NZ755866B2 - Anti-fibrotic compounds - Google Patents

Anti-fibrotic compounds

Info

Publication number
NZ755866B2
NZ755866B2 NZ755866A NZ75586618A NZ755866B2 NZ 755866 B2 NZ755866 B2 NZ 755866B2 NZ 755866 A NZ755866 A NZ 755866A NZ 75586618 A NZ75586618 A NZ 75586618A NZ 755866 B2 NZ755866 B2 NZ 755866B2
Authority
NZ
New Zealand
Prior art keywords
phenyl
methoxy
acrylamido
benzoic acid
propynyloxy
Prior art date
Application number
NZ755866A
Other versions
NZ755866A (en
Inventor
Thomas Miller
Nikolaos Papaioannou
Original Assignee
Certa Therapeutics Pty Ltd
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
Application filed by Certa Therapeutics Pty Ltd filed Critical Certa Therapeutics Pty Ltd
Priority claimed from PCT/US2018/016272 external-priority patent/WO2018144620A1/en
Publication of NZ755866A publication Critical patent/NZ755866A/en
Publication of NZ755866B2 publication Critical patent/NZ755866B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
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    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
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Abstract

Provided herein are anti-fibrotic compounds, in particular those of Formula (I), that inhibit the TGF-beta signaling pathway. Also provided are pharmaceutical compositions comprising the anti-fibrotic compounds, and methods of treating diseases or conditions associated with fibrosis, inflammation, and benign or malignant neoplastic diseases in a subject by administering a compound or composition described herein. (Formula (I)) nd benign or malignant neoplastic diseases in a subject by administering a compound or composition described herein. (Formula (I))

Description

WO 44620 ANTI-FIBROTIC COMPOUNDS Cross-Reference to Related Applications The present application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application Serial No. 62/454,358, filed February 3, 2017. The entirety of which is incorporated herein by reference.
Field of the Invention The t ion relates generally to compounds that inhibit fibrosis, and use of the compounds in the treatment of medical disorders, in particular conditions associated with tissue fibrosis.
Background of the Invention Tranilast (n-[3,4-dimethoxycinnamoyl] anthranilic acid) is an anti-fibrotic agent ed in Japan for the treatment of fibrotic skin disorders such as s and scleroderma.
Although the precise mechanisms and mode of action are not completely understood, its ability to inhibit ERK phosphorylation, a major intermediate in the TGF-P signalling y, may underlie its antifibrotic effects, with known actions of tranilast ing the inhibition of TGFP-induced extracellular matrix production in a range of cell types. Tranilast has also been shown to attenuate TGF-P-induced collagen synthesis in cardiac lasts using an mental model of diabetic cardiac disease.
Fibrosis is a common response to a range of tissue s that may lead to organ dysfunction. Diseases that are characterized by such ogical fibrosis include c cirrhosis, pulmonary interstitial fibrosis, glomerulonephritis, heart failure (ischaemic and nonischaemic ), diabetic nephropathy, scleroderma, ive scar tissue post surgery or device insertion, progressive kidney disease, glomerulonephritis, hypertension, heart failure due to ischaemic heart disease, valvular heart disease or hypertensive heart disease and hypertrophic scars. In addition, the elaboration of pathological matrix also has a role in fibroproliferative tumor progression and metastasis.
Diabetic subjects have a two- to five-fold increase risk of developing heart failure. In addition to ischaemic heart disease, heart failure in diabetes is also associated with a cardiomyopathy, independent of coronary artery e. This so-called "diabetic cardiomyopathy" is characterised histologically by myocardial fibrosis with reduced myocardial elasticity, impaired contractility and overt cardiac dysfunction. Accordingly, strategies that reduce the pathological accumulation of extracellular matrix have been advocated as potential therapies for the treatment and prevention of heart failure in both diabetic and nondiabetic states.
Current treatment of c heart failure focuses on the modulation of the neurohormonal activation that typically develops in response to the evolving onal abnormalities. However, despite such therapy, frequently used in combination, c dysfunction continues to progress in the majority of patients. Given the importance of pathological is in adverse cardiac remodelling, a potential role of antifibrotic agents has been suggested. Studies conducted over more than a decade have consistently indicated a major role for the prosclerotic growth factor, orming growth factor-P (TGF-P) in organ fibrosis and dysfunction, such that blockade of its expression and action represent an ant eutic target. ast has also been shown to reduce inflammation in allergic diseases, such as allergic rhinitis and bronchial asthma, etc., and have anti-proliferative activity.
However, it has recently been shown that genetic factors in certain patients, specifically a Gilbert’s syndrome UGT1A1 t, confers susceptibility to tranilast-induced hyperbilirubinemia. Such hyperbilirubinemia may be ated with tranilast itself or the formation, in vivo, of the following tranilast metabolite, An ongoing need exists to identify and provide drugs with potential anti-fibrotic, anti­ inflammatory, and anti-proliferative or anti-neoplastic activity for the ent or prevention of diseases associated with fibrosis, diseases characterized by inflammation and neoplastic disease (both benign and malignant), and as atives/adjuncts to tranilast.
Summary of the Invention In one aspect, provided are compounds of Formula I: Z-r3 <1 (R6)m r2-y> or pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, es, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs thereof, wherein: Tis AYK, X is O, NR10, -NR10C(O)-, or a bond; Y is O, NR10, -C(0)NR10 or a bond; Z is O, NR10, or a bond; R and R are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, arylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R and R1 2 are each optionally substituted with 1-3 independent substituents R ;o or R and R together with the atoms to which they are attached form a heterocyclyl ring;1 2 R is en, heteroalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl,o heteroarylalkyl, heterocyclyl, or cyclylalkyl, wherein R is optionally substituted with 1-3a independent tuents R ;o R4 and R5 are hydrogen; each occurrence of R6 is, independently, halogen, cyano, alkyl, l, l, haloalkyl, hydroxyl, alkoxy, aryl, heteroaryl, heterocyclyl, NRaRb, or -S(0)2RC; G is C(0)R7 or hydrogen; R7is OH or NHR9; m is 0, 1, or 2; each occurrence of R is, independently, alkyl, alkynyl, hydroxyl, alkoxy, carboxyl, oxo, o aryl, heteroaryl, heterocyclyl, -NRaRb, -S(0)2RC, or -C02Rd; R9is heteroaryl, heterocyclyl, or -S(0)2RC, n R9is optionally substituted with 1-3 independent substituents R ;o R is hydrogen or alkyl optionally substituted with 1-3 independent substituents R ; and10 8 each ence of Ra, Rb, Rc, and Rd is, independently, hydrogen, acyl, alkyl, l, alkynyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, heterocyclyl, i-6 alkyl, C(0)Ci_6 alkyl, or Ra and Rb together with the atoms to which they are attached form a heterocyclyl ring; provided that when G is hydrogen, then m is not 0; provided that when G is C(0)R7, R7 is OH, and -Z-R3 is H, then at least one of -X-R1 and-Y-R is-O-heterocyclyl or heterocyclyl, or R and R together with the atoms to which they are attached form a heterocyclyl ring; provided that when-X-R is H, then neither-Y-R nor-Z-R are hydrogen;1 2 3 provided that when-Y-R is H, then neither-X-R nor-Z-R are hydrogen; and2 13 ed that when-Z-R is H, then neither-X-R nor-Y-R are hydrogen.
Exemplary compounds of Formula I include, but are not d to: (E)-N-(2-fluorophenyl)(3-methoxy(propyn-1 -yloxy)phenyl)acrylamide (1); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(5-methyl-lH-l,2,4-triazol yl)phenyl)acrylamide (2); (E)-N-(2-chlorophenyl)(3-methoxy(propyn-l-yloxy)phenyl)acrylamide (3); (E)-N-(2-bromophenyl)(3-methoxy(propyn-l-yloxy)phenyl)acrylamide (4); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(o-tolyl)acrylamide (5); (E)-N-(2-cyanophenyl)(3-methoxy(propyn-l-yloxy)phenyl)acrylamide (6); (E)-N-(3,4-dichlorophenyl)(3-methoxy(propyn-l-yloxy)phenyl)acrylamide (7); (E)-N-(2-(2H-tetrazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (16); (E)-N-(2-(l,2,4-oxadiazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (17); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(5-methyl-l,2,4-oxadiazol yl)phenyl)-acrylamide (18); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(5-oxo-4,5-dihydro-1,2,4- zol-3 -yl)phenyl)acrylamide (19); (E)-N-(2-(l,2,4-oxadiazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (20); (E)-N-(2-(l,3,4-oxadiazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (21); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(l-methyl-lH-pyrazol yl)phenyl)-acrylamide (22); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(3-methyl-lH-l,2,4-triazol-lyl )phenyl)acryl-amide (23); (E)-N-(2-(lH-pyrazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (24); (E)-N-(2-(lH-imidazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (25); (3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(l-methyl-lH-imidazol yl)phenyl)acrylamide (26); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N- (methylsulfonyl)benzamide (27); (3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(3-methyl-l,2,4-oxadiazol yl)phenyl)acryl-amide (28); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(5-methyl-l,3,4-oxadiazol yl)phenyl)-acrylamide (29); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2H-tetrazol yl)benzamide (31); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(l-methylpiperidin yl)benzamide (36); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(oxetan yl)benzamide (38); (3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(pyridin yl)benzamide (44); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(l-methyl-lH-pyrazol- 4-yl)benzamide (47); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(l-methyl-lH-pyrazol- 3-yl)benzamide (48); (3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(piperidin yl)benzamide (49); (E)(3-(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)acrylamido)benzoic acid (51); (E)-N-(3-cyanophenyl)[2-[2-(dimethylamino)ethoxy]methoxypropynoxyphenyl ]propenamide (76); ((E)-N-(2-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxy(propyn-lyloxy )phenyl)acrylamide (77); (E)(3-(2-(2-(dimethylamino)ethoxy)methoxy(propyn-lyloxy l)acrylamido)-benzoic acid (78); (E)-N-(2-cyanophenyl)[3-methoxy(l-methylazetidinyl)oxypropynoxyphenyl ]propenamide (79); 2-[[(E)(3-methoxypropynoxypyrrolidinyloxyphenyl)prop enoyl]amino]benzoic acid (80); (E)-N-(2-cyanophenyl)[3-methoxy(l-methylpyrrolidinyl)oxypropynoxyphenyl ]propenamide (81); (E)-N-(2-cyanophenyl)(3-methoxypropynoxypyrrolidinyloxy-phenyl)prop- 2-enamide (82); 2-[[(E)[3-methoxy(4-piperidyloxy)propynoxy-phenyl]prop enoyl]amino]benzoic acid (83); 2-[[(E)[3-methoxy(2-morpholinoethoxy)propynoxy-phenyl]prop enoyl]amino]benzoic acid (84); (E)-N-(2-cyanophenyl)[3-methoxy(2-morpholinoethoxy)propynoxyphenyl ]propenamide (85); 2-[[(E)[2-[3-(dimethylamino)propoxy]methoxypropynoxy-phenyl]prop enoyl]amino]benzoic acid (86); (E)-N-(2-cyanophenyl)[2-[3-(dimethylamino)propoxy]methoxypropynoxyphenyl ]propenamide (87); (E)-N-(2-cyanophenyl)[3-methoxy(4-piperidyloxy)propynoxy-phenyl]prop enamide (88); (E)-N-(2-cyanophenyl)[3-methoxy[(l-methylpiperidyl)oxy]propynoxyphenyl ]propenamide (89); 2-[[(E)[4-(cyclopropylmethoxy)[2-(dimethylamino)ethoxy]methoxyphenyl ]propenoyl]amino]benzoic acid (90); (E)-N-(3-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide (91); (E)-N-(2-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide (92); (3-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide (93); (E)-N-(2-cyanophenyl)[2-[2-(dimethylamino)ethoxy]methoxy-phenyl]prop enamide (94); (E)(3-(3,4-dimethoxy(propyn-l-yloxy)phenyl)acrylamido)benzoic acid (95); (E)(3-(3,4-dimethoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (96); (E)(3-(3-methoxy(4-methylpiperazin-l-yl)phenyl)acrylamido)benzoic acid (97); (E)(3-(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)acrylamido)benzoic acid (98); (E)(3-(3-methoxy( 1-methyl-1,2,3,6-tetrahydropyridin yl)phenyl)acrylamido)benzoic acid (99); (E)(3-(4-methoxymorpholinophenyl)acrylamido)benzoic acid (101); (3-(3-methoxymorpholinophenyl)acrylamido)benzoic acid (103); (E)(3-(4-methoxy( 1-methyl-1,2,3,6-tetrahydropyridin yl)phenyl)acrylamido)benzoic acid (104); 2-[[(E)(4-methyl-2,3-dihydro-l,4-benzoxazinyl)propenoyl]amino]benzoic acid (107); (E)-N-(2-(l,2,4-oxadiazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (108); (E)(3-(4-methyloxo-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (109); (E)(3-(4-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (HO); (E)(3-(3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (ill); (E)(3-(4-methyloxo-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (112); (E)(3-ethyl(propyn-l-yloxy)phenyl)-N-(2-(3-methyl-lH-l,2,4-triazol-lyl )phenyl)-acrylamide (114); (E)(3-(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)acrylamido)benzoic acid (116); (E)chloro(3-(2-(2-(dimethylamino)ethoxy)-3,4- dimethoxyphenyl)acrylamido)benzoic acid (117); (E)-N-(4-fluorophenyl)(3-methoxy(l,2,3,6-tetrahydropyridin yl)phenyl)acrylamide (120); yanophenyl)(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)cyclopropane carboxamide (121); 2-(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)-N-(4-fluorophenyl)cyclopropane- 1-carboxamide (122); (E)(3-ethyl(propyn-l-yloxy)phenyl)-N-(2-fluorophenyl)acrylamide (123); (E)-A/-(4-cyanophcnyl)(3-cthyl(propyn-l )phcnyl)acrylamidc (124); (E)(3-ethyl(propyn-l-yloxy)phenyl)-N-(4-fluorophenyl)acrylamide (125); (E)(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)-N-(2- phenyl)acrylamide (127); (E)(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)-N-(4- fluorophenyl)acrylamide (128); (E)-N-(4-cyanophenyl)(2-(2-(dimethylamino)ethoxy)-3,4- dimethoxyphenyl)acrylamide (129); (E)(3-(4-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (130); (E)-N-(4-cyanophenyl)(3-methoxy((l-methylpyrrolidin yl)oxy)phenyl)acrylamide (131); (E)-N-(4-fluorophenyl)(3-methoxy((l-methylpyrrolidin yl)oxy)phenyl)acrylamide (132); N-(4-fluorophenyl)(3-methoxy(propyn-lyloxy )phenyl)cyclopropanecarboxamide (133); N-(4-cyanophenyl)(3-methoxy(propyn-lyloxy )phenyl)cyclopropanecarboxamide (135); N-(4-fluorophenyl)(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)cyclopropane- 1-carboxamide (136); yanophenyl)(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)cyclopropane- 1-carboxamide (137); luorophenyl)(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)cyclopropane carboxamide (138); (E)-N-(4-cyanophenyl)(3-methoxy( 1,2,3,6-tetrahydropyridin yl)phenyl)acrylamide (139); (E)(3-methoxy( 1,2,3,6-tetrahydropyridinyl)phenyl)-N-(2-(3-methyl-lH-1,2,4- triazol-1 - yl)phenyl) acrylamide (140); (E)-N-(2-fluorophenyl)(3-methoxy(l,2,3,6-tetrahydropyridin yl)phenyl)acrylamide (141); N-(4-fluorophenyl)(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)cyclopropane carboxamide (143); 2-(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)-N-(2-(3-methyl-lH-1,2,4- triazol-1 -yl)phenyl)cyclopropanecarboxamide (144); N-(2-fluorophenyl)(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)cyclopropane carboxamide (145); (E)-N-(3-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide (147); hlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropane-lcarboxamide (148); N-(4-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol yl)methoxy)phenyl)cyclopropanecarboxamide (149); (E)-N-(3-chlorophenyl)(4-methoxymorpholinophenyl)acrylamide (151); (E)-N-(2-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide (152); (E)-N-(4-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide (153); N-(4-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropane-lcarboxamide (154); N-(2-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropane-lcarboxamide (155); N-(3-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol hoxy)phenyl)cyclopropanecarboxamide (156); N-(2-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol yl)methoxy)phenyl)cyclopropanecarboxamide (157); 2-(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)-N-(3- (methylsulfonyl)phenyl) cyclopropanecarboxamide (158); (E)-N-(2-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol yl)methoxy)phenyl)acrylamide (159); (E)-N-(3-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol yl)methoxy)phenyl)acrylamide (160); and pharmaceutically acceptable salts thereof.
In another aspect, provided are the following compounds: (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-phenylacrylamide (8); methyl (E)-l-(3-(3-methoxy(propyn-l-yloxy)phenyl)acryloyl)-l,2,3,4- tetrahydroquinolinecarboxylate (9) (E)-l-(3,4-dihydroquinolin-l(2H)-yl)(3-methoxy(propyn-l-yloxy)phenyl)prop- -one (10); (E)-l-(3,4-dihydroquinoxalin-l(2H)-yl)(3-methoxy(propyn-lyloxy )phenyl)propen-1 -one (11); (E)-l-(2,3-dihydro-4H-benzo[b][l,4]oxazinyl)(3-methoxy(propyn-lyloxy )phenyl)propen-1 -one (12); (E)-N-((trans)aminocyclohexyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (13); (E)-l-(4-hydroxy-3,4-dihydroquinolin-l(2H)-yl)(3-methoxy(propyn-lyloxy )phenyl)propen-1 -one (14); (E)-l-(3-hydroxy-lH-indazol-l-yl)(3-methoxy(propyn-l-yloxy)phenyl)prop en-l-one (15); (E)-N-(2-(dimethylamino)ethyl)(3-(3-methoxy(propyn lyloxy) phenyl) acrylamido) benzamide (30); (E)-N-(3-(dimethylamino)propyl)(3-(3-methoxy(propyn-lyloxy )phenyl)acrylamido) benzamide (32); (3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2- methoxyethyl)benzamide (33); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2-(4-methylpiperazinl-yl )ethyl)benzamide (34); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2-morpholino ethyl)benzamide (35); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-((l-methylpiperidin yl)methyl)benzamide (37); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-((tetrahydrofuran yl)methyl)benzamide (39); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-((l-methyl-lH- imidazolyl)methyl)benzamide (40); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(pyridin yl)benzamide (41); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2-(pyridin yl)ethyl)benzamide (42); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(pyridin ylmethyl)benzamide (43); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(pyridin ylmethyl)benzamide (45); (3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2-(pyridin yl)ethyl)benzamide (46); (E)(3-(3-methoxy(piperidinylmethoxy)phenyl)acrylamido)benzoic acid (50); (E)(3-(4-((3,5-dimethylisoxazolyl)methoxy)methoxyphenyl)acrylamido)benzoic acid (52); (E)(3-(3-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (53); (E)(3-(3-methoxy(oxetanylmethoxy)phenyl)acrylamido)benzoic acid (54); (E)(3-(3-methoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (55); (E)(3-(3-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (56); (E)(3-(3-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (57); (E)(3-(3-methoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (58); (E)(3-(3-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (59); (3-(3-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (60); (E)(3-(4-methoxy(2-methoxyethoxy)phenyl)acrylamido)benzoic acid (61); (E)(3-(4-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (62); (E)(3-(4-methoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (63); (E)(3-(4-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (64); (E)(3-(4-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (65); (E)(3-(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (66); (E)(3-(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (67); (E)(3-(3-methoxy((4-methylpiperazin-l-yl)methyl)phenyl)acrylamido)benzoic acid (68); (E)(3-(3-methoxy(morpholinomethyl)phenyl)acrylamido)benzoic acid (69); (E)(3-(4-methoxy(((l-methylpiperidinyl)oxy)methyl)phenyl)acrylamido)benzoic acid (70) (E)(3-(4-methoxy((propyn-l-yloxy)methyl)phenyl)acrylamido)benzoic acid (71); (3-(3-methoxy((propyn-l-yloxy)methyl)phenyl)acrylamido)benzoic acid (72); (E)(3-(4-methoxy(methoxymethyl)phenyl)acrylamido)benzoic acid (73); (E)(3-(4-methoxy((propyn-l-ylamino)methyl)phenyl)acrylamido)benzoic acid (74); (E)(3-(3-methoxy((propyn-l-ylamino)methyl)phenyl)acrylamido)benzoic acid (75); (E)(3-(4-ethylmethoxyphenyl)acrylamido)benzoic acid (100); )[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid (102); (E)(3-(3-ethylmethoxyphenyl)acrylamido)benzoic acid (105); (E)(3-(3-(cyclopropylmethyl)methoxyphenyl)acrylamido)benzoic acid (106); (E)-l-(2H-benzo[b][l,4]oxazin-4(3H)-yl)(3-ethyl(propyn-l-yloxy)phenyl)prop- 2-en-l-one (113); (E)-1 -(2H-benzo[b] [ 1,4]oxazin-4(3H)-yl)-3 -(2-(2-(dimethylamino)ethoxy)-3,4- dimethoxyphenyl)-propen-1 -one (115); (E)-l-(2H-benzo[b][l,4]oxazin-4(3H)-yl)(3-methoxy((l-methylpyrrolidin yl)oxy)phenyl)propen-1 -one (118); (2H-benzo[b] [ 1,4]oxazin-4(3H)-yl)(2-(3-methoxy(propyn-1 -yloxy) phenyl) cyclopropyl) one (119); (3-ethyl(propyn-l-yloxy)phenyl)-l-(3-hydroxy-lH-indazol-l-yl)propen-l- one (126); (3-hydroxy- IH-indazol- l-yl)(2-(3-methoxy(propyn- l-yloxy)phenyl)cyclopropyl) methanone (134); (E)-l-(3-hydroxy-lH-indazol-l-yl)(3-methoxy( 1,2,3,6-tetrahydropyridin yl)phenyl)propen-l-one (142); (3-hydroxy-lH-indazol-l-yl)(2-(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl) cyclopropyl)methanone (146); (E)(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)-N-(pyridin yl)acrylamide (150); and ceutically acceptable salts thereof.
In another aspect, provided are pharmaceutical compositions comprising any nd of the present disclosure (e.g., compound of Formula I, 2-[[(E)[4-(cyclopropylmethyl) methoxyphenyl]propenoyl]amino]benzoic acid)) or a pharmaceutically acceptable salt f, and a pharmaceutically acceptable excipient.
In another aspect, provided are methods of disease or condition associated with fibrosis in a t in need thereof, the method comprising administering any compound of the present disclosure {e.g., compound of Formula I, 2-[[(E)[4-(cyclopropylmethyl) methoxyphenyl]propenoyl]amino]benzoic acid)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any compound of the present disclosure (e.g.. compound of Formula I, 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]prop enoyl]amino]benzoic acid)) or pharmaceutically acceptable salt thereof, to the subject. In certain embodiments, the e or ion ated with fibrosis is selected from the group ting of fibrotic skin disorders, lung disease, heart disease, kidney disease, and cirrhosis of the liver. In certain embodiments, the the disease or condition associated with fibrosis is kidney disease. In certain embodiments, the kidney disease is progressive kidney disease, glomerulonephritis, diabetic kidney disease, diabetic nephropathy, ic lupus, primary glomerulonephritis, membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental ulosclerosis, secondary glomerulonephritis, or ischemic nephropathy. In certain embodiments, the disease or ion associated with fibrosis is focal segmental ulosclerosis.
