetan-3-yl)piperidin-3-amine in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3- aminopropanamide hydrochloride, respectively. The TFA salt of (i?)-N-(3-chloro-4- fluorophenyl)-N'-hydroxy-2-((l-(oxetan-3-yl)piperidin-3-yl)amino)-7H-imidazo[4,5- Z>]pyridine-7-carboximidarnide was isolated as an off-white solid. C21H23CIFN7O2. 460.2/462.2 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 11.39 (br. s, 1H), 8.95 (s, 1H), 8.17 (br. s, 1H), 7.98 (d, J = 6.2 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 6.93 (d, J = 6.2 Hz, 1H), 6.59 (dt, J = 8.9, 3.5 Hz, 1H), 4.75 - 4.55 (m, 4H), 4.20 - 4.05 (m, 2H), 3.80 - 3.60 (m, 2H), 2.84 - 2.59 (m, 2H), 2.10 - 1.80 (m, 2H), 1.80 - 1.51 (m, 2H).19F NMR (377 MHz, DMSO-d6) δ -74.6 (9F), -126.8 (IF). Example 501: A^-(3-chloro-4-fluorophenyl)-A^'-hydroxy-2-((2-(4-methyl-3- oxopiperazin-l-yl)ethyl)amino)-iH-imidazo[4,5-Z>]pyridine-7-carboximidamide
Figure imgf000438_0001
[0996] Example 501 was made analogously to Example 229 using 3-(2-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one and 4-(2-aminoethyl)-l -methylpiperazin-2-one in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3- aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4- fluorophenyl)-N'-hydroxy-2-((2-(4-methyl-3-oxopiperazin-l-yl)ethyl)amino)-7H- imidazo[4,5-Z>]pyridine-7-carboximidamide was isolated as an off-white solid.
C2oH22ClFN802. 461.2/463.1 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 11.36 (br. s, 1H), 8.95 (s, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 6.59 (m, 1H), 3.80 - 3.60 (m, 3H), 3.45 - 3.35 (m, 3H), 3.25 - 3.05 (m, 2H), 3.05 - 2.90 (m, 2H), 2.85 (s, 3H).19F NMR (377 MHz, DMSO-d6) δ -74.7 (9F), -126.7 (IF).
Example 502: iV-(3-chloro-4-fluorophenyl)-2-((2-(3,3-difluoropiperidin-l- yl)ethyl)amino)-/V'-hydroxy-iH-imidazo[4,5-Z>]pyridine-7-carboximidamide
Figure imgf000438_0002
[0997] Example 502 was made analogously to Example 229 using 3-(2-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 2-(3,3-difluoropiperidin-l-yl)ethan-l- amine in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3- aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4- fluorophenyl)-2-((2-(3,3-difluoropiperidin-l-yl)ethyl)amino)-N'-hydroxy-7H- imidazo[4,5- )]pyridine-7-carboximidamide was isolated as an off-white solid.
C20H21CIF3N7O. 468.3/470.2 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 8.95 (s, 1H), 7.98 (d, J = 6.2 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.02 (dd, J = 6.5, 2.7 Hz, 1H), 6.93 (d, J = 6.2 Hz, 1H), 6.59 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 3.66 (m, 2H), 3.10 (m, 2H), 2.90 (m, 2H), 2.75 (m, 2H), 1.97 (m, 2H), 1.77 (m, 2H).19F NMR (377 MHz, DMSO-d6) δ -84.9 (9F), -108.4 (2F), -136.8 (IF).
Example 503: 2-((l-acetylpyrrolidin-3-yl)amino)-iV-(3-chloro-4-fluorophenyl)-iV'- hydroxy-iH-imidazo[4,5-Z>]pyridine-7-carboximidamide
Figure imgf000439_0001
[0998] Example 503 was made analogously to Example 229 using 3-(2-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and l-(3-aminopyrrolidin-l-yl)ethan-l-one in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3- aminopropanamide hydrochloride, respectively. The TFA salt of 2-((l-acetylpyrrolidin- 3-yl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-7H-irnidazo[4,5-/)]pyridine-7- carboximidamide was isolated as an off-white solid. C19H19CIFN7O2. 432.4/434.1 (M+l). 'H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.96 (s, 1H), 7.98 (dd, J = 6.3, 4.2 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 6.3, 2.6 Hz, 1H), 6.94 (dd, J = 7.9, 6.3 Hz, 1H), 6.60 (dt, J = 9.3, 3.3 Hz, 1H), 4.54 - 4.36 (m, 2H), 3.77 (m, 1H), 3.59 (m, 1H), 2.34 - 2.11 (m, 2H), 2.07 (m, 1H), 1.96 (d, J = 11.3 Hz, 3H).19F NMR (376 MHz, DMSO-d6) δ -74.5, -126.5. Example 504: iV-(3-chloro-4-fluorophenyl)-/V'-hydroxy-2-((l- (methylsulfonyl)pyrrolidin-3-yl)amino)-iH-imidazo[4,5-Z>]pyridine-7- carboximidamide
Figure imgf000440_0001
[0999] Example 504 was made analogously to Example 229 using 3-(2-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and l-(methylsulfonyl)pyrrolidin-3 -amine in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3- aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4- fluorophenyl)-N'-hydroxy-2-((l-(methylsulfonyl)pyrrolidin-3-yl)amino)-/H- imidazo[4,5-Z>]pyridine-7-carboximidamide was isolated as an off-white solid.
C18H19CIFN7O3S. 468.4/470.2 (M+1). ΧΗ ΝΜΚ (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.96 (s, 1H), 7.99 (d, J = 6.3 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.03 (dd, J = 6.5, 2.7 Hz, 1H), 6.95 (d, J = 6.3 Hz, 1H), 6.60 (ddd, J = 9.0, 4.1, 2.8 Hz, 1H), 4.55 - 4.42 (m, 2H), 3.59 (m, 1H), 3.27 (m, 1H), 2.95 (s, 3H), 2.37 - 2.21 (m, 2H), 2.05 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ -74.5, -126.5.
Example 505: A^-(3-chloro-4-fluorophenyl)-A^'-hydroxy-2-((3- (methylsulfonyl)propyl)amino)-iH-imidazo[4,5-Z>]pyridine-7-carboximidamide
Figure imgf000440_0002
[01000] Example 505 was made analogously to Example 229 using 3-(2-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3-(methylsulfonyl)propan-l -amine hydrochloride and N-ethyl-N-isopropylpropan-2-amine in place of 3-(2-chloro-4,5- difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((3- (methylsulfonyl)propyl)amino)-/H-imidazo[4,5-/)]pyridine-7-carboximidamide was isolated as an off-white solid. CI7HI8C1FN603S. 441.3/443.1 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 11.39 (br. s, 1H), 8.95 (s, 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.04 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 6.59 (ddd, J = 9.0, 4.0, 2.7 Hz, 1H), 3.56 (m, 2H), 3.20 (m, 2H), 3.00 (s, 3H), 2.04 (p, J = 7.1 Hz, 2H).19F NMR (377 MHz, DMSO-d6) δ -74.2 (6F), -126.3 (IF).
Example 506: iV-(3-chloro-4-fluorophenyl)-2-(((l,l-dioxidotetrahydrothiophen-3- yl)methyl)amino)-/V'-hydroxy-iH-imidazo[4,5-Z»]pyridine-7-carboximidamide
Figure imgf000441_0001
[01001] Example 506 was made analogously to Example 229 using 3-(2-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3-(aminomethyl)tetrahydrothiophene 1,1- dioxide hydrochloride and N-ethyl-N-isopropylpropan-2-amine in place of 3-(2-chloro- 4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-7-yl)-4-(3- chloro-4-fluorophenyl)-l ,2,4-oxadiazol-5(4H)-one and 3-aminopropanamide
hydrochloride, respectively. The TFA salt of N-(3-chloro-4-fluorophenyl)-2-(((l,l- dioxidotetrahydrothiophen-3-yl)methyl)amino)-N'-hydroxy-7H-imidazo[4,5-/)]pyridine- 7-carboximidamide was isolated as an off-white solid. CigHigClFNeC S. 453.3/455.1 (M+1). ¾ NMR (400 MHz, DMSO-d6) δ 8.95 (br. s, 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.10 (t, J = 9.0 Hz, 1H), 7.03 (dd, J = 6.4, 2.7 Hz, 1H), 6.93 (d, J = 6.2 Hz, 1H), 6.59 (m, 1H), 3.56 (m, 2H), 3.24 (m, 2H), 3.08 (m, 1H), 2.91 (dd, J = 13.2, 9.5 Hz, 1H), 2.74 (d, J = 11.6 Hz, 1H), 2.25 (m, 1H), 1.86 (dq, J = 13.1, 9.3 Hz, 1H).19F NMR (376 MHz, DMSO- d6) δ -74.4, -126.5.
Example 507: A^-(3-chloro-4-fluorophenyl)-2-((3-((4- fluorophenyl)sulfonyl)propyl)amino)-A^'-hydroxy-iH-imidazo[4,5-Z>]pyridine-7- carboximidamide
Figure imgf000442_0001
[01002] Example 507 was made analogously to Example 229 using 3-(2-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3-((4-fluorophenyl)sulfonyl)propan-l- amine in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3- aminopropanamide hydrochloride, respectively. The TFA salt of N-(3-chloro-4- fluorophenyl)-2-((3-((4-fluorophenyl)sulfonyl)propyl)amino)-N'-hydroxy-7H- imidazo[4,5-Z>]pyridine-7-carboximidamide was isolated as an off-white solid.
C22Hi9ClF2N603S. 521.4/523.1 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 11.38 (br. s, 1H), 8.94 (s, 1H), 7.97 (m, 3H), 7.51 (m, 2H), 7.10 (t, J = 9.0 Hz, 1H), 7.03 (dd, J = 6.5, 2.7 Hz, 1H), 6.92 (d, J = 6.3 Hz, 1H), 6.59 (dt, J = 9.0, 3.5 Hz, 1H), 3.50 (m, 2H), 3.43 (m, 2H), 1.89 (p, J = 7.1 Hz, 2H).19F NMR (376 MHz, DMSO-d6) δ -74.4, -105.2, -
126.5.
Example 508: (i?)-A-(3-chloro-4-fluorophenyl)-A^'-hydroxy-2-((l-(oxetan-3- yl)pyrrolidin-3-yl)amino)-iH-imidazo[4,5-Z>]pyridine-7-carboximidamide
Figure imgf000443_0001
[01003] Example 508 was made analogously to Example 229 using 3-(2-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-7-yl)-4-(3-chloro-4- fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and (i?)-l-(oxetan-3-yl)pyrrolidin-3-amine in place of 3-(2-chloro-4,5-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo[d]imidazol-7-yl)-4-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-5(4H)-one and 3- aminopropanamide hydrochloride, respectively. The TFA salt of (i?)-N-(3-chloro-4- fluorophenyl)-N'-hydroxy-2-((l-(oxetan-3-yl)pyrrolidin-3-yl)amino)-7H-imidazo[4,5- Z>]pyridine-7-carboximidamide was isolated as an off-white solid. C20H21CIFN7O2. 446.4/448.2 (M+l). ¾ NMR (400 MHz, DMSO-d6) δ 11.30 (br. s, 1H), 8.93 (s, 1H), 7.99 (d, J = 6.1 Hz, 1H), 7.09 (t, J = 9.0 Hz, 1H), 7.03 - 6.92 (m, 2H), 6.58 (ddd, J = 8.9, 4.0, 2.7 Hz, 1H), 4.78 (t, J = 7.4 Hz, 2H), 4.69 - 4.55 (m, 3H), 4.47 (m, 1H), 3.8 - 3.3 (m, 5H), 2.09 (d, J = 11.6 Hz, 1H).19F NMR (376 MHz, DMSO-d6) δ -74.6, -126.7.
Biological Examples
[01004] Activity testing was conducted in the Examples below using methods described herein and those well known in the art.
Example 509. Cell-based (HeLa) Assay for Measurement of IDOl Inhibition
[01005] To measure IDOl inhibition in tissue culture, HeLa cells were treated with a test compound in the presence of IFNy, which induces IDOl expression. Following incubation, cell supematants were assayed for kynurenine levels, an indicator of IDOl activity.
[01006] HI -HeLa cells (ATCC #CRL-1958) were seeded in 384-well plates (Greiner #82051-282) at a volume of 50 ulVwell in DMEM (Corning #15-018-CM) supplemented with 10% FBS (Corning #35-011-CV) and 1% P/S/G (Corning #30-009-CL) at a density of 1,250 cells/well and incubated overnight at 37°C, 5% CO2/100% humidity. The following day, the test compounds were added in DMSO (0.5% final) at various concentrations, and IDOl was inducibly expressed by the addition of 50 uL/well of 50ng/mL of INFy (Peprotech #300-02) in cell plating media. As a positive control, 50 uL of the cell plating media without IFNy was added to several wells. Following a 48 hour incubation, the plates were spun down at 1,200 RPM for 5 min at 10 °C. 65 μίΛ βΙΙ of the supernatant was then transferred to new 384-well plates (Thermo #262160) that contained 10 uL/well of 30% TCA (Sigma #T0699), and the plates were sealed and incubated at 60°C for 30 min. The plates were then centrifuged for 15 min at 2,000 RPM at 10 °C. 40 μίΛ βΙΙ of the supernatant was transferred to new 384-well plates (Thermo #262160) and was reacted with 40 μΕΛ βΙΙ of 2% (w/v) p-dimethlyaminobenzaldehyde (Sigma #156417) in glacial acetic acid (Sigma #A6283). The reaction was incubated at room temperature for 10 min and absorbance at 480 nm was read using a PerkinElmer Envision plate reader.
[01007] Data in Table 1 were normalized based on positive (- IFNy) and negative (+ IFNy) controls and EC50 values were calculated from the fit of the dose-response curves to a four-parameter equation. All EC50 values represent geometric mean values of a minimum of four determinations. These assays generally produced results within 2-fold of the reported mean.
Table 1
Figure imgf000444_0001
Example No. Name ECso (nM)
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-7-
7 (trifluoromethyl)-lH-benzimidazole-4- 926 carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3H-
8 1792 benzimidazole-4-carboximidamide
N-(3-chloro-4-fluorophenyl)-6-fluoro-N'-
9 hydroxy-7-methyl-3H-benzimidazole-4- 634 carboximidamide
N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-
10 438 hydroxy-3H-benzimidazole-4-carboximidamide
6-chloro-N-(3-chloro-4-fluorophenyl)-N'-
11 7604 hydroxy-3H-benzimidazole-4-carboximidamide
7-bromo-N-(3-chloro-4-fluorophenyl)-N'-
12 660 hydroxy-3H-benzimidazole-4-carboximidamide
2-amino-N-(3-chloro-4-fluorophenyl)-6,7-
13 difluoro-N'-hydroxy-3H-benzimidazole-4- 2739 carboximidamide
2-amino-N-(3-bromo-4-fluorophenyl)-6,7-
14 difluoro-N'-hydroxy-3H-benzimidazole-4- 494 carboximidamide
2-amino-N-(3-bromophenyl)-6,7-difluoro-N'-
15 570 hydroxy-3H-benzimidazole-4-carboximidamide
2-amino-N-(3-chlorophenyl)-6,7-difluoro-N'-
16 607 hydroxy-3H-benzimidazole-4-carboximidamide
2-amino-6, 7 -difluoro-N- [4-fluoro-3 -
17 (trifluoromethyl)phenyl]-N'-hydroxy-3H- 1092 benzimidazole-4-carboximidamide
2-amino-N-(3-bromophenyl)-7-fluoro-N'-
18 312 hydroxy-3H-benzimidazole-4-carboximidamide
2-amino-N-(3-bromo-4-fluorophenyl)-7-fluoro-
19 N'-hydroxy-3H-benzimidazole-4- 456 carboximidamide
2-amino-N-(3-chlorophenyl)-7-fluoro-N'-
20 404 hydroxy-3H-benzimidazole-4-carboximidamide
2-amino-7-fluoro-N-[4-fluoro-3-
21 (trifluoromethyl)phenyl]-N'-hydroxy-3H- 725 benzimidazole-4-carboximidamide
2-amino-N-(3-chloro-4-fluorophenyl)-7-fluoro-
22 N'-hydroxy-3H-benzimidazole-4- 382 carboximidamide
N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-
23 hydroxy-2-(2-morpholin-4-ylethylamino)-3H- 346 benzimidazole-4-carboximidamide
24 N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2- 1923
(((3 -methoxy propy l)amino)methy 1)- 1 H- benzo[d]imidazole-7-carboximidamide Example No. Name ECso (nM)
25 N-(3-chlorophenyl)-2- 1457
(((cyclopropylmethyl)amino)methyl)-4,5- difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
26 N-(3-chlorophenyl)-2-((dimethylamino)methyl)- 1212
4,5-difluoro-N'-hydroxy-lH-benzo[d]imidazole- 7-carboximidamide
27 N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2- 839
((isopropylamino)methyl)-lH-benzo[d]imidazole-
7-carboximidamide
28 N-(3-chlorophenyl)-2-((ethylamino)methyl)-4,5- 801 difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
29 N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2- 1541
(hydroxymethyl)-lH-benzo[d]imidazole-7- carboximidamide
30 N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2- 1 106
((methylamino)methyl)-lH-benzo[d]imidazole-7- carboximidamide
31 2-(aminomethyl)-N-(3-chlorophenyl)-4,5- 1680 difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-
32 hydroxy-2-morpholin-4-yl-3H-benzimidazole-4- 9276 carboximidamide
N-(3-chloro-4-fluorophenyl)-7-fluoro-N'-
33 hydroxy-2-(2-methylsulfonylethylamino)-3H- 1833 benzimidazole-4-carboximidamide
N-(3-Chloro-4-fluorophenyl)-4-fluoro-N'-
34 hydroxy-2-((2-mo holinoethyl)amino)-lH- 6739 benzo[d]imidazole-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-
35 hydroxy-2-(2-methylsulfonylethylamino)-3H- 2153 benzimidazole-4-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-[2-(4,4- difluoropiperidin- 1 -yl)ethyl amino] -6,7-difluoro-
36 712
N'-hydroxy-3H-benzimidazole-4- carboximidamide
N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-
37 hydroxy-2-(l -morpholin-4-ylpropan-2-ylamino)- 514
3H-benzimidazole-4-carboximidamide
N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-
38 hydroxy-2-(methylamino)-3H-benzimidazole-4- 607 carboximidamide
N-(3-chloro-4-fluorophenyl)-2-[3-
39 (dimethylamino)propylamino]-6,7-difluoro-N'- 473 hydroxy-3H-benzimidazole-4-carboximidamide Example No. Name ECso (nM)
N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-
40 hydroxy-2-(2-methoxyethylamino)-3H- 1523 benzimidazole-4-carboximidamide
N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-
41 hydroxy-2-(2-pyrrolidin- 1 -ylethylamino)-3H- 240 benzimidazole-4-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-[2-
42 (diethylamino)ethylamino]-6,7-difluoro-N'- 247 hydroxy-3H-benzimidazole-4-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-[2-
43 (dimethylamino)ethylamino]-6,7-difluoro-N'- 136 hydroxy-3H-benzimidazole-4-carboximidamide
N-(3-chlorophenyl)-6,7-difluoro-N'-hydroxy-2-
44 (l-methylpiperidin-3-yl)-3H-benzimidazole-4- 1645 carboximidamide
N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-
45 hydroxy-2-[(3-methoxypropylamino)methyl]-lH- 1324 benzimidazole-4-carboximidamide
N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-
46 hydroxy-2-(hydroxymethyl)-3H-benzimidazole-4- 835 carboximidamide
2-(aminomethyl)-N-(3-chloro-4-fluorophenyl)-
47 6,7-difluoro-N'-hydroxy-lH-benzimidazole-4- 1075 carboximidamide
N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-
48 hydroxy-2-(methylaminomethyl)-lH- 434 benzimidazole-4-carboximidamide
N-(3-chloro-4-fluorophenyl)-2- [(cyclopropylmethylamino)methyl]-6,7-difluoro-
49 1057
N'-hydroxy-lH-benzimidazole-4- carboximidamide
N-(3-chloro-4-fluorophenyl)-2-
50 (ethylaminomethyl)-6,7-difluoro-N'-hydroxy-lH- 457 benzimidazole-4-carboximidamide
N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-
51 hy droxy-2- [(propan-2-ylamino)methy 1] - 1 H- 566 benzimidazole-4-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-
52 [(dimethylamino)methyl]-6,7-difluoro-N'- 526 hydroxy-lH-benzimidazole-4-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-[2-
53 (dimethylamino)ethyl]-6,7-difluoro-N'-hydroxy- 916 lH-benzimidazole-4-carboximidamide
N-(3-bromo-4-fluorophenyl)-2-[2-
54 (dimethylamino)ethyl]-6,7-difluoro-N'-hydroxy- 461 lH-benzimidazole-4-carboximidamide Example No. Name ECso (nM)
N-(3-bromophenyl)-2-[2-(dimethylamino)ethyl]-
55 6,7-difluoro-N'-hydroxy-lH-benzimidazole-4- 379 carboximidamide
N-(3-chlorophenyl)-2-[2-(dimethylamino)ethyl]-
56 6,7-difluoro-N'-hydroxy-lH-benzimidazole-4- 562 carboximidamide
N-(3-chloro-4-fluorophenyl)-6,7-difluoro-N'-
57 hy droxy-2- [2-(methylamino)ethy 1] - 1 H- 1093 benzimidazole-4-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-[2-
58 (diethylamino)ethyl]-6,7-difluoro-N'-hydroxy- 786 lH-benzimidazole-4-carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-lH-
59 208 imidazo[4,5-b]pyridine-7-carboximidamide
N-(5-chloro-2-fluorophenyl)-N'-hydroxy-lH-
60 322 imidazo[4,5-b]pyridine-7-carboximidamide
N-(5-bromo-2,4-difluorophenyl)-N'-hydroxy-lH-
61 371 imidazo[4,5-b]pyridine-7-carboximidamide
N-(5-chloro-2,4-difluorophenyl)-N'-hydroxy-lH-
62 385 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3,5-dichloro-4-fluorophenyl)-N'-hydroxy-lH-
63 774 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-2,4-difluorophenyl)-N'-hydroxy-lH-
64 813 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-cyclopropyl-4-fluorophenyl)-N'-hydroxy-
65 1809 lH-imidazo[4,5-b]pyridine-7-carboximidamide
N'-hy droxy-N- [4-(trifluoromethoxy)phenyl] - 1 H-
66 4871 imidazo[4,5-b]pyridine-7-carboximidamide
N-(l-benzofuran-4-yl)-N'-hydroxy-lH-
67 583 imidazo[4,5-b]pyridine-7-carboximidamide
N-(l-benzofuran-6-yl)-N'-hydroxy-lH-
68 890 imidazo[4,5-b]pyridine-7-carboximidamide
N-(l-benzofuran-7-yl)-N'-hydroxy-lH-
69 1339 imidazo[4,5-b]pyridine-7-carboximidamide
N-(l-benzofuran-5-yl)-N'-hydroxy-lH-
70 1479 imidazo[4,5-b]pyridine-7-carboximidamide
N-(5-bromo-2-fluorophenyl)-N'-hydroxy-3H-
71 207 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3 -bromo-5 -fluorophenyl)-N'-hy droxy- 1 H-
72 280 imidazo[4,5-b]pyridine-7-carboximidamide
N'-hy droxy-N- [3-(trifluoromethyl)phenyl] - 1 H-
73 373 imidazo[4,5-b]pyridine-7-carboximidamide
N-(2,2-difluoro-l,3-benzodioxol-5-yl)-N'-
74 hydroxy-3H-imidazo[4,5-b]pyridine-7- 923 carboximidamide
N-[3-fluoro-5-(trifluoromethyl)phenyl]-N'-
75 hydroxy-lH-imidazo[4,5-b]pyridine-7- 2109 carboximidamide Example No. Name ECso (nM)
N-(2,5-dichlorophenyl)-N'-hydroxy-lH-
76 769 imidazo[4,5-b]pyridine-7-carboximidamide
N-(4-fluoro-3-phenylphenyl)-N'-hydroxy-lH-
77 2289 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-but-l-ynyl-4-fluorophenyl)-N'-hydroxy-lH-
78 2641 imidazo[4,5-b]pyridine-7-carboximidamide
N-[3-(2-cyclopropylethynyl)-4-fluorophenyl]-N'-
79 hydroxy-lH-imidazo[4,5-b]pyridine-7- 3223 carboximidamide
N-(3-bromophenyl)-N'-hydroxy-3H-imidazo[4,5-
80 111 b]pyridine-7-carboximidamide
N-(3-bromo-4-fluorophenyl)-N'-hydroxy-3H-
81 140 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chlorophenyl)-N'-hydroxy-3H-imidazo[4,5-
82 160 b]pyridine-7-carboximidamide
N-[4-fluoro-3-(trifluoromethyl)phenyl]-N'-
83 hydroxy-3H-imidazo[4,5-b]pyridine-7- 315 carboximidamide
N-(4-fluoro-3-prop-l-ynylphenyl)-N'-hydroxy-
84 445
3H-imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-bromo-4-chlorophenyl)-N'-hydroxy-3H-
85 462 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3,4-dichlorophenyl)-N'-hydroxy-3H-
86 639 imidazo[4,5-b]pyridine-7-carboximidamide
N-(4-chlorophenyl)-N'-hydroxy-3H-imidazo[4,5-
87 846 b]pyridine-7-carboximidamide
N-(4-bromophenyl)-N'-hydroxy-3H-imidazo[4,5-
88 916 b]pyridine-7-carboximidamide
N-(4-fluorophenyl)-N'-hydroxy-3H-imidazo[4,5-
89 943 b]pyridine-7-carboximidamide
N-(3-cyano-4-fluorophenyl)-N'-hydroxy-lH-
90 1047 imidazo[4,5-b]pyridine-7-carboximidamide
N'-hydroxy-N-[4-(trifluoromethyl)phenyl]-3H-
91 2240 imidazo[4,5-b]pyridine-7-carboximidamide
N'-hydroxy-N-(3-methoxyphenyl)-3H-
92 3892 imidazo[4,5-b]pyridine-7-carboximidamide
N-(4-fluoro-3-propan-2-ylphenyl)-N'-hydroxy-
93 5096 lH-imidazo[4,5-b]pyridine-7-carboximidamide
N'-hydroxy-N-(4-methylphenyl)-3H-imidazo[4,5-
94 6350 b]pyridine-7-carboximidamide
N-(3 -ethyny lphenyl)-N'-hy droxy- 1 H-
95 302 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-ethylphenyl)-N'-hydroxy-lH-imidazo[4,5-
96 803 b]pyridine-7-carboximidamide
N-(3-ethynyl-4-fluorophenyl)-N'-hydroxy-lH-
97 380 imidazo[4,5-b]pyridine-7-carboximidamide
N-[3-(difluoromethyl)phenyl]-N'-hydroxy-lH-
98 550 imidazo[4,5-b]pyridine-7-carboximidamide Example No. Name ECso (nM)
N'-hy droxy-N- [3-(trifluoromethoxy)phenyl] - 1 H-
99 602 imidazo[4,5-b]pyridine-7-carboximidamide
N' -hy droxy-N-pheny 1 - 1 H-imidazo [4,5-
100 770 b]pyridine-7-carboximidamide
N-[4-fluoro-3-(trifluoromethoxy)phenyl]-N'-
101 hydroxy-lH-imidazo[4,5-b]pyridine-7- 845 carboximidamide
N'-hy droxy-N-naphthalen-2-yl- 1 H-imidazo [4,5 -
102 1928 b]pyridine-7-carboximidamide
N-(3-chloronaphthalen-2-yl)-N'-hydroxy-lH-
103 8075 imidazo[4,5-b]pyridine-7-carboximidamide
N'-hy droxy-N-naphthal en- 1 -yl- 1 H-imidazo [4,5 -
104 1966 b]pyridine-7-carboximidamide
N-(4-chloronaphthalen-l-yl)-N'-hydroxy-lH-
105 3032 imidazo[4,5-b]pyridine-7-carboximidamide
N-(4-fluoro-3-methoxyphenyl)-N'-hydroxy-lH-
106 5536 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-
107 methyl-lH-imidazo[4,5-b]pyridine-7- 1925 carboximidamide
N-(3-chloro-4-fluorophenyl)-2-ethyl-N'-hydroxy-
108 3192 lH-imidazo[4,5-b]pyridine-7-carboxirnidamide
N-(3-chloro-4-fluorophenyl)-2-cyclopropyl-N'-
109 hydroxy-lH-imidazo[4,5-b]pyridine-7- 1386 carboximidamide
N-(3-chl oro-4-fluorophenyl)-N' -hydroxy -2-
110 (methoxy methyl)- 1 H-imi dazo [4, 5 -b] py ridine-7 - 2320 carboximidamide
4-(3 -chl oro-4-fluoropheny l)-3 - [2-
111 (hydroxymethyl)-lH-imidazo[4,5-b]pyridin-7-yl]- 4452 l,2,4-oxadiazol-5-one
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-
112 (mo holin-4-ylmethyl)-3H-imidazo[4,5- 9531 b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-
113 [(dimethylamino)methyl]-N'-hydroxy-3H- 1837 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-
114 (ethylaminomethyl)-N'-hydroxy-3H-imidazo[4,5- 927 b]pyridine-7-carboximidamide
2-[(benzylamino)methyl]-N-(3-chloro-4-
115 fluorophenyl)-N'-hydroxy-3H-imidazo[4,5- 1761 b]pyridine-7-carboximidamide
N-(3-chl oro-4-fluorophenyl)-N' -hydroxy -2-
116 [(propan-2-ylamino)methyl]-3H-imidazo[4,5- 740 b]pyridine-7-carboximidamide Example No. Name ECso (nM)
N-(3-chloro-4-fluorophenyl)-2-
117 [(cyclopropylmethylamino)methyl]-N'-hydroxy- 765
3H-imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-
118 [(2,2,2-trifluoroethylamino)methyl]-3H- 4644 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-
119 [(cyclopropylamino)methyl]-N'-hydroxy-3H- 2150 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(3-
120 methoxypropylamino)methyl]-3H-imidazo[4,5- 1334 b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-
121 [(pyridin-2-ylmethylamino)methyl]-3H- 1373 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[[3-
122 methoxypropyl(methyl)amino] methyl] - 1H- 1883 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[[(2-
123 methoxyphenyl)methylamino] methyl] - 1 H- 1909 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2-
124 methoxyethylamino)methyl]-3H-imidazo[4,5- 2059 b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2-
125 pyridin-2-ylethylamino)methyl]-3H-imidazo[4,5- 2083 b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-
126 [(pyridin-3-ylmethylamino)methyl]-3H- 2280 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-
127 [(oxan-2-ylmethylamino)methyl] - 1H- 2364 imidazo[4,5-b]pyridine-7-carboximidamide
2-(anilinomethyl)-N-(3-chloro-4-fluorophenyl)-
128 N'-hydroxy-3H-imidazo[4,5-b]pyridine-7- 2399 carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-
129 [(oxan-3-ylmethylamino)methyl] - 1H- 2575 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-
130 [(pyrimidin-2-ylmethylamino)methyl]-3H- 2815 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(3-
131 mo holin-4-ylpropylamino)methyl]-3H- 3016 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-
132 [(oxan-4-ylamino)methyl]-lH-imidazo[4,5- 3433 b]pyridine-7-carboximidamide Example No. Name ECso (nM)
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-
133 [(pyridin-4-ylmethylamino)methyl]-3H- 3711 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-
134 [(pyrazin-2-ylmethylamino)methyl] - 1H- 3988 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-
135 [(oxolan-3-ylmethylamino)methyl]-lH- 5105 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-[[2-
136 (dimethylamino)ethylamino]methyl]-N'-hydroxy- 6274
3H-imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2-
137 pyrimidin-2-ylethylamino)methyl]-3H- 7492 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(3-
138 hydroxypropylamino)methyl]-lH-imidazo[4,5- 8239 b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-
139 (py rroli din- 1 -y lmethy l)-3H-imi dazo [4,5- 1400 b]pyridine-7-carboximidamide
N-(3-chl oro-4-fluorophenyl)-N' -hydroxy -2-
140 (piperidin-l-ylmethyl)-3H-imidazo[4,5- 1609 b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-[(2,2-
141 dimethylpropylamino)methyl] -N'-hy droxy- 1 H- 1677 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-[(2,2-
142 difluoroethylamino)methyl] -N'-hy droxy- 1H- 5155 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[[(3-
143 hydroxy-2,2-dimethylpropyl)amino]methyl]-lH- 7346 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(l,3-
144 thiazol-2-ylmethylamino)methyl] - 1H- 8228 imidazo[4,5-b]pyridine-7-carboximidamide