In another aspect, ed are kits comprising any compound of the present disclosure (e.g., compound of Formula I, 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]prop enoyl]amino]benzoic acid)) or a pharmaceutically acceptable salt f, or a pharmaceutical composition comprising any compound of the present disclosure (e.g., compound of Formula I, 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid)) or pharmaceutically acceptable salt thereof. In certain embodiments, the kits further comprise instructions for administration (e.g., human stration).
The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, Figures, and Claims.
Brief Description of the gs Figure 1 shows a pharmacokinetic profile plot (plasma concentration vs. time) after administration of 2 mg/kg, 20 mg/kg, 75 mg/kg, and 350 mg/kg of 116 to male SD rats.
Figure 2 shows shows a pharmacokinetic profile plot (plasma concentration vs. time) after daily administration (5 days) of 75 mg/kg, and 350 mg/kg of 116 to male SD rats.
Figure 3 shows a pharmacokinetic profile plot (% IC50 coverage vs. time) after administration of 2 mg/kg, 20 mg/kg, 75 mg/kg, and 350 mg/kg of 116 to male SD rats in comparison to known values of a known compound, (E)(3-(3-methoxy(propyn-lyloxy )phenyl)acrylamido)benzoic acid.
Figure 4 shows a cokinetic profile plot (plasma tration vs. time) after administration of 2 mg/kg, 20 mg/kg, 75 mg/kg, and 350 mg/kg of 107 to male SD rats.
Figure 5 shows shows a pharmacokinetic profile plot a concentration vs. time) after daily administration (5 days) of 75 mg/kg, and 350 mg/kg of 107 to male SD rats.
Figure 6 shows a pharmacokinetic profile plot (% IC50 coverage vs. time) after administration of 2 mg/kg, 20 mg/kg, 75 mg/kg, and 350 mg/kg of 107 to male SD rats in ison to known values of a known compound, (E)(3-(3-methoxy(propyn-lyloxy )phenyl)acrylamido)benzoic acid.
Figure 7 shows a pharmacokinetic e plot (plasma concentration vs. time) after administration of 2 mg/kg, 20 mg/kg, 75 mg/kg, and 350 mg/kg of 102 to male SD rats.
Figure 8 shows shows a pharmacokinetic profile plot (plasma concentration vs. time) after daily administration (5 days) of 75 mg/kg, and 350 mg/kg of 102 to male SD rats.
Figure 9 shows a pharmacokinetic profile plot (% IC50 coverage vs. time) after administration of 2 mg/kg, 20 mg/kg, 75 mg/kg, and 350 mg/kg of 102 to male SD rats in comparison to known values of a known compound, (E)(3-(3-methoxy(propyn-lyloxy )phenyl)acrylamido)benzoic acid.
Definitions Chemical definitions Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the ic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally d as described therein. Additionally, general principles of organic chemistry, as well as specific functional es and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 Edition, Cambridge University rd Press, Cambridge, 1987. nds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For e, the compounds described herein can be in the form of an individual enantiomer, diastereomer or ric isomer, or can be in the form of a e of stereoisomers, including racemic mixtures and es enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al. Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et ah. Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical tions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally asses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
In a formula, JVW is a single bond where the stereochemistry of the moieties immediately ed thereto is not specified, — is absent or a single bond, and = or is a single or double bond.
Unless ise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of F with F, or the ement of C with C or C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological .
When a range of values is listed, it is intended to encompass each value and sub-range within the range. For e "Ci_6 alkyl" is intended to encompass, Ci, C2, C3, C4, C5, Q,, C\-e, C1-5, Ci_4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and Cs_6 alkyl.
The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
The term "alkyl" refers to a radical of a straight-chain or branched saturated arbon group having from 1 to 10 carbon atoms ("Ci-io alkyl"). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C1-9 alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("Ci-g alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C1-7 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("Ci_6 alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-5 alkyl"). In some embodiments, an alkyl group has 1 to 4 carbon atoms ("Ci_4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("Ci alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-6 alkyl"). Examples of Ci_6 alkyl groups e methyl (Ci), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., nbutyl , utyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3- methylbutanyl, tertiary amyl), and hexyl (Ce) (e.g., l). Additional examples of alkyl groups include yl (C7), n-octyl (Cg), and the like. Unless otherwise specified, each ce of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents (e.g., n, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-10 alkyl (such as unsubstituted Ci_6 alkyl, e.g., -CH3 (Me), tituted ethyl (Ft), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl , unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1-10 alkyl (such as substituted C1-6 alkyl, e.g., -CF3, Bn).
The term "haloalkyl" is a substituted alkyl group, wherein one or more of the en atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms ("Ci_g haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms ("Ci_6 kyl"). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("Ci_4 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C1-3 haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C1-2 haloalkyl"). Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CC13, -CFCI2, -CF2C1, and the like.
WO 44620 The term "heteroalkyl" refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more al position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain roCi-20 ). In some embodiments, a alkyl group is a saturated group having 1 to 18 carbon atoms and 1 or more atoms within the parent chain ("heteroCi-ig alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi_i6 alkyl"). In some ments, a heteroalkyl group is a saturated group having 1 to 14 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi_i4 alkyl"). In some embodiments, a alkyl group is a saturated group having 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain roCi-12 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to carbon atoms and 1 or more heteroatoms within the parent chain roCi-10 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi.g alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-6 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain ("heteroCi_4 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain ("heteroCi-3 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain ("heteroCi_2 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom roCi alkyl"). In some embodiments, the heteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and at least one unsaturated carbon, such as a carbonyl group. For example, a alkyl group may comprise an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups. Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi_2o alkyl.
In certain embodiments, the alkyl group is an unsubstituted heteroCi_io alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi_io alkyl.
The term "alkenyl" refers to a radical of a straight-chain or ed hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds {e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C2-9 alkenyl"). In some embodiments, an l group has 2 to 8 carbon atoms ("C2-8 alkenyl"). In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C2-7 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2-5 l"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-3 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2- butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like.
Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. onal examples of alkenyl include heptenyl (C7), octenyl (Cg), octatrienyl (Cg), and the like. Unless ise specified, each instance of an alkenyl group is independently tituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-10 alkenyl. In n embodiments, the l group is a substituted C2-10 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified {e.g., -CH=CHCH3 or ) may be an (E)- or (Z)-double bond.
The term oalkenyl" refers to an alkenyl group, which further es at least one heteroatom {e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within {i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2 io alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-9 l").
In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, WO 44620 and 1 or more heteroatoms within the parent chain ("heteroCi-g alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroCi-? l"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroCi-e alkenyl"). In some embodiments, a alkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroCi-s alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-4 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 atom within the parent chain ("heteroCi-s alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroCi-e alkenyl"). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroCi-io alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroCi-io alkenyl.
The term yl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C2-10 alkynyl"). In some ments, an alkynyl group has 2 to 9 carbon atoms ("C2-9 alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C2-8 alkynyl"). In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C2-7 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C2-6 alkynyl"). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C2-5 alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2-4 l"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C2-3 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). The one or more -carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. es of C2-6 alkenyl groups include the entioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional es of alkynyl e heptynyl (C7), octynyl (Cg), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted l") with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10 alkynyl.
The term "heteroalkynyl" refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (/.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a alkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroCi io l"). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroCi-g l").
In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain roCi-g alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroCi-? alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroCi-e alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain roCi-s alkynyl"). In some embodiments, a alkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain ("heteroC2-4 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 atom within the parent chain ("heteroCi-s alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroCi-e alkynyl"). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted Ci-io alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroCi-io alkynyl.
The term "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms ("C3-14 carbocyclyl") and zero heteroatoms in the non-aromatic ring . In some embodiments, a carbocyclyl group has 3 to ring carbon atoms ("C3-10 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C3-8 yclyl"). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("€3.7 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("€3.6 carbocyclyl"). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C4-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms ("C5-6 yclyl"). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C5-10 carbocyclyl"). Exemplary €3.6 carbocyclyl groups include, without limitation, ropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like.
Exemplary C3-8 yclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cg), cyclooctenyl (Cg), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cg), and the like. Exemplary C3-10 yclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), ecenyl (C10), octahydro-lH-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the ing examples illustrate, in certain ments, the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic carbocyclyl") or tricyclic system ("tricyclic carbocyclyl")) and can be saturated or can n one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems n the carbocyclyl ring, as defined above, is fused with one or more aryl or aryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a tuted €3.14 carbocyclyl.
"Carbocyclylalkyl" is a subset of " and refers to an alkyl group substituted by an carbocyclyl group, wherein the point of attachment is on the alkyl moiety.
In some embodiments, cyclyl" is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms ("C3_i4 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C3-10 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-8 lkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("€3.6 cycloalkyl"). In some ments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C4_6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-10 cycloalkyl"). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of €3.6 cycloalkyl groups include the aforementioned Cs_6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of €3.8 cycloalkyl groups e the aforementioned C3-6 cycloalkyl groups as well as eptyl (C?) and cyclooctyl (Cg). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In n embodiments, the lkyl group is an tituted €3.14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl.
"Cycloalkylalkyl" is a subset of "alkyl" and refers to an alkyl group substituted by an cycloalkyl group, wherein the point of attachment is on the alkyl moiety.
The term "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently ed from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclyl"). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl") or clic (e.g., a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl") or tricyclic system ("tricyclic heterocyclyl")), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more yclyl groups wherein the point of attachment is either on the yclyl or cyclyl ring, or ring systems wherein the cyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring s in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
In some embodiments, a heterocyclyl group is a 5-10 ed non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1- 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 ed heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered cyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 ed heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, nyl, oxiranyl, and thiiranyl. Exemplary 4-membered cyclyl groups containing 1 atom include, without limitation, azetidinyl, oxetanyl, and thietanyl.
Exemplary 5-membered heterocyclyl groups containing 1 heteroatom e, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and lanyl. Exemplary -membered heterocyclyl groups containing 3 atoms include, without tion, triazolinyl, oxadiazolinyl, and azolinyl. Exemplary 6-membered heterocyclyl groups ning 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
Exemplary ered heterocyclyl groups ning 3 heteroatoms e, without limitation, triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, yl, oxepanyl and thiepanyl. Exemplary 8-membered WO 44620 heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, nyl, isoindolinyl, obenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, droisochromenyl, decahydronaphthyridinyl, decahydro-l,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, imidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, 1.4.5.7- tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H- furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH-pyrrolo[2,3- b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro- lH-pyrrolo[2,3-b]pyridinyl, 4.5.6.7- tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4- tetrahydro-l,6-naphthyridinyl, and the like.
"Heterocyclylalkyl" is a subset of "alkyl" and refers to an alkyl group substituted by an heterocyclyl group, wherein the point of attachment is on the alkyl moiety.
The term "aryl" refers to a radical of a monocyclic or clic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 7t ons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms ed in the aromatic ring system ("C6-14 aryl"). In some embodiments, an aryl group has 6 ring carbon atoms ("Ce aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("Cio aryl"; e.g., naphthyl such as 1-naphthyl and thyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C14 aryl"; e.g., anthracyl). "Aryl" also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms ue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, the aryl group is an unsubstituted Ce-u aryl- In certain embodiments, the aryl group is a substituted Ce-u aryl.
"Arylalkyl" is a subset of "alkyl" and refers to an alkyl group substituted by an aryl group, wherein the point of ment is on the alkyl moiety.
WO 44620 The term oaryl" refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 71 electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring atoms provided in the aromatic ring system, wherein each atom is independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring s wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused clic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, inyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
In some embodiments, a aryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms ed in the aromatic ring system, wherein each heteroatom is independently selected from en, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is ndently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each atom is ndently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered aryl has 1 ring heteroatom ed from nitrogen, , and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.
Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, l, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, t limitation, imidazolyl, pyrazolyl, yl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms e, without limitation, tetrazolyl. Exemplary 6- membered heteroaryl groups containing 1 atom include, without limitation, pyridinyl.
Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, nyl and tetrazinyl, respectively. Exemplary 7- membered heteroaryl groups ning 1 heteroatom include, without limitation, yl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, lyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, idazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl groups include, without tion, naphthyridinyl, pteridinyl, quinolinyl, nolinyl, cinnolinyl, quinoxalinyl, azinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.
"Heteroaryalkyl" is a subset of "alkyl" and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.
The term "silyl" refers to the group -Si(Raa)3, n Raa is as defined herein.
The term "boronyl" refers to s, boronic acids, boronic esters, borinic acids, and borinic esters, e.g., l groups of the formula -B(Raa)2, -B(ORcc)2, and -BRaa(ORcc), wherein Raa and Rcc are as defined herein.
The term "phosphine" refers to the group -P(RCC)3, n Rcc is as defined herein. An exemplary ino group is triphenylphosphine.
The term "phosphono" refers to the group -0(P=0)(0Rcc)Raa, wherein Raa and Rcc are as defined herein.
The term "phosphoramido" refers to the group -0(P=0)(N(Rbb)2)2, wherein each Rbb is as defined herein.
The term "stannyl" refers to the group c)3, wherein Rcc is as defined herein.
The term "germyl" refers to the group -Ge(Rcc)3, wherein Rcc is as defined herein.
The term "arsenyl" refers to the group -As(Rcc)3, wherein Rcc is as defined herein.
The term "oxo" refers to the group =0, and the term "thiooxo" refers to the group =S.
The term "halo" or "halogen" refers to fluorine (fluoro, -F), ne (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).
The term "hydroxyl" or xy" refers to the group -OH. The term "substituted hydroxyl" or "substituted hydroxyl," by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from -ORaa, -ON(Rbb)2, -OC(=0)SRaa, -OC(=0)Raa, -OC02Raa, -OC(=0)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -OC(=NRbb)N(Rbb)2, -OS(=0)Raa, -OS02Raa, -OSi(Raa)3, -OP(Rcc)2, -OP(Rcc)3+X", -OP(ORcc)2, -OP(ORcc)3+X", -OP(=0)(Raa)2, -OP(=0)(ORcc)2, and -0P(=0)(N(Rbb)2)2, wherein X", Raa, Rbb, and Rcc are as defined herein.
The term "amino" refers to the group -NH2. The term ituted amino," by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the "substituted amino" is a monosubstituted amino or a disubstituted amino group.
The term ubstituted amino" refers to an amino group wherein the nitrogen atom directly ed to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from -NH(Rbb), -NHC(=0)Raa, -NHC02Raa, 0)N(Rbb)2, -NHC(=NRbb)N(Rbb)2, Raa, -NHP(=0)(ORcc)2, and -NHP(=0)(N(Rbb)2)2, wherein Raa, Rbb and Rcc are as defined herein, and wherein Rbb of the group -NH(Rbb) is not hydrogen.
The term "disubstituted amino" refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from -N(Rbb)2, -NRbbC(=0)Raa, -NRbbC02Raa, (=0)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, 02Raa, -NRbbP(=0)(0Rcc)2, and -NRbbP(=0)(N(Rbb)2)2, n Raa, Rbb, and Rcc are as d herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.
The term "trisubstituted amino" refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups ed from -N(Rbb)3 and )3+X-, wherein Rbb and X- are as defined herein.
The term "sulfonyl" refers to a group selected from -S02N(Rbb)2, -S02Raa, and - S02ORaa, wherein Raa and Rbb are as defined herein.
The term "sulfinyl" refers to the group -S(=0)Raa, wherein Raa is as d herein.
The term "acyl" refers to a group having the general formula -C(=0)R , -C(=0)ORxl, -C(=0)C(=0)Rxl, -C(=0)SRxl, -C(=0)N(Rxl)2, -C(=S)RX1, -C(=S)N(RX1)2, -C(=S)0(Rx1), -C(=S)S(RX1), -C(=NRX1)RX1, -C(=NRxl)ORxl, -C(=NRX1)SRX1, and -C(=NRX1)N(RX1)2, wherein RX1 is hydrogen; halogen; substituted or unsubstituted yl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or tituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; tuted or unsubstituted alkynyl; tuted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, ticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or dialkylamino , mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or diheteroarylamino ; or two R groups taken together form a 5- to 6-membered heterocyclic ring.
Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-C02H), ketones, acyl halides, esters, amides, , carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, l, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, no, amino, azido, nitro, hydroxyl, thiol, halo, ticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, ryl, kyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, ioxy, arylthioxy, y, and the like, each of which may or may not be further substituted).
The term "carbonyl" refers a group wherein the carbon directly attached to the parent molecule is sp hybridized, and is substituted with an , nitrogen or sulfur atom, e.g., a group selected from ketones (e.g., -C(=0)Raa), carboxylic acids (e.g., -COiH), aldehydes (- CHO), esters (e.g., -C02Raa,-C(=0)SRaa, -C(=S)SRaa), amides (e.g., -C(=0)N(Rbb)2, - C(=0)NRbbS02Raa, -C(=S)N(Rbb)2), and imines (e.g., -C(=NRbb)Raa, -C(=NRbb)ORaa), - C(=NRbb)N(Rbb)2), wherein Raa and Rbb are as defined herein.
Affixing the suffix "-ene" to a group indicates the group is a divalent , e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.
A group is optionally substituted unless expressly provided otherwise. The term "optionally substituted" refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, l, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. "Optionally substituted" refers to a group which may be substituted or unsubstituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, ituted" or "unsubstituted" heteroalkyl, "substituted" or stituted" heteroalkenyl, ituted" or "unsubstituted" heteroalkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one en present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously o transformation such as by rearrangement, cyclization, elimination, or other reaction.
Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term "substituted" is contemplated to include substitution with all permissible tuents of organic compounds, and includes any of the substituents described herein that results in the ion of a stable compound. The present ion contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable tuent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The invention is not intended to be limited in any manner by the exemplary substituents bed herein. ary carbon atom substituents include, but are not d to, halogen, -CN, -N02, -N3, -S02H, -S03H, -OH, -ORaa, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3+X", -N(ORcc)Rbb, -SH, -SRaa, -SSRCC, -C(=0)Raa, -C02H, -CHO, -C(ORcc)3, -C02Raa, -0C(=0)Raa, -0C02Raa, -C(=0)N(Rbb)2, -0C(=0)N(Rbb)2, -NRbbC(=0)Raa, -NRhhC02Raa, -NRbbC(=0)N(Rbb)2, bb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=0)NRbbS02Raa, -NRbbS02Raa, -S02N(Rbb)2, -S02Raa, -S020Raa, aa, -S(=0)Raa, -0S(=0)Raa, -Si(Raa)3, -OSi(Raa)3 N(Rbb)2, -C(=0)SRaa, -C(=S)SRaa, )SRaa, -SC(=0)SRaa, -0C(=0)SRaa, -SC(=0)0Raa, )Raa, -P(=0)(Raa)2, -P(=0)(0Rcc)2,-0P(=0)(Raa)2, -0P(=0)(0Rcc)2, -P(=0)(N(Rbb)2)2, )(N(Rbb)2)2, -NRbbP(=0)(Raa)2, -NRbbP(=0)(0Rcc)2, -NRbbP(=0)(N(Rbb)2)2, -P(RCC)2, -P(ORcc)2, -P(RCC)3+X", -P(ORcc)3+X", -P(Rcc)4, -P(ORcc)4,-OP(Rcc)2, -OP(Rcc)3+X", -OP(ORcc)2, -OP(ORcc)3+X", -OP(Rcc)4, -OP(ORcc)4, -B(Raa)2, -B(ORcc)2, -BRaa(ORcc), CMo alkyl, CMo perhaloalkyl, C2_io alkenyl, C2. alkynyl, heteroCi_io alkyl, heteroC2_io alkenyl, C2_io alkynyl, C3_io carbocyclyl, 3-14 membered cyclyl, Ce-u aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; wherein X- is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=0)Raa, =NNRbbC(=0)ORaa, =NNRbbS(=0)2Raa, =NRbb, or =NORcc; WO 44620 2018/016272 each instance of Raa is, ndently, selected from Cmo alkyl, Cmo perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroCi-10 alkyl, heteroC2-io alkenyl, heteroC2-io alkynyl, C3-10 carbocyclyl, 3-14 membered cyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two R aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, alkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of Rbb is, independently, selected from en, -OH, -ORaa, -N(RCC)2, -CN, -C(=0)Raa, -C(=0)N(Rcc)2, -C02Raa, a, -C(=NRcc)ORaa, -C(=NRcc)N(Rcc)2, -S02N(Rcc)2, -S02Rcc, -S020Rcc, , -C(=S)N(Rcc)2, -C(=0)SRcc, -C(=S)SRcc, -P(=0)(Raa)2, -P(=0)(0Rcc)2, -P(=0)(N(Rcc)2)2, Cmo alkyl, Cmo perhaloalkyl, Cmo alkenyl, Cmo alkynyl, heteroCmo alkyl, heteroC2_io alkenyl, heteroC2_i oalkynyl, C;vm carbocyclyl, 3-14 membered heterocyclyl, Ce-w aryl, and 5-14 membered heteroaryl, or two Rbb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, alkyl, heteroalkenyl, alkynyl, yclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; n X- is a counterion; each instance of Rcc is, independently, selected from hydrogen, Cmo alkyl, Cmo perhaloalkyl, Cmo alkenyl, Cmo alkynyl, heteroC mo alkyl, heteroC2_io alkenyl, heteroC2_io alkynyl, Cmo carbocyclyl, 3-14 membered heterocyclyl, Co-14 aryl, and 5-14 membered heteroaryl, or two Rcc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and aryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of Rdd is, independently, selected from halogen, -CN, -N02, -N3, -S02H, -SO3H, -OH, -ORee, f)2, -N(Rff)2, -N(Rff)3+X", -N(ORee)Rff, -SH, -SRee, , -C(=0)Ree, -C02H, -C02Ree, -OC(=0)Ree, -OC02Ree, -C(=0)N(Rff)2, -OC(=0)N(Rff)2, -NRffC(=0)Ree, -NRffC02Ree, -NRffC(=0)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffS02Ree, -S02N(Rff)2, -S02Ree, -S02ORee, -OS02Ree, -S(=0)Ree, e)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=0)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=0)(ORee)2, -P(=0)(Ree)2, -OP(=0)(Ree)2, -OP(=0)(ORee)2, Ci_6 alkyl, Ci_6 perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, heteroCi_6 alkyl, heteroCi-e alkenyl, heteroCi-e alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, -10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, yclyl, heterocyclyl, aryl, and aryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups, or two geminal Rdd substituents can be joined to form =0 or =S; wherein X- is a counterion; each instance of Ree is, independently, ed from Ci_6 alkyl, Ci_6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 alkyl, C2-6 alkenyl, heteroC2-6 alkynyl, €3.10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; each instance of R is, independently, selected from hydrogen, Ci_6 alkyl, Ci_6 ff perhaloalkyl, C2-6 alkenyl, C2-6 l, heteroCi_6 alkyl, heteroC2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl and 5-10 membered heteroaryl, or two Rff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently tuted with 0, 1, 2, 3, 4, or 5 Rgg groups; each ce of Rgg is, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6 alkyl, -ON(Ci_6 alkyl)2, -N(Ci.6 alkyl)2, -N(Ci_6 alkyl)3+X-, -NH(Ci.6 alkyl)2+X-, -NH2(Ci_6 alkyl)+X", -NH3+X", -N(OCi.6 (Ci.6 , -N(OH)(Ci_6 alkyl), -NH(OH), -SH, -SC1.6 alkyl, -SS(Ci-6 , -C(=0)(Ci.6 alkyl), -C02H, -C02(Ci^ , -OC(=0)(Ci_ 6 alkyl), -0C02(Ci-6 alkyl), -C(=0)NH2, -C(=0)N(Ci.6 alkyl)2, -OC(=0)NH(Ci.6 alkyl), -NHC(=0)(Ci_6 alkyl), -N(Ci.6 alkyl)C(=0)( Ci.6 alkyl), -NHC02(Ci^ alkyl), -NHC(=0)N(Ci_ 6 alkyl)2, 0)NH(Ci_6 alkyl), -NHC(=0)NH2, -C(=NH)0(Ci.6 , -OC(=NH)(Ci.6 alkyl), -OC(=NH)OCi-6 alkyl, -C(=NH)N(Ci.6 alkyl)2, -C(=NH)NH(Ci-6 alkyl), -C(=NH)NH2, -OC(=NH)N(Ci.6 alkyl)2, -OC(=NH)NH(Ci-6 alkyl), -OC(=NH)NH2, NH)N(Ci.6 alkyl)2, -NHC(=NH)NH2, -NHS02(Ci.6 alkyl), -S02N(Ci.6 alkyl)2, -S02NH(Ci_6 alkyl), -SO2NH2, -S02(Ci_6 alkyl), -S020(Ci_6 alkyl), -0S02(Ci.6 alkyl), -SO(Ci.6 alkyl), -Si(Ci_6 alkyl)3, i.6 alkyl)3 -C(=S)N(Ci-6 alkyl)2, H(Ci.6 alkyl), C(=S)NH2, -C(=0)S(Ci-6 alkyl), -C(=S)SCi.6 alkyl, -SC(=S)SCi.6 alkyl, -P(=0)(OCi-6 alkyl)2, -P(=0)(Ci.6 alkyl)2, -OP(=0)(Ci_6 alkyl)2, -OP(=0)(OCi_6 alkyl)2, Ci_6 alkyl, Ci_6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi_6 alkyl, heteroCi-e alkenyl, heteroCi-e alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 ed heterocyclyl, 5-10 membered heteroaryl; or two l Rgg substituents can be joined to form =0 or =S; wherein X- is a counterion.