N- [ [7 - [(Z)-N-(3 -chloro-4-fluorophenyl)-N'-
145 hy droxy carbamimidoyl]-3H-imidazo[4,5- 9760 b] py ri din-2-y 1] methyl] acetamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-
146 thiophen-2-yl-3H-imidazo [4,5 -b] pyridine-7- 4215 carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-
147 pyridin-3-yl-lH-imidazo[4,5-b]pyridine-7- 1935 carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-(lH-
148 pyrrol-2-yl)-lH-imidazo[4,5-b]pyridine-7- 2229 carboximidamide Example No. Name ECso (nM)
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-(lH-
149 imidazol-2-yl)-lH-imidazo[4,5-b]pyridine-7- 529 carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-(lH-
150 pyrazol-5-yl)-lH-imidazo[4,5-b]pyridine-7- 8480 carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-(5-
151 methyl-lH-imidazol-2-yl)-lH-imidazo[4,5- 463 b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2S)-
152 pyrrolidin-2-yl]-lH-imidazo[4,5-b]pyridine-7- 4036 carboximidamide
2-amino-N-(3 -chl oro-4-fluoropheny 1)-N' -
153 hydroxy-lH-imidazo[4,5-b]pyridine-7- 897 carboximidamide
N-(3-chloro-4-fluorophenyl)-2-
154 (cyclopropylamino)-N'-hydroxy-lH-imidazo[4,5- 529 b]pyridine-7-carboximidamide
2-anilino-N-(3-chloro-4-fluorophenyl)-N'-
155 hydroxy-lH-imidazo[4,5-b]pyridine-7- 2146 carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-(2-
156 phenylethylamino)-lH-imidazo[4,5-b]pyridine-7- 769 carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2,2,2-
157 trifluoroethylamino)-lH-imidazo[4,5-b]pyridine- 1088
7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-
158 (methylamino)-lH-imidazo[4,5-b]pyridine-7- 460 carboximidamide
propan-2-yl N-[7-[(Z)-N-(3-chloro-4-
159 fluorophenyl)-N'-hydroxycarbamimidoyl]-lH- 453 imidazo[4,5-b]pyridin-2-yl]carbamate
ethyl N-[7-[(Z)-N-(3-chloro-4-fluorophenyl)-N'-
160 hydroxycarbamimidoyl]-lH-imidazo[4,5- 423 b]pyridin-2-yl]carbamate
N-(3-chloro-4-fluorophenyl)-2-
161 (cyclopropylmethylamino)-N'-hydroxy-lH- 655 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-[(3,3-
162 difluorocyclobutyl)amino] -N'-hydroxy- 1H- 4017 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-(ethylamino)-N'-
163 hydroxy-lH-imidazo[4,5-b]pyridine-7- 1084 carboximidamide
N-(3-chloro-4-fluorophenyl)-2-
164 (cyclobutylamino)-N'-hydroxy-lH-imidazo[4,5- 798 b]pyridine-7-carboximidamide Example No. Name ECso (nM)
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-
165 (propan-2-ylamino)-lH-imidazo[4,5-b]pyridine- 705
7-carboximidamide
N-(3-chlorophenyl)-N'-hydroxy-2-(methylamino)-
166 383 lH-imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-[2-
167 (diethylamino)ethylamino]-N'-hydroxy-lH- 2912 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-(2-
168 mo holin-4-ylethylamino)-lH-imidazo[4,5- 1158 b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-(dimethylamino)-
169 N'-hydroxy-lH-imidazo[4,5-b]pyridine-7- 6269 carboximidamide
2-(chloromethyl)-N-[4-fluoro-3-
170 (trifluoromethyl)phenyl] -N'-hydroxy- 1H- 1936 imidazo[4,5-b]pyridine-7-carboximidamide
N-[4-fluoro-3-(trifluoromethyl)phenyl]-N'-
171 hydroxy-2-(hydroxymethyl)-lH-imidazo[4,5- 4000 b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-(l-
172 hydroxyethyl)-lH-imidazo[4,5-b]pyridine-7- 3858 carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-
173 [hydroxy(phenyl)methyl]-lH-imidazo[4,5- 9700 b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-
174 [cyclopropyl(hydroxy)methyl] -N'-hydroxy- 1H- 7086 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-(2-
175 hy droxy propan-2-y 1)- 1 H-imi dazo [4, 5 -b] py ridine- 6417
7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2,2,2-
176 trifluoro- 1 -hydroxy ethyl)- ΙΗ-imi dazo [4,5 - 4201 b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-
177 (hydroxymethyl)-lH-imidazo[4,5-b]pyridine-7- 1674 carboximidamide
N-(3-chl oro-4-fluorophenyl)-N' -hydroxy -2-
178 (methylaminomethyl)-lH-imidazo[4,5- 1477 b]pyridine-7-carboximidamide
2-(aminomethyl)-N-(3-chloro-4-fluorophenyl)-N'-
179 hydroxy-lH-imidazo[4,5-b]pyridine-7- 7664 carboximidamide
2-(benzenesulfonamidomethyl)-N-(3-chloro-4-
180 fluorophenyl)-N'-hydroxy-lH-imidazo[4,5- 1406 b]pyridine-7-carboximidamide Example No. Name ECso (nM)
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-
181 (methanesulfonamidomethyl)-3H-imidazo[4,5- 8969 b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-
182 [(pyrimidin-2-ylamino)methyl]-3H-imidazo[4,5- 6401 b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-(2-
183 hydroxyethyl)-lH-imidazo[4,5-b]pyridine-7- 2401 carboximidamide
N-(3-chloro-4-fluorophenyl)-2-[2-
184 (dimethylamino)ethyl]-N'-hydroxy-3H- 593 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-[2-
185 (diethylamino)ethyl] -N'-hydroxy- 1H- 531 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-[2- [cyclopropylmethyl(methyl)amino] ethyl] -N'-
186 565 hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide
N-(3-chloro-4-fluorophenyl)-2-[2-[2,2-
187 difluoroethy l(methyl)amino] ethyl] -N'-hy droxy- 3405 lH-imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[2-
188 (methylamino)ethyl]-3H-imidazo[4,5-b]pyridine- 1513
7-carboximidamide
2-(2-aminoethyl)-N-(3-chloro-4-fluorophenyl)-N'-
189 hydroxy-3H-imidazo[4,5-b]pyridine-7- 1777 carboximidamide
N-(3-Chloro-4-fluorophenyl)-N'-hydroxy-2-(2-
190 ((2-methoxyethyl)amino)ethyl)-lH-imidazo[4,5- 1513 b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-(2-
191 mo holin-4-ylethyl)-3H-imidazo[4,5-b]pyridine- 2824
7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-(2-
192 piperidin- 1 -ylethyl)- 1 H-imidazo [4,5 -b] pyridine- 241
7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-(2-
193 pyrrolidin-l-ylethyl)-lH-imidazo[4,5-b]pyridine- 358
7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[2-[2-
194 methoxy ethyl(methyl)amino] ethyl] - 1H- 504 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-[2-
195 (dimethylamino)-l -hydroxy ethyl]-N'-hy droxy- 1158 lH-imidazo[4,5-b]pyridine-7-carboximidamide Example No. Name ECso (nM)
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(2-
196 methylpropylamino)methyl] - lH-imidazo [4,5 - 1330 b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-3-
197 methylimidazo[4,5-b]pyridine-7- 5456 carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[2-(2-
198 methoxyethylamino)ethyl]-3H-imidazo[4,5- 2339 b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-[3-
199 (dimethylamino)propyl]-6,7-difluoro-N'-hydroxy- 4488
3H-benzimidazole-4-carboximidamide
N-(3-chloro-4-fluorophenyl)-7-fluoro-N'-
200 hydroxy-2-(3-morpholin-4-ylpropylamino)-3H- 564 benzimidazole-4-carboximidamide
N-(3-chloro-4-fluorophenyl)-2-[2-
201 (dimethylamino)ethylamino]-7-fluoro-N'- 428 hydroxy-3H-benzimidazole-4-carboximidamide
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-[(l-
202 methylpiperidin-2-yl)methylamino] - 1H- 2090 imidazo[4,5-b]pyridine-7-carboximidamide
N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-[(l-
203 methylpyrrolidin-3-yl)amino]-lH-imidazo[4,5- 1344 b]pyridine-7-carboximidamide
204 N-(3-chloro-4-fluorophenyl)-2-(2- 2195
(ethylamino)ethyl)-N'-hydroxy-3H-imidazo[4,5- b]pyridine-7-carboximidamide
205 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2- 2823
(isopropylamino)ethyl)-3H-imidazo[4,5- b]pyridine-7-carboximidamide
206 N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-(2- 2295
(isobutylamino)ethyl)-3H-imidazo[4,5- b]pyridine-7-carboximidamide
207 N-(3-chloro-4-fluorophenyl)-2-(2- 1257
(cyclopropylamino)ethyl)-N'-hydroxy-3H- imidazo[4,5-b]pyridine-7-carboximidamide
209 2-(2-(2-amino-4,5-dihydro- lH-imidazol- 1 - 5000 yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N'- hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide
210 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- >10000 hydroxy-2-(2-(methylsulfonamido)ethyl)-lH- benzo[d]imidazole-7-carboximidamide
211 2-(2-aminoethyl)-N-(3-chloro-4-fluorophenyl)- >10000
4,5-difluoro-N'-hydroxy-lH-benzo[d]imidazole-
7-carboximidamide Example No. Name ECso (nM)
212 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2- 876 methoxyethyl)amino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide
213 tert-butyl (2-(7-(N-(3-chloro-4-fluorophenyl)-N'- 3623 hydroxycarbamimidoyl)-4,5-difluoro-lH- benzo[d]imidazol-2-yl)ethyl)carbamate
214 N-(3-chloro-4-fluorophenyl)-2-((2-(4,4- 1908 difluoropiperidin- 1 -yl)ethyl)amino)-N'-hydroxy- lH-imidazo[4,5-b]pyridine-7-carboximidamide
215 N-(3-chloro-4-fluorophenyl)-2-((2- 1195
(dimethylamino)ethyl)amino)-N'-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide
216 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2- 2009
(methylamino)ethyl)amino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide
217 N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-((l- 2870 methylazepan-3-yl)amino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide
218 N-(3-chloro-4-fluorophenyl)-2-((2-(l , 1 - >10000 dioxidothiomo holino)ethyl)amino)-N'-hydroxy- lH-imidazo[4,5-b]pyridine-7-carboximidamide
219 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2- 3829
((2-methoxyethyl)(methyl)amino)ethyl)amino)- lH-imidazo[4,5-b]pyridine-7-carboximidamide
220 N-(3-chloro-4-fluorophenyl)-2-((2-((2,2- 2383 difluoroethyl)(methyl)amino)ethyl)amino)-N'- hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide
221 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((3- 899 mo holinopropyl)amino)- 1 H-imidazo[4,5 - b]pyridine-7-carboximidamide
222 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2- 1521
(piperidin-l-yl)ethyl)amino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide
223 N-(3-chloro-4-fluorophenyl)-2-((2- 2182 cy cl ohexy 1 ethy l)amino)-N' -hy droxy- 1 H- imidazo[4,5-b]pyridine-7-carboximidamide
224 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2- 3735
(tetrahydro-2H-pyran-4-yl)ethyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide
225 N-(3-chloro-4-fluorophenyl)-2-((2,2- 2190 difluoroethyl)amino)-N'-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide
226 N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2- >10000
(oxetan-3 -y 1 amino)- 1 H-imidazo [4, 5 -b] py ri dine-7- carboximidamide Example No. Name ECso (nM)
227 N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2- 2195
((tetrahydrofuran-3-yl)amino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide
228 N-(3-chl oro-4-fluorophenyl)-N' -hydroxy -2- 2135
((tetrahy dro-2H-py ran-4-yl)amino)- 1 H- imidazo[4,5-b]pyridine-7-carboximidamide
229 3-((7-(N-(3-chloro-4-fluorophenyl)-N'- >10000 hydroxycarbamimidoyl)-4,5-difluoro-lH- benzo[d]imidazol-2-yl)amino)propanamide
230 N-(3-chloro-4-fluorophenyl)-2-((2-((2,2- 3836 difluoroethyl)amino)ethyl)amino)-N'-hydroxy- lH-imidazo[4,5-b]pyridine-7-carboximidamide
231 N-(3-chloro-4-fluorophenyl)-2-((2- 291
(cyclopropyl(methyl)amino)ethyl)amino)-N'- hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide
232 N-(3-chloro-4-fluorophenyl)-2-((2- 460
(cyclopropyl(2- methoxyethyl)amino)ethyl)amino)-N'-hydroxy- lH-imidazo[4,5-b]pyridine-7-carboximidamide
233 2-((2-(azetidin-l-yl)ethyl)amino)-N-(3-chloro-4- 1122 fluorophenyl)-N'-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide
234 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((3- 698 methoxypropyl)amino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide
235 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(2- 4818 oxopyrrolidin-l-yl)ethyl)amino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide
236 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2- 4765
(mo holinosulfonyl)ethyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide
237 N-(3-chloro-4-fluorophenyl)-2-((2-(3- 442 fluoropiperidin- 1 -yl)ethyl)amino)-N'-hy droxy- lH-imidazo[4,5-b]pyridine-7-carboximidamide
238 N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2-((2- 853 mo holinoethyl)amino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide
239 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2- 1212
(methyl(tetrahydro-2H-pyran-4- yl)amino)ethyl)amino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide
240 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2- 590
(isopropyl(methyl)amino)ethyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide
241 2-(((l-aminocyclopropyl)methyl)amino)-N-(3- 1374 chloro-4-fluorophenyl)-N'-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide Example No. Name ECso (nM)
257 N-(3-bromo-4-fluorophenyl)-N'-hydroxy-2- 241
(methylamino)-lH-imidazo[4,5-b]pyridine-7- carboximidamide
242 2-((2-(l-aminocyclopropyl)ethyl)amino)-N-(3- 1626 chloro-4-fluorophenyl)-N'-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide
258 2-(2-(azepan-l-yl)ethyl)-N-(3-chloro-4- 844 fluorophenyl)-N'-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide
259 2-(2-(azetidin-l-yl)ethyl)-N-(3-chloro-4- 1299 fluorophenyl)-N'-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide
260 (R)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2- 3205
(2-(3-hydroxypyrrolidin-l-yl)ethyl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide
261 (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2- 3453
(2-(3-hydroxypyrrolidin-l-yl)ethyl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide
262 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2-(4- 3238 hydroxypiperidin-l-yl)ethyl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide
263 N-(3-bromo-4-fluorophenyl)-2-(2- 559
(dimethylamino)ethyl)-N'-hy droxy- 1 H- imidazo[4,5-b]pyridine-7-carboximidamide
264 N-(3-chlorophenyl)-2-(2-(dimethylamino)ethyl)- 722
N'-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide
265 N-(3-bromophenyl)-2-(2-(dimethylamino)ethyl)- 501
N'-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide
266 N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-(2- >10000
(methylsulfonamido)ethyl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide
267 N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-(2- >10000
(sulfamoylamino)ethyl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide
268 N-(3-chlorophenyl)-N'-hy droxy -2-(2-(pyrrolidin- 952 l-yl)ethyl)-lH-imidazo[4,5-b]pyridine-7- carboximidamide
269 N-(3-bromophenyl)-N'-hy droxy -2-(2-(pyrrolidin- 979 l-yl)ethyl)-lH-imidazo[4,5-b]pyridine-7- carboximidamide
270 N-(2-(7-(N-(3-chloro-4-fluorophenyl)-N'- >10000 hy droxy carbamimidoyl)-lH-imidazo[4,5- b]pyridin-2-yl)ethyl)acetamide
271 N-(3-chl orophenyl)-N'-hy droxy -2-(2-(piperidin-l- 602 yl)ethyl)-lH-imidazo[4,5-b]pyridine-7- carboximidamide Example No. Name ECso (nM)
272 N-(3-bromophenyl)-N'-hydroxy-2-(2-(piperidin- 477 l-yl)ethyl)-lH-imidazo[4,5-b]pyridine-7- carboximidamide
273 Methyl (2-(7-(N-(3-chloro-4-fluorophenyl)-N'- >10000 hydroxycarbamimidoyl)-lH-imidazo[4,5- b]pyridin-2-yl)ethyl)carbamate
274 N-(3-chloro-4-fluorophenyl)-2-(2-((2,4- 1966 dimethoxybenzyl)amino)ethyl)-N'-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide
275 2-(2-(4-benzylpiperidin-l-yl)ethyl)-N-(3-chloro- 675
4-fluorophenyl)-N'-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide
276 2-(2-(3-azabicyclo[3.3.1]nonan-3-yl)ethyl)-N-(3- 618 chloro-4-fluorophenyl)-N'-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide
277 2-(2-(3-azabicyclo[3.2.1]octan-3-yl)ethyl)-N-(3- 576 chloro-4-fluorophenyl)-N'-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide
278 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((l - 1073 methylpiperidin-3-yl)amino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide
279 (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2- 5279
((2-(3-hydroxypyrrolidin-l-yl)ethyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide
280 (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2- >10000
(3-hydroxypyrrolidin-l-yl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide
281 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((l -(2- 1257 methoxyethyl)pyrrolidin-3-yl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide
282 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((4- >10000 methylmorpholin-3-yl)methyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide
283 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2- 2719
(pyrrolidin-l-yl)ethyl)amino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide
287 N-(3-chloro-4-fluorophenyl)-2- 1669
((ethylamino)methyl)-4-fluoro-N'-hydroxy-lH- benzo[d]imidazole-7-carboximidamide
288 N-(3-chloro-4-fluorophenyl)-2- 1816
((dimethylamino)methyl)-4-fluoro-N'-hydroxy- lH-benzo[d]imidazole-7-carboximidamide
289 -(3-chloro-4-fluorophenyl)-4-fluoro-N'-hydroxy- 2232
2-((isopropylamino)methyl)-lH- benzo[d]imidazole-7-carboximidamide
290 N-(3-chloro-4-fluorophenyl)-4-fluoro-N'- 1292 hy droxy-2-((methylamino)methyl)- 1 H- benzo[d]imidazole-7-carboximidamide Example No. Name ECso (nM)
291 2-(aminomethyl)-N-(3-chloro-4-fluorophenyl)-4- 2647 fluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
292 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 3317 hydroxy-2-((2-hydroxy-2-methylpropyl)amino)- lH-benzo[d]imidazole-7-carboximidamide
293 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 3003 hydroxy-2-((2-hydroxypropyl)amino)-lH- benzo[d]imidazole-7-carboximidamide
294 2-((7-(N-(3-chloro-4-fluorophenyl)-N'- 9954 hydroxycarbamimidoyl)-4,5-difluoro-lH- benzo[d]imidazol-2-yl)amino)acetamide
295 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 3264 hydroxy-2-((2 -hydroxy ethyl)amino)-lH- benzo[d]imidazole-7-carboximidamide
296 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- >10000 hydroxy-2-((3-hydroxycyclobutyl)amino)-lH- benzo[d]imidazole-7-carboximidamide
297 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 1153 hydroxy-2-((3-(pyridin-2-ylamino)propyl)amino)- lH-benzo[d]imidazole-7-carboximidamide
298 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 9558 hydroxy-2-((2-sulfamoylethyl)amino)-lH- benzo[d]imidazole-7-carboximidamide
299 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 3443 hydroxy-2-(((l-methyl-lH-pyrazol-5- yl)methyl)amino)-lH-benzo[d]imidazole-7- carboximidamide
300 2-((2-(lH-pyrazol-l-yl)ethyl)amino)-N-(3-chloro- 3572
4-fluorophenyl)-4,5-difluoro-N'-hydroxy-lH- benzo[d]imidazole-7-carboximidamide
301 2-((7-(N-(3-chloro-4-fluorophenyl)-N'- 3960 hydroxycarbamimidoyl)-4,5-difluoro-lH- benzo[d]imidazol-2-yl)amino)-N,N- dimethylacetamide
302 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- >10000 hydroxy-2-(2 -hydroxy -2-methy lpropyl)-l H- benzo[d]imidazole-7-carboximidamide
303 N-(3-chloro-4-fluorophenyl)-2-((4- 2935
(dimethylamino)butyl)amino)-4,5-difluoro-N'- hydroxy-lH-benzo[d]imidazole-7- carboximidamide
304 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- >10000 hydroxy-2-((piperidin-3-ylmethyl)amino)-lH- benzo[d]imidazole-7-carboximidamide
305 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((l- 3494 methylpiperidin-2-yl)methyl)- 1 H-imidazo [4,5 - b]pyridine-7-carboximidamide Example No. Name ECso (nM)
306 N-(3-bromophenyl)-N'-hydroxy-2-((2- 681 ηιο !ιο1ίηο6^1)α ι1ηο)-1Η-ίηιίάαζο[4,5- b]pyridine-7-carboximidamide
307 N-(3-chloro-4-fluorophenyl)-5-fluoro-N'- 209 hydroxy-4-methoxy-lH-benzo[d]imidazole-7- carboximidamide
325 N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2- >10000
(piperidin-2-ylmethyl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide
326 N-(3-chloro-4-fluorophenyl)-2-(l- 4054
(dimethylamino)propan-2-yl)-N'-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide
327 N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-(2- 7619
(methylamino)propyl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide
328 N-(3-chloro-4-fluorophenyl)-2-(2- 3242
(dimethylamino)propyl)-N'-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide
329 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2- 5000
(py rroli din-2-y lmethy 1)- 1 H-imi dazo [4,5- b]pyridine-7-carboximidamide
330 N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2- 414
((2-(py rrolidin- 1 -yl)ethyl)amino)- 1H- benzo[d]imidazole-7-carboximidamide
331 N-(3-bromophenyl)-4,5-difluoro-N'-hydroxy-2- 692
((2-(py rrolidin- 1 -yl)ethyl)amino)- 1H- benzo[d]imidazole-7-carboximidamide
333 2-((2-aminoethyl)amino)-N-(3-chloro-4- 1386 fluorophenyl)-4,5-difluoro-N'-hydroxy-lH- benzo[d]imidazole-7-carboximidamide
334 N-(2-((7-(N-(3-chloro-4-fluorophenyl)-N'- 6119 hydroxycarbamimidoyl)-4,5-difluoro-lH- benzo[d]imidazol-2-yl)amino)ethyl)acetamide
335 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- >10000 hydroxy-2-((2-(methylsulfonamido)ethyl)amino)- lH-benzo[d]imidazole-7-carboxirnidamide
336 N-(3-chloro-4-fluorophenyl)-2-((2- >10000
(cyclopropanesulfonamido)ethyl)amino)-4,5- difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
337 Methyl (2-((7-(N-(3-chloro-4-fluorophenyl)-N'- 4405 hydroxycarbamimidoyl)-4,5-difluoro-lH- benzo[d]imidazol-2-yl)amino)ethyl)carbamate
338 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- >10000 hydroxy-2-((2-(sulfamoylamino)ethyl)amino)- lH-benzo[d]imidazole-7-carboxirnidamide Example No. Name ECso (nM)
339 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- >10000 hydroxy-2-((2-(phenylsulfonamido)ethyl)amino)- lH-benzo[d]imidazole-7-carboximidamide
340 N-(3-chloro-4-fluorophenyl)-2-((2- 1781 cyanoethyl)amino)-4,5-difluoro-N'-hydroxy-lH- benzo[d]imidazole-7-carboximidamide
341 N-(3-chloro-4-fluorophenyl)-2-((2-(3- >10000 ethylureido)ethyl)amino)-4,5-difluoro-N'- hydroxy-lH-benzo[d]imidazole-7- carboximidamide
342 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 8493 hydroxy-2-((pyridin-2-ylmethyl)amino)-lH- benzo[d]imidazole-7-carboximidamide
343 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 3857 hydroxy-2-((pyridin-3-ylmethyl)amino)-lH- benzo[d]imidazole-7-carboximidamide
344 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 3058 hydroxy-2-((pyridin-3-ylmethyl)amino)-lH- benzo[d]imidazole-7-carboximidamide
345 2-(((lH-imidazol-2-yl)methyl)amino)-N-(3- 3843 chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy- lH-benzo[d]imidazole-7-carboximidamide
346 2-chloro-N-(3-chloro-4-fluorophenyl)-4,5- 8468 difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
347 2-((2-aminobenzyl)amino)-N-(3-chloro-4- 3269 fluorophenyl)-4,5-difluoro-N'-hydroxy-lH- benzo[d]imidazole-7-carboximidamide
348 N-(3-chloro-4-fluorophenyl)-2-((2- 3431
(dimethylamino)benzyl)amino)-4,5-difluoro-N'- hydroxy-lH-benzo[d]imidazole-7- carboximidamide
349 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 2544 hydroxy-2-(((l-methyl-lH-imidazol-2- yl)methyl)amino)-lH-benzo[d]imidazole-7- carboximidamide
350 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 7031 hydroxy-2-((pyrimidin-2-ylmethyl)amino)-lH- benzo[d]imidazole-7-carboximidamide
351 N-(3 -chloro-4-fluorophenyl)-2-((3 - 432
(dimethylamino)-2,2-dimethylpropyl)amino)-4,5- difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
352 N-(3 -chloro-4-fluorophenyl)-2-((3 - 437
(dimethylamino)-2-methylpropyl)amino)-4,5- difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide Example No. Name ECso (nM)
353 N-(3 -chloro-4-fluorophenyl)-2-((3 - 1295
(dimethylamino)butyl)amino)-4,5-difluoro-N'- hydroxy-lH-benzo[d]imidazole-7- carboximidamide
354 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 1207 hydroxy-2-((2-(l-methylpyrrolidin-2- yl)ethyl)amino)-lH-benzo[d]imidazole-7- carboximidamide
355 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 2021 hydroxy-2-((2-(l-methylpiperidin-2- yl)ethyl)amino)-lH-benzo[d]imidazole-7- carboximidamide
356 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 3264 hydroxy-2-(((4-methylmorpholin-2- yl)methyl)amino)-lH-benzo[d]imidazole-7- carboximidamide
357 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((4- 3239 methylmorpholin-2-yl)methyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide
358 N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-(((l- 8791 methy 1- 1 H-py razol -5 -y l)methy l)amino)- 1 H- imidazo[4,5-b]pyridine-7-carboximidamide
368 N-(3-chloro-4-fluorophenyl)-4-fluoro-N'- 4004 hydroxy-2-((2-mo holinoethyl)amino)-lH- benzo[d]imidazole-7-carboximidamide
369 N-(3-chloro-4-fluorophenyl)-N' -hydroxy -N- >10000 methyl-lH-imidazo[4,5-b]pyridine-7- carboximidamide
370 2-amino-N-(3-chloro-4-fluorophenyl)-5-fluoro- 1078
N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
371 2-amino-N-(3-chlorophenyl)-5-fluoro-N'- 644 hydroxy-lH-benzo[d]imidazole-7- carboximidamide
372 2-amino-N-(3-bromophenyl)-5-fluoro-N'- 483 hydroxy-lH-benzo[d]imidazole-7- carboximidamide
373 2-amino-N-(3-bromo-4-fluorophenyl)-5-fluoro- 736
N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
374 N-(3-chloro-4-fluorophenyl)-2-((2-(l , 1 - 2399 dioxidothiomo holino)ethyl)amino)-4,5- difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
375 N-(3-chloro-4-fluorophenyl)-2-((2- 1190
(diethylamino)ethyl)amino)-4-fluoro-N'-hydroxy- lH-benzo[d]imidazole-7-carboximidamide Example No. Name ECso (nM)
376 N-(3-chloro-4-fluorophenyl)-4-fluoro-N'- 1258 hydroxy-2-((2-(pyrrolidin-l-yl)ethyl)amino)-lH- benzo[d]imidazole-7-carboximidamide
377 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 838 hydroxy-2-((2-mo holinopropyl)amino)-lH- benzo[d]imidazole-7-carboximidamide
378 N-(3 -chloro-4-fluorophenyl)-2-(( 1 - 1396
(dimethylamino)propan-2-yl)amino)-4,5-difluoro- N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
379 N-(3-chloro-4-fluorophenyl)-2-((2- 435
(dimethylamino)ethyl)amino)-5-fluoro-N'- hydroxy-lH-benzo[d]imidazole-7- carboximidamide
380 N-(3-chloro-4-fluorophenyl)-5-fluoro-N'- 1388 hydroxy-2-((2-(pyrrolidin-l-yl)ethyl)amino)-lH- benzo[d]imidazole-7-carboximidamide
381 N-(3-chloro-4-fluorophenyl)-2-((3- 3025
(dimethylamino)-2,2-dimethylpropyl)amino)-4- fluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
382 N-(3-bromo-4-fluorophenyl)-2-((2- 608
(dimethylamino)ethyl)amino)-4-fluoro-N'- hydroxy-lH-benzo[d]imidazole-7- carboximidamide
383 N-(3 -bromophenyl)-2-((2- 319
(dimethylamino)ethyl)amino)-4-fluoro-N'- hydroxy-lH-benzo[d]imidazole-7- carboximidamide
384 N-(3-chlorophenyl)-2-((2- 290
(dimethylamino)ethyl)amino)-4-fluoro-N'- hydroxy-lH-benzo[d]imidazole-7- carboximidamide
385 N-(3 -chlorophenyl)-2-((3 - 580
(dimethylamino)propyl)amino)-4,5-difluoro-N'- hydroxy-lH-benzo[d]imidazole-7- carboximidamide
386 N-(3 -bromophenyl)-2-((3 - 559
(dimethylamino)propyl)amino)-4,5-difluoro-N'- hydroxy-lH-benzo[d]imidazole-7- carboximidamide
387 N-(3 -bromo-4-fluorophenyl)-2-((3 - 692
(dimethylamino)propyl)amino)-4,5-difluoro-N'- hydroxy-lH-benzo[d]imidazole-7- carboximidamide
388 N-(3 -chloro-4-fluorophenyl)-2-((3 - 939
(dimethylamino)propyl)amino)-4-fluoro-N'- hydroxy-lH-benzo[d]imidazole-7- carboximidamide Example No. Name ECso (nM)
389 N-(3 -chloro-4-fluorophenyl)-2-((3 - 1157
(dimethylamino)propyl)amino)-5-fluoro-N'- hydroxy-lH-benzo[d]imidazole-7- carboximidamide
390 2-((2-(benzyl(methyl)amino)ethyl)amino)-N-(3- 1017 chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy- lH-benzo[d]imidazole-7-carboximidamide
391 N-(3-chloro-4-fluorophenyl)-2-(2- 1480
((cyclohexylmethyl)(methyl)amino)ethyl)-N'- hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide
392 N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-(2- 1226
(methyl(neopentyl)amino)ethyl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide
393 N-(3-chloro-4-fluorophenyl)-2-(2- 1794
(cyclohexyl(methyl)amino)ethyl)-N'-hy droxy- 1 H- imidazo[4,5-b]pyridine-7-carboximidamide
394 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 332 hydroxy-2-((2-(methyl((tetrahydro-2H-pyran-4- yl)methyl)amino)ethyl)amino)- 1H- benzo[d]imidazole-7-carboximidamide
395 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 757 hydroxy-2-((2-(methylamino)ethyl)amino)-lH- benzo[d]imidazole-7-carboximidamide
396 2-(2-(benzyl(methyl)amino)ethyl)-N-(3-chloro-4- 790 fluorophenyl)-N'-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide
397 N-(3-chloro-4-fluorophenyl)-2-((2-((2- 1317 ethylbutyl)(methyl)amino)ethyl)amino)-4,5- difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
398 N-(3-chloro-4-fluorophenyl)-2-((2- 555
((cyclopropylmethyl)(methyl)amino)ethyl)amino)
-4,5-difluoro-N'-hydroxy-lH-benzo[d]imidazole- 7-carboximidamide
399 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(2- 1329
(methyl((tetrahydro-2H-pyran-4- yl)methyl)amino)ethyl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide
400 2-(2-(((l,4-dioxan-2- 2814 yl)methyl)(methyl)amino)ethyl)-N-(3-chloro-4- fluorophenyl)-N'-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide
401 N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2-(2- 581
(methyl(2-(tetrahydro-2H-pyran-4- yl)ethyl)amino)ethyl)- 1 H-imidazo [4,5 -b] pyridine- 7-carboximidamide Example No. Name ECso (nM)
402 N-(3-chloro-4-fluorophenyl)-2-((2- 561
(cyclopropylamino)ethyl)amino)-N'-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide
403 N-(3-chloro-4-fluorophenyl)-2-((2- 192
(cyclopropyl(ethyl)amino)ethyl)amino)-N'- hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide
404 N-(2-((7-(N-(3-chloro-4-fluorophenyl)-N'- >10000 hydroxycarbamimidoyl)-lH-imidazo[4,5- b]pyridin-2-yl)amino)ethyl)acetamide
405 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2- 7112
(methylsulfonamido)ethyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide
406 N-(3-chloro-4-fluorophenyl)-2-((2- 185
(cyclopropyl(isopropyl)amino)ethyl)amino)-N'- hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide
407 N-(3-chloro-4-fluorophenyl)-2-((2- 2122
(cyclopropyl(2- hydroxyethyl)amino)ethyl)amino)-N'-hydroxy- lH-imidazo[4,5-b]pyridine-7-carboximidamide
427 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((5- 1071 methyl-l,3,4-oxadiazol-2-yl)methyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide
429 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 1346 hydroxy-2-(((4-methylmo holin-3- yl)methyl)amino)-lH-benzo[d]imidazole-7- carboximidamide
430 N-(3 -bromophenyl)-2-((2- 180
(dimethylamino)ethyl)amino)-4,5-difluoro-N'- hydroxy-lH-benzo[d]imidazole-7- carboximidamide
431 N-(3-chlorophenyl)-2-((2- 139
(dimethylamino)ethyl)amino)-4,5-difluoro-N'- hydroxy-lH-benzo[d]imidazole-7- carboximidamide
432 N-(3-bromo-4-fluorophenyl)-2-((2- 253
(dimethylamino)ethyl)amino)-4,5-difluoro-N'- hydroxy-lH-benzo[d]imidazole-7- carboximidamide
433 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((3- 882 mo holinopropyl)amino)- 1 H-benzo [d] imidazole- 7-carboxamide
434 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 1240 hydroxy-2-((3-(pyrrolidin-l-yl)propyl)amino)- lH-benzo[d]imidazole-7-carboximidamide Example No. Name ECso (nM)
435 2-(((3R)-4-amino-l-methylpyrrolidin-3- 1814 yl)amino)-N-(3-chloro-4-fluorophenyl)-4,5- difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
436 N-(3-chloro-4-fluorophenyl)-2-((2- 2015
(dimethylamino)-2-phenylethyl)amino)-4,5- difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
437 N-(3-chloro-4-fluorophenyl)-2-(((lR,2R)-2- 998
(dimethylamino)cyclohexyl)amino)-4,5-difluoro- N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
438 N-(3-chloro-4-fluorophenyl)-2-(((l- 838
(dimethylamino)cyclopentyl)methyl)amino)-4,5- difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
439 N-(3-chloro-4-fluorophenyl)-2-(((lS*,3S*)-3- 6799
(dimethylamino)cyclohexyl)amino)-4,5-difluoro- N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
440 N-(3-chloro-4-fluorophenyl)-2-(((lS,3R)-3- 6660
(dimethylamino)cyclohexyl)amino)-4,5-difluoro- N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
441 N-(3 -chloro-4-fluorophenyl)-2-((( 1 - >10000
(dimethylamino)cyclobut l)methyl)amino)-4,5- difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
442 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 2881 hydroxy-2-((l -methylpiperidin-4-yl)amino)- 1H- benzo[d]imidazole-7-carboximidamide
443 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 389 hydroxy-2-((l-methylpiperidin-3-yl)amino)-lH- benzo[d]imidazole-7-carboximidamide
444 N-(3-chloro-4-fluorophenyl)-2-(((lS,2S)-2- 3144
(dimethylamino)cyclohexyl)amino)-4,5-difluoro- N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
445 (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 1946 hydroxy-2-(piperidin-3-ylamino)-lH- benzo[d]imidazole-7-carboximidamide
446 (R)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 1490 hydroxy-2-(piperidin-3-ylamino)-lH- benzo[d]imidazole-7-carboximidamide
447 (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 325 hydroxy-2-((l-methylpyrrolidin-3-yl)amino)-lH- benzo[d]imidazole-7-carboximidamide Example No. Name ECso (nM)
448 N-(3 -chloro-4-fluorophenyl)-2-((3 - 1118
(dimethylamino)-2-hydroxypropyl)amino)-4,5- difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
449 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 6249 hydroxy-2-((2-(4-methyl-3-oxopiperazin-l- yl)ethyl)amino)-lH-benzo[d]imidazole-7- carboximidamide
450 N-(3-chloro-4-fluorophenyl)-2-(((l- 1586
(dimethylamino)cyclohexyl)methyl)amino)-4,5- difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
451 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 205 hydroxy-2-((l -methylazepan-3-yl)amino)- 1H- benzo[d]imidazole-7-carboximidamide
452 (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 568 hy droxy-2-((2-(3 -hy droxypyrrolidin- 1 - yl)ethyl)amino)-lH-benzo[d]imidazole-7- carboximidamide
453 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 651 hydroxy-2-((l-(2-methoxyethyl)piperidin-3- yl)amino)-lH-benzo[d]imidazole-7- carboximidamide
454 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 247 hydroxy-2-((l-(2-methoxyethyl)pyrrolidin-3- yl)amino)-lH-benzo[d]imidazole-7- carboximidamide
455 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 376 hydroxy-2-((l-isopropylpiperidin-3-yl)amino)- lH-benzo[d]imidazole-7-carboximidamide
456 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 274 hy droxy-2-((2-(3 -methoxy azetidin- 1 - yl)ethyl)amino)-lH-benzo[d]imidazole-7- carboximidamide
457 (R)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 271 hydroxy-2-((l-methylpyrrolidin-3-yl)amino)-lH- benzo[d]imidazole-7-carboximidamide
458 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 261 hy droxy-2-(((3R,4R)-4-methoxy- 1 - methylpyrrolidin-3 -yl)amino)- 1 H- benzo[d]imidazole-7-carboximidamide
459 (S)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy- 337
2-(( 1 -methylpiperidin-3 -yl)amino)- 1H- benzo[d]imidazole-7-carboximidamide
460 (R)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy- 193
2-(( 1 -methylpiperidin-3 -yl)amino)- 1H- benzo[d]imidazole-7-carboximidamide Example No. Name ECso (nM)
461 N-(3-chloro-4-fluorophenyl)-2-((2- 472
(dimethylamino)cyclopentyl)amino)-4,5-difluoro- N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
462 (S)-2-(azepan-3-ylamino)-N-(3-chloro-4- 1429 fluorophenyl)-4,5-difluoro-N'-hydroxy-lH- benzo[d]imidazole-7-carboximidamide
463 (R)-2-(azepan-3-ylamino)-N-(3-chloro-4- 1020 fluorophenyl)-4,5-difluoro-N'-hydroxy-lH- benzo[d]imidazole-7-carboximidamide
464 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 2346 hydroxy-2-(pyrrolidin-3-ylamino)-lH- benzo[d]imidazole-7-carboximidamide
465 (R)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 957 hydroxy-2-((l-(oxetan-3-yl)piperidin-3- yl)amino)-lH-benzo[d]imidazole-7- carboximidamide
466 N-(3-chloro-4-fluorophenyl)-2-(((l,4- 685 dimethylpiperidin-2-yl)methyl)amino)-4,5- difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
467 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 2116 hydroxy-2-((mo holin-3-ylmethyl)amino)-lH- benzo[d]imidazole-7-carboximidamide
468 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- >10000 hydroxy-2-(((3R,4S)-4-hydroxypyrrolidin-3- yl)amino)-lH-benzo[d]imidazole-7- carboximidamide
469 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 959 hydroxy-2-(((lR,5R)-8-methyl-8- azabicy clo[3.2.1] octan-2-yl)amino)- 1H- benzo[d]imidazole-7-carboximidamide
470 (S)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 4200 hydroxy-2-((2-(2-(trifluoromethyl)pyrrolidin-l- yl)ethyl)amino)-lH-benzo[d]imidazole-7- carboximidamide
471 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2- 852
(((hexahydro-lH-pyrrolizin-7a-yl)methyl)amino)- N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
472 N-(3-chloro-4-fluorophenyl)-2-(((3,3- 2452 dimethylazetidin-2-yl)methyl)amino)-4,5- difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
473 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 1034 hydroxy-2-((4-(pyrrolidin-l-yl)tetrahydro-2H- pyran-3-yl)amino)-lH-benzo[d]imidazole-7- carboximidamide Example No. Name ECso (nM)
474 2-(((l S,2R)-2-aminocyclohexyl)amino)-N-(3- 7584 chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy- lH-benzo[d]imidazole-7-carboximidamide
475 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 1993 hydroxy-2-((2-methyl-l,2,3,4- tetrahydroisoquinolin-4-yl)amino)-lH- benzo[d]imidazole-7-carboximidamide
476 N-(3-chloro-4-fluorophenyl)-2-(((3S,4S)-4- 468
(diethylamino)tetrahydrofuran-3-yl)amino)-4,5- difluoro-N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide
477 2-((l,4-oxazepan-6-yl)amino)-N-(3-chloro-4- 1525 fluorophenyl)-4,5-difluoro-N'-hydroxy-lH- benzo[d]imidazole-7-carboximidamide
478 N-(3-chloro-4-fluorophenyl)-2-((2-((2S,6R)-2,6- 1011 dimethylmo holino)ethyl)amino)-N'-hydroxy- lH-imidazo[4,5-b]pyridine-7-carboximidamide
479 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2- 1069
(((3R,4R)-4-methoxy-l-methylpyrrolidin-3- yl)amino)- lH-imidazo [4,5 -b] pyridine-7- carboximidamide
480 N-(3-chloro-4-fluorophenyl)-2-(((3R,4R)-4- 1194
(diethylamino)tetrahydrofuran-3-yl)amino)-N'- hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide
481 (S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2- 760
((2-(2-(trifluoromethyl)pyrrolidin-l- yl)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7- carboximidamide
482 (R)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2- 2653
Figure imgf000471_0001
imidazo[4,5-b]pyridine-7-carboximidamide
483 N-(3-chloro-4-fluorophenyl)-2-((2-(2,6- 668 dimethylmo holino)propyl)amino)-N'-hydroxy- lH-imidazo[4,5-b]pyridine-7-carboximidamide
484 N-(3-chloro-4-fluorophenyl)-2-((2-(2,6- 566 dimethylmo holino)-2-methylpropyl)amino)-N'- hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide
485 N-(3-chloro-4-fluorophenyl)-2-((2-(2,5- 639 dimethylmoφholino)ethyl)amino)-N'-hydroxy- lH-imidazo[4,5-b]pyridine-7-carboximidamide
486 N-(3 -chloro-4-fluorophenyl)-2-((( 1 R,2R)-2- 284
(dimethylamino)cyclopentyl)amino)-4,5-difluoro- N'-hydroxy-lH-benzo[d]imidazole-7- carboximidamide Example No. Name ECso (nM)
487 N-(3-chloro-4-fluorophenyl)-2-((2- 1361
(dimethylamino)ethyl)thio)-N'-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide
488 N-(3-chloro-4-fluorophenyl)-2-((2- 3012
(dimethylamino)ethyl)thio)-4,5-difluoro-N'- hydroxy-lH-benzo[d]imidazole-7- carboximidamide
489 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 289 hy droxy-2-((2-(2-(hy droxymethyl)piperidin- 1 - yl)ethyl)amino)-lH-benzo[d]imidazole-7- carboximidamide
490 N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- 186 hydroxy-2-((2-(2-(hydroxymethyl)pyrrolidin-l- yl)ethyl)amino)-lH-benzo[d]imidazole-7- carboximidamide
491 N-(3-chloro-4-fluorophenyl)-2-((2-(3,3- 917 difluoropyrrolidin-l-yl)ethyl)amino)-N'-hydroxy- lH-imidazo[4,5-b]pyridine-7-carboximidamide
492 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2- 5660 sulfamoylethyl)amino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide
493 N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2- 7215
(methylsulfonyl)ethyl)amino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide
494 N-(3-chloro-4-fluorophenyl)-N' -hydroxy -2- >10000
((pyrimidin-2-ylmethyl)amino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide

Claims

is claimed is: A compound of Formula I:
Figure imgf000473_0001
I wherein
R1 is mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, Ci^ haloalkyl, Ci^ haloalkoxy, Ci-e alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, wherein two of the optional substituents can join to form an additional partially saturated heterocyclic ring; and wherein each Ci-β alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, - N(R20)(R22) and C3-6 cycloalkyl;
X is N or CR2c;
R2a, R2b, and R2c are independently hydrogen, hydroxyl, halo, CN, Ci^ haloalkyl, Ci-6 haloalkoxy, Ci-β alkoxy, or C1-6 alkyl;
R2d and R2e are independently hydrogen, Ci^ haloalkyl, C1-6 haloalkoxy, or Ci^ alkyl; n and m are independently 0, 1, 2, or 3; each Rn and Rm are independently hydrogen, hydroxyl, halo, Ci-6 alkoxy, Ci^ alkyl, C3-6 cycloalkyl, aryl, heterocyclyl, or heteroaryl; or two Rn or Rm join to form a C3-6 cycloalkyl; and wherein each Ci- alkoxy, C1-6 alkyl, C3-6 cycloalkyl aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, - N(R20)(R22), C2* alkenyl, C2^ alkynyl, haloalkyl, haloalkoxy, Ci-β alkoxy, Ci^ alkyl, and C3-6 cycloalkyl;
L is a bond, -NR3-, -C(0)-NR3-, -NR3-C(0)-, -NR3S02-, -NR3S02-NR3-, - S02NR3-, -0-, -S-, or -S(0)r, where t is 0, 1 or 2; each R3 is independently hydrogen, Ci^ alkyl, C3-6 cycloalkyl, aryl, heterocyclyl, or heteroaryl; and
Rl is hydrogen, alkyl, alkoxy, -C(0)R20, -C(0)OR20, -NC(0)OR20, -
N(R20)(R22), -C(O)N(R20)(R22), -S02R20, -N(R20)SO2(R21), -N(R20)SO2- N(R21)(R22), -SO2N(R20)(R22), C3-15 cycloalkyl, aryl, heteroaryl, or heterocyclyl, provided that when Rl is alkoxy, -NC(0)OR20, - N(R20)(R22), -N(R20)SO2(R21), -N(R20)SO2-N(R21)(R22), or - SO2N(R20)(R22), and m is 0, then L is a bond; wherein said Ci^ alkyl, Ci^ alkoxy, C3 5 cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -N02, Ci_ 6 haloalkyl, haloalkoxy, -C(0)R20, -N(R20)(R22), -S02R20, - N(R20)SO2(R21), -N(R20)SO2-N(R21)(R22), -SO2N(R20)(R22), cycloalkyl, -CN, Ci-6 alkoxy, Ci^ alkyl, and heterocyclyl; and wherein said heterocyclyl is optionally substituted with one or two oxo; wherein said C3-6 cycloalkyl, Ci^ alkyl or Ci^ alkoxy is optionally substituted with one, two, or three substituents
independently selected from hydroxyl, halo, -N02, Ci-6 haloalkyl, Ci^ haloalkoxy, Ci-6 alkoxy, - N(R20)(R22), -S02R20, -N(R20)SO2(R22), -N(R20)SO2- N(R21)(R22)-, and -SO2N(R20)(R22); and said alkyl is optionally substituted with aryl; 20 21 22
R , R , and are independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, aryl, heterocyclyl, and heteroaryl; wherein said aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three halogen; or a pharmaceutically acceptable salt, isomer, or mixture thereof.
2. The compound of claim 1, wherein the compound is represented by Formula IV:
Figure imgf000475_0001
IV or a pharmaceutically acceptable salt, isomer, or mixture thereof.
3. The compound of claim 1 or 2 wherein R1 is bi cyclic aryl or heteroaryl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, Ci-6 haloalkyl, C1-6 haloalkoxy, alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, and C3-6 cycloalkyl; or a pharmaceutically acceptable salt, isomer, or mixture thereof.
4. The compound of claim 1 or 2 wherein R1 is phenyl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -CN, Ci^ haloalkyl, Ci^ haloalkoxy, Ci-β alkoxy, Ci^ alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, and wherein two of the optional substituents can j oin to form an additional partially saturated heterocyclic ring; or a pharmaceutically acceptable salt, isomer, or mixture thereof.
5. The compound of claim 1 or 2 wherein R1 is selected from the group consiting of
Figure imgf000476_0001
Figure imgf000477_0001
6. The compound of any one of the preceding claims wherein X is N; or a pharmaceutically acceptable salt, isomer, or mixture thereof.
7. The compound of any one of claims 1-4 wherein X is CR2c; or a pharmaceutically acceptable salt, isomer, or mixture thereof.
8. The compound of any one of the preceding claims wherein L is a bond; or a pharmaceutically acceptable salt, isomer, or mixture thereof.
9. The compound of any one of claims 1-6 wherein L is -NR3; or a pharmaceutically acceptable salt, isomer, or mixture thereof.
10. The compound of any one of the preceding claims wherein Rl is hydrogen; or a pharmaceutically acceptable salt, isomer, or mixture thereof.
11. The compound of any one of claims 1-8 wherein Rl is Ci^ alkyl optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -N02, Ci-6 haloalkyl, Ci^ haloalkoxy, C3-6 cycloalkyl, -CN, and Ci^ alkoxy; or a pharmaceutically acceptable salt, isomer, or mixture thereof.
12. The compound of any one of claims 1-8 wherein Rl is C3 5 cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein said cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -N02, C1-6 haloalkyl, haloalkoxy, C3-6 cycloalkyl, -CN, C1-6 alkoxy and Ci-6 alkyl; or a pharmaceutically acceptable salt, isomer, or mixture thereof.
13. The compound of any one of claims 1-7 wherein L is -NR3 and Rl is C3-15 cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein said cycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, -N02, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, - CN, and Ci^ alkoxy; or a pharmaceutically acceptable salt, isomer, or mixture thereof.
14. The compounds of any one of claims 1-6 wherein the group
Figure imgf000478_0001
is selected from the group consisting of:
Figure imgf000478_0002
Figure imgf000479_0001
477
Figure imgf000480_0001
478
Figure imgf000481_0001
479
Figure imgf000482_0001
480
Figure imgf000483_0001
481
Figure imgf000484_0001
482
Figure imgf000485_0001
, , and ; or a pharmaceutically acceptable salt, isomer, or mixture thereof.