Nitrogen atoms can be tuted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary en atom tuents include, but are not limited to, hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=0)Raa, N(Rcc)2, -C02Raa, -S02Raa, -C(=NRbb)Raa, -C(=NRcc)ORaa, -C(=NRcc)N(Rcc)2, Rcc)2, -S02Rcc, -S02ORcc, , -C(=S)N(Rcc)2, -C(=0)SRcc, -C(=S)SRcc, -P(=0)(ORcc)2, -P(=0)(Raa)2, -P(=0)(N(Rcc)2)2, Ci-io alkyl, Cuo perhaloalkyl, C2.i0 alkenyl, C2-io l, heteroCi-ioalkyl, heteroC2-ioalkenyl, heteroC2-ioalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-u aryl, and 5-14 membered heteroaryl, or two Rcc groups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein Raa, Rbb, Rcc and Rdd are as defined herein.
In certain embodiments, the substituent present on the en atom is an nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include, but are not limited to, -OH, -ORaa, -N(RCC)2, -C(=0)Raa, -C(=0)N(Rcc)2, -C02Raa, -S02Raa, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRcc)N(Rcc)2, -S02N(Rcc)2, -S02Rcc, -S02ORcc, -SORaa, -C(=S)N(Rcc)2, -C(=0)SRcc, -C(=S)SRcc, Cuo alkyl {e.g., aralkyl, heteroaralkyl), C2-io alkenyl, C2-io alkynyl, heteroCi_io alkyl, heteroC2_io alkenyl, C2_io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1,2, 3, 4, or 5 Rdd groups, and wherein Raa, Rbb, Rcc and Rdd are as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 edition, John Wiley & Sons, 1999, incorporated herein by reference.
For example, nitrogen protecting groups such as amide groups {e.g., -C(=0)Raa) include, but are not d to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, ylpropanamide, picolinamide, 3- pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, onitophenylacetamide , o-nitrophenoxyacetamide, acetoacetamide, (N’- dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(onitrophenyl )propanamide, 2-methyl(o-nitrophenoxy)propanamide, 2-methyl(ophenylazophenoxy )propanamide, 4-chlorobutanamide, 3-methylnitrobutanamide, onitrocinnamide , ylmethionine derivative, o-nitrobenzamide and o- (benzoyloxymethyl)benzamide.
Nitrogen protecting groups such as carbamate groups (e.g., -C(=0)0Raa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9- (2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl- [9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4- methoxyphenacyl carbamate (Phenoc), trichloroethyl ate (Troc), 2- hylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-!- methylethyl carbamate ), l,l-dimethylhaloethyl carbamate, 1,1-dimethyl-2,2- dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl ate (TCBOC), 1- methyl-l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l-methylethyl ate (t-Bumeoc), 2-(2'- and 4'-pyridyl)cthyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl ate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N- hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl ate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl ate (Bmpc), 2- phosphonioethyl ate (Peoc), 2-triphenylphosphonioisopropyl carbamate , 1,1- dimethylcyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl) chromonylmethyl carbamate (Tcroc), ophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxynitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl WO 44620 carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, pdecyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N- dimethylcarboxamido)benzyl carbamate, l,l-dimethyl(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl ate, di(2-pyridyl)methyl carbamate, nylmethyl carbamate, ethyl carbamate, ynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1- methylcyclohexyl carbamate, 1-methylcyclopropylmethyl carbamate, 1-methyl(3,5- dimethoxyphenyl)ethyl carbamate, 1-methyl-l-(p-phenylazophenyl)ethyl carbamate, 1-methyl phenylethyl carbamate, 1-methyl-l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p- (phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.
Nitrogen ting groups such as sulfonamide groups {e.g., -S(=0)2Raa) include, but are not d to, p-toluenesulfonamide (Ts), esulfonamide, 2,3,6-trimethyl methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl methoxybenzenesulfonamide (Pme), 6-tetramethylmethoxybenzenesulfonamide (Mte), oxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6- dimethoxymethylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchromansulfonamide (Pmc), methanesulfonamide (Ms), P-trimethylsilylethanesulfonamide (SES), 9- cenesulfonamide, 4-(4/,8/-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.
Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(lO)- acyl derivative, N'-p-1o 1 ucncsu 1 fony 1 aminoacyl derivative, N'-phcnylaminothioacyl derivative, N-benzoylphenylalanyl derivative, ylmethionine derivative, 4,5-diphenyloxazolin one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5- dimethylpyrrole, N-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexanone, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan one, 1-substituted 3,5-dinitropyridone, N-methylamine, N-allylamine, N-[2- (trimethylsilyl)ethoxy]methylamine (SEM), Nacetoxypropylamine, N-(l-isopropylnitro oxopyroolinyl)amine, quaternary um salts, N-benzylamine, N-di(4- methoxyphenyl)methylamine, Ndibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4- methoxyphenyl)diphenylmethyl]amine (MMTr), Nphenylfluorenylamine (PhF), N-2,7- dichlorofluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), colylamino N’- oxide, N-l,l-dimethylthiomethyleneamine, N-benzylideneamine, N-pmethoxybenzylideneamine , enylmethyleneamine, N- [(2-pyridyl)mesityl] methyleneamine, N-(N’ ,N’ -dimethylaminomethylene)amine, N,N’ -isopropylidenediamine, N-pnitrobenzylideneamine , cylideneamine, Nchlorosalicylideneamine, N-(5-chloro hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyloxo-lcyclohexenyl )amine, N-borane derivative, N-diphenylborinic acid derivative, N- [phenyl(pentaacylchromium- or tungsten)acyl]amine, er chelate, N-zinc chelate, N- nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, onitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitromethoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In certain embodiments, a nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), oxybenzyl (PMB), 3,4-dimethoxybenzyl , p-methoxyphenyl (PMP), 2,2,2- trichloroethyloxycarbonyl (Troc), nylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).
In certain ments, the substituent present on an oxygen atom is an oxygen ting group (also referred to herein as an "hydroxyl protecting group"). Oxygen protecting groups include, but are not limited to, -Raa, -N(Rbb)2, -C(=0)SRaa, -C(=0)Raa, a, -C(=0)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=0)Raa, -S02Raa, -Si(Raa)3, -P(Rcc)2, -P(Rcc)3+X",-P(ORcc)2, c)3+X", -P(=0)(Raa)2, -P(=0)(0Rcc)2, and -P(=0)(N(Rbb) 2)2, wherein X-, Raa, Rbb, and Rcc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in ting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), pmethoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), xymethyl, enyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1- methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S ,S -dioxide, 1 - [(2-chloromethyl)phenyl] methoxypiperidin- 4-yl (CTMP), oxanyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7aoctahydro-7 ,8,8-trimethyl-4,7-methanobenzofuranyl, 1-ethoxyethyl, l-(2-chloroethoxy)ethyl, 1 -methyl-1 -methoxyethyl, 1 -methyl-1 -benzyloxyethyl, 1 -methyl-1 -benzyloxyfluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, onitrobenzyl , p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- picolyl, 4-picolyl, ylpicolyl o, diphenylmethyl, p,p’-dinitrobenzhydryl, 5- dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’- bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(imidazol-lyl )bis(4',4"-dimethoxyphenyl)methyl, l,l-bis(4-methoxyphenyl)-l'-pyrenylmethyl, 9-anthryl, 9- (9-phenyl)xanthenyl, henyloxo)anthryl, l,3-benzodithiolanyl, benzisothiazolyl S,S- dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, tbutyldimethylsilyl ), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, xylylsilyl, nylsilyl, diphenylmethylsilyl (DPMS), lmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, rophenoxyacetate, 3- phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, toate, ate, 4-methoxycrotonate, benzoate, lbenzoate , 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4- dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, xynapththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4- azidobutyrate, 4-nitromethylpentanoate, o-(dibromomethyl)benzoate, 2- formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloromethylphenoxyacetate, 2,6-dichloro ,3 -tetramethylbutyl)phenoxyacetate, 2,4-bis( 1,1 -dimethylpropyl)phenoxyacetate, diphenylacetate, isobutyrate, monosuccinoate, (E)methylbutenoate, o- (methoxyacyl)benzoate, a-naphthoate, nitrate, alkyl N,N,N’,N’-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). In certain ments, an oxygen protecting group is silyl. In certain embodiments, an oxygen protecting group is t- butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), hyl silyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), l (Bz), allyl carbonate, 2,2,2-trichloroethyl ate (Troc), 2- trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2- trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), ydropyranyl (THP), tetrahydrofuranyl (THE), oxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).
In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). Sulfur protecting groups include, but are not limited to, -Raa, -N(Rbb)2, -C(=0)SRaa, Raa, -C02Raa, N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -S(=0)Raa, -S02Raa, -Si(Raa)3, -P(RCC)2, -P(Rcc)3+X-,-P(ORcc)2, -P(ORcc)3+X_, -P(=0)(Raa)2, (0Rcc)2, and -P(=0)(N(Rbb) 2)2, wherein Raa, Rbb, and Rcc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 edition, John Wiley & Sons, 1999, incorporated herein by reference. In WO 44620 n embodiments, a sulfur protecting group is acetamidomethyl, t-Bu, opyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.
A "counterion" or "anionic counterion" is a negatively charged group ated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (/.
Exemplary counterions include halide ions (e.g., F , CE, BE, F), NO-, , CIO4 , OH-, H2PO4 , HOOF. HSO4 , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, ptoluenesulfonate , benzenesulfonate, 10-camphor sulfonate, naphthalenesulfonate, naphthalenesulfonic acidsulfonate, 1-sulfonic acidsulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, ate, gluconate, and the like), BF4-, PF4 , PF6-, AsF6-, SbF6-, B[3,5-(CF3)2C6H3]4]-, B(C6F5)4-, BPh4 , Al(OC(CF3)3)4-, and carborane anions (e.g., CB| 1H12 or (HCB11 McsBiy) ). Exemplary counterions which may be multivalent include CO32-, HP042-, P04’-. BA)?2-, S042-, , carboxylate anions (e.g., tartrate, citrate, te, maleate, malate, malonate, gluconate, ate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.
The term "leaving group" is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March’s Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, E,O-dimethy 1 hydroxy 1 amino, pixyl, and haloformates. In some cases, the leaving group is a sulfonic acid ester, such as toluenesulfonate (tosylate, -OTs), esulfonate (mesylate, -OMs), benzenesulfonyloxy (brosylate, -OBs), )2(CF2)3CF3 (nonaflate, -ONf), or trifluoromethanesulfonate (triflate, -OTf). In some cases, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate, such as 2- nitrobenzenesulfonyloxy.The leaving group may also be a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other iting examples of g groups are water, ammonia, alcohols, ether moieties, thioether moieties, zinc halides, magnesium moieties, diazonium salts, and copper moieties. Further ary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and activated substituted yl groups (e.g., )SRaa, -0C(=0)Raa, -OCOiR11, - 0C(=0)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -OC(=NRbb)N(Rbb)2, -0S(=0)Raa, - 0S02Raa, -OP(Rcc)2, -OP(Rcc)3, -0P(=0)2Raa, -0P(=0)(Raa)2, -0P(=0)(0Rcc)2, - 2N(Rbb)2, and -0P(=0)(NRbb)2, wherein Raa, Rbb, and Rcc are as defined herein).
The term "unsaturated bond" refers to a double or triple bond.
The term urated" or "partially unsaturated" refers to a moiety that includes at least one double or triple bond.
The term "saturated" refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.
As used herein, use of the phrase "at least one instance" refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.
A "non-hydrogen group" refers to any group that is d for a particular variable that is not hydrogen.
These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The invention is not ed to be limited in any manner by the above exemplary listing of substituents.
Other definitions The following definitions are more general terms used throughout the present application.
As used herein, the term "salt" refers to any and all salts, and encompasses pharmaceutically acceptable salts.
The term "pharmaceutically able salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in t with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a able benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. es of ceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other ceutically able salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, entanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate , lactobionate, lactate, laurate, lauryl sulfate, , maleate, malonate, esulfonate, thalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, ylpropionate, phosphate, picrate, pivalate, propionate, stearate, ate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(Ci_4 alkyl)^ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic um, quaternary ammonium, and amine cations formed using rions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
The term "solvate" refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include en bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THE, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates e pharmaceutically acceptable solvates and further include both stoichiometric solvates and oichiometric solvates. In n instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. "Solvate" encompasses both on-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.
The term "hydrate" refers to a nd that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound les in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R x H2O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R-0.5 H2O)), and drates (x is a number greater than 1, e.g., dihydrates (R-2 H2O) and hexahydrates (R-6 H2O)).
The term "tautomers" or "tautomeric" refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, ing temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may zed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-tolactim , enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.
It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the ement of their atoms in space are termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". isomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the le s the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate, or e f). All polymorphs have the same elemental composition. ent crystalline forms usually have different X-ray diffraction patterns, ed spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and lity.
Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
The term "prodrugs" refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, e ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have ty in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or d release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs e acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides ed by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple tic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester type gs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Ci-g alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, €7.12 tuted aryl, and €7.12 arylalkyl esters of the nds described herein may be preferred.
The terms "composition" and "formulation" are used interchangeably.
A "subject" to which administration is contemplated refers to a human (/.
In certain embodiments, the plant is a cultivated plant. In certain embodiments, the plant is a dicot. In certain embodiments, the plant is a monocot. In n embodiments, the plant is a flowering plant. In some embodiments, the plant is a cereal plant, e.g., maize, corn, wheat, rice, oat, barley, rye, or millet. In some embodiments, the plant is a legume, e.g., a bean plant, e.g., soybean plant. In some embodiments, the plant is a tree or shrub.
The term "biological sample" refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and ting the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal , cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., ed by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
The term "target tissue" refers to any ical tissue of a subject (including a group of cells, a body part, or an organ) or a part f, including blood and/or lymph vessels, which is the object to which a compound, particle, and/or composition of the ion is delivered. A target tissue may be an al or unhealthy tissue, which may need to be treated. A target tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or thy, which may need to be ted. In n embodiments, the target tissue is the liver. In certain embodiments, the target tissue is the lung. A "non-target " is any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and/or lymph vessels, which is not a target tissue.
The term "administer," "administering," or "administration" refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described , or a composition thereof, in or on a t.
The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be stered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms {e.g., in light of a history of symptoms).
Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
The terms "condition," "disease," and der" are used interchangeably.
An "effective amount" of a nd described herein refers to an amount sufficient to elicit the desired ical response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the cokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In n embodiments, an effective amount is a therapeutically effective amount. In n embodiments, an effective amount is a prophylactic treatment. In certain ments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound bed herein in multiple doses.
A "therapeutically effective " of a compound described herein is an amount ient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a eutic t in the treatment of the condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces, or avoids symptoms, signs, or causes of the condition, and/or enhances the eutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for fibrosis inhibition. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating diseases associated with is. In certain embodiments, a therapeutically effective amount is an amount sufficient for fibrosis inhibition and ng diseases associated with fibrosis.
A "prophylactically effective amount" of a compound described herein is an amount sufficient to prevent a condition, or one or more signs or symptoms associated with the condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term "prophylactically effective amount" can encompass an amount that es overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for fibrosis tion. In certain embodiments, a prophylactically effective amount is an amount ient for treating diseases associated with fibrosis. In certain embodiments, a prophylactically effective amount is an amount sufficient for fibrosis inhibition and treating diseases associated with fibrosis.
As used herein, the term "inhibit" or "inhibition" in the context of the TGF-P signalling pathway, for example, refers to a reduction in the activity of TGF-P or another enzyme in the TGF-P ling pathway (e.g., ERK), a reduction in the activity of TGF-P induced proline incorporation in cells, and/or a reduction in the activity of TGF-P d extracellular matrix production. In some embodiments, the term refers to a reduction of the level of enzyme activity (e.g., TGF-P activity), a reduction in the activity of TGF-P induced proline incorporation in cells, and/or a ion in the activity of TGF-P induced extracellular matrix tion, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of enzyme activity. In some embodiments, the term refers to a reduction of the level of enzyme ty (e.g., TGF-P activity), a reduction in the activity of TGF-P induced proline oration in cells, and/or a reduction in the activity of TGF-P induced ellular matrix production, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of enzyme activity.
] The term n or malignant neoplastic disease" as used herein refers to any growth or tumour caused by abnormal and uncontrolled cell division. In certain embodiments, the malignant neoplastic disease may be cancer.
The term "cancer" refers to a malignant neoplasm (Stedman ’s Medical nary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990). Exemplary cancers include, but are not limited to, acoustic a; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix ; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g.,meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; oid tumor; cervical cancer (e.g., al adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, le thic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral us cell oma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal )); hematological s (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and dgkin lymphoma (NHL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell ma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom’s macroglobulinemia), hairy cell ia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma/leukemia, eral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis des, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell ma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia/lymphoma as described above; and multiple myeloma ), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a.
Wilms’ tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma,small cell lung cancer (SCLC), all cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); ytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid asia (AMM) a.k.a. myelofibrosis (ME), chronic idiopathic ibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor ET), carcinoid tumor); osteosarcoma (e.g., bone ); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal oma, ovarian adenocarcinoma); papillary adenocarcinoma; atic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget’s disease of the penis and m); pinealoma; ive neuroectodermal tumor (PNT); plasma cell sia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor ), osarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland oma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva).
The term otherapy" refers to a therapeutic agent that promotes the treatment of disease by inducing, enhancing, or ssing an immune response. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies.
Immunotherapies are typically, but not always, biotherapeutic agents. us immunotherapies are used to treat cancer. These include, but are not limited to, monoclonal dies, adoptive cell transfer, cytokines, ines, vaccines, and small molecule inhibitors.
The term "small molecule" or "small molecule eutic" refers to molecules, whether lly occurring or artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight. Typically, a small molecule is an organic nd (i.e., it contains carbon). The small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.). In certain embodiments, the molecular weight of a small molecule is not more than about 1,000 g/mol, not more than about 900 g/mol, not more than about 800 g/mol, not more than about 700 g/mol, not more than about 600 g/mol, not more than about 500 g/mol, not more than about 400 g/mol, not more than about 300 g/mol, not more than about 200 g/mol, or not more than about 100 g/mol. In certain embodiments, the molecular weight of a small molecule is at least about 100 g/mol, at least about 200 g/mol, at least about 300 g/mol, at least about 400 g/mol, at least about 500 g/mol, at least about 600 g/mol, at least about 700 g/mol, at least about 800 g/mol, or at least about 900 g/mol, or at least about 1,000 g/mol. Combinations of the above ranges (e.g., at least about 200 g/mol and not more than about 500 g/mol) are also possible. In certain embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (C.F.R.)). The small le may also be complexed with one or more metal atoms and/or metal ions. In this instance, the small molecule is also referred to as a "small organometallic molecule." Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, more ably humans. Small molecules include, but are not limited to, radionuclides and imaging . In certain embodiments, the small molecule is a drug. Preferably, though not necessarily, the drug is one that has already been deemed safe and ive for use in humans or animals by the appropriate governmental agency or regulatory body. For example, drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460, incorporated herein by nce; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589, WO 44620 incorporated herein by reference. All listed drugs are considered acceptable for use in accordance with the t invention.
The term "therapeutic agent" refers to any substance having therapeutic properties that produce a desired, y beneficial, effect. For e, therapeutic agents may treat, ameliorate, and/or prevent disease. Therapeutic agents, as disclosed herein, may be biologies or small le therapeutics.
The term "chemotherapeutic agent" refers to a therapeutic agent known to be of use in chemotherapy for cancer.
The term "kidney disease", as used herein, may refer to a disorder of at least one kidney in a subject that compromises the on of the kidney. The kidney disease may result from a primary pathology of the kidney (e.g., injury to the ulus or tubule), or another organ (e.g., as) which adversely affects the ability of the kidney to perform biological functions. A kidney disease in the human can be the direct or indirect effect of disease. Examples of a kidney e as a result or consequence of an indirect effect on the kidneys is kidney disease as a consequence of diabetes or systemic lupus. A kidney disease may be the result or a consequence of any change, damage, or trauma to the glomerulus, tubules or interstitial tissue in either the renal cortex or renal medulla of the .