15. A compound selected from the group consisting of:
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-4-methyl-lH-benzo[d]imidazole-7- carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-4-(trifluoromethoxy)-lH- benzo[d]imidazole-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-6-fluoro-N-hydroxy-lH-benzo[d]imidazole-7- carboximidamide,
N-(3-Chloro-4-fluorophenyl)-5-fluoro-N-hydroxy-lH-benzo[d]imidazole-7- carboximidamide,
N-(3-Chloro-4-fluorophenyl)-4-fluoro-N-hydroxy-lH-benzo[d]imidazole-7- carboximidamide,
4-Chloro-N-(3-chloro-4-fluorophenyl)-N-hydroxy-lH-benzo[d]imidazole-7- carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-4-(trifluoromethyl)-lH- benzo[d]imidazole-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-lH-benzo[d]imidazole-7- carboximidamide,
N-(3-Chloro-4-fluorophenyl)-6-fluoro-N-hydroxy-7-methyl-3H-benzimidazole- 4-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-lH-benzo[d]imidazole-7- carboximidamide,
6-Chloro-N-(3-chloro-4-fluorophenyl)-N-hydroxy-lH-benzo[d]imidazole-4- carboximidamide, 4-Bromo-N-(3-chloro-4-fluorophenyl)-N-hydroxy-lH-benzo[cf]imidazole-7- carboximidamide,
2-Amino-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-lH- benzo[d]imidazole-7-carboximidamide,
2-Amino-N-(3-bromo-4-fluorophenyl)-4,5-difluoro-N -hydroxy- 1H- benzo[d]imidazole-7-carboximidamide,
2-Amino-N-(3-bromophenyl)-4,5-difluoro-N-hydroxy-lH-benzo[d]imidazole-7- carboximidamide,
2-Amino-N-(3-chlorophenyl)-4,5-difluoro-N-hydroxy-lH-benzo[d]imidazole-7- carboximidamide,
2-Amino-4,5-difluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N-hydroxy-lH- benzo[d]imidazole-7-carboximidamide,
2-Amino-N-(3-bromophenyl)-4-fluoro-N-hydroxy-lH-benzo[d]imidazole-7- carboximidamide,
2-Amino-N-(3-bromo-4-fluorophenyl)-4-fluoro-N-hydroxy-lH- benzo[d]imidazole-7-carboximidamide,
2-Amino-N-(3-chlorophenyl)-4-fluoro-N-hydroxy-lH-benzo[d]imidazole-7- carboximidamide,
2-Amino-4-fluoro-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N'-hydroxy-lH- benzo[d]imidazole-7-carboximidamide,
2-Amino-N-(3-chloro-4-fluorophenyl)-4-fluoro-N-hydroxy-lH- benzo[d]imidazole-7-carboximidamide,
2-Amino-N-(3-chloro-4-fluorophenyl)-4-fluoro-N-hydroxy-lH- benzo[d]imidazole-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-((2- mo holinoethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide, N-(3-Chlorophenyl)-4,5-difluoro-N-hydroxy-2-(((3- methoxypropyl)amino)methyl)-lH-benzo[d]imidazole-7- carboximidamide,
N-(3-Chlorophenyl)-2-(((cyclopropylmethyl)amino)methyl)-4,5-difluoro-N- hydroxy-lH-benzo[cf]imidazole-7-carboximidamide,
N-(3-Chlorophenyl)-2-((dimethylamino)methyl)-4,5-difluoro-N-hydroxy-lH- benzo[cf|imidazole-7-carboximidamide
N-(3-Chlorophenyl)-4,5-difluoro-N-hydroxy-2-((isopropylamino)methyl)-lH- benzo[cf|imidazole-7-carboximidamide,
N-(3-Chlorophenyl)-2-((ethylamino)methyl)-4,5-difluoro-N-hydroxy-lH- benzo[cf|imidazole-7-carboximidamide,
N-(3-Chlorophenyl)-4,5-difluoro-N-hydroxy-2-(hydroxymethyl)-lH- benzo[cf|imidazole-7-carboximidamide,
N-(3-Chlorophenyl)-4,5-difluoro-N-hydroxy-2-((methylamino)methyl)-lH- benzo[cf|imidazole-7-carboximidamide,
2-(Aminomethyl)-N-(3-chlorophenyl)-4,5-difluoro-N-hydroxy-lH- benzo[cf|imidazole-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-morpholino-lH-benzo- [d]imidazole-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-4-fluoro-N-hydroxy-2-((2-
(methylsulfonyl)ethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-CWoro-4-fluorophenyl)-4-fluoro-N-hydroxy-2-((2- mo holinoethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-((2-
(methylsulfonyl)ethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-((2-(4,4-difluoropiperidin-l-yl)ethyl)amino)-4,5- difluoro-N'-hydroxy-lH-benzo[d]imidazole-7-carboximidamide, N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-((l-morpholinopropan- 2-yl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-(methylamino)-lH- benzo[d]imidazole-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5-difluoro- N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-((2- methoxyethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-((2-(pyrrolidin-l- yl)ethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-4,5-difluoro-N- hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-N- hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-Chlorophenyl)-4,5-difluoro-N-hydroxy-2-(l-methylpiperidin-3-yl)-lH- benzo[d]imidazole-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-6,7-difluoro-N-hydroxy-2-(((3- methoxypropyl)amino)methyl)-lH-benzo[d]imidazole-4- carboximidamide,
N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-(hydroxymethyl)-lH- benzo[d]imidazole-7-carboximidamide,
2-(Aminomethyl)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-lH- benzo[d]imidazole-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-((methylamino)methyl)- lH-benzo[d]imidazole-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-(((cyclopropylmethyl)amino)methyl)-4,5- difluoro-N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide, N-(3-Chloro-4-fluorophenyl)-2-((ethylamino)methyl)-6,7-difluoro-N-hydroxy- lH-benzo[d]imidazole-4-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-6,7-difluoro-N-hydroxy-2-
((isopropylamino)methyl)-lH-benzo[d]imidazole-4-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-((dimethylamino)methyl)-6,7-difluoro-N- hydroxy-lH-benzo[d]imidazole-4-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N- hydroxy-lH-benzo[d]imidazole-4-carboximidamide,
N-(3-Bromo-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N- hydroxy-lH-benzo[d]imidazole-4-carboximidamide,
N-(3-Bromophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N-hydroxy-lH- benzo[d]imidazole-4-carboximidamide,
N-(3-CUorophenyl)-2-(2-(dimethylamino)ethyl)-6,7-difluoro-N'-hydroxy-lH- benzo[d]imidazole-4-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-6,7-difluoro-N-hydroxy-2-(2-(methylamino)ethyl)- lH-benzo[d]imidazole-4-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-(2-(diethylamino)ethyl)-4,5-difluoro-N-hydroxy- lH-benzo[d]imidazole-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(5-Chloro-2-fluorophenyl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(5-Bromo-2,4-difluorophenyl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(5-Chloro-2,4-difluorophenyl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide, N-(3,5-Dichloro-4-fluorophenyl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-Chloro-2,4-difluorophenyl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-Cyclopropyl-4-fluorophenyl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-Hydroxy-N-(4-(trifluoromethoxy)phenyl)-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(Benzofuran-4-yl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(Benzofuran-6-yl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(Benzofuran-7-yl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(benzofuran-5-yl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(5-Bromo-2-fluorophenyl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-Bromo-5-fluorophenyl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-Hydroxy-N-(3-(trifluoromethyl)phenyl)-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(2,2-Difluorobenzo[d][l,3]dioxol-5-yl)-N-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-Fluoro-5-(trifluoromethyl)phenyl)-N-hydroxy-lH-imidazo[4,5-b]pyridine- 7-carboximidamide,
N-(2,5-Dichlorophenyl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(6-Fluoro-[l,l'-biphenyl]-3-yl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide, N-(3-(But-l-yn-l-yl)-4-fluorophenyl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-(Cyclopropylethynyl)-4-fluorophenyl)-N-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-Bromophenyl)-N-hydroxy-lH-imidazo[4,5- )]pyridine-7-carboximidamide,
N-(3-Bromo-4-fluorophenyl)-N-hydroxy-lH-imidazo[4,5- )]pyridine-7- carboximidamide,
N-(3-Chlorophenyl)-N-hydroxy-lH-imidazo[4,5- )]pyridine-7-carboximidamide,
N-(4-Fluoro-3-(trifluoromethyl)phenyl)-N-hydroxy-lH-imidazo[4,5- )]pyridine- 7-carboximidamide,
N-(4-Fluoro-3-(prop-l-yn-l-yl)phenyl)-N-hydroxy-lH-imidazo[4,5- )]pyridine- 7-carboximidamide,
N-(3-Bromo-4-chlorophenyl)-N-hydroxy-lH-imidazo[4,5- )]pyridine-7- carboximidamide,
N-(3,4-Dichlorophenyl)-N-hydroxy-lH-imidazo[4,5- )]pyridine-7- carboximidamide,
N-(4-Chlorophenyl)-N-hydroxy-lH-imidazo[4,5- )]pyridine-7-carboximidamide,
N-(4-Bromophenyl)-N-hydroxy-lH-imidazo[4,5- )]pyridine-7-carboximidamide,
N-(4-Fluorophenyl)-N-hydroxy-lH-imidazo[4,5- )]pyridine-7-carboximidamide,
N-(3-Cyano-4-fluorophenyl)-N-hydroxy-lH-imidazo[4,5- )]pyridine-7- carboximidamide,
N-Hydroxy-N-(4-(trifluoromethyl)phenyl)-lH-imidazo[4,5- )]pyridine-7- carboximidamide,
N-Hydroxy-N-(3-methoxyphenyl)-lH-imidazo[4,5- )]pyridine-7- carboximidamide, N-(4-Fluoro-3-isopropylphenyl)-N-hydroxy-lH-imidazo[4,5- )]pyridine-7- carboximidamide,
N-Hydroxy-N-(^-tolyl)-lH-imidazo[4,5- )]pyridine-7-carboximidamide,
N-(3-Ethynylphenyl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-Ethylphenyl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Ethynyl-4-fluorophenyl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-(Difluoromethyl)phenyl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-Hy droxy-N-(3 -(trifluoromethoxy )phenyl)- lH-imidazo [4,5 -b] pyridine-7- carboximidamide,
N-Hydroxy-N-phenyl-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(4-Fluoro-3-(trifluoromethoxy)phenyl)-N-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-Hydroxy-N-(naphthalen-2-yl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloronaphthalen-2-yl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-hydroxy-N-(naphthalen-l -yl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(4-Chloronaphthalen-l-yl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(4-Fluoro-3-methoxyphenyl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-methyl-lH-imidazo[4,5-b]pyridine-7- carboximidamide, N-(3-Chloro-4-fluorophenyl)-2-ethyl-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-cyclopropyl-N-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(methoxymethyl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
4-(3-Chloro-4-fluorophenyl)-3-(2-(hydroxymethyl)-lH-imidazo[4,5-b]pyridin-7- yl)-l,2,4-oxadiazol-5(4H)-one,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(mo holinomethyl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-((dimethylamino)methyl)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-((ethylamino)methyl)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
2-((Benzylamino)methyl)-N-(3-chloro-4-fluorophenyl)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-((isopropylamino)methyl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-(((cyclopropylmethyl)amino)methyl)-N-hydroxy- lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(((2,2,2- trifluoroethyl)amino)methyl)-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-((cyclopropylamino)methyl)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(((3-methoxypropyl)amino)methyl)- lH-imidazo[4,5-b]pyridine-7-carboximidamide, N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(((pyridin-2- ylmethyl)amino)methyl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(((3- methoxypropyl)(methyl)amino)methyl)-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(((2-methoxybenzyl)amino)methyl)- lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(((2-methoxyethyl)amino)methyl)- lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(((2-(pyridin-2- yl)ethyl)amino)methyl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(((pyridin-3- ylmethyl)amino)methyl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-((((tetrahydro-2H-pyran-2- yl)methyl)amino)methyl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-((phenylamino)methyl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-((((tetrahydro-2H-pyran-3- yl)methyl)amino)methyl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(((pyrimidin-2- ylmethyl)amino)methyl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(((3- mo holinopropyl)amino)methyl)-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(((tetrahydro-2H-pyran-4- yl)amino)methyl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(((pyridin-4- ylmethyl)amino)methyl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide, N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(((pyrazin-2- ylmethyl)amino)methyl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-((((tetrahydrofuran-3- yl)methyl)amino)methyl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-(((2-(dimethylamino)ethyl)amino)methyl)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(((2-(pyrimidin-2- yl)ethyl)amino)methyl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(((3-hydroxypropyl)amino)methyl)- lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(pyrrolidin- 1 -ylmethyl)- 1H- imidazo[4,5-Z>]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(piperidin-l-ylmethyl)-lH- imidazo[4,5-Z>]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-((neopentylamino)methyl)-lH- imidazo[4,5-Z>]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-(((2,2-difluoroethyl)amino)methyl)-N-hydroxy- lH-imidazo[4,5- )]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(((3-hydroxy-2,2- dimethylpropyl)amino)methyl)-lH-imidazo[4,5- )]pyridine-7- carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(((thiazol-2-ylmethyl)amino)methyl)- lH-imidazo[4,5- )]pyridine-7-carboximidamide,
N-((7-(N-(3-Chloro-4-fluorophenyl)-N-hydroxycarbamimidoyl)-lH-imidazo[4,5- b]pyridin-2-yl)methyl)acetamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(thiophen-2-yl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide, N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(pyridin-3-yl)-lH-imidazo[4,5- Z>]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(lH-pyrrol-2-yl)-lH-imidazo[4,5- Z>]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(lH-imidazol-2-yl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(lH-pyrazol-5-yl)-lH-imidazo[4,5- Z>]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(4-methyl-lH-imidazol-2-yl)-lH- imidazo[4,5-Z>]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(pyrrolidin-2-yl)-lH-imidazo[4,5- Z>]pyridine-7-carboximidamide,
2-Amino-N-(3-chloro-4-fluorophenyl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-(cyclopropylamino)-N-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(phenylamino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(phenethylamino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-((2,2,2-trifluoroethyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(methylamino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
Isopropyl (7-(N-(3-chloro-4-fluorophenyl)-N -hydroxy carbamimidoyl)-lH- imidazo[4,5-b]pyridin-2-yl)carbamate, Ethyl (7-(N-(3-chloro-4-fluorophenyl)-N -hydroxy carbamimidoyl)-lH- imidazo[4,5-b]pyridin-2-yl)carbamate,
N-(3-Chloro-4-fluorophenyl)-2-((cyclopropylmethyl)amino)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-((3,3-difluorocyclobutyl)amino)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-(ethylamino)-N-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-(cyclobutylamino)-N-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(isopropylamino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-Chlorophenyl)-N-hydroxy-2-(methylamino)-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-N-hydroxy-lH- imidazo[4,5-Z>]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-((2-morpholinoethyl)amino)-lH- imidazo[4,5-Z>]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-(dimethylamino)-N-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
2-(Chloromethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N-hydroxy-3H- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(4-Fluoro-3-(trifluoromethyl)phenyl)-N -hydroxy -2-(hy droxymethyl)-3H- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(l-hydroxyethyl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide, N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(hydroxy(phenyl)methyl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-(cyclopropyl(hydroxy)methyl)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(2-hydroxypropan-2-yl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(2,2,2-trifluoro- 1 -hydroxy ethyl)- 1H- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(hydroxymethyl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-((methylamino)methyl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
2-(Aminomethyl)-N-(3-chloro-4-fluorophenyl)-N-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(phenylsulfonamidomethyl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(methylsulfonamidomethyl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-((pyrimidin-2-ylamino)methyl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(2-hydroxyethyl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-(2-(diethylamino)ethyl)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide, N-(3-Chloro-4-fluorophenyl)-2-(2-((cyclopropylmethyl)(methyl)amino)ethyl)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-(2-((2,2-difluoroethyl)(methyl)amino)ethyl)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(2-(methylamino)ethyl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
2-(2-Aminoethyl)-N-(3-chloro-4-fluorophenyl)-N-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(2-((2-methoxyethyl)amino)ethyl)- lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(2-morpholinoethyl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(2-(piperidin-l-yl)ethyl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3 -Chloro-4-fluorophenyl)-N-hy droxy-2-(2-(py rrolidin- 1 -yl)ethyl)- 1H- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-(2-((2- methoxyethyl)(methyl)amino)ethyl)-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-(2-(dimethylamino)-l -hydroxy ethyl)-N-hy droxy- lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-((isobutylamino)methyl)-lH- imidazo[4,5-Z>]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-3-methyl-3H-imidazo[4,5-b]pyridine-7- carboximidamide,