The term "kidney disease", as used herein, may refer to a progressive kidney disease that over time (e.g., days, weeks, months, years) leads to a loss of renal function.
The kidney disease may include, but is not limited to, a progressive glomerular kidney disease including, without limitation, diabetic nephropathy (e.g., as a consequence of Type I or Type II diabetes or systemic lupus), primary glomerulonephritis (e.g., membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal tal glomerulosclerosis) or secondary glomerulonephritis (e.g., diabetic nephropathy, ischemic nephropathy).
The term "renal function", as used herein, refers to a physiological property of the kidney, such as the ability to retain protein y preventing proteinuria. Renal function can be assessed using methods known in the art such as ining one or more of ular filtration rate (e.g., creatinine clearance), excretion of protein in urine, blood urea nitrogen, and serum or plasma creatinine.
A progressive kidney disease treated by the compositions and methods described herein es any kidney disease that can, ultimately, lead to end-stage renal disease. A progressive kidney e that can be treated by the compositions and methods of the invention can be, for example, associated with endogenous iron deposit in the kidney (e.g., glomerulus, tubules).
"Diabetic cardiomyopathy" refers to any one or more cardiac pathology and/or ction in a subject, which is a complication of either Type I or Type II diabetes in the subject. The diabetes may be symptomatic or omatic. Cardiac pathology which is characteristic of diabetic myopathy includes myocellular hypertrophy, myocardial fibrosis, and in some cases left ventricular hypertrophy. The pathologies which are plated arise independently from complications arising from coronary artery disease, although both diabetic complications and coronary artery cations may be present in the same subject. Diastolic dysfunction, such as an impairment in early diastolic filling, a prolongation of isovolumetric relaxation and increased atrial filling is also characteristic of diabetic cardiomyopathy, and may be identified using Doppler methods such as Doppler nsional echocardiography (for example Redford MM et al., "Burden of systolic and diastolic dysfunction in the community".
JAMA (2003) 289:194-203) or radionuclide imaging for early or mild dysfunction and by standard echocardiograph testing for more severe ction.
"Cardiac fibrosis" refers to the formation of fibrous tissue, including ar and extracellular components, in the lining and muscle of the heart. If present in sufficient quantities, the fibrous tissue will result in a decrease in the contractility and/or relaxation of one or more regions of the heart, resulting in functional deficit in cardiac output.
Detailed Description of Certain ments ed herein are anti-fibrotic compounds. The compounds may t fibrosis. The compounds may inhibit the TGF-P ling pathway. The compounds may inhibit TGF-P, or another enzyme in the TGF-P signalling pathway (e.g., ERK). The compounds may inhibit TGF- P induced proline oration in cells. The compounds may inhibit TGF-P induced extracellular matrix production. The compounds may inhibit collage biosynthesis. In one aspect, the disclosure provides compounds of Formula I, and ceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical itions thereof. In another aspect, the sure provides 2- [[(E)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid, and pharmaceutically acceptable salts, solvates, es, polymorphs, co-crystals, tautomers, stereoisomers, isotopically d derivatives, prodrugs, and ceutical compositions thereof. The compounds are useful for the treatment and/or prevention of diseases or conditions associated with fibrosis (e.g., kidney disease, c disease), inflammation, and/or a benign or ant neoplastic disease in a subject in need thereof.
Compounds The compounds described herein interact with the TGF-P signalling y. As described herein, the therapeutic effect may be a result of inhibition of TGF-P or another enzyme in the TGF-P signalling pathway {e.g., ERK). A compound may be provided for use in any composition, kit, or method described herein as a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
In one aspect, disclosed is a compound of Formula I: Z'R XT^N (R6)m R2-Y- or a pharmaceutically acceptable salt thereof; wherein R4 a R5 Tis R5 or X is O, NR10, -NR10C(O)-, or a bond; Y is O, NR10, -C(0)NR10-, or a bond; Z is O, NR10, or a bond; R and R are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R and R1 2 are each optionally substituted with 1-3 independent substituents R ;o or R and R together with the atoms to which they are attached form a heterocyclyl ring;1 2 R is hydrogen, alkyl, heteroalkyl, alkenyl, l, cycloalkyl, lkylalkyl, arylalkyl, a heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R3 is optionally substituted with 1-3 independent tuents R ;o R4 and R5 are hydrogen; each occurrence of R6 is, independently, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, yl, alkoxy, aryl, heteroaryl, heterocyclyl, NRaRb, or -S(0)2RC; G is C(0)R7 or en; R7is OH or NHR9; m is 0, 1, or 2; each occurrence of R is, independently, alkyl, alkynyl, hydroxyl, alkoxy, carboxyl, oxo, o aryl, aryl, heterocyclyl, -NRaRb, -S(0)2RC, or -C02Rd; R9is heteroaryl, cyclyl, or -S(0)2RC, wherein R9is optionally substituted with 1-3 independent substituents R ;o R is hydrogen or alkyl optionally substituted with 1-3 independent substituents R ; and each occurrence of Ra, Rb, Rc, and Rd is, independently, hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, heterocyclyl, C(0)0Ci_6 alkyl, C(0)Ci_6 alkyl, or Ra and Rb together with the atoms to which they are attached form a heterocyclyl ring; provided that when G is hydrogen, then m is not 0; provided that when G is , R7 is OH, and -Z-R3 is H, then at least one of -X-R1 and-Y-R is-O-heterocyclyl or cyclyl, or R and R together with the atoms to which they are attached form a heterocyclyl ring; provided that when -X-R1 is H, then neither -Y-R2 nor -Z-R3 are hydrogen; provided that when-Y-R is H, then neither-X-R nor-Z-R are hydrogen; and provided that when-Z-R is H, then neither-X-R nor-Y-R are hydrogen.3 12 In certain embodiments, AkKR4 Tis X is O, NR10, -NR10C(O)-, or a bond; Y is O, NR10, -C(0)NR10 or a bond; Z is O, NR10, or a bond; R1 and R2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, lkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, n R and R1 2 are each optionally substituted with 1-3 independent substituents R ;o or R and R together with the atoms to which they are attached form a heterocyclyl ring;1 2 R is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, lkylalkyl, arylalkyl,a heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R is optionally substituted with 1-3a ndent tuents R ;o R4 and R5 are hydrogen; each occurrence of R6 is, independently, n, cyano, alkyl, alkenyl, l, haloalkyl, hydroxyl, alkoxy, aryl, heteroaryl, heterocyclyl, NRaRb, or -S(0)2RC; G is C(0)R7 or hydrogen; R7is OH or NHR9; m is 0 or 1; each occurrence of R is, independently, alkyl, alkynyl, hydroxyl, alkoxy, carboxyl, oxo, o aryl, heteroaryl, heterocyclyl, -NRaRb, -S(0)2RC, or -C02Rd; R9is heteroaryl, heterocyclyl, or -S(0)2RC, wherein R9is optionally substituted with 1-3 independent substituents R ;o R is hydrogen or alkyl optionally substituted with 1-3 independent tuents R ; and each occurrence of Ra, Rb, Rc, and Rd is, independently, hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, heterocyclyl, C(0)0Ci_6 alkyl, C(0)Ci_6 alkyl, or Ra and Rb together with the atoms to which they are attached form a heterocyclyl ring; provided that when G is hydrogen, then m is not 0; provided that when G is C(0)R7, R7 is OH, and -Z-R3 is H, then at least one of -X-R1 and-Y-R is-O-heterocyclyl or heterocyclyl, or R and R together with the atoms to which they are attached form a heterocyclyl ring; ed that -R is H, then neither-Y-R nor-Z-R are hydrogen;1 2 3 provided that when-Y-R is H, then neither-X-R nor-Z-R are hydrogen; and2 13 ] provided that when-Z-R is H, then neither-X-R nor-Y-R are hydrogen.3 12 WO 44620 R4 a R5 In certain embodiments, T is R5 . In certain embodiments, T is In certain embodiments, X is O, NR10, or a bond. In certain embodiments, X is O or a bond. In certain embodiments, X is O. In certain embodiments, X is a bond. In certain embodiments, Y is NR10. In certain embodiments, X is -NR10C(O)-.
In certain embodiments, Y is O, NR10, or a bond. In certain embodiments, Y is O or a bond. In certain embodiments, Y is O. In certain embodiments, Y is a bond. In certain embodiments, Y is NR10. In certain ments, Y is -NR10C(O)-.
In certain embodiments, Z is O or a bond. In certain embodiments, Z is O. In certain embodiments, Z is a bond. In certain embodiments, Z is NR10.
In certain embodiments, R1 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclyl, or cyclylalkyl, wherein R is ally tuted with 1-3 independent tuents R .
In certain embodiments, R1 is alkyl, alkynyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R1 is optionally substituted with 1-3 independent substituents R .o In certain embodiments, R1 is alkyl, alkynyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R1 is optionally substituted with an alkyl group.
In certain embodiments, R1 is alkyl. In certain embodiments, R1 is C1-4 alkyl. In certain embodiments, R1 is alkynyl. In certain embodiments, R1 is C2-4 alkynyl. In certain embodiments, R1 is cycloalkylalkyl. In certain embodiments, R1 is ropylmethyl. In certain embodiments, R1 is heterocyclyl optionally substituted with an alkyl group. In certain embodiments, R1 is pyrrolidinyl, tetrahydropyridinyl, morpholinyl, or piperazinyl, optionally substituted with an alkyl group. In certain embodiments, R1 is heterocyclylalkyl optionally tuted with an alkyl group. In certain embodiments, R1 is oxetanylmethyl.
In certain embodiments, R is hydrogen, alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R is optionally tuted with 1-3 ndent substituents R .
In certain embodiments, R is alkyl, alkynyl, arylalkyl, heterocyclyl, 2 arylalkyl, or heterocyclylalkyl, wherein R is optionally substituted with 1-3 independent substituents R .o In n embodiments, R is alkyl, alkynyl, heterocyclyl, heteroarylalkyl, or2 heterocyclylalkyl, wherein R is ally substituted with an alkyl group.2 In certain embodiments, R is alkyl or heteroarylalkyl ally substituted with an 2 alkyl group.
In certain embodiments, R is alkyl. In n embodiments, R is Ci_4 alkyl. In certain2 2 embodiments, R is l. In certain embodiments, R is C2-4 alkynyl. In certain embodiments, 2 2 R is heterocyclyl optionally substituted with an alkyl group. In certain embodiments, R is morpholinyl or tetrahydopyridinyl, optionally substituted with an alkyl group. In certain embodiments, R is heterocyclylalkyl optionally substituted with an alkyl group. In certain embodiments, R is heteroarylalkyl optionally tuted with one or two alkyl groups. In certain embodiments, R is pyrazolylmethyl ally substituted with one or two alkyl groups.
In certain embodiments, R and R together with the atoms to which they are ed form a heterocyclyl ring.
In n embodiments, R is hydrogen, heteroalkyl, alkyl, alkynyl, heteroarylalkyl,a heterocyclyl, or heterocyclylalkyl, wherein R is optionally tuted with 1-3 independenta substituents R .o In certain ments, R is hydrogen, alkyl, l, heteroarylalkyl, heterocyclyl, a or heterocyclylalkyl, wherein R3 is optionally substituted with -NRaRb or alkyl.
In certain embodiments, R3 is alkyl optionally substituted with -NRaRb. In certain embodiments, R is alkyl optionally substituted with -N(Me)2. In certain embodiments, R is C1-4 alkyl optionally substituted with -N(Me)2. In certain embodiments, R is l. In certaina embodiments, R is C2-4 alkynyl. In certain embodiments, R is heteroarylalkyl. In certain 3 3 embodiments, R is pyridinylmethyl. In certain embodiments, R is heterocyclyl. In certain embodiments, R is pyrrolidinyl, piperidinyl, or inyl. In certain embodiments, R is heterocyclylalkyl. In certain embodiments, R3 is morpholinylethyl or linylmethyl.
In certain embodiments, each ence of R6 is, independently, halogen, cyano, alkyl, heteroaryl, heterocyclyl, or -S(0)2RC. In certain embodiments, each occurrence of R6is halogen. In certain embodiments, each occurrence of R6 is F, Cl, Br, or I. In certain embodiments, each occurrence of R6 is F, Cl, or Br. In certain embodiments, each occurrence of R6 is F. In certain embodiments, each ence of R6 is Cl. In certain embodiments, each occurrence of R6 is Br. In certain embodiments, each occurrence of R6 is cyano. In certain embodiments, each occurrence of R6 is alkyl. In certain embodiments, each occurrence of R6 is Ci_4 alkyl. In certain embodiments, each occurrence of R6is methyl. In certain embodiments, WO 44620 each occurrence of R6is aryl. In certain embodiments, each occurrence of R6is triazolyl, tetrazolyl, oxadiazolyl, pyrazolyl, or imidazolyl. In certain embodiments, each occurrence of R6 is heterocyclyl. In certain embodiments, each occurrence of R6is ooxadiazolyl or oxodihydrooxadiazolyl. In certain embodiments, each occurrence of R6is -S(0)2RC. In certain ments, each occurrence of R6is -S(0)2Me.
In certain embodiments, G is C(0)R . In certain embodiments, G is hydrogen. n In n embodiments, R is OH. In certain embodiments, R is NHR .
In certain embodiments, m is 0 or 1. In certain embodiments, m is 0 or 2. In certain embodiments, m is 1 or 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2.
In certain embodiments, R9 is heteroaryl, heterocyclyl, or RC. In certain ments, R9 is heteroaryl optionally substituted with up to two alkyl groups. In certain embodiments, R9 is tetrazolyl, pyridinyl, pyrazolyl, imidazolyl, or triazolyl, each of which is optionally substituted with up to two alkyl groups. In certain embodiments, R9 is heterocyclyl optionally substituted with up to two alkyl groups. In certain ments, R9 is oxetanyl or piperidinyl, each of which is optionally substituted with up to two alkyl groups. In certain embodiments, R9 is -S(0)2RC. In certain embodiments, R9 is -S(0)2Me.
In certain embodiments, R10 is hydrogen or alkyl. In certain embodiments, R10 is hydrogen. In certain embodiments, R10is Ci_4 alkyl. In certain embodiments, R10is methyl.
] In certain ments, the compound of a I is of Formula I-a: Z'R XT^N (R6)m R2-Y- or a pharmaceutically able salt thereof.
In certain embodiments, the compound of Formula I is of Formula I-b or Formula I-c: Z-R3 O Z-R3 X(R6)m O (R6)m R2-Y- r2-y- N N H H R-X R-X I-b, I-c, or a pharmaceutically acceptable salt thereof.
] In certain embodiments, X is O or a bond; Y is O or a bond; Z is O or a bond; R and R2 are ndently hydrogen, alkyl, alkynyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R and R are each optionally substituted with 1 or 2 independent substituents R ;or R and R together with the atoms to which they are attached form a8 1 2 cyclyl ring; R is hydrogen, alkyl, alkynyl, heteroarylalkyl, heterocyclyl, or a heterocyclylalkyl, wherein R is ally substituted with 1 or 2 independent substituents R ; each occurrence of R6 is, independently, halogen, cyano, alkyl, heteroaryl, heterocyclyl, or - S(0)2Rc; m is 1 or 2; each occurrence of R8 is, independently, alkyl or NRaRb; and each occurrence of Ra, Rb, and Rc is, independently, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and cyclyl.
In certain embodiments, X is O. In certain embodiments, X is a bond.
In certain embodiments, Y is O. In certain ments, Y is a bond.
In certain embodiments, Z is O. In certain embodiments, Z is a bond.
In certain embodiments, R1 is hydrogen, alkyl, alkynyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R1 is optionally tuted with 1 or 2 independent substituents R .o In certain embodiments, R1 is alkyl, alkynyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R is optionally substituted with 1 or 2 independent substituents R .
In certain embodiments, R1 is alkyl, alkynyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R1 is optionally substituted with an alkyl group.
] In certain embodiments, R1 is alkyl. In certain embodiments, R1 is C1-4 alkyl. In certain embodiments, R1 is l. In certain embodiments, R1 is C2-4 alkynyl. In certain embodiments, R1 is cycloalkylalkyl. In n embodiments, R1 is cyclopropylmethyl. In certain embodiments, R1 is heterocyclyl optionally substituted with an alkyl group. In certain embodiments, R1 is pyrrolidinyl, tetrahydropyridinyl, morpholinyl, or piperazinyl, optionally substituted with an alkyl group. In certain embodiments, R1 is cyclylalkyl optionally substituted with an alkyl group. In certain embodiments, R1 is oxetanylmethyl.
In certain embodiments, R is hydrogen, alkyl, alkynyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R is optionally substituted with 1 or2 2 independent substituents R .o In certain ments, R is alkyl, alkynyl, heteroarylalkyl, heterocyclyl, or 2 heterocyclylalkyl, wherein R2 is optionally substituted with 1 or 2 independent substituents R8.
In certain embodiments, R is alkyl, alkynyl, cyclyl, heteroarylalkyl, or heterocyclylalkyl, wherein R is optionally substituted with an alkyl 2 ] In certain ments, R is alkyl or heteroarylalkyl optionally substituted with an alkyl group.
In certain embodiments, R is alkyl. In certain embodiments, R is Ci_4 alkyl. In certain embodiments, R is alkynyl. In certain embodiments, R is C2-4 l. In certain ments, 2 2 R is heterocyclyl optionally substituted with an alkyl group. In certain embodiments, R is morpholinyl or tetrahydopyridinyl, optionally substituted with an alkyl group. In certain embodiments, R is cyclylalkyl optionally substituted with an alkyl group. In certain embodiments, R is heteroarylalkyl optionally substituted with one or two alkyl . In certain embodiments, R is pyrazolylmethyl optionally substituted with one or two alkyl groups.
In certain embodiments, R and R together with the atoms to which they are attached form a heterocyclyl ring.
In certain embodiments, R is hydrogen, alkyl, alkynyl, heteroarylalkyl, heterocyclyl,a or heterocyclylalkyl, wherein R is optionally tuted with 1 or 2 independent substituents R .3 8 ] In certain embodiments, R is hydrogen, alkyl, alkynyl, heteroarylalkyl, heterocyclyl, a or heterocyclylalkyl, wherein R3 is optionally substituted with -NRaRb or alkyl.
In certain embodiments, R3 is alkyl optionally substituted with -NRaRb. In n embodiments, R is alkyl optionally substituted with -N(Me)2. In certain embodiments, R is C1-4 alkyl optionally substituted with -N(Me)2. In n embodiments, R is alkynyl. In certain a embodiments, R3is C2-4 alkynyl. In certain embodiments, R3is heteroarylalkyl. In certain embodiments, R is pyridinylmethyl. In n embodiments, R is heterocyclyl. In certain embodiments, R is pyrrolidinyl, piperidinyl, or azetidinyl. In certain ments, R is3 3 heterocyclylalkyl. In n embodiments, R is morpholinylethyl or morpholinylmethyl.a ] In certain embodiments, each occurrence of R6 is, independently, halogen, cyano, alkyl, heteroaryl, heterocyclyl, or -S(0)2RC. In certain embodiments, each occurrence of R6is halogen. In certain embodiments, each occurrence of R6 is F, Cl, Br, or I. In certain embodiments, each occurrence of R6 is F, Cl, or Br. In certain embodiments, each occurrence of R6 is F. In certain embodiments, each occurrence of R6 is Cl. In certain embodiments, each occurrence of R6 is Br. In certain embodiments, each ence of R6 is cyano. In certain embodiments, each occurrence of R6 is alkyl. In certain embodiments, each occurrence of R6 is Ci_4 alkyl. In certain embodiments, each occurrence of R6is methyl. In certain embodiments, each occurrence of R6is heteroaryl. In certain embodiments, each occurrence of R6is triazolyl, tetrazolyl, oxadiazolyl, lyl, or imidazolyl. In certain embodiments, each occurrence of R6 is heterocyclyl. In certain embodiments, each occurrence of R6is dihydrooxadiazolyl or ydrooxadiazolyl. In certain embodiments, each occurrence of R6is -S(0)2RC. In certain embodiments, each occurrence of R6is -S(0)2Me.
In certain embodiments, m is 1. In certain embodiments, m is 2.
In certain embodiments, the compound of Formula I-b is of Formula I-b-1: Z-R3 O R2-Y> I-b-1, or a ceutically acceptable salt thereof.
In n embodiments, R6is F, Cl, Br, or cyano. In certain embodiments, R6is F, Cl, or cyano. In certain embodiments, R6is F or cyano. In certain embodiments, R6is F. In certain embodiments, R6is cyano.
In certain embodiments, the nd of Formula I-c is of Formula I-c-1: Z-R3 O I-c-1, or a pharmaceutically acceptable salt f.
In certain embodiments, R6is F, Cl, Br, or cyano. In certain embodiments, R6is F, Cl, or cyano. In certain embodiments, R6is F or cyano. In n embodiments, R6is F. In certain embodiments, R6is cyano.
] In certain embodiments, the compound of Formula I is of Formula I-d or Formula I-e: O O (R6)m (R6)m R2-Y- r2-y- N N H H R-X R-X Id, I-e, or a pharmaceutically acceptable salt thereof.
] In certain embodiments, X is O or a bond;Y is O or a bond; provided that at least one of X and Y is O; R and R are independently, alkyl, alkynyl, arylalkyl, heterocyclyl, or heterocyclylalkyl, wherein said heteroarylalkyl, heterocyclyl, and heterocyclylalkyl are optionally substituted with 1 or 2 independent alkyl groups; each ence of R6 is, independently, halogen, cyano, alkyl, heteroaryl, heterocyclyl, or -S(0)2RC; m is 1 or 2; and each occurrence of Rc is alkyl.
] In certain embodiments, X is O. In certain embodiments, X is a bond.
In n embodiments, Y is O. In certain embodiments, Y is a bond.
In certain embodiments, R1 is alkyl, alkynyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein said heteroarylalkyl, heterocyclyl, and heterocyclylalkyl are ally substituted with 1 or 2 independent alkyl groups.
In certain embodiments, R1 is alkyl. In certain embodiments, R1 is C1-4 alkyl. In certain embodiments, R1 is alkynyl. In certain embodiments, R1 is C2-4 l. In certain embodiments, R1 is cyclyl ally substituted with an alkyl group. In certain embodiments, R1 is pyrrolidinyl, tetrahydropyridinyl, morpholinyl, or zinyl, optionally substituted with an alkyl group. In certain embodiments, R1 is cyclylalkyl optionally substituted with an alkyl group. In certain embodiments, R1 is oxetanylmethyl.
In certain embodiments, R is alkyl, alkynyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R is optionally substituted with 1-3 independent substituents R .2 8 In certain embodiments, R is alkyl, alkynyl, heteroarylalkyl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl, wherein said heteroarylalkyl, cyclyl, and heterocyclylalkyl are optionally substituted with 1 or 2 independent alkyl groups.
In certain embodiments, R is alkyl or heteroarylalkyl optionally substituted with an alkyl group.
In certain embodiments, R is alkyl. In certain embodiments, R is Ci_4 alkyl. In certain embodiments, R is alkynyl. In certain embodiments, R is C2-4 l. In certain embodiments, 2 2 R is heterocyclyl optionally substituted with an alkyl group. In n embodiments, R is morpholinyl or tetrahydopyridinyl, optionally substituted with an alkyl group. In certain embodiments, R is heterocyclylalkyl optionally substituted with an alkyl group. In certain embodiments, R is arylalkyl optionally substituted with one or two alkyl groups. In 2 certain embodiments, R2 is pyrazolylmethyl optionally substituted with one or two alkyl groups.
In certain embodiments, R and R together with the atoms to which they are ed form a heterocyclyl ring.
In n ments, each occurrence of R6 is, independently, halogen, cyano, alkyl, heteroaryl, heterocyclyl, or -S(0)2RC. In certain embodiments, each occurrence of R6is halogen. In certain embodiments, each occurrence of R6 is F, Cl, Br, or I. In certain embodiments, each occurrence of R6 is F, Cl, or Br. In certain embodiments, each occurrence of R6 is F. In certain embodiments, each ence of R6 is Cl. In certain embodiments, each occurrence of R6 is Br. In certain embodiments, each occurrence of R6 is cyano. In certain embodiments, each occurrence of R6 is alkyl. In certain embodiments, each occurrence of R6 is Ci_4 alkyl. In n embodiments, each occurrence of R6is methyl. In certain embodiments, each occurrence of R6is heteroaryl. In certain embodiments, each occurrence of R6is triazolyl, tetrazolyl, oxadiazolyl, pyrazolyl, or imidazolyl. In certain embodiments, each occurrence of R6 is heterocyclyl. In certain ments, each occurrence of R6is ooxadiazolyl or oxodihydrooxadiazolyl. In certain embodiments, each occurrence of R6is -S(0)2RC. In certain ments, each occurrence of R6is -S(0)2Me.
In certain embodiments, m is 1. In certain embodiments, m is 2.
In certain embodiments, the compound of Formula I-d is of a I-d-1: R2-Y> I-d-1, or a pharmaceutically acceptable salt thereof.
In certain embodiments, R6is F, Cl, Br, or cyano. In certain embodiments, R6is F, Cl, or cyano. In certain embodiments, R6is F or cyano. In certain ments, R6is F. In certain embodiments, R6is cyano.
In certain embodiments, the compound of Formula I-e is of Formula I-e-1: R2-Y> WO 44620 2018/016272 I-e-1, or a pharmaceutically acceptable salt thereof.
In certain embodiments, R6is F, Cl, Br, or cyano. In certain ments, R6is F, Cl, or cyano. In certain embodiments, R6is F or cyano. In certain embodiments, R6is F. In certain embodiments, R6is cyano.
In certain embodiments, the compound of Formula I is of Formula I-f: OR3 O (R6)m H G or a ceutically acceptable salt thereof; wherein G is CO2H or en; W is CN or hydrogen; m is 0 or 1; provided that when G is CO2H, then W is hydrogen; and when W is CN, then G is en; and provided that when G and W are both hydrogen, then m is 1.
In certain embodiments, R and R are independently alkyl, l, alkynyl, 1 2 cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R and R are each optionally substituted with 1-3 independent substituents R ; or R and R together with the atoms to which they are attached form a heterocyclyl ring; R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R is optionally substituted with 1-3 independent substituents R ; R is halogen, cyano, alkyl, haloalkyl, hydroxyl, alkoxy, carboxyl, aryl, heteroaryl, heterocyclyl, - C(0)NRaRb, -S(0)2Rc, or NRaRb; m is 0 or 1; q is 0 or 1; n is 0 or 1; and m + n + q is 1 or 2; provided that when n is 1, then q is 0; and when q is 1, then n is 0.
In certain embodiments, R1 is alkyl, alkenyl, alkynyl, lkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R1 is optionally substituted with 1-3 independent substituents R .o In certain embodiments, R1 is alkyl, alkynyl, lkylalkyl, heteroarylalkyl, cyclyl, or heterocyclylalkyl, wherein R1 is optionally substituted with 1-3 independent tuents R .o In certain embodiments, R1 is alkyl, alkynyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R1 is optionally substituted with an alkyl group.
In n embodiments, R1 is alkyl. In certain embodiments, R1 is C1-4 alkyl. In certain embodiments, R1 is l. In certain embodiments, R1 is C2-4 alkynyl. In certain embodiments, R1 is cycloalkylalkyl. In certain embodiments, R1 is cyclopropylmethyl. In n embodiments, R1 is heterocyclyl optionally substituted with an alkyl group. In certain embodiments, R1 is pyrrolidinyl, tetrahydropyridinyl, morpholinyl, or zinyl, optionally substituted with an alkyl group. In certain embodiments, R1 is cyclylalkyl optionally substituted with an alkyl group. In certain embodiments, R1 is oxetanylmethyl.
In certain embodiments, R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R and R are each1 2 optionally substituted with 1-3 ndent substituents R .o In certain embodiments, R is alkyl, alkynyl, heteroarylalkyl, heterocyclyl, 2 heteroarylalkyl, or heterocyclylalkyl, wherein R is optionally substituted with 1-3 independent substituents R .o In certain embodiments, R is alkyl, alkynyl, heterocyclyl, heteroarylalkyl, or2 heterocyclylalkyl, wherein R is optionally substituted with an alkyl group.2 In certain embodiments, R is alkyl or heteroarylalkyl optionally substituted with an alkyl group.
] In certain ments, R2 is alkyl. In certain embodiments, R2 is Ci_4 alkyl. In certain embodiments, R is alkynyl. In certain embodiments, R is C2-4 alkynyl. In n embodiments, R is heterocyclyl optionally substituted with an alkyl group. In certain embodiments, R is linyl or tetrahydopyridinyl, optionally substituted with an alkyl group. In certain embodiments, R is heterocyclylalkyl optionally substituted with an alkyl group. In certain embodiments, R is heteroarylalkyl optionally substituted with one or two alkyl groups. In certain embodiments, R is pyrazolylmethyl optionally substituted with one or two alkyl groups.
] In certain embodiments, R and R together with the atoms to which they are attached 1 2 form a heterocyclyl ring.
In certain embodiments, R and R are independently alkyl, alkynyl, or1 2 cycloalkylalkyl. In certain embodiments, R and R are alkyl. In certain embodiments, R and R12 12 are Ci-4 alkyl.
In n embodiments, R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,a kyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R is optionally substituteda with 1-3 independent substituents R .o In certain embodiments, R is alkyl, heteroalkyl, heterocyclyl, arylalkyl, ora heterocyclylalkyl, wherein R is optionally substituted with 1-3 independent substituents R .3 8 In certain embodiments, R is hydrogen, alkyl, alkynyl, heteroarylalkyl, heterocyclyl, a or heterocyclylalkyl, wherein R3 is optionally substituted with -NRaRb or alkyl.
] In certain embodiments, R3 is alkyl substituted with NRaRb, heterocyclyl substituted with alkyl, unsubstituted heterocyclyl, unsubstituted heteroarylalkyl, or unsubstituted heterocyclylalkyl.
In certain embodiments, R3 is Ci_4 alkyl substituted with NRaRb; wherein each occurrence of Ra and Rb is alkyl.
In certain embodiments, R3 is alkyl optionally substituted with -NRaRb. In certain embodiments, R is alkyl optionally substituted with -N(Me)2. In n embodiments, R is Ci_4 alkyl optionally substituted with -N(Me)2. In certain embodiments, R is alkynyl. In certaina embodiments, R is C2-4 l. In certain embodiments, R is heteroarylalkyl. In certain 3 3 embodiments, R is pyridinylmethyl. In certain ments, R is heterocyclyl. In certain embodiments, R3 is pyrrolidinyl, piperidinyl, or azetidinyl. In certain embodiments, R3 is heterocyclylalkyl. In certain embodiments, R is morpholinylethyl or morpholinylmethyl.a In certain embodiments, each occurrence of R6 is, independently, halogen, cyano, alkyl, aryl, heterocyclyl, or RC. In certain embodiments, each ence of R6is halogen. In certain embodiments, each occurrence of R6 is F, Cl, Br, or I. In certain ments, each occurrence of R6 is F, Cl, or Br. In certain embodiments, each occurrence of R6 is F. In certain embodiments, each occurrence of R6 is Cl. In certain embodiments, each occurrence of R6 is Br. In certain embodiments, each occurrence of R6 is cyano. In certain embodiments, each ence of R6 is alkyl. In certain embodiments, each occurrence of R6 is C1-4 alkyl. In certain embodiments, each occurrence of R6is methyl. In certain embodiments, each occurrence of R6is heteroaryl. In certain embodiments, each occurrence of R6is triazolyl, tetrazolyl, oxadiazolyl, pyrazolyl, or olyl. In certain ments, each occurrence of R6 is heterocyclyl. In certain embodiments, each occurrence of R6is dihydrooxadiazolyl or oxodihydrooxadiazolyl. In n embodiments, each occurrence of R6is -S(0)2RC. In certain embodiments, each ence of R6is -S(0)2Me.
In certain embodiments, G is CO2H. In certain embodiments, G is hydrogen.
In certain embodiments, W is CN. In certain embodiments, W is hydrogen.
In certain embodiments, m is 0. In certain embodiments, m is 1.
In certain embodiments, the compound of a I is of Formula I-g: OR3 O or a pharmaceutically acceptable salt thereof.
In certain embodiments, R6is F, Cl, Br, or cyano. In certain embodiments, R6is F, Cl, or cyano. In certain embodiments, R6is F or cyano. In certain ments, R6is F. In certain ments, R6is cyano.
In certain embodiments, the compound of Formula I is a compound of Formula I-h: OR3 O or a pharmaceutically acceptable salt thereof.
In certain embodiments, R is en, alkyl, alkynyl, heteroarylalkyl, cyclyl, or heterocyclylalkyl, wherein R is optionally substituted with 1-3 independent tuents R .3 8 In certain embodiments, R is hydrogen, alkyl, alkynyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R3 is optionally substituted with -NRaRb or alkyl.
In certain embodiments, R3 is alkyl optionally substituted with -NRaRb. In certain embodiments, R3 is C1-4 alkyl substituted with NRaRb; wherein each occurrence of Ra and Rb is alkyl. In certain embodiments, R is alkyl optionally substituted with -N(Me)2. In certain embodiments, R is C1-4 alkyl optionally substituted with -N(Me)2. In certain embodiments, R is 3 3 ethyl tuted with NRaRb; wherein each occurrence of Ra and Rb is C1-4 alkyl. In n embodiments, R3 is ethyl substituted with NRaRb; n each occurrence of Ra and Rb is methyl, ethyl, or propyl. In n embodiments, R3 is ethyl tuted with NRaRb; wherein each occurrence of Ra and Rb is methyl. In certain embodiments, R3 is alkynyl. In certain embodiments, R is C2-4 alkynyl. In certain embodiments, R is heteroarylalkyl. In certain embodiments, R is pyridinylmethyl. In certain embodiments, R is heterocyclyl. In certain3 3 embodiments, R is pyrrolidinyl, piperidinyl, or azetidinyl. In certain embodiments, R is3 3 heterocyclylalkyl. In certain embodiments, R is morpholinylethyl or morpholinylmethyl.a In certain embodiments, the compound of a I is a compound of the formula: O O or a pharmaceutically acceptable salt thereof.
In certain embodiments, the compound of Formula I is a compound of the formula I-i: R9 ,Y- N ph 7\R H / x co2h or a pharmaceutically acceptable salt thereof.
In certain embodiments, X is O, NR10, -NR10C(O)-, or CRllaRllb; Y is O, NR10, - C(0)NR10-, or llb; provided that at least one of X and Y is not CRllaRllb; each occurrence of Rg and Rh is, independently, hydrogen, alkyl, or alkynyl, or Rg and Rh together with the carbon atom to which they are ed form a carbonyl; t is 1, 2, or 3; each occurrence of R10 is, ndently, hydrogen or alkyl, wherein R10is ally substituted with 1-3 independent substituents R ; each occurrence of Ro lla and Rlib is, independently, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, wherein each Rlla and Rllb are optionally tuted with 1-3 independent substituents R ; each occurrence of R is, independently, alkyl, alkynyl, hydroxyl, alkoxy, carboxyl, oxo, aryl, heteroaryl, heterocyclyl, NRaRb, -S(0)2RC, or -C02Rd; and each occurrence of Ra, Rb, Rc, and Rd is, independently, hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, heterocyclyl, C(0)0Ci-6 alkyl, -6 alkyl, or Ra and Rb together with the atoms to which they are attached form a heterocyclyl ring.
In certain embodiments, X is O or NR10. In n embodiments, X is O or NR10; and R10is hydrogen or alkyl. In certain embodiments, X is O. In certain embodiments, X is NR10. In certain embodiments, X is NR10; and R10is alkyl. In certain embodiments, X is NR10; and R10is Ci_4 alkyl. In certain ments, X is NR10; and R10 is methyl.
In certain embodiments, Y is O or NR10. In certain embodiments, Y is O or NR10; and R10is hydrogen or alkyl. In certain embodiments, Y is O. In n embodiments, Y is NR10. In certain embodiments, Y is NR10; and R10is alkyl. In certain embodiments, Y is NR10; and R10is Ci_4 alkyl. In certain embodiments, Y is NR10; and R10 is methyl.
In certain embodiments, X is O or NR10; and Y is O or NR10. In certain ments, X is O or NR10; Y is O or NR10; and R10 is hydrogen or alkyl. In certain embodiments, X is O or NR10; Y is O or NR10; and R10 is hydrogen or C1-4 alkyl. In certain embodiments, X is O or NR10; Y is O or NR10; and R5 is Ci_4 alkyl. In certain embodiments, X is O or NR10; Y is O or NR10; and R10 is methyl, ethyl, propyl, or butyl. In certain ments, X is O; Y is NR10; and R10 is C1-4 alkyl. In certain embodiments, X is O; Y is NR10; and R10is methyl, ethyl, propyl, or butyl.
In certain embodiments, X is O; Y is NR10; and R10is methyl.
In certain embodiments, Rg is hydrogen or alkyl. In certain embodiments, Rg is hydrogen or Ci_4 alkyl. In n embodiments, Rg is hydrogen, halogen, or Ci_2 alkyl. In certain embodiments, Rg is hydrogen.
In certain embodiments, Rh is hydrogen or alkyl. In certain embodiments, Rh is hydrogen or Ci_4 alkyl. In n embodiments, Rh is hydrogen or Ci_2 alkyl. In certain embodiments, Rh is hydrogen.
In certain embodiments, each occurrence of Rg and Rh is, independently, hydrogen or alkyl. In certain embodiments, each occurrence of Rg and Rh is, ndently, hydrogen or C1-4 alkyl. In certain ments, each occurrence of Rg and Rh is, independently, hydrogen, halogen, or Ci_2 alkyl. In certain embodiments, each occurrence of Rg and Rh is hydrogen. In certain embodiments, Rg and Rh together with the carbon atom to which they are attached form a carbonyl.
In certain embodiments, t is 1, 2, or 3. In n embodiments, t is 1 or 2. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3.
In certain embodiments, the nd of Formula I is a compound of Formula I-j: or a pharmaceutically acceptable salt thereof, wherein: In certain embodiments, X is O, NR10, or CRllaRllb; Y is O, NR10, or CRllaRllb; provided that at least one of X and Y is not CRllaRllb; each occurrence of R10 is, independently, hydrogen or alkyl, wherein R is ally substituted with 1-3 independent substituents R ; each occurrence of Rlla and Rllb is, independently, alkyl, alkynyl, lkyl, cycloalkylalkyl, wherein each Rlla and Rllb are optionally tuted with 1-3 independent substituents R8; each occurrence of R is, independently, alkyl, alkynyl, hydroxyl, alkoxy, yl, oxo, aryl, o heteroaryl, heterocyclyl, NRaRb, -S(0)2RC, or -COiR1'; and each occurrence of Ra, Rb, Rc, and Rd is, independently, hydrogen, acyl, alkyl, l, alkynyl, heteroalkyl, lkyl, heterocyclylalkyl, aryl, heteroaryl, heterocyclyl, C(0)OCi_6 alkyl, C(0)Ci_6 alkyl, or Ra and Rb er with the atoms to which they are attached form a heterocyclyl ring.
In certain embodiments, X is O or NR10. In certain embodiments, X is O or NR10; and R10 is hydrogen or alkyl. In certain embodiments, X is O. In certain embodiments, X is NR10. In certain embodiments, X is NR10; and R10 is alkyl. In certain embodiments, X is NR10; and R10 is Ci_4 alkyl. In certain embodiments, X is NR10; and R10 is methyl.
In certain ments, Y is O or NR10. In certain embodiments, Y is O or NR10; and R10is hydrogen or alkyl. In certain embodiments, Y is O. In certain embodiments, Y is NR10. In certain embodiments, Y is NR10; and R10is alkyl. In certain embodiments, Y is NR10; and R10is Ci_4 alkyl. In certain embodiments, Y is NR10; and R10 is methyl.
In certain embodiments, X is O or NR10; and Y is O or NR10. In certain embodiments, X is O or NR10; Y is O or NR10; and R10 is hydrogen or alkyl. In certain embodiments, X is O or NR10; Y is O or NR10; and R10 is hydrogen or Ci_4 alkyl. In n ments, X is O or NR10; Y is O or NR10; and R5 is Ci_4 alkyl. In certain embodiments, X is O or NR10; Y is O or NR10; and R10 is methyl, ethyl, propyl, or butyl. In certain embodiments, X is O; Y is NR10; and R10 is C1-4 alkyl. In n embodiments, X is O; Y is NR10; and R10is methyl, ethyl, propyl, or butyl.
In certain embodiments, X is O; Y is NR10; and R10is methyl.
] In certain embodiments, the compound of Formula I is a compound of the formula: or a pharmaceutically acceptable salt thereof.
Examples of the compound of Formula I include, but are not limited to (E)-N-(2-fluorophenyl)(3-methoxy(propyn-1 -yloxy)phenyl)acrylamide (1); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(5-methyl-lH-l,2,4-triazol yl)phenyl)acrylamide (2); (2-chlorophenyl)(3-methoxy(propyn-l-yloxy)phenyl)acrylamide (3); (E)-N-(2-bromophenyl)(3-methoxy(propyn-l-yloxy)phenyl)acrylamide (4); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(o-tolyl)acrylamide (5); (E)-N-(2-cyanophenyl)(3-methoxy(propyn-l-yloxy)phenyl)acrylamide (6); (E)-N-(3,4-dichlorophenyl)(3-methoxy(propyn-l-yloxy)phenyl)acrylamide (7); (E)-N-(2-(2H-tetrazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (16); (E)-N-(2-(l,2,4-oxadiazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (17); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(5-methyl-l,2,4-oxadiazol yl)phenyl)-acrylamide (18); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3 -yl)phenyl)acrylamide (19); (E)-N-(2-(l,2,4-oxadiazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (20); (2-(l,3,4-oxadiazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (21); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(l-methyl-lH-pyrazol yl)phenyl)-acrylamide (22); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(3-methyl-lH-l,2,4-triazol-lyl )phenyl)acryl-amide (23); (E)-N-(2-(lH-pyrazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (24); (E)-N-(2-(lH-imidazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (25); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(l-methyl-lH-imidazol nyl)acrylamide (26); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N- lsulfonyl)benzamide (27); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(3-methyl-l,2,4-oxadiazol yl)phenyl)acryl-amide (28); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(5-methyl-l,3,4-oxadiazol yl)phenyl)-acrylamide (29); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2H-tetrazol yl)benzamide (31); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(l-methylpiperidin yl)benzamide (36); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(oxetan yl)benzamide (38); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(pyridin yl)benzamide (44); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(l-methyl-lH-pyrazol- 4-yl)benzamide (47); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(l-methyl-lH-pyrazol- 3-yl)benzamide (48); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(piperidin zamide (49); (E)(3-(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)acrylamido)benzoic acid (51); (E)-N-(3-cyanophenyl)[2-[2-(dimethylamino)ethoxy]methoxypropynoxyphenyl 2-enamide (76); ((E)-N-(2-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxy(propyn-lyloxy )phenyl)acrylamide (77); (E)(3-(2-(2-(dimethylamino)ethoxy)methoxy(propyn-lyloxy )phenyl)acrylamido)-benzoic acid (78); (E)-N-(2-cyanophenyl)[3-methoxy(l-methylazetidinyl)oxypropynoxyphenyl ]propenamide (79); 2-[[(E)(3-methoxypropynoxypyrrolidinyloxyphenyl)prop enoyl]amino]benzoic acid (80); (E)-N-(2-cyanophenyl)[3-methoxy(l-methylpyrrolidinyl)oxypropynoxyphenyl ]propenamide (81); (E)-N-(2-cyanophenyl)(3-methoxypropynoxypyrrolidinyloxy-phenyl)prop- 2-enamide (82); 2-[[(E)[3-methoxy(4-piperidyloxy)propynoxy-phenyl]prop enoyl]amino]benzoic acid (83); 2-[[(E)[3-methoxy(2-morpholinoethoxy)propynoxy-phenyl]prop amino]benzoic acid (84); (E)-N-(2-cyanophenyl)[3-methoxy(2-morpholinoethoxy)propynoxyphenyl ]propenamide (85); 2-[[(E)[2-[3-(dimethylamino)propoxy]methoxypropynoxy-phenyl]prop enoyl]amino]benzoic acid (86); (E)-N-(2-cyanophenyl)[2-[3-(dimethylamino)propoxy]methoxypropynoxyphenyl ]propenamide (87); (E)-N-(2-cyanophenyl)[3-methoxy(4-piperidyloxy)propynoxy-phenyl]prop enamide (88); (E)-N-(2-cyanophenyl)[3-methoxy[(l-methylpiperidyl)oxy]propynoxyphenyl ]propenamide (89); 2-[[(E)[4-(cyclopropylmethoxy)[2-(dimethylamino)ethoxy]methoxyphenyl ]propenoyl]amino]benzoic acid (90); (E)-N-(3-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide (91); (E)-N-(2-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide (92); (E)-N-(3-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide (93); (E)-N-(2-cyanophenyl)[2-[2-(dimethylamino)ethoxy]methoxy-phenyl]prop enamide (94); (3-(3,4-dimethoxy(propyn-l-yloxy)phenyl)acrylamido)benzoic acid (95); (E)(3-(3,4-dimethoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (96); (3-(3-methoxy(4-methylpiperazin-l-yl)phenyl)acrylamido)benzoic acid (97); (E)(3-(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)acrylamido)benzoic acid (98); (E)(3-(3-methoxy( 1-methyl-1,2,3,6-tetrahydropyridin yl)phenyl)acrylamido)benzoic acid (99); (E)(3-(4-methoxymorpholinophenyl)acrylamido)benzoic acid (101); (E)(3-(3-methoxymorpholinophenyl)acrylamido)benzoic acid (103); (E)(3-(4-methoxy( 1-methyl-1,2,3,6-tetrahydropyridin yl)phenyl)acrylamido)benzoic acid (104); 2-[[(E)(4-methyl-2,3-dihydro-l,4-benzoxazinyl)propenoyl]amino]benzoic acid (107); (E)-N-(2-(l,2,4-oxadiazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (108); (E)(3-(4-methyloxo-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (109); (E)(3-(4-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (HO); (E)(3-(3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (ill); (E)(3-(4-methyloxo-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (112); (3-ethyl(propyn-l-yloxy)phenyl)-N-(2-(3-methyl-lH-l,2,4-triazol-lyl )phenyl)-acrylamide (114); (E)(3-(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)acrylamido)benzoic acid (116); (E)chloro(3-(2-(2-(dimethylamino)ethoxy)-3,4- dimethoxyphenyl)acrylamido)benzoic acid (117); (E)-N-(4-fluorophenyl)(3-methoxy(l,2,3,6-tetrahydropyridin nyl)acrylamide (120); N-(4-cyanophenyl)(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)cyclopropane carboxamide (121); 2-(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)-N-(4-fluorophenyl)cyclopropane- 1-carboxamide (122); (E)(3-ethyl(propyn-l-yloxy)phenyl)-N-(2-fluorophenyl)acrylamide (123); (E)-A/-(4-cyanophcnyl)(3-cthyl(propyn-l -yloxy)phcnyl)acrylamidc (124); (E)(3-ethyl(propyn-l-yloxy)phenyl)-N-(4-fluorophenyl)acrylamide (125); (E)(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)-N-(2- fluorophenyl)acrylamide (127); (2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)-N-(4- fluorophenyl)acrylamide (128); (E)-N-(4-cyanophenyl)(2-(2-(dimethylamino)ethoxy)-3,4- dimethoxyphenyl)acrylamide (129); (E)(3-(4-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (130); (E)-N-(4-cyanophenyl)(3-methoxy((l-methylpyrrolidin yl)oxy)phenyl)acrylamide (131); (E)-N-(4-fluorophenyl)(3-methoxy((l-methylpyrrolidin yl)oxy)phenyl)acrylamide (132); N-(4-fluorophenyl)(3-methoxy(propyn-lyloxy )phenyl)cyclopropanecarboxamide (133); N-(4-cyanophenyl)(3-methoxy(propyn-lyloxy )phenyl)cyclopropanecarboxamide (135); N-(4-fluorophenyl)(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)cyclopropane- 1-carboxamide (136); yanophenyl)(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)cyclopropane- 1-carboxamide (137); N-(2-fluorophenyl)(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)cyclopropane carboxamide (138); (E)-N-(4-cyanophenyl)(3-methoxy( 1,2,3,6-tetrahydropyridin yl)phenyl)acrylamide (139); (E)(3-methoxy( 1,2,3,6-tetrahydropyridinyl)phenyl)-N-(2-(3-methyl-lH-1,2,4- triazol-1 - yl)phenyl) acrylamide (140); (E)-N-(2-fluorophenyl)(3-methoxy(l,2,3,6-tetrahydropyridin yl)phenyl)acrylamide (141); N-(4-fluorophenyl)(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)cyclopropane carboxamide (143); 2-(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)-N-(2-(3-methyl-lH-1,2,4- triazol-1 -yl)phenyl)cyclopropanecarboxamide (144); luorophenyl)(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)cyclopropane carboxamide (145); (3-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide (147); N-(3-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropane-lcarboxamide (148); N-(4-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol yl)methoxy)phenyl)cyclopropanecarboxamide (149); (E)-N-(3-chlorophenyl)(4-methoxymorpholinophenyl)acrylamide (151); (E)-N-(2-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide (152); (E)-N-(4-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide (153); N-(4-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropane-lcarboxamide (154); N-(2-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropane-lcarboxamide (155); N-(3-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol yl)methoxy)phenyl)cyclopropanecarboxamide (156); N-(2-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol yl)methoxy)phenyl)cyclopropanecarboxamide (157); 2-(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)-N-(3- (methylsulfonyl)phenyl) cyclopropanecarboxamide (158); (E)-N-(2-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol yl)methoxy)phenyl)acrylamide (159); (E)-N-(3-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol hoxy)phenyl)acrylamide (160); and pharmaceutically acceptable salts thereof.