A^-(3-Chloro-4-fluorophenyl)-^-hydroxy-2-[2-(2-methoxyethylamino)ethyl]-3H- imidazo[4,5-b]pyridine-7-carboximidamide, N-(3-Chloro-4-fluorophenyl)-2-[3-(dimethylamino)propyl]-6,7-difluoro-N- hydroxy-3H-benzimidazole-4-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-7-fluoro-N-hydroxy-2-(3-morpholin-4- ylpropylamino)-3H-benzimidazole-4-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-2-[2-(dimethylamino)ethylamino]-7-fluoro-N- hydroxy-3H-benzimidazole-4-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-[(l -methylpiperidin-2- yl)methylamino]-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-Chloro-4-fluorophenyl)-N-hydroxy-2-[(l -methylpyrrolidin-3-yl)amino]- lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-(2-(ethylamino)ethyl)-N-hydroxy-3H- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-(2-(isopropylamino)ethyl)-3H- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-(2-(isobutylamino)ethyl)-3H- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-(2-(cyclopropylamino)ethyl)-N-hydroxy-3H- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-(2-((cyclopropylmethyl)amino)ethyl)-N-hydroxy- 3H-imidazo[4,5-b]pyridine-7-carboximidamide,
2-(2-(2-amino-4,5-dihydro-lH-imidazol-l-yl)ethyl)-N-(3-chloro-4-fluorophenyl)- N-hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-(2-
(methylsulfonamido)ethyl)-lH-benzo[d]imidazole-7-carboximidamide,
2-(2-aminoethyl)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-lH- benzo[d]imidazole-7-carboximidamide, N-(3-chloro-4-fluorophenyl)-N-hydroxy-2-((2-methoxyethyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide, tert-butyl (2-(7-(N-(3-chloro-4-fluorophenyl)-N-hydroxycarbamimidoyl)-4,5- difluoro-lH-benzo[d]imidazol-2-yl)ethyl)carbamate,
N-(3-chloro-4-fluorophenyl)-2-((2-(4,4-difluoropiperidin-l-yl)ethyl)amino)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((2-(methylamino)ethyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((l-methylazepan-3-yl)amino)- 1H- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(lJ-dioxidothiomorpholino)ethyl)amino)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N-hydroxy-2-((2-((2- methoxyethyl)(methyl)amino)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-((2,2- difluoroethyl)(methyl)amino)ethyl)amino)-N-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((3-mo holinopropyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((2-(piperi din-l-yl)ethyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-cyclohexylethyl)amino)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((2-(tetrahy dro-2H-pyran-4- yl)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide, N-(3-chloro-4-fluorophenyl)-2-((2,2-difluoroethyl)amino)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-(oxetan-3-ylamino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N-hydroxy-2-((tetrahydrofuran-3-yl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((tetrahy dro-2H-pyran-4-yl)amino)- lH-imidazo[4,5-b]pyridine-7-carboximidamide,
3-((7-(N-(3-chloro-4-fluorophenyl)-N-hydroxycarbamimidoyl)-4,5-difluoro-lH- benzo[d]imidazol-2-yl)amino)propanamide),
N-(3-chloro-4-fluorophenyl)-2-((2-((2,2-difluoroethyl)amino)ethyl)amino)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(methyl)amino)ethyl)amino)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(2- methoxyethyl)amino)ethyl)amino)-N-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
2-((2-(azetidin- 1 -yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N -hydroxy- 1H- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N-hydroxy-2-((3-methoxypropyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((2-(2-oxopyrrolidin-l - yl)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N-hydroxy-2-((2-
(mo holinosulfonyl)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(3-fluoropiperidin-l-yl)ethyl)amino)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide, N-(3-bromo-4-fluorophenyl)-N-hydroxy-2-((2-morpholinoethyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chl oro-4-fluorophenyl)-N -hydroxy -2-((2-(methyl(tetr ahy dro-2H-pyran-4- yl)amino)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N-hydroxy-2-((2-
(isopropyl(methyl)amino)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
2-(((l-aminocyclopropyl)methyl)amino)-N-(3-chloro-4-fluorophenyl)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
2-((2-(l-aminocyclopropyl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
2-((2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethyl)amino)-N-(3-chloro-4- fluorophenyl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
2-((2-(7-oxa-4-azaspiro[2.5]octan-4-yl)ethyl)amino)-N-(3-chloro-4- fluorophenyl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
(R)-(3-chloro-4-fluorophenyl)-2-((2-(3-fluoropyrrolidin-l-yl)ethyl)amino)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
(S)-(3-chloro-4-fluorophenyl)-2-((2-(3-fluoropyrrolidin-l-yl)ethyl)amino)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
2-((2-(2-azabicyclo[4.1.0]heptan-2-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)- N-hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
2-((2-(4-azaspiro[2.5]octan-4-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(3-fluoroazetidin-l-yl)ethyl)amino)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide, N-(3-chloro-4-fluorophenyl)-2-((2-(3,3-difluoroazetidin-l-yl)ethyl)amino)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
2-((2-(4-azaspiro[2.4]heptan-4-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((3-(3-fluoropiperidin-l-yl)propyl)amino)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((2-(phenylamino)ethyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N-hydroxy-2-((2-
(methyl(phenyl)amino)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-(((l,l-dioxidotetrahydro-2H-thiopyran-3- yl)methyl)amino)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-ethoxycyclopropyl)amino)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-bromo-4-fluorophenyl)-N-hydroxy-2-(methylamino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
2-(2-(azepan-l-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
2-(2-(azetidin- 1 -yl)ethyl)-N-(3 -chloro-4-fluorophenyl)-N -hydroxy- 1H- imidazo[4,5-b]pyridine-7-carboximidamide,
(R)-N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-(2-(3-hy droxypyrrolidin-1- yl)ethyl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
(S)-N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-(2-(3-hy droxypyrrolidin-1- yl)ethyl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-(2-(4-hydroxypiperidin-l-yl)ethyl)- lH-imidazo[4,5-b]pyridine-7-carboximidamide, N-(3-bromo-4-fluorophenyl)-2-(2-(dimethylamino)ethyl)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chlorophenyl)-2-(2-(dimethylamino)ethyl)-N-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-bromophenyl)-2-(2-(dimethylamino)ethyl)-N-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N-hydroxy-2-(2-(methylsulfonamido)ethyl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-(2-(sulfamoylamino)ethyl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chlorophenyl)-N-hydroxy-2-(2-(pyrrolidin-l-yl)ethyl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-bromophenyl)-N-hydroxy-2-(2-(pyrrolidin-l-yl)ethyl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(2-(7-(N-(3-chloro-4-fluorophenyl)-N-hydroxycarbamimidoyl)-lH- imidazo[4,5-b]pyridin-2-yl)ethyl)acetamide,
N-(3-chlorophenyl)-N -hydroxy -2-(2-(piperidin-l-yl)ethyl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-bromophenyl)-N -hydroxy -2-(2-(piperidin-l-yl)ethyl)-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
Methyl (2-(7-(N-(3-chloro-4-fluorophenyl)-N -hydroxy carbamimidoyl)-lH- imidazo[4,5-b]pyridin-2-yl)ethyl)carbamate,
N-(3-chloro-4-fluorophenyl)-2-(2-((2,4-dimethoxybenzyl)amino)ethyl)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
2-(2-(4-benzylpiperidin-l-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide, 2-(2-(3-azabicyclo[3.3.1]nonan-3-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
2-(2-(3-azabicyclo[3.2.1]octan-3-yl)ethyl)-N-(3-chloro-4-fluorophenyl)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((l-methylpiperi din-3-yl)amino)- 1H- imidazo[4,5-b]pyridine-7-carboximidamide,
(S)-N-(3-chloro-4-fluorophenyl)-N-hydroxy-2-((2-(3-hydroxypyrrolidin-l- yl)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
(S)-N-(3-chloro-4-fluorophenyl)-N-hydroxy-2-(3-hydroxypyrrolidin-l-yl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((l-(2-methoxy ethyl)pyrrolidin-3- yl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chl oro-4-fluorophenyl)-N -hydroxy -2-(((4-methylmo holin-3- yl)methyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N-hydroxy-2-((2-(pyrrolidin-l-yl)ethyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N-hydroxy-2-(((4-
((methylsulfonyl)methyl)tetrahydro-2H-pyran-4-yl)methyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((2-(methylsulfonyl)benzyl)amino)- lH-imidazo[4,5-b]pyridine-7-carboximidamide,
2-((l-acetylpiperidin-3-yl)amino)-N-(3-chloro-4-fluorophenyl)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((ethylamino)methyl)-4-fluoro-N-hydroxy-lH- benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((dimethylamino)methyl)-4-fluoro-N-hydroxy- lH-benzo[d]imidazole-7-carboximidamide, N-(3-chloro-4-fluorophenyl)-4-fluoro-N-hydroxy-2-((isopropylamino)methyl)- lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4-fluoro-N-hydroxy-2-((methylamino)methyl)-lH- benzo[d]imidazole-7-carboximidamide,
2-(aminomethyl)-N-(3-chloro-4-fluorophenyl)-4-fluoro-N-hydroxy-lH- benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N -hydroxy -2-((2-hydroxy-2- methylpropyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-((2- hydroxypropyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
2-((7-(N-(3-chloro-4-fluorophenyl)-N-hydroxycarbamimidoyl)-4,5-difluoro-lH- benzo[d]imidazol-2-yl)amino)acetamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-((2- hydroxyethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N -hydroxy -2-((3- hydroxycyclobutyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N -hydroxy -2-((3-(pyri din-2- ylamino)propyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-((2- sulfamoylethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N -hydroxy -2-((( 1 -methyl- lH-py razol- 5-yl)methyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
2-((2-(lH-pyrazol-l-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro- N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
2-((7-(N-(3-chloro-4-fluorophenyl)-N-hydroxycarbamimidoyl)-4,5-difluoro-lH- benzo[d]imidazol-2-yl)amino)-N,N-dimethylacetamide, N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N -hydroxy -2-(2 -hydroxy -2- methylpropyl)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((4-(dimethylamino)butyl)amino)-4,5-difluoro-N- hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N -hydroxy -2-((piperidin-3- ylmethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((l-methylpiperi din-2-yl)methyl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-bromophenyl)-N -hydroxy -2-((2-morpholinoethyl)amino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-5-fluoro-N-hydroxy-4-methoxy-lH- benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((pyridin-2-ylmethyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
2-((2-(lH-pyrazol-l-yl)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-N-hydroxy- lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N-hydroxy-2-(((l-methyl-lH-pyrazol-3- yl)methyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N-hydroxy-2-((4,4,4-trifluorobutyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((3, 3, 3-trifluoropropyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((2-(2-methoxy ethoxy)ethyl)amino)- lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((3-(cyclopropyl(methyl)amino)propyl)amino)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide, N-(3-chloro-4-fluorophenyl)-2-((3-(cyclopropylamino)propyl)amino)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((3-(cyclopropyl(ethyl)amino)propyl)amino)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(4-fluoropiperidin-l-yl)ethyl)amino)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N-hydroxy-2-((2-(2,2,2- trifluoroethoxy)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-chloro-4-fluorophenyl)-N-hydroxy-2-((3-(2,2,2- trifluoroethoxy)propyl)amino)-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((2-(3-methoxypiperi din-1- yl)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((3-(difluoromethoxy)propyl)amino)-N-hydroxy- lH-imidazo[4,5-b]pyridine-7-carboximidamide,
(R)-N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-(((tetrahy drofuran-2- yl)methyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
(S)-N-(3-chl oro-4-fluorophenyl)-N -hydroxy -2-(((tetrahy drofur an-2- yl)methyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((2-(tetrahy drofur an-2- yl)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-(piperidin-2-ylmethyl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-(l-(dimethylamino)propan-2-yl)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-(2-(methylamino)propyl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide, N-(3-chloro-4-fluorophenyl)-2-(2-(dimethylamino)propyl)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-(pyrrolidin-2-ylmethyl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chlorophenyl)-4,5-difluoro-N-hydroxy-2-((2-(pyrrolidin-l-yl)ethyl)amino)- lH-benzo[d]imidazole-7-carboximidamide,
N-(3-bromophenyl)-4,5-difluoro-N-hydroxy-2-((2-(pyrrolidin-l-yl)ethyl)amino)- lH-benzo[d]imidazole-7-carboximidamide,
N-(3-bromo-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-((2-(pyrrolidin-l- yl)ethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
2-((2-aminoethyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy- lH-benzo[d]imidazole-7-carboximidamide,
N-(2-((7-(N-(3-chloro-4-fluorophenyl)-N -hydroxy carbami mi doyl)-4,5-difluoro- lH-benzo[d]imidazol-2-yl)amino)ethyl)acetamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-((2-
(methylsulfonamido)ethyl)amino)-lH-benzo[d]imidazole-7- carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropanesulfonamido)ethyl)amino)-4,5- difluoro-N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
Methyl (2-((7-(N-(3-chloro-4-fluorophenyl)-N -hydroxy carbamimidoyl)-4,5- difluoro-lH-benzo[d]imidazol-2-yl)amino)ethyl)carbamate,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-((2-
(sulfamoylamino)ethyl)amino)-lH-benzo[d]imidazole-7- carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-((2-
(pheny 1 sulf onami do)ethy l)amino)- lH-benzo [d] imidazol e-7 - carboximidamide, N-(3-chloro-4-fluorophenyl)-2-((2-cyanoethyl)amino)-4,5-difluoro-N -hydroxy- lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(3-ethylureido)ethyl)amino)-4,5-difluoro-N- hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N -hydroxy -2-((pyridin-2- ylmethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N -hydroxy -2-((pyridin-3- ylmethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N -hydroxy -2-((pyridin-3- ylmethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
2-(((lH-imidazol-2-yl)methyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro- N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
2-chloro-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-lH- benzo[d]imidazole-7-carboximidamide,
2-((2-aminobenzyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy- lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)benzyl)amino)-4,5-difluoro- N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-(((l-methyl-lH- imidazol-2-yl)methyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N -hydroxy -2-((pyrimidin-2- ylmethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)-2,2-dimethylpropyl)amino)- 4,5-difluoro-N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)-2-methylpropyl)amino)-4,5- difluoro-N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide, N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)butyl)amino)-4,5-difluoro-N- hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N -hydroxy -2-((2-(l-methylpyrrolidin- 2-yl)ethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N -hydroxy -2-((2-(l-methylpiperidin-2- yl)ethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chl oro-4-fluorophenyl)-4,5-difluoro-N -hydroxy -2-(((4-methylmorpholin-2- yl)methyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chl oro-4-fluorophenyl)-N -hydroxy -2-(((4-methylmorpholin-2- yl)methyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N-hydroxy-2-(((l-methyl-lH-pyrazol-5- yl)methyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
2-((7-(N-(3-chloro-4-fluorophenyl)-N-hydroxycarbamimidoyl)-lH-imidazo[4,5- b]pyridin-2-yl)amino)-N^V-dimethylacetamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-(3-(hy droxymethyl)azeti din-l-yl)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((oxetan-3-ylmethyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N-hydroxy-2-((2-(l-methyl-lH-imidazol-2- yl)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((3-(pyri din-2- ylamino)propyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-(neopentylamino)-lH-imi dazo[4,5- b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-(isobutylamino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide, N-(3-chl oro-4-fluorophenyl)-N -hydroxy -2-(((tetrahy dro-2H-pyran-2- yl)methyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chl oro-4-fluorophenyl)-N -hydroxy -2-(((tetrahy drofuran-3- yl)methyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4-fluoro-N-hydroxy-2-((2-mo holinoethyl)arrlino)- lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -N-methyl-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
2-amino-N-(3-chloro-4-fluorophenyl)-5-fluoro-N-hydroxy-lH- benzo[d]imidazole-7-carboximidamide,
2-amino-N-(3-chlorophenyl)-5-fluoro-N-hydroxy-lH-benzo[d]imidazole-7- carboximidamide,
2-amino-N-(3-bromophenyl)-5-fluoro-N-hydroxy-lH-benzo[d]imidazole-7- carboximidamide,
2-amino-N-(3-bromo-4-fluorophenyl)-5-fluoro-N-hydroxy-lH- benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(14-dioxidothiomo holino)ethyl)arrlino)-4,5- difluoro-N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(diethylamino)ethyl)amino)-4-fluoro-N- hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4-fluoro-N-hydroxy-2-((2-(pyrrolidin-l- yl)ethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-((2- mo holinopropyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((l-(dimethylamino)propan-2-yl)amino)-4,5- difluoro-N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide, N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-5-fluoro-N- hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-5-fluoro-N-hydroxy-2-((2-(pyrrolidin-l- yl)ethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)-2,2-dimethylpropyl)amino)- 4-fluoro-N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-bromo-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4-fluoro-N- hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-bromophenyl)-2-((2-(dimethylamino)ethyl)amino)-4-fluoro-N-hydroxy-lH- benzo[d]imidazole-7-carboximidamide,