In another aspect, disclosed are the following compounds: (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-phenylacrylamide (8); methyl (E)-l-(3-(3-methoxy(propyn-l-yloxy)phenyl)acryloyl)-l,2,3,4- tetrahydroquinolinecarboxylate (9) (E)-l-(3,4-dihydroquinolin-l(2H)-yl)(3-methoxy(propyn-l-yloxy)phenyl)prop- 2-en-l-one (10); (E)-l-(3,4-dihydroquinoxalin-l(2H)-yl)(3-methoxy(propyn-lyloxy )phenyl)propen-1 -one (11); (E)-l-(2,3-dihydro-4H-benzo[b][l,4]oxazinyl)(3-methoxy(propyn-lyloxy )phenyl)propen-1 -one (12); (E)-N-((trans)aminocyclohexyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (13); (E)-l-(4-hydroxy-3,4-dihydroquinolin-l(2H)-yl)(3-methoxy(propyn-lyloxy l)propen-1 -one (14); (E)-l-(3-hydroxy-lH-indazol-l-yl)(3-methoxy(propyn-l-yloxy)phenyl)prop en-l-one (15); (2-(dimethylamino)ethyl)(3-(3-methoxy(propyn lyloxy) phenyl) acrylamido) ide (30); (E)-N-(3-(dimethylamino)propyl)(3-(3-methoxy(propyn-lyloxy )phenyl)acrylamido) benzamide (32); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2- methoxyethyl)benzamide (33); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2-(4-methylpiperazinl-yl )ethyl)benzamide (34); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2-morpholino ethyl)benzamide (35); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-((l-methylpiperidin yl)methyl)benzamide (37); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-((tetrahydrofuran yl)methyl)benzamide (39); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-((l-methyl-lH- imidazolyl)methyl)benzamide (40); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(pyridin ylmethyl)benzamide (41); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2-(pyridin yl)ethyl)benzamide (42); (3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(pyridin ylmethyl)benzamide (43); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(pyridin ylmethyl)benzamide (45); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2-(pyridin yl)benzamide (46); (E)(3-(3-methoxy(piperidinylmethoxy)phenyl)acrylamido)benzoic acid (50); (E)(3-(4-((3,5-dimethylisoxazolyl)methoxy)methoxyphenyl)acrylamido)benzoic acid (52); (E)(3-(3-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (53); (E)(3-(3-methoxy(oxetanylmethoxy)phenyl)acrylamido)benzoic acid (54); (E)(3-(3-methoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (55); (E)(3-(3-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (56); (E)(3-(3-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (57); (3-(3-methoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (58); (E)(3-(3-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (59); (E)(3-(3-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (60); (E)(3-(4-methoxy(2-methoxyethoxy)phenyl)acrylamido)benzoic acid (61); (E)(3-(4-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (62); (E)(3-(4-methoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (63); (E)(3-(4-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (64); (E)(3-(4-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (65); (3-(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (66); (E)(3-(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (67); (E)(3-(3-methoxy((4-methylpiperazin-l-yl)methyl)phenyl)acrylamido)benzoic acid (68); (E)(3-(3-methoxy(morpholinomethyl)phenyl)acrylamido)benzoic acid (69); (E)(3-(4-methoxy(((l-methylpiperidinyl)oxy)methyl)phenyl)acrylamido)benzoic acid (70) (E)(3-(4-methoxy((propyn-l-yloxy)methyl)phenyl)acrylamido)benzoic acid (71); (E)(3-(3-methoxy((propyn-l-yloxy)methyl)phenyl)acrylamido)benzoic acid (72); (E)(3-(4-methoxy(methoxymethyl)phenyl)acrylamido)benzoic acid (73); (E)(3-(4-methoxy((propyn-l-ylamino)methyl)phenyl)acrylamido)benzoic acid (74); (E)(3-(3-methoxy((propyn-l-ylamino)methyl)phenyl)acrylamido)benzoic acid (75); (E)(3-(4-ethylmethoxyphenyl)acrylamido)benzoic acid (100); 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid (102); (E)(3-(3-ethylmethoxyphenyl)acrylamido)benzoic acid (105); (E)(3-(3-(cyclopropylmethyl)methoxyphenyl)acrylamido)benzoic acid (106); (E)-l-(2H-benzo[b][l,4]oxazin-4(3H)-yl)(3-ethyl(propyn-l-yloxy)phenyl)prop- 2-en-l-one (113); (E)-1 -(2H-benzo[b] [ 1,4]oxazin-4(3H)-yl)-3 -(dimethylamino)ethoxy)-3,4- dimethoxyphenyl)-propen-1 -one (115); (E)-l-(2H-benzo[b][l,4]oxazin-4(3H)-yl)(3-methoxy((l-methylpyrrolidin yl)oxy)phenyl)propen-1 -one (118); (2H-benzo[b] [ azin-4(3H)-yl)(2-(3-methoxy(propyn-1 -yloxy) phenyl) ropyl) methanone (119); (E)(3-ethyl(propyn-l-yloxy)phenyl)-l-(3-hydroxy-lH-indazol-l-yl)propen-l- one (126); (3-hydroxy- azol- l-yl)(2-(3-methoxy(propyn- l-yloxy)phenyl)cyclopropyl) methanone (134); (E)-l-(3-hydroxy-lH-indazol-l-yl)(3-methoxy( 1,2,3,6-tetrahydropyridin yl)phenyl)propen-l-one (142); (3-hydroxy-lH-indazol-l-yl)(2-(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl) cyclopropyl)methanone (146); (E)(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)-N-(pyridin yl)acrylamide (150); and pharmaceutically acceptable salts thereof.
For example, disclosed is a compound of the formula: or a pharmaceutically acceptable salt thereof.
In certain embodiments, the compound of Formula I inhibits TGF-P induced proline incorporation in cells with an IC50 of less than 100,000 pM, less than 50,000 pM, less than ,000 pM, less than 10,000 pM, less than 5,000 pM, less than 2,500 pM, less than 1,000 pM, less than 900 pM, less than 800 pM, less than 700 pM, less than 600 pM, less than 500 pM, less than 400 pM, less than 300 pM, less than 200 pM, less than 100 pM, less than 90 pM, less than 80 pM, less than 70 pM, less than 60 pM, less than 50 pM, less than 40 pM, less than 30 pM, less than 20 jaM, less than 10 jjM, less than 5 jjM, less than 4 jaM, less than 3 jaM, less than 2 jaM, or less than 1 jaM.
In certain embodiments, any compound disclosed herein (e.g., 2-[[(£’)[4- propylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid) inhibits TGF-P induced e incorporation in cells with an IC50 of less than 100,000 pM, less than 50,000 pM, less than 20,000 pM, less than 10,000 pM, less than 5,000 pM, less than 2,500 pM, less than 1,000 pM, less than 900 pM, less than 800 pM, less than 700 pM, less than 600 pM, less than 500 pM, less than 400 pM, less than 300 pM, less than 200 pM, less than 100 pM, less than 90 pM, less than 80 pM, less than 70 pM, less than 60 pM, less than 50 pM, less than 40 pM, less than 30 pM, less than 20 pM, less than 10 pM, less than 5 pM, less than 4 pM, less than 3 pM, less than 2 pM, or less than 1 pM.
Pharmaceutical Compositions, Kits, and Administration The present disclosure provides ceutical compositions comprising a compound {e.g., compound of Formula I, 2-[[(£’)[4-(cyclopropylmethyl)methoxyphenyl]prop enoyl]amino]benzoic acid) or a pharmaceutically able salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodmg thereof, and optionally a pharmaceutically able excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound {e.g., compound of Formula I, 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
In certain ments, the compound {e.g., compound of Formula I, 2-[[(E)[4- (cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid) is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain ments, the ive amount is an amount effective for treating a disease or condition associated with fibrosis in a subject in need thereof.
In certain embodiments, the effective amount is an amount effective for preventing disease or ion associated with fibrosis in a subject in need f. In certain embodiments, the effective amount is an amount effective for treating fibrotic skin disorders {e.g., keloids, hypertrophic scars, derma) in a subject in need thereof. In certain embodiments, the ive amount is an amount effective for preventing fibrotic skin disorders (e.g., keloids, hypertrophic scars, scleroderma) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating kidney disease in a subject in need f.
In certain embodiments, the effective amount is an amount effective for preventing kidney disease in a t in need thereof. In certain embodiments, the effective amount is an amount effective for treating an inflammatory disease in a subject in need thereof. In certain ments, the effective amount is an amount effective for preventing an inflammatory e in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a benign or malignant neoplastic disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a benign or malignant neoplastic disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for reducing the risk of developing a disease (e.g., fibrosis, fibrotic skin disorders, kidney disease, inflammatory disease, or benign or malignant neoplastic disease) in a subject in need thereof. In n embodiments, the effective amount is an amount effective for inhibiting the activity (e.g., nt activity, such as increased activity) of a protein in a t or cell.
In certain embodiments, the subject is an . The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the t is a mammal. In certain embodiments, the subject is a man mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In n embodiments, the t is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the t is a fish or reptile.
In certain embodiments, the effective amount is an amount effective for inhibiting the ty of the TGF-P signaling pathway by at least about 10%, at least about 20%, at least about %, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of the TGF-P signaling pathway by a range between a percentage described in this paragraph and r percentage described in this aph, inclusive.
The present disclosure provides pharmaceutical compositions comprising a nd {e.g., compound of Formula I, 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]prop enoyl]amino]benzoic acid) for use in treating a disease or ion associated with is in a subject in need thereof. In certain embodiments, the composition is for use in treating fibrotic skin disorders {e.g., keloids, hypertrophic scars, derma). In certain embodiments, the composition is for use in treating a lung disease {e.g., pulmonary fibrosis). In certain embodiments, the composition is for use in treating heart disease {e.g., ischaemic heart disease, valvular heart disease, hypertensive heart disease, diabetic cardiomyopathy, hypertension). In certain embodiments, the composition is for use in treating kidney disease. In certain embodiments, the composition is for use in treating cirrhosis of the liver. In certain embodiments, the composition is for use in treating kidney disease, n the kidney disease is progressive kidney disease, glomerulonephritis, diabetic kidney disease, diabetic nephropathy, systemic lupus, primary glomerulonephritis, membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis, secondary glomerulonephritis, or ischemic pathy.
A compound or composition, as described , can be administered in combination with one or more additional pharmaceutical agents {e.g., therapeutically and/or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity {e.g., activity {e.g., potency and/or efficacy) in ng a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, and/or in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit ion, and/or modify distribution in a subject or cell. It will also be appreciated that the y ed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In n embodiments, a pharmaceutical composition described herein including a compound described herein and an onal pharmaceutical agent exhibit a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.
The compound or ition can be administered concurrently with, prior to, or uent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination ies. Pharmaceutical agents include therapeutically active agents.
Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or nary use by the U.S. Food and Drug stration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, ccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the onal pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g., proliferative disease, hematological cancer, autoimmune disease, and/or inflammatory disease). Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those ed individually.
] The onal pharmaceutical agents include, but are not d to, anti-proliferative agents, anti-cancer , anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, and anti-viral agents. In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In n embodiments, the additional pharmaceutical agent is an immunotherapy. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In n embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the anti-cancer agents include, but are not limited to, epigenetic or transcriptional modulators (e.g., DNA transferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), cell signaling pathway inhibitors (e.g., tyrosine n kinase tors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, ans retinoic acids, anti-estrogens (e.g., tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g., goscrclin and leuprolide), anti­ androgens (e.g. flutamide and bicalutamide), photodynamic therapies (e.g., vertoporfin (BPDMA ), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BADMHA)), nitrogen mustards (e.g., cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g., carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g., busulfan and treosulfan), triazenes (e.g. azine, temozolomide), platinum containing compounds (e.g. cisplatin, latin, oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g. paclitaxel or a axel equivalent such as nanoparticle albumin-bound paclitaxel (ABRAXANE), docosahexaenoic acid bound-paclitaxel aclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel umex, 3, XYOTAX), the activated prodmg (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, e.g., 2'-paclitaxel methyl 2- glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g. etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, irinotecan, irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors (e.g. rexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin, and , ribonuclotide reductase inhibitors (e.g. hydroxyurea and deferoxamine), uracil analogs (e.g. 5-fluorouracil (5-FU), floxuridine, doxifluridine, ratitrexed, r-uracil, capecitabine), cytosine analogs (e.g. cytarabine (ara C), cytosine arabinoside, and fludarabine), purine analogs (e.g. mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g. l-methylphenylpyridinium ion), cell cycle inhibitors (e.g. staurosporine), actinomycin (e.g. actinomycin D, dactinomycin), cin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracycline (e.g. daunorubicin, doxorubicin, ted liposomal doxorubicin, idarubicin, epimbicin, pirarubicin, zorubicin, mitoxantrone), MDR tors (e.g. verapamil), Ca2+ ATPase inhibitors (e.g. thapsigargin), thalidomide, lenalidomide, pomalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTINTM, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib ec®, CGP57148B, STI-571), lapatinib (TYKERB®, ®), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA®), semaxanib (semaxinib, ), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab IN®), mab (RETUXAN®), mab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus EL®), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOKTM), SGX523, PF-04217903, PF-02341066, PE-299804, BMS-777607, ABT-869, MP470, BIBE 1120 (VARGATEF®), AP24534, JNJ- 26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)), mTOR inhibitors (e.g., rapamycin, temsirolimus 79), imus (RAD- 001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi s), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, lan, leurosidine, leurosine, chlorambucil, tedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethyl melamine.
In certain embodiments, the compounds bed herein or pharmaceutical compositions can be administered in combination with an anti-cancer y including, but not limited to, surgery, radiation therapy, and lantation (e.g., stem cell transplantation, bone marrow transplantation).
In certain embodiments, the compound or pharmaceutical composition is a solid. In certain ments, the compound or pharmaceutical composition is a powder. In certain ments, the compound or pharmaceutical composition can be dissolved in a liquid to make a solution. In n embodiments, the compound or pharmaceutical composition is dissolved in water to make an aqueous solution. In n embodiments, the pharmaceutical composition is a liquid for parental injection. In certain embodiments, the pharmaceutical composition is a liquid for oral stration (e.g., ingestion). In certain embodiments, the pharmaceutical composition is a liquid (e.g., s solution) for intravenous injection. In certain embodiments, the pharmaceutical composition is a liquid (e.g., aqueous on) for subcutaneous ion.
After formulation with an appropriate pharmaceutically acceptable excipient in a desired dosage, the pharmaceutical compositions of this invention can be administered to humans and other animals orally, parenterally, intracisternally, intraperitoneally, topically, bucally, or the like, depending on the disease or condition being treated.
In certain embodiments, a pharmaceutical composition comprising a compound (e.g., compound of Formula I, 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]prop enoyl]amino]benzoic acid) is stered, orally or parenterally, at dosage levels of each pharmaceutical composition sufficient to deliver from about 0.001 mg/kg to about 200 mg/kg in one or more dose administrations for one or several days (depending on the mode of administration). In certain ments, the effective amount per dose varies from about 0.001 mg/kg to about 200 mg/kg, about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about mg/kg, from about 0.1 mg/kg to about 10 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired eutic and/or prophylactic effect. In certain ments, the compounds described herein may be at dosage levels sufficient to deliver from about 0.001 mg/kg to about 200 mg/kg, from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, ably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and/or prophylactic effect. The desired dosage may be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, en, or more administrations). In certain embodiments, the ition described herein is stered at a dose that is below the dose at which the agent causes non-specific effects.
] In n embodiments, the pharmaceutical composition is administered at a dose of about 0.001 mg to about 1000 mg per unit dose. In n ments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 200 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 100 mg per unit dose. In certain embodiments, pharmaceutical composition is stered at a dose of about 0.01 mg to about 50 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 10 mg per unit dose. In certain embodiments, the ceutical composition is administered at a dose of about 0.1 mg to about 10 mg per unit dose.
Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such atory methods include the steps of bringing the composition comprising a compound {e.g., compound of Formula I, 2-[[(E)[4- (cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid) into association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the t into a desired single- or multi-dose unit.
Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, a "unit dose" is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient on of such a dosage, such as, for example, one-half or one-third of such a dosage.
Relative amounts of the active ient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w/w) active ingredient.
Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, e active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
Exemplary diluents include calcium carbonate, sodium carbonate, calcium ate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium ate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, ed sugar, and mixtures thereof.
Exemplary granulating and/or sing agents include potato starch, corn starch, a , sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, -exchange , calcium carbonate, silicates, sodium carbonate, linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium ymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and es thereof.
Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, n, egg yolk, casein, wool fat, terol, wax, and in), colloidal clays (e.g. bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl earate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, rylic acid, acrylic acid polymer, and yvinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered ose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan arate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80)), polyoxyethylene esters (e.g. polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, WO 44620 and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor™), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), lene glycol monolaurate, triethanolamine oleate, sodium oleate, ium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamer-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.
Exemplary binding agents e starch (e.g. cornstarch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl ose, hydroxypropyl methylcellulose, rystalline cellulose, cellulose acetate, inyl-pyrrolidone), ium aluminum silicate (Veegum), and larch alactan), alginates, polyethylene oxide, polyethylene glycol, inorganic m salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof. ary vatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the vative is a chelating agent.
Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium e, disodium edetate, trisodium edetate, calcium disodium e, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, dine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, butanol, hydroxybenzoate, and phenylethyl l.
Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, betacarotene , citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
Other preservatives include erol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), ted hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SEES), sodium bisulfite, sodium metabisulfite, potassium e, ium sulfite, Glydant Plus, Phenonip, methylparaben, l 115, Germaben II, Neolone, Kathon, and Euxyl.
Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic m phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, ium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic ium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, sic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer’s solution, ethyl alcohol, and mixtures f.
Exemplary lubricating agents include magnesium stearate, m stearate, stearic acid, silica, talc, malt, glyceryl behanate, enated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures f.
Exemplary l oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, le, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, , com, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, er, lemon, litsea , macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange , palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, wer, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric ceride, ethicone, l sebacate, dimethicone 360, pyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, symps, and elixirs. In addition to the active agents, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, lizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, , and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, agents of the invention are mixed with solubilizing agents such CREMOPHOR EL® (polyethoxylated castor oil), alcohols, oils, ed oils, glycols, polysorbates, extrins, polymers, and combinations thereof.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be ated according to the known art using suitable dispersing or wetting agents and suspending . Sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the able vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and ic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or ding medium. For this purpose any bland fixed oil can be employed including tic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of e solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active agent is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or ers such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, ymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and ite clay, and i) lubricants such as talc, calcium stearate, magnesium te, solid polyethylene s, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
] Solid compositions of a similar type may also be employed as fillers in soft and hardfilled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may ally contain opacifying agents and can also be of a composition that they e the active ient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hardfilled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The active agents can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other gs well known in the pharmaceutical formulating art. In such solid dosage forms the active agent may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also se, as is normal practice, onal substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and rystalline ose. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering . They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Formulations suitable for topical administration include liquid or iquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments, or pastes; or solutions or suspensions such as drops. Formulations for topical administration to the skin surface can be prepared by sing the drug with a dermatologically acceptable carrier such as a , cream, ointment, or soap. Useful carriers are capable of forming a film or layer over the skin to localize application and t removal. For topical stration to internal tissue surfaces, the agent can be dispersed in a liquid tissue adhesive or other substance known to enhance adsorption to a tissue surface. For example, hydroxypropylcellulose or fibrinogen/thrombin solutions can be used to advantage. atively, tissue-coating solutions, such as pectin-containing formulations can be used. lmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of an agent to the body. Such dosage forms can be made by dissolving or dispensing the agent in the proper medium. Absorption ers can also be used to increase the flux of the agent across the skin.