N-(3-chlorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4-fluoro-N-hydroxy-lH- benzo[d]imidazole-7-carboximidamide,
N-(3-chlorophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-N- hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-bromophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5-difluoro-N- hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-bromo-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-4,5-difluoro- N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-4-fluoro-N- hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)propyl)amino)-5-fluoro-N- hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
2-((2-(benzyl(methyl)amino)ethyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5- difluoro-N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-(2-((cyclohexylmethyl)(methyl)amino)ethyl)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide, N-(3-chloro-4-fluorophenyl)-N-hydroxy-2-(2-(methyl(neopentyl)amino)ethyl)- lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-(2-(cyclohexyl(methyl)amino)ethyl)-N -hydroxy- lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N -hydroxy -2-((2-(methyl((tetrahydro- 2H-pyran-4-yl)methyl)amino)ethyl)amino)-lH-benzo[d]imidazole-7- carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-((2-
(methylamino)ethyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
2-(2-(benzyl(methyl)amino)ethyl)-N-(3-chloro-4-fluorophenyl)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-((2-ethylbutyl)(methyl)amino)ethyl)amino)- 4,5-difluoro-N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-
((cyclopropylmethyl)(methyl)amino)ethyl)amino)-4,5-difluoro-N- hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-(2-(methyl((tetr ahy dro-2H-pyran-4- yl)methyl)amino)ethyl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
2-(2-(((l,4-dioxan-2-yl)methyl)(methyl)amino)ethyl)-N-(3-chloro-4- fluorophenyl)-N-hydroxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-chl oro-4-fluorophenyl)-N -hydroxy -2-(2-(methyl(2-(tetr ahy dro-2H-pyran-4- yl)ethyl)amino)ethyl)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropylamino)ethyl)amino)-N-hydroxy- lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(ethyl)amino)ethyl)amino)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide, N-(2-((7-(N-(3-chloro-4-fluorophenyl)-N-hydroxycarbamimidoyl)-lH- imidazo[4,5-b]pyridin-2-yl)amino)ethyl)acetamide,
N-(3-chloro-4-fluorophenyl)-N-hydroxy-2-((2-
(methylsulfonamido)ethyl)amino)-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(isopropyl)amino)ethyl)amino)- N-hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropyl(2- hydroxyethyl)amino)ethyl)amino)-N-hydroxy-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
2-((2-aminoethyl)amino)-N-(3-chloro-4-fluorophenyl)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chl oro-4-fluorophenyl)-N -hydroxy -2-(((5-oxopyrrolidin-3- yl)methyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
2-(((lH-pyrazol-5-yl)methyl)amino)-N-(3-chloro-4-fluorophenyl)-N-hydroxy- lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-((7-(N-(3-chloro-4-fluorophenyl)-N-hydroxycarbamimidoyl)-lH- imidazo[4,5-b]pyridin-2-yl)amino)propyl)acetamide,
2-((3-aminopropyl)amino)-N-(3-chloro-4-fluorophenyl)-N-hydroxy-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((2-(sulfamoylamino)ethyl)amino)- lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((2-(phenylsulfonamido)ethyl)amino)- lH-imidazo[4,5-b]pyridine-7-carboximidamide,
Methyl (2-((7-(N-(3-chloro-4-fluorophenyl)-N -hydroxy carbamimidoyl)-lH- imidazo[4,5-b]pyridin-2-yl)amino)ethyl)carbamate,
N-(3-chloro-4-fluorophenyl)-2-((2-(cyclopropanesulfonamido)ethyl)amino)-N- hydroxy-lH-imidazo[4,5-b]pyridine-7-carboximidamide, N-(3-chloro-4-fluorophenyl)-N-hydroxy-2-((2-
((trifluoromethyl)sulfonamido)ethyl)amino)-lH-imidazo[4,5-b]pyridine- 7-carboximidamide,
2-(((lH-imidazol-2-yl)methyl)amino)-N-(3-chloro-4-fluorophenyl)-N-hydroxy- lH-imidazo[4,5-b]pyridine-7-carboximidamide,
2-(((lH-imidazol-5-yl)methyl)amino)-N-(3-chloro-4-fluorophenyl)-N-hydroxy- lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-(((3 -methyl- 1, 2,4-oxadiazol-5- yl)methyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-bromophenyl)-N -hydroxy -2-(methylamino)-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
Methyl (3-((7-(N-(3-chloro-4-fluorophenyl)-N-hydroxycarbamimidoyl)-lH- imidazo[4,5-b]pyridin-2-yl)amino)propyl)carbamate,
N-(3-bromophenyl)-N -hydroxy -2 -methoxy-lH-imidazo[4,5-b]pyridine-7- carboximidamide,
N-(3-bromophenyl)-N-hydroxy-2-((2-(methylsulfonyl)ethyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-bromophenyl)-N -hydroxy -2-((2-(methylsulfonamido)ethyl)amino)-lH- imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-bromophenyl)-N -hydroxy -2-((2-sulfamoylethyl)amino)-lH-imidazo[4,5- b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-(((5 -methyl- 1, 3,4-oxadiazol-2- yl)methyl)amino)-lH-imidazo[4,5-b]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N -hydroxy -2-(((l-methylpiperidin-2- yl)methyl)arnino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chl oro-4-fluorophenyl)-4,5-difluoro-N -hydroxy -2-(((4-methylmorpholin-3- yl)methyl)arnino)-lH-benzo[d]imidazole-7-carboximidamide, N-(3-bromophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-N -hydroxy- lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chlorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-N-hydroxy- lH-benzo[d]imidazole-7-carboximidamide,
N-(3-bromo-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)amino)-4,5-difluoro-N- hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-((3-mo holinopropyl)amino)-lH- benzo[d]imidazole-7-carboxamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N -hydroxy -2-((3-(pyrrolidin-l- yl)propyl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
2-(((3i?)-4-amino-l-methylpyrrolidin-3-yl)amino)-N-(3-chloro-4-fluorophenyl)- 4,5-difluoro-N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)-2^henylethyl)amino)-4,5- difluoro-N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-(((7i?,2i?)-2-(dimethylamino)cyclohexyl)amino)- 4,5-difluoro-N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-(((l-(dimethylamino)cyclopentyl)methyl)amino)- 4,5-difluoro-N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-(((7^,3^-3-(dimethylamino)cyclohexyl)amino)- 4,5-difluoro-N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-(((lS,3R)-3-(dimethylamino)cyclohexyl)amino)- 4,5-difluoro-N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-(((l-(dimethylamino)cyclobutyl)methyl)amino)- 4,5-difluoro-N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N -hydroxy -2-((l -methylpiperi din-4- yl)amino)-lH-benzo[d]imidazole-7-carboximidamide, N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N -hydroxy -2-((l -methylpiperi din-3- yl)amino)-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-(((7^,2^-2-(dimethylamino)cyclohexyl)amino)- 4,5-difluoro-N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
(5)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N -hydroxy -2-(piperidin-3- y 1 amino)- 7H-benzo [d] imidazol e-7 -carboximi damide,
(i?)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(piperidin-3- y 1 amino)- 7H-benzo [d] imidazol e-7 -carboximi damide,
(5 -N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((l-methylpyrrolidin- 3-yl)amino)-lH-benzo[d]imidazole-7-carboxirnidamide,
N-(3-chloro-4-fluorophenyl)-2-((3-(dimethylamino)-2-hydroxypropyl)amino)- 4,5-difluoro-N'-hydroxy-7H-benzo[(i|imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(4-methyl-3- oxopiperazin-l-yl)ethyl)amino)-7H-benzo[cf]imidazole-7- carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-(((l-(dimethylamino)cyclohexyl)methyl)amino)- 4,5-difluoro-N'-hydroxy-7H-benzo[(i]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((l-methylazepan-3- yl)amino)-7H-benzo[cf]imidazole-7-carboximi damide,
(5 -N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(3- hydroxypyrrolidin-l-yl)ethyl)amino)-7H-benzo[cf]imidazole-7- carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((l-(2- methoxyethyl)piperidin-3-yl)amino)-7H-benzo[cf]imidazole-7- carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-((l-(2- methoxyethyl)pyrrolidin-3-yl)amino)-lH-benzo[d]imidazole-7- carboximidamide, N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((l-isopropylpiperidin-3- yl)amino)-7H-benzo[cf|imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(3-methoxyazetidin- l-yl)ethyl)amino)-7H-benzo[(i|imidazole-7-carboximidamide,
(i?)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((l-methylpyrrolidin- 3-yl)amino)-7H-benzo[(i|imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((3i?,4i?)-4-methoxy-l- methylpyrrolidin-3-yl)amino)-7H-benzo[(i|imidazole-7-carboximidamide,
(5 -N-(3-chlorophenyl)-4,5-difluoro-N-hydroxy-2-((l-methylpiperidin-3- yl)amino)-7H-benzo[cf]imidazole-7-carboximidamide,
(7?)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((l-methylpiperidin-3- yl)amino)-7H-benzo[cf]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)cyclopentyl)amino)-4,5- difluoro-N'-hydroxy-7H-benzo[(i|imidazole-7-carboximidamide,
(5 -2-(azepan-3-ylamino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy- 7H-benzo[cf]imidazole-7-carboximidamide,
(7?)-2-(azepan-3-ylamino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy- 7H-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(pyrrolidin-3-ylamino)- 7H-benzo[cf]imidazole-7-carboximidamide,
(7?)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((l-(oxetan-3- yl)piperidin-3-yl)amino)-7H-benzo[(i|imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-(((l,4-dimethylpiperidin-2-yl)methyl)amino)-4,5- difluoro-N'-hydroxy-7H-benzo[(i|imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((mo holin-3- ylmethyl)amino)-7H-benzo[cf]imidazole-7-carboximidamide, N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((3i?,45 -4- hydroxypyrrolidin-3-yl)amino)-lH-benzo[d]imidazole-7- carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-(((li?,5i?)-8-methyl-8- azabicyclo[3.2.1]octan-2-yl)amino)-7H-benzo[cf|imidazole-7- carboximidamide,
(5)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(2-
(trifluoromethyl)pyrrolidin-l-yl)ethyl)amino)-7H-benzo[ci|imidazole-7- carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-2-(((hexahydro-lH-pyrrolizin-7a- yl)methyl)amino)-N-hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-(((3,3-dimethylazetidin-2-yl)methyl)amino)-4,5- difluoro-N'-hydroxy-7H-benzo[(i|imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N -hydroxy -2-((4-(pyrrolidin-l- yl)tetrahydro-2H-pyran-3-yl)amino)-lH-benzo[d]imidazole-7- carboximidamide,
2-(((15',2i?)-2-aminocyclohexyl)amino)-N-(3-chloro-4-fluorophenyl)-4,5- difluoro-N'-hydroxy-7H-benzo[(i|imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-methyl-l,2,3,4- tetrahydroisoquinolin-4-yl)amino)-lH-benzo[cf]imidazole-7- carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-(((35',45 -4-(diethylamino)tetrahydrofuran-3- yl)amino)-4,5-difluoro-N'-hydroxy-lH-benzo[ci|imidazole-7- carboximidamide,
2-((l,4-oxazepan-6-yl)amino)-N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'- hydroxy-lH-benzo[cf]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-((25',67?)-2,6- dimethylmorpholino)ethyl)amino)-N'-hydroxy-7H-imidazo[4,5- )]pyridine-7-carboximidamide, N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((3i?,4i?)-4-methoxy-l- methylpyrrolidin-3-yl)amino)-7H-imidazo[4,5- )]pyridine-7- carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-(((3i?,4i?)-4-(diethylamino)tetrahydrofuran-3- yl)amino)-N'-hydroxy-7H-imidazo[4,5- )]pyridine-7-carboximidamide,
(<S)-N-(3-chloro-4-fluorophenyl)-N -hydroxy -2-((2-(2-(trifluoromethyl)pyrrolidin- l-yl)ethyl)amino)-7H-imidazo[4,5- )]pyridine-7-carboximidamide,
(i?)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-(((4-methylmo holin-3- yl)methyl)amino)-7H-imidazo[4,5- )]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(2,6-dimethylmo holino)propyl)amino)-N'- hydroxy-7H-imidazo[4,5- )]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(2,6-dimethylmo holino)-2- methylpropyl)amino)-N'-hydroxy-7H-imidazo[4,5- )]pyridine-7- carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(2,5-dimethylmo holino)ethyl)amino)-N'- hydroxy-7H-imidazo[4,5- )]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-(((17?,27?)-2-(dimethylamino)cyclopentyl)amino)- 4,5-difluoro-N'-hydroxy-7H-benzo[(i]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)thio)-N'-hydroxy-7H- imidazo[4,5-Z>]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(dimethylamino)ethyl)thio)-4,5-difluoro-N- hydroxy-lH-benzo[d]imidazole-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N'-hydroxy-2-((2-(2-
(hydroxymethyl)piperidin-l-yl)ethyl)amino)-7H-benzo[cf|imidazole-7- carboximidamide,
N-(3-chloro-4-fluorophenyl)-4,5-difluoro-N-hydroxy-2-((2-(2-
(hydroxymethyl)pyrrolidin-l-yl)ethyl)amino)-7H-benzo[cf|imidazole-7- carboximidamide, N-(3-chloro-4-fluorophenyl)-2-((2-(3,3-difluoropyrrolidin-l-yl)ethyl)amino)-N'- hydroxy-7H-imidazo[4,5- )]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-sulfamoylethyl)amino)-7H- imidazo[4,5-Z>]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(methylsulfonyl)ethyl)amino)-7H- imidazo[4,5-Z>]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((pyrimidin-2-ylmethyl)amino)-7H- imidazo[4,5-Z>]pyridine-7-carboximidamide,
(7?)-N-(3-chlorophenyl)-4,5-difluoro-N'-hydroxy-2-((l-(2- methoxyethyl)pyrrolidin-3-yl)amino)-7H-benzo[cf]imidazole-7- carboximidamide,
(7?)-N-(3-bromophenyl)-4,5-difluoro-N'-hydroxy-2-((l-(2- methoxyethyl)pyrrolidin-3-yl)amino)-7H-benzo[cf]imidazole-7- carboximidamide,
(S)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((l-(oxetan-3-yl)piperidin-3- yl)amino)-7H-imidazo[4,5- )]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((l-(2-methoxyethyl)piperidin-3- yl)amino)-7H-imidazo[4,5- )]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((l-cyclopropylpyrrolidin-3-yl)amino)-N- hydroxy-7H-imidazo[4,5- )]pyridine-7-carboximidamide,
(7?)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((l-(oxetan-3-yl)piperidin-3- yl)amino)-7H-imidazo[4,5- )]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((2-(4-methyl-3-oxopiperazin-l- yl)ethyl)amino)-7H-imidazo[4,5- )]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((2-(3,3-difluoropiperidin-l-yl)ethyl)amino)-N'- hydroxy-7H-imidazo[4,5- )]pyridine-7-carboximidamide,
2-((l-acetylpyrrolidin-3-yl)amino)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-7H- imidazo[4,5-Z>]pyridine-7-carboximidamide, N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((l-(methylsulfonyl)pyrrolidin-3- yl)amino)-7H-imidazo[4,5- )]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((3-(methylsulfonyl)propyl)amino)- 7H-imidazo[4,5- )]pyridine-7-carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-(((l,l-dioxidotetrahydrothiophen-3- yl)methyl)amino)-N'-hydroxy-7H-imidazo[4,5- )]pyridine-7- carboximidamide,
N-(3-chloro-4-fluorophenyl)-2-((3-((4-fluorophenyl)sulfonyl)propyl)amino)-N'- hydroxy-7H-imidazo[4,5- )]pyridine-7-carboximidamide, and
(7?)-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-2-((l-(oxetan-3-yl)pyrrolidin-3- yl)amino)-7H-imidazo[4,5- )]pyridine-7-carboximidamide; or a pharmaceutically acceptable salt, isomer, or mixture thereof.
16. A pharmaceutical composition comprising a compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt, isomer, or mixture thereof, and at least one pharmaceutically acceptable vehicle.
17. A method for method of treating a human, who has or is suspected of having a disease or condition responsive or believed to be responsive to the inhibition of IDOl activity, comprising administering to the human a compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt, isomer, or mixture thereof.
18. A method of inhibiting the activity of an IDOl protein by contacting the protein with the compound of any of claims 1-15, or a pharmaceutically acceptable salt, isomer, or mixture thereof.
19. A method of inhibiting growth or a proliferation of cancer cells, comprising administering an effective amount of the compound of any of claims 1-15, or a pharmaceutically acceptable salt, isomer, or mixture thereof.
20. A method of inhibiting immunosuppression in a patient comprising administering to said patient an effective amount of a compound of any one of claims 1-15, or a pharmaceutically acceptable salt, isomer, or mixture thereof.
21. A method of treating cancer, viral infection, depression, a neurodegenerative disorder, trauma, age-related cataracts, organ transplant rej ection, or an autoimmune disease in a patient comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1 -15, or a pharmaceutically acceptable salt, isomer, or mixture thereof.
22. The method of claim 21 further comprising administering to said patient an antiviral agent, a chemotherapeutic, an immunosuppressant, radiation, an anti-tumor vaccine, an antiviral vaccine, cytokine therapy, or a tyrosine kinase inhibitor.
23. The method of claim 21 further comprising administering to said patient an HBV inhibitor or an HIV inhibitor.
24. The compound, a pharmaceutically acceptable salt, isomer, or a mixture thereof of any of claims 1-15 for use in therapy.
25. The compound, a pharmaceutically acceptable salt, isomer, or a mixture thereof of any of claims 1-15 for use in a method of treating cancer, viral infection, depression, a neurodegenerative disorder, trauma, age-related cataracts, organ transplant rej ection, or an autoimmune disease.
26. Use of the compound, a pharmaceutically acceptable salt, isomer, or a mixture thereof of any of claims 1 -15 for the manufacture of a medicament for treatment of cancer, viral infection, depression, a neurodegenerative disorder, trauma, age-related cataracts, organ transplant rejection, or an autoimmune disease.
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