The rate can be controlled by either providing a rate controlling membrane or by dispersing the agent in a polymer matrix or gel.
Additionally, the carrier for a topical formulation can be in the form of a hydroalcoholic system (e.g., quids and gels), an anhydrous oil or silicone based system, or an emulsion system, ing, but not limited to, oil-in-water, water-in-oil, water-in-oil-in-water, and -water-in-silicone emulsions. The emulsions can cover a broad range of consistencies including thin lotions (which can also be suitable for spray or l delivery), creamy lotions, light creams, heavy creams, and the like. The ons can also include microemulsion systems. Other suitable topical rs include anhydrous solids and semisolids (such as gels and sticks); and aqueous based mousse systems.
Also encompassed by the disclosure are kits {e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container {e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, ed kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or nd described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.
Thus, in one , provided are kits including a first container comprising a compound or pharmaceutical ition described herein. In certain ments, the kits are useful for ng a disease {e.g., proliferative disease, hematological cancer, autoimmune disease, inflammatory disease) in a subject in need thereof. In certain embodiments, the kits are useful for ting a disease {e.g., a disease or condition associated with fibrosis, a benign or malignant neoplastic disease, inflammatory disease) in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease {e.g., a disease or condition associated with fibrosis, a benign or malignant neoplastic disease, inflammatory disease) in a subject in need thereof. In certain embodiments, the kits are useful for ting the activity {e.g., aberrant activity, such as increased activity) of the TGF-P signaling pathway in a subject or cell.
In certain ments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In n embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease {e.g., a e or condition associated with fibrosis, a benign or malignant stic disease, inflammatory disease) in a t in need thereof. In certain embodiments, the kits and instructions provide for ting a disease (e.g., a disease or condition ated with fibrosis, a benign or malignant neoplastic disease, inflammatory disease) in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease (e.g., a disease or condition associated with fibrosis, a benign or malignant neoplastic disease, inflammatory disease) in a subject in need thereof. In certain embodiments, the kits and instructions e for inhibiting the activity (e.g., aberrant activity, such as increased activity) of the TGF-P signaling y in a subject or cell. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate ition. s of Treatment Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process, and the deposition of tive tissue can rate the architecture and function of the underlying organ or tissue. Fibrosis is the pathological state of excess deposition of fibrous tissue, as well as the process of connective tissue deposition in healing. Defined by the pathological accumulation of extracellular matrix (ECM) proteins, fibrosis results in scarring and thickening of the affected tissue. Thus, it is an exaggerated wound healing response which eres with normal organ function.
The most well characterized pro-fibrotic mediator is TGF-P, which is released by macrophages as well as any damaged tissue between surfaces called interstitium. Other soluble mediators of fibrosis include connective tissue growth factor , platelet-derived growth factor (PDGF), and Interleukin 4 (IL-4). These initiate signal transduction pathways such as the AKT/mTOR and SMAD pathways that tely lead to the proliferation and activation of fibroblasts, which deposit extracellular matrix into the surrounding connective tissue. ore, use of a compound that inhibits mediators of fibrosis (e.g., TGF-P) provides a method of treating diseases that rely on fibrotic activity.
The present disclosure provides methods for treating a disease or condition associated with is. In certain embodiments, the application es a method of treating fibrotic skin disorders (e.g., keloids, rophic scars, derma). In certain embodiments, the application provides a method of treating lung disease (e.g., pulmonary fibrosis). In certain embodiments, the ation provides a method of treating heart disease (e.g., ischaemic heart disease, valvular heart disease, hypertensive heart disease, diabetic cardiomyopathy, ension). In certain ments, the application provides a method of treating cirrhosis of the liver. In certain embodiments, the application provides a method of treating kidney disease.
In n embodiments, the application provides a method of treating progressive kidney disease, glomerulonephritis, diabetic kidney disease, diabetic nephropathy, systemic lupus, primary glomerulonephritis, membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, nous focal segmental glomerulosclerosis, secondary glomerulonephritis, or ischemic nephropathy. In certain embodiments, the application provides a method of treating focal tal glomerulosclerosis. In certain embodiments, the application provides a method of treating benign or malignant neoplastic disease. In n embodiments, the application provides a method of treating inflammation. In certain embodiments, the application provides a method of inhibiting the TGF-P signaling pathway.
In certain embodiments, the methods se administering to a subject in need thereof (e.g., a subject suffering from a disease associated with fibrosis) a compound that interacts with TGF-P, for example, a compound that is an inhibitor of TGF-P or the TGF-P signaling pathway. In certain ments, the methods comprise stering a nd (e.g., compound of Formula I, 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]prop enoyl]amino]benzoic acid), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, ically enriched derivative, or prodrug, or composition thereof, to a t in need thereof. In some embodiments, the method comprises administering a pharmaceutical composition sing a compound (e.g., compound of Formula I, 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched tive, or prodrug, or composition thereof, to a subject in need thereof.
The t disclosure also provides a compound (e.g., compound of Formula I, 2- [[(E)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition f, for use in the treatment of a disease or condition associated with fibrosis, benign or malignant neoplastic disease, or inflammation. In certain embodiments, the disease or condition associated with fibrosis is fibrotic skin disorders (e.g., keloids, rophic scars, scleroderma). In certain ments, the disease or condition associated with fibrosis is lung disease (e.g., pulmonary fibrosis). In certain embodiments, the disease or condition associated with is is heart disease (e.g., mic heart disease, valvular heart disease, hypertensive heart disease, diabetic cardiomyopathy, hypertension). In certain embodiments, the disease or condition associated with is is cirrhosis of the liver. In certain embodiments, the disease or condition associated with is is kidney disease. In certain embodiments, the kidney disease is kidney disease is progressive kidney disease, glomerulonephritis, diabetic kidney e, diabetic nephropathy, systemic lupus, primary glomerulonephritis, membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis, secondary glomerulonephritis, or ischemic nephropathy.
The present disclosure also es uses of a compound (e.g., compound of Formula I, 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, ically enriched derivative, or prodrug, or composition thereof, in the manufacture of a medicament for the treatment of a disease or condition associated with fibrosis, benign or ant neoplastic disease, or inflammation. In certain ments, the disease or condition associated with fibrosis is ic skin disorders (e.g., keloids, hypertrophic scars, scleroderma).
In certain embodiments, the disease or condition associated with is is lung disease (e.g., pulmonary fibrosis). In certain embodiments, the disease or ion associated with fibrosis is heart disease (e.g., ischaemic heart disease, valvular heart e, hypertensive heart disease, diabetic cardiomyopathy, hypertension). In certain embodiments, the disease or condition associated with fibrosis is cirrhosis of the liver. In certain embodiments, the disease or condition ated with fibrosis is kidney disease. In certain embodiments, the kidney disease is kidney disease is progressive kidney disease, glomerulonephritis, diabetic kidney disease, diabetic nephropathy, systemic lupus, primary glomerulonephritis, membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative ulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental ulosclerosis, secondary glomerulonephritis, or ischemic nephropathy.
In n embodiments, the methods of the invention comprise administering to the subject an effective amount of a compound (e.g., compound of Formula I, 2-[[(E)[4- (cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically ive amount.
In certain embodiments, the subject being treated is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject is a mammal. In certain embodiments, the subject being treated is a human.In certain embodiments, the subject is a icated , such as a dog, cat, cow, pig, horse, sheep, or goat. In certain ments, the subject is a ion animal, such as a dog or cat. In certain embodiments, the t is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal. ] n methods described herein may comprise administering one or more additional pharmaceutical agent(s) in combination with the compounds described herein. The additional pharmaceutical s) may be administered at the same time as the compound (e.g., compound of a I, 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid), or at different times than the compound (e.g., compound of a I, 2-[[(E)[4- (cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid). For example, the compound (e.g., compound of a I, 2-[[(E)[4-(cyclopropylmethyl) methoxyphenyl]propenoyl]amino]benzoic acid) and any additional pharmaceutical agent(s) may be on the same dosing schedule or different dosing schedules. All or some doses of the compound (e.g., compound of Formula I, 2-[[(E)[4-(cyclopropylmethyl) methoxyphenyl]propenoyl]amino]benzoic acid) may be administered before all or some doses of an additional ceutical agent, after all or some does an additional pharmaceutical agent, within a dosing schedule of an additional pharmaceutical agent, or a combination thereof. The timing of administration of the compound (e.g., compound of Formula I, 2-[[(E)[4- (cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid) and additional pharmaceutical agents may be different for different additional pharmaceutical agents.
Examples In order that the ion described herein may be more fully tood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.
Mass spectra were ed on a Micromass ZQ™, single quadrapole mass spectrometer. ^ Nuclear magnetic resonance (NMR) spectroscopy was d out using a Bmker instrument operating at 400 MHz using the stated solvent at around room temperature, unless otherwise stated. Characteristic chemical shifts (8) are given in parts-per-million using conventional abbreviations for designation of major peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of ts; m, multiplet; br, broad.
] Preparative HPLC purification was accomplished using the following platforms: Reverse phase preparative-HPLC using a Gilson preparative HPLC system (322 pump; 156 UV/ VIS or; GX281 liquid handler). The GX281 liquid handler acted as both auto-sampler and fraction collector. Preparative purification was performed using Phenomenex Gemini C18 at 150 x 25 mm x 10 pm or YMC -Actus Triart C18 150 x 30 mm x 5 pm columns. Appropriate focused gradients were selected based on acetonitrile and methanol t systems under acidic or basic conditions. The standard gradient used 20% gradient difference over 10 min. After each run a 2.0 min 100% acetonitrile wash was performed followed by a 1.5 min re-equilibration at the initial conditions. A flow rate of 25 mL/min was used throughout. The modifiers used for acidic/basic conditions were trifluoroacetic acid s (0.1% v/v), a (0.05% v/v; pH = ) and hydrochloric acid aqueous (0.1% v/v) respectively. The purification was lled by Trilution LC software and triggered by a threshold collection value at 220 nm or 254 nm.
Collected fractions were analyzed by LCMS nt LCMS with 1100/1200 LC systems and 6110/6140 Mass System). The ons that contained desired product were concentrated by vacuum centrifugation and the resultant residue passed through a freeze-drying cycle.
Alternatively, preparative HPLC purification was performed by reverse phase HPLC using a Waters Fractionlynx preparative HPLC system (2525 pump, 998 UV/VIS TM or, 2767 liquid handler) or an equivalent HPLC system such as a Gilson Trilution® UV directed system. The Waters® 2767 liquid r acted as both auto-sampler and fraction collector. The columns used for the preparative purification of the compounds were a Waters Sunfire® OBD Phenomenex Luna® Phenyl Hexyl or Waters Xbridge® Phenyl at 10 pm 19 x 150 mm or Waters CSH Phenyl Hexyl, 19 x 150 mm, 5 pm column. riate focused gradients TM were selected based on acetonitrile and methanol solvent systems under either acidic or basic conditions. The ers used under acidic/basic conditions were formic acid or trifluoroacetic acid (0.1% V/V) and ammonium bicarbonate (10 mM) respectively. The purification was controlled by Waters Fractionlynx software through monitoring at 210-400 nm, and triggered aTM threshold collection value at 260 nm and, when using the Fractionlynx , the presence of target TM molecular ion as observed under APi conditions. Collected fractions were analyzed by LCMS (Waters y® systems with Waters® SQD).
Analytical methods ical Method 1: Using an Agilent 1200\G1956A LC-MS spectrometer and an Agilent 1200\G1956A. Method details are: 1) mobile phase: A: 0.025% NH3*H20 in water ( v/v) ; B: Acetonitrile ; 2) Gradient: B% from 10% to 80% within 3.5 mins. 3) Flow rate: 0.8 mL/min. 4) Column Temp: 40°C; 5) Detector: DAD 220nm & 254nm. ical Method 2: Analytical UPLC-MS was performed on a Waters y I- Class UPLC with Waters Diode Array Detector (210-400 nm) coupled to a Waters SQD2 single quadrapole UPLC mass spectrometer using an HSS C18 column (1.8um 100 x 2.1mm plus guard). Method details are: 1) mobile phase: A: 0.1% formic acid (v/v) in water; B: 0.1% formic acid (v/v) in acetonitrile; 2) Gradient 0-1.2 min 95% A 5% B, 1.2 -3.5 min linear gradient to 0% A 100% B, 3.5-4.9 min 0% A 100% B, 4.9 - 5.0 min gradient to 95% A 5% B, 5.0 min - 6.0 min 95% A to 5% B. 3) Flow rate 0.5 mL/min. ical Method 3: Analytical UPLC-MS was performed on a Waters Acquity I- Class UPLC with Waters Diode Array Detector (210-400 nm) coupled to a Waters SQD2 single quadrapole UPLC mass spectrometer using a BEH Shield RP18 column (1.7um 100 x 2.1mm. plus guard dge). Method details are: 1) mobile phase: A: lOmM ammonium bicarbonate in water; B: acetonitrile; 2) Gradient 0-1.2 min 95% A 5% B, 1.2 -3.5 min linear gradient to 0% A 100% B, 3.5-4.9 min 0% A 100% B, 4.9 - 5.0 min gradient to 95% A 5% B, 5.0 min - 6.0 min 95% A to 5% B. 3) Flow rate 0.5 mL/min.
Analytical Method 4: Using an Agilent 1200 LC & Agilent 6110 MSD system and an Agilent Eclipse Plus C18 4.6*100mm 3.5pm. Method s are: 1) mobile phase: A: 0.0375% TEA in water (v/v); B: 0.01875% TEA in Acetonitrile (v/v)); 2) Gradient: B% from 0% to 60% within 6 mins. 3) Flow rate: 1.0 mL/min. 4) Column Temp: 50°C; 5) Detector: DAD 210nm, 215nm, 220nm & 254nm.
Analytical Method 5: Using a SHIMADZU 020 system and a Chromolith® Flash RP-18E 25-2 MM. Method details are: 1) mobile phase: A: 0.0375% TEA in water (v/v); B: 0.01875% TEA in Acetonitrile (v/v)); 2) Gradient: B% from 0% to 60% within 3.5 mins. 3) Flow rate: 0.8 mL/min. 4) Column Temp: 50°C; 5) Detector: PDA 220nm & 254nm.
Analytical Method 6: Using an Agilent 1200\G1956A system and a Xbridge C18 2.1*50 mm, Sum. Method details are: 1) mobile phase: A: 0.025% NFUfUO in water (v/v) ; B: Acetonitrile; 2) Gradient: B% from 0% to 60% within 3.5 mins. 3) Flow rate: 0.8 mL/min. 4) Column Temp: 40°C; 5) Detector: DAD 220nm & 254nm.
Analytical Method 7: Using a SHIMADZU LC-20AB system and an Innovation C18 UPLC Column 2.1X30mm,2.6um. Method details are: 1) mobile phase: A: 0.0375% TEA in water (v/v); B: 0.01875% TEA in Acetonitrile (v/v); 2) Gradient: B% from 0% to 80% within 5.5 mins. 3) Flow rate: 0.8 mL/min. 4) Column Temp: 50°C; 5) Detector: PDA(220nm, 254nm & 215nm). ] ical Method 8: Using an Agilent 1200\G1956A system and a e C18 2.1*50mm, Sum. Method details are: 1) mobile phase: A: 0.025% NHyHiO in water (v/v; B: itrile; 2) Gradient: B% from 0% to 80% within 3.5 mins. 3) Flow rate: 0.8 mL/min. 4) Column Temp: 40°C; 5) Detector: DAD (220 & .
Analytical Method 9: Using a SHIMADZU LCMS-2020 system and a Chromolith® Flash RP-18E 25-2 MM. Method s are: 1) mobile phase: A: 0.0375% TEA in water (v/v); B: 0.01875% TEA in Acetonitrile (v/v); 2) Gradient: B% from 0% to 95% within 3.5 mins. 3) Flow rate: 0.8 mL/min. 4) Column Temp: 50°C; 5) Detector: PDA (220nm & 254nm). ical Method 10: Using an Agilent 1200\G1956A system and a Chromolith® Flash RP-18E 25-2 MM. Method details are: 1) mobile phase: A: 0.0375% TFA in water (v/v); B: 0.01875% TFA in Acetonitrile (v/v); 2) Gradient: B% from 0% to 95% within 3.5 mins. 3) Flow rate: 0.8 mL/min. 4) Column Temp: 50°C; 5) Detector: DAD (220nm & 254nm).
Analytical Method 11: Using an Agilent 1200 LC & Agilent 6110 MSD system and an Agilent ZORBAX 5pm SB-Aq, 2.1*50mm. Method details are: 1) mobile phase: A: % TFA in water (v/v); B: 0.01875% TFA in Acetonitrile (v/v); 2) Gradient: B% from 0% to 90% within 3.4 mins. 3) Flow rate: 0.8 . 4) Column Temp: 50°C; 5) Detector: DAD (210nm, 215nm, 220nm & .
Analytical Method 12: Using an Agilent 1200 LC & Agilent 6110 MSD system and an Agilent ZORBAX 5pm SB-Aq, mm. Method details are: 1) mobile phase: A: 0.0375% TFA in water (v/v); B: 0.01875% TFA in Acetonitrile (v/v); 2) Gradient: B% from 10% to 100% within 3.4 mins. 3) Flow rate: 0.8 mL/min. 4) Column Temp: 50°C; 5) Detector: DAD (210nm, 215nm, 220nm & 254nm).
Analytical Method 13: Using an Agilent 1200 LC & Agilent 6110 MSD system and a Agilent ZORBAX 5pm SB-Aq, 2.1*50mm. Method s are: 1) mobile phase: A: A: 0.05% NFF-fUO in water (v/v); B: Acetonitrile (v/v); 2) Gradient: B% from 5% to 90% within 3.4 mins. 3) Flow rate: 0.8 mL/min. 4) Column Temp: 40°C; 5) Detector: DAD (210nm, 215nm, 220nm & 254nm).
General Methods (R6)m (R6)m Z-R3 HO Z-R3 O R2-Y. (COR7)„ R2-Y 70 N H (COR7)n R'-X R1-X 1-A 1-C ] Many of the compounds described below can be prepared according to the scheme above. An de (1-A where X-R , Y-R , and Z-R can represent appropriate substituents) is reacted with an 3-oxo(phenylamino)propanoic acid (1-B in which R6 and R7can be appropriate substituents) to afford the desired /V-phenylcinnamamide analogues (1-C). This condensation is typically performed at an elevated temperature, for example 110°C, in a suitable solvent such as toluene or pyridine over a reaction time consistent with the reactivity of the substrates, for example 16 hours. The reaction is typically catalyzed by a suitable base such as piperidine. The starting materials 1-A and 1-B can be commercially available or prepared according to methods known to those skilled in the art. Suitable substituted N- phenylcinnamamide products (1-C) can also be further derivatized.
(R6)m (R6)m Z-R3 Z-R3 0 Z-R3 0 2B (COR7)n r2-y- r2-y. r2-y. ■0 "OR20 H (COR7)n R1-X R'-X r'-x 1-A 2-A 1-C Alternatively, aldehyde 1-A can be converted to the cinnamic acid (2-A, where R 20 can be either H or a substituent such as methyl or ethyl) by reaction with malonic acid or a malonic acid monoester (scheme . Such reactions are typically performed in a solvent such as pyridine in the presence of a suitable base, for example piperidine, and are conducted at an elevated temperature for example 100 to 120 °C. Alternatively, the transformation can be accomplished using a Wittig or Wadsworth-Emmons reaction in which the de is reacted with a phosphonate, such as triethylphosphonoacetate, in the ce of a base, such as sodium hydride, and in an aprotic solvent such as THE. These reactions are commonly med at ambient temperature. Cinnamyl esters formed in this way can be converted to the acid using a hydroxide base. atively the cinnamic acids or cinnamyl esters can be commercially ble or prepared from commercially available cinnamic acids or esters.
The cinnamic acid 2-A is converted to the /V-phenylcinnamamide 1-C using a coupling agent such as HATU in the ce of a suitable base, for example diisopropylethylamine and the aniline 2-B. These reactions are performed in an inert solvent such as dichloromethane or iV.iV-di methyl formamidc and can be performed at room temperature or elevated ature depending on the reactivity of the substrates. atively, the acid (2-B) can first be transformed into an acid chloride using, for example, oxalyl chloride. The acid chloride is then reacted with an aniline (2-C) in the ce of a suitable base such as trimethylamine or pyridine and in an inert solvent such as dichloromethane or tetrahydrofuran.
The starting materials 2-A or 2-B can be commercially available or ed according to methods known to those d in the art. The /V-phenylcinnamamide products can also be further modified.
Compound Synthesis (/?)-Af-(2-fluorophenyl)(3-methoxy(propyn- l-yloxy)phenyl)acrylamide (1) o o .0. .0.
'OH N H2N H To a suspension of -(3-methoxypropynoxy-phenyl)propenoic acid (0.5 g, 2.15 mmol, 1.0 ) in dichloromethane (5 mL) was added oxalyl chloride (376 pL, 4.30 mmol, 2.0 equiv.) and the mixture was stirred at 25 °C for 30 minutes. The on mixture was concentrated under reduced pressure to give (£’)(3-methoxy(propyn-lyloxy l)acryloyl chloride as a yellow solid, which was used directly without further purification (0.6 g).
To a solution of 2-fluoroaniline (46 pL, 0.479 mmol, 1.2 equiv.) in dichloromethane (5 mL) was added (£’)(3-methoxypropynoxy-phenyl)propenoyl chloride (0.1 g, 0.399 mmol, 1.0 equiv.) and triethylamine (166 pL, 1.20 mmol, 3.0 equiv.) and the mixture was stirred at 25 °C for 12 hours. The e was concentrated under reduced pressure and the residue purified by preparative HPLC to give the desired product as a yellow solid (0.030 g, 23 %); H NMR (CD3OD, 400 MHz) 5 8.07 - 8.05 (m, 1H), 7.63 (d, /= 15.6 Hz, 1H), 7.26 -7.24 (m, 1H), 7.20 - 7.16 (m, 4H), 7.09 (d, /= 8.4 Hz, 1H), 6.84 (d, 7= 15.6 Hz, 1H), 4.81 (d, /= 2.4 Hz, 2H), 3.91 (s, 3H), 2.98 (t, / = 2.4 Hz, 1H); MS (ESI+) m/z 326.2 (M+H)+; 99.5% purity, RT 2.31 min (Method 10).
Ex ure Data Method o 1H NMR (DMSO-d6, 400 MHz) 5 Prepared according 2 .0. % N 12.99 (hr. s„ 1H), 8.66 (d, J = 7.2 H to the method for 1 hr N Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), HN^ starting from 2-(5- 7.61 (d, J = 15.6 Hz, 1H), 7.35 (s, mcthyl-1 H-\ ,2,4- (E)(3-methoxy(propyn- 1H), 7.26 - 7.23 (m, 2H), 7.09 - 7.07 triazolyl)aniline l-yloxy)phenyl)-N-(2-(5-methyl- (m, 2H), 6.69 (d, J = 15.6 Hz, 1H), 1H-1,2,4-triazol 4.85 (d, J = 2.0 Hz, 2H), 3.86 (s, yl)phenyl)acrylamide 3H), 3.59 (t, J = 2.0 Hz, 1H), 2.41 (s, 3H); MS (ESI+) m/z 389.3 (M+H)+; 98.6% purity, RT 1.99 min (Method 8) 3 1H NMR (CD3OD, 400 MHz) 5 7.96 0 1^ Prepared according N (d, J = 8.0 Hz, 1H), 7.64 (d, / = 15.6 H to the method for 1 Cl Hz, 1H), 7.47 (d, J = 6.8 Hz, 1H), starting from 2- -(2-chl()i'ophcnyl)(3- 7.30 - 7.29 (m, 1H), 7.28 - 7.27 (m, chi oroani line methoxy(propyn-l - 1H), 7.19 - 7.18 (m, 2H), 7.12 - 7.10 yloxy)phenyl)acrylamide (m, 1H), 7.00 (d, J = 15.6 Hz, 1H), 4.81 (d, J = 2.4 Hz, 2H), 3.90 (s, 3H), 2.98 (t, J = 2.4 Hz, 1H); MS (ESI+) m/z 342.2/344.1 (M+H)+; 99.6% purity, RT 2.22 min (Method 4 iH NMR (CDC13, 400 MHz) 5 8.52 Prepared according (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), to the method for 1 ^o- Br 7.72 (d, J = 16.0 Hz, 1H), 7.60 - starting from 2- (£)-/V-(2-hi'omophcnyl)(3- 7.56 (m, 1H), 7.38 - 7.34 (m, 1H), bromoaniline methoxy(propyn-l - 7.19 - 7.16 (m, 1H), 7.12-7.11 (m, yloxy)phenyl)acrylamide 1H), 7.07 - 6.98 (m, 2H), 6.48 (d, J =16.0 Hz, 1H), 4.82 (d, J = 4.0 Hz, 2H), 3.96 (s, 3H), 2.55 (t, J = 4.0 Hz, 1H); MS (ESI+) m/z 386.1/388.1 (M+H)+; 96.3% purity, RT 2.18 min (Method 10) 1H NMR (DMSO-d6, ) 5 0 Prepared according .0. 9.37 (s, 1H), 7.52 (d, J = 15.6 Hz, to the method for 1 ^O' 1H), 7.25 (d, /= 10.8 Hz, 1H), 7.22 starting from o- (E)(3-methoxy(propyn- -7.18 (m, 4H), 7.09 - 7.07 (m, 2H), toluidine 1 -yloxy)phcnyl)-/V-(o- 6.88 (d, J= 15.6 Hz, 1H), 4.84 (d, J tolyl)acrylamide = 2.4 Hz, 2H), 3.84 (s, 3H), 3.59 (t, J = 2.4 Hz, 1H ), 2.25 (s, 3H ); MS (ESI+) m/z 322.2 (M+H)+; 100% purity, RT 2.01 min (Method 10) 6 o 1H NMR (CD3OD, 400 MHz) 5 7.40 Prepared according .0. (d, /= 8.8 Hz, 1H), 7.72 (d, /= 15.6 to the method for 1 CN Hz, 1H), 7.68 - 7.66 (m, 2H), 7.36 - starting from 2- (£)-/V-(2-cyanophcnyl)(3- 7.34 (m, 1H), 7.27 - 7.26 (m, 1H), aminobenzonitrile methoxy(propyn-l - 7.20 - 7.19 (m, 1H), 7.11 - 7.09 (m, yloxy)phenyl)acrylamide 1H), 6.80 (d, /= 15.6 Hz, 1H), 4.81 (d, 7=2.4 Hz, 2H), 3.91 (s, 3H), 2.98 (t, 7= 2.4 Hz, 1H); MS (ESI+) m/z 333.2 (M+H)+; 96.7% purity, RT 1.92 min (Method 10) 7 06* 1H NMR dg, 400 MHz) 5 ed according .44 (s, 1H), 8.11 (d, 7 = 1.2 Hz, to the method for 1 1H), 7.60 - 7.55 (m, 3H), 7.26 - 7.25 starting from 3, 4- (m, 1H), 7.20 (d, 7 = 8.4 Hz, 1H), dichloroaniline (£’)-/V-(3,4-dichloi'ophcnyl)(3- 7.09 (d, 7 = 8.4 Hz, 1H), 6.67 (d, 7 = methoxy(propyn-l - 15.6 Hz, 1H), 4.84 (d, 7 = 2.0 Hz, yloxy)phenyl)acrylamide 2H), 3.84 (s, 3H), 3.59 (t, 7=2.0 Hz, 1H); MS (ESI+) m/z 376.1/378.1/380.1 (M+H)+; 95.8% purity, RT 2.4 min (Method 10) (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-phenylacrylamide (8) .0. jO .0.
‘OH vQ H2N H To a solution of (T)(3-mcthoxypropynoxy-phcnyl)propcnoic acid (0.1 g, 0.431 mmol, 1.0 equiv.) and HATU (0.327 g, 0.861 mmol, 2.0 equiv.) in N,N- dimethylformamide (2 mL) was added ropylethylamine (015 mL, 0.861 mmol, 2.0 ) and the mixture was stirred at 30 °C for 1 hour. Then aniline (59 pL, 0.646 mmol, 1.5 equiv.) was added and the reaction was stirred at 30 °C for another 2 hours. The reaction liquid was diluted with methanol (3 mL) and the resulting mixture was purified by ative HPLC to give the desired product as a yellow solid (25 mg, 19%); ^ NMR (DMSO-Je, 400 MHz) 8 10.14 (s, 1H), 7.72 - 7.69 (m, 2H), 7.54 (d, /= 16.0 Hz, 1H), 7.35 - 7.31 (m, 2H), 7.26 - 7.25 (m, 1H), 7.24 - 7.23 (m, 1H), 7.10 - 7.04 (m, 2H), 6.73 (d, / = 15.6 Hz, 1H), 4.85 (d, / = 2.4 Hz, 2H), 3.85 (s, 3H), 3.60 (t, / = 2.4 Hz, 1H). MS (ESI+) m/z 308.1 (M+H)+; 100% purity, RT 2.94 min (Method 11).
Ex ure Data Method 9 o *H NMR (400 MHz, : d, Prepared according N ppm 7.68 (1H, d, J = 15.3 Hz), 7.32 to the method for 8 ^0 .0^ - 7.24 (2H, m), 7.26 (2H, s), 7.22 - starting from (E) 7.16 (2H, m), 7.06 (2H, dd, J = 1.8, 0 (3-methoxyprop- 8.3 Hz), 7.08 - 6.98 (2H, m), 7.00 2-ynoxymethyl (£T)-l-(3-(3-methoxy- (2H, d, J = 8.3 Hz), 6.96 - 6.95 (1H, phenyl)prop 4-(propyn-l- m), 6.68 (1H, d, J = 15.8 Hz), 4.79 enoic acid and yloxy)phenyl)acryloyl)- (2H, d, J = 2.3 Hz), 4.22 - 4.14 (1H, methyl 1,2,3,4- 1,2,3,4-tetrahydroquinoline- m), 3.90 - 3.85 (4H, m), 3.85 - 3.77 tetrahydroquinoline 4-carboxylate (1H, m), 3.73 - 3.72 (3H, m), 2.53 - carboxylate 2.51 (1H, m), 2.47 - 2.37 (1H, m), 2.23 - 2.13 (1H, m). MS: (ESI+) m/z 406(M+H)+ 97.74% purity, RT = 3.33min., (Method 2)._________ O *H NMR (400 MHz, CDC13): d, Prepared according .0. ppm 7.68 (1H, d, J = 16.2 Hz), 7.24 to the method for 8 -7.11 (4H, m), 7.08 - 6.94 (3H, m), starting from (E) 6.74 (1H, d, J = 15.8 Hz), 4.78 (2H, (3-methoxyprop- d, J = 2.5 Hz), 3.95 - 3.90 (2H, m), y- (E)-\ -(3,4-dihydroquinolin- 3.85 (3H, s), 2.79 - 2.74 (2H, m), phenyl)prop 1 yl)(3-methoxy 2.53 - 2.51 (1H, m), 2.06 - 1.97 (2H, enoic acid and (propyn-l- m). MS: (ESI+) m/z 348.2(M+H)+ 1,2,3,4- yloxy)phenyl)propen-1 - 99.45% , RT = 3.47min., tetrahydroquinoline one (Method 2)._____________________ 11 O 1HNMR(400MHz, CDC13): d, Prepared according .0. rY ppm 7.69 (1H, d, J = 14.9 Hz), 7.11 to the method for 8 k/NH - 6.98 (5H, m), 6.92 (1H, d, J = 15.3 starting from (E) Hz), 6.68 - 6.63 (2H, m), 4.79 (2H, (3-methoxyprop- d, J = 2.5 Hz), 4.16 - 4.07 (1H, m), 2-ynoxy- (E)-\ -(3,4-dihydroquinoxalin- 4.02 - 3.97 (2H, m), 3.86 (3H, s), phenyl)prop 1 (2/7) -yl) -3 -(3 -methoxy 3.54 - 3.50 (2H, m), 2.53 - 2.51 (1H, enoic acid and (propyn-l- m). MS: (ESI+) m/z 349(M+H)+ 1,2,3,4- yloxy)phenyl)propen-1 - 92.91% purity, RT = 3.23min., tetrahydroquinoxali one (Method 2)._____________________ ne 12 O Prepared according .0. N"> 1HNMR(400MHz, : d, to the method for 8 ppm 7.73 (1H, d, J = 15.3 Hz), 7.22 starting from (E) - 7.15 (1H, m), 7.14 - 7.08 (2H, m), (3-methoxyprop- 7.05 - 6.99 (2H, m), 6.98 - 6.87 (3H, 2-ynoxy- (£)-1 -(2,3 -dihydro-4H- m), 4.80 (2H, d, J = 2.3 Hz), 4.39 - phenyl)prop benzofb] [ 1,4]oxazinyl) 4.35 (2H, m), 4.10 - 4.06 (2H, m), enoic acid and 3,4- (3-methoxy(propyn-l - 3.88 (3H, s), 2.54 - 2.52 (1H, m). dihydro-2H- phenyl)propen-1 - MS: (ESI+) m/z 350(M+H)+ 99% benzofb] [1,4] oxazi one purity, RT = 3.39min., (Method 2). ne 13 O ‘H NMR (400 MHz, Prepared ing CDC13) 7.51 (1H, d, J=15.4 Hz), to the method for 8 H NH2 7.10 - 7.07 (1H, m), 7.06 - 7.02 (1H, starting from (E) m), 6.97 (1H, d, J=8.3 Hz), 6.41 (3-methoxyprop- (1H, d, J=14.9 Hz), 6.00 - 5.93 (1H, 2-ynoxy- ((trans) m), 4.78 (2H, d, J=2.5 Hz), 3.89 phenyl)prop aminocyclohexyl) -3 -(3 - (3H, s), 3.77 - 3.66 (1H, m), 2.68 - enoic acid and methoxy(propyn-l - 2.59 (1H, m), 2.54 - 2.51 (1H, m), treins-c yc I oh c x an c - yloxy)phenyl) acrylamide 2.01 - 1.96 (2H, m), 1.77 - 1.66 (2H, 1,2-diamine m), 1.33 - 1.19 (4H, m); MS: (ESI+) m/z 329.2(M+H)+ 99.01% purity, RT = 2.87min., (Method 3). 14 /°' 0 1^ ‘H NMR (400 MHz, Prepared according % DMSO) 5 7.59(d,/= 15.7 Hz, to the method for ^0' 'OH 1H), 7.54 (d, J= 6.9 Hz, 1H), 7.34 - 16 ng from (£T)-l-(4-hydroxy-3,4- 7.29 (m, 2H), 7.28 - 7.17 (m, 3H), (£)(3-mcthoxydihydroquinolin-1 (2//)-yl) 7.09 (d, J= 8.6 Hz, 1H), 6.92 (d, J = 4-(propyn-l- (3-methoxy(propyn-l - 15.7 Hz, 1H), 5.54 (d, J= 5.6 Hz, yloxy)phenyl) acryli yloxy)phenyl)propen-1 - 1H), 4.87 (d, J= 2.3 Hz, 2H), 4.70 - c acid and 1,2,3,4- one 4.64 (m, 1H), 4.13 - 4.05 (m, 1H), ydroquinolin- 3.83 (s, 3H), 3.76 - 3.67 (m, 1H), 4-ol 3.63 (t, J= 2.3 Hz, 1H), 2.23 - 2.13 (m, 1H), 1.90 - 1.80 (m, 1H). MS (ESI+) m/z 364.2 (M+H)+; 99.8% purity, RT 3.06 min (Method 2) /°' o ‘H NMR (400 MHz, Prepared according N DMSO) 5 12.21 - 12.16 (m, 1H), to the method for OH 8.46 (d, J= 8.3 Hz, 1H), 7.87 (d, J = 16 starting from {E)-\ -(3-hydroxy-1 H-indazol- 6.6 Hz, 2H), 7.74 - 7.69 (m, 2H), (£)(3-mcthoxyyl) -3 -(3 -methoxy(prop- 7.49.7.43 (m, 2H), 7.39 (dd, J = pyn-l- 2-yn-1 -yloxy)phenyl)prop 8.3 Hz, J= 1.8 Hz, 1H), 7.18 (d, J = yloxy)phenyl) acryli en-l-one 8.6 Hz, 1H), 4.93 (d, /= 2.3 Hz, c acid and 3- 2H), 3.92 (s, 3H), 3.66 (t, J= 2.3 indazolinone Hz, 1H); MS (ESI+) m/z 349.3 ; 98.9% purity, RT 2.60 min (Method 3) (E)-N-(2-(2H-tetrazolyl)phenyl)(3-methoxy(propyn-l-yloxy)phenyl)acrylamide o o .0. .0.
'OH h2n N Nx N N ^ N \ // HN-N HN-N To a solution of (T)(3-mcthoxy(propyn-l -yloxyjphcnyl(acrylic acid (0.1 g, 0.431 mmol, 1.0 equiv.) and 2-(2H-tetrazolyl)aniline (0.083 g, 0.516 mmol, 1.2 equiv.) in dichloromethane (3 mL) were added A^iV-diisopropylcthylaminc (0.225 mL, 1.29 mmol, 3.0 equiv.) and HATU (0.245 g, 0.645 mmol, 1.5 equiv.). The reaction mixture was stirred at 25°C for 16 hours and trated under reduced pressure. The residue was purified by preparative HPLC to give the desired product as a light yellow solid (0.025 g, 15%); ^ NMR (DMSO-r/e, 400MHz) 5 12.45 (br. s., 1H), 8.71 - 7.65 (m, 1H), 7.19 (dd, /i = 8.0 Hz, J2=2.0 Hz, 1H), 7.63 (d,/= 15.6 Hz, 1H), 7.38 - 7.25 (m, 3H), 7.16 - 7.08 (m, 3H), 6.75 (d,/= 15.6 Hz, 1H), 4.85 (d, /= 2.0 Hz, 2H), 3.88 (s, 3H), 3.61 (t, / = 2.0 Hz, 1H); MS (ESI+) m/z 398.1 (M+Na)+; 95.9% purity, RT 1.95 min d 10).
(E)-N-(2-(l,2,4-oxadiazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (17) a) -(2-(N-hydroxycarbamimidoyl)phenyl)(3-methoxy(propyn-l- yloxy)phenyl) -acrylamide vO o .0. .0.
H H HN NH N \ To a solution of (£,)-/V-(2-cyanophenyl)(3-methoxy(propyn-l- yloxy)phenyl)acrylamide (1.00 g, 3.01 mmol, 1.0 equiv.) (6) and hydroxylamine hydrochloride (0.418 g, 6.02 mmol, 2.0 ) in l (13 mL) was added a solution of sodium bicarbonate (0.505 g, 6.02 mmol, 2.0 equiv.) in water (2 mL) and the mixture was d at 80 °C for 12 hours. The mixture was cooled to 20 °C and concentrated under reduced pressure to give a residue, which was dissolved in dichloromethane/ethanol (20/1, 200 mL) and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was ated in dichloromethane/methanol (50/1, 40 mL) to give the desired t as a light yellow solid. (0.6 g, 69%); MS (ESI+) m/z 366.1 (M+H)+. b) (/?)-/V-(2-(l,2,4-oxadiazolyl)phenyl)(3-methoxy(propyn-l- yloxy)phenyl)acrylamide o o .0. .0.
N N H H HN\ NH 1ST N OH b-U To a suspension of ((L)-A/-(2-(A/-hydroxycarbamimidoyl)phcnyl)(3-mcthoxy (propyn-l-yloxy)phenyl)acrylamide (0.08 g, 0.218 mmol, 1.0 equiv.) in trimethoxymethane (2.91 g, 27.4 mmol, 3 mL, 125 equiv.) was added 4-methylbenzenesulfonic acid (0.004 g, 0.022 mmol, 0.1 equiv.) and the mixture stirred at 100 °C for 12 hours. The e was concentrated under reduced pressure to give a residue, which was triturated with methanol (2 mL) and the solid collected by filtration to give the desired product as a light yellow solid (0.045 g, 52%); H 1 NMR (DMSO-de, 400MHz) 5 10.07 (br. s., 1H), 9.81 (s, 1H), 8.24 (d, /= 8.0 Hz, 1H), 8.03 (d, / = 8.0 Hz, 1H), 7.61 - 7.59 (m, 1H), 7.56 (d, / = 15.6 Hz, 1H), 7.34 - 7.33 (m, 2H), 7.2 (d, / = 8.4 Hz, 1H), 7.08 (d, / = 8.4 Hz, 1H), 6.80 (d, / = 15.6 Hz, 1H), 4.85 (d, / = 2.0 Hz, 2H), 3.82 (s, 3H), 3.60 (t, /= 2.0 Hz, 1H); MS (ESI+) m/z 398.2 (M+Na)+; 94.4% purity, RT 2.18 min (Method 10). (/?)(3-methoxy( propyn-l -yloxy)phenyl)-N-(2-(5-methyl-l ,2,4-oxadiazol yl)phenyl)-acrylamide (18) o O .0. .0.
N N H H HN\ NH N ^ NK To a solution of ((T)-A/-(2-(A/-hydroxycarbamimidoyl)phcnyl)(3-mcthoxy(prop- 2-yn-l-yloxy)phenyl)acrylamide (0.1 g, 0.273 mmol, 1.0 equiv.) in toluene (1 mL) and ne (1 mL) was added acetyl chloride (0.043 g, 0.547 mmol, 2.0 equiv.) and the mixture was stirred at 20°C for 30 minutes, then heated to 110 °C for 12 hours. The mixture was concentrated under reduced pressure to give a residue, which was triturated in methanol (2 mL) and the solid collected by filtration to give the desired t as a light yellow solid (0.042 g, 38%); ^ NMR (DMSO-de, 400 MHz) 5 10.18 (s, 1H), 8.36 (d, 7= 7.6 Hz, 1H), 8.02 (d, /= 7.6 Hz, 1H), 7.61 -7.56 (m, 2H), 7.35 - 7.24 (m, 3H), 7.08 (d, 7=8.0 Hz, 1H), 6.81 (d, 7= 16.0 Hz, 1H), 4.85 (d, 7 = 2.0 Hz, 2H), 3.85 (s, 3H), 3.60 (t, 7 = 2.0 Hz, 1H), 2.73 (s, 3H); MS (ESI+) m/z 390.1 (M+H)+; 95.5% purity, RT 2.95 min (Method 8). (/?)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol yl)phenyl)acrylamide (19) o o .0. N N H HN\ NH To a sion of ((L)-A/-(2-(A/-hydroxycarbamimidoyl)phcnyl)(3-mcthoxy (propyn-l-yloxy)phenyl)acrylamide (0.120 g, 0.328 mmol, 1.0 ) in ethanol (2.5 mL) was added sodium methoxide (0.213 g, 0.985 mol, 25%, 3.0 equiv.) and dimethyl carbonate (110 pL, 1.31 mmol, 4.0 equiv.). The mixture was stirred at 90 °C for 15 hours, cooled to 20 °C and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by ative HPLC to give the desired product as a light yellow solid (0.020 g, 15%); ^ NMR (DMSO-76, 400 MHz) 5 10.63 (br. s., 1H), 8.23 (d, 7= 8.0 Hz, 1H), 7.71 (d, 7= 8.0 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.30 (s, 1H), 7.27 - 7.22 (m, 2H), 7.08 (d, 7 = 8.0 Hz, 1H), 6.71 (d, 7 = 16.0 Hz, 1H), 4.85 (d, 7 = 2.0 Hz, 2H), 3.84 (s, 3H), 3.59 (t, 7 = 2.0 Hz, 1H); MS (ESI+) m/z 414.1 (M+Na)+; 96.4% purity, RT 1.59 min (Method 8).
(E)-N-(2-(l,2,4-oxadiazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (20) a) (E)-N-((dimethylamino)methylene)nitrobenzamide o2n o2n O-^ nh2 To the solution of 2-nitrobenzamide (1.4 g, 8.43 mmol, 1.0 equiv.) was added N,N- dimethylformamide dimethyl acetal (5.02 g, 42.1 mmol, 5.0 equiv.) and the reaction mixture was stirred at 120 °C for 2 hours. The mixture was concentrated under d pressure and the residue purified by silica gel chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1) to afford (Tj-N-ddi methyl ami no) mcthylcnc)nitrobcnzamidc as a yellow solid (1.20 g crude) which was used without further purification. MS (ESI+) m/z 222.1 . b) 5-(2-nitrophenyl)-l,2,4-oxadiazole o2n o2n O N N O VN To a solution of hydroxylamine hydrochloride (0.98 g, 14.1 mmol, 1.3 equiv.) in sodium hydroxide (5 M, 2.8 mL, 1.3 equiv.) was added (E)-N- (dimethylaminomethylene)nitrobenzamide (2.4 g, 10.8 mmol, 1.0 equiv.) portion-wise over 5 s at 20 °C and the mixture stirred at 20 °C for 0.5 hour. The mixture was diluted with water (10 mL) and extracted with romethane (10 mL x 3). The organic layer was dried and concentrated under d pressure to give (L)-A/-((hydroxyamino)mcthylcnc) nitrobenzamide (1.20 g) which was used ly without further purification.
A mixture of (E)-N-((hydroxyamino)methylene)nitrobenzamide (0.9 g, 4.30 mmol, 1.0 equiv.) in acetic acid (7 mL) and dioxane (7 mL) was stirred at 90 °C for 2 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ethenethyl acetate 10:1 to 5:1) to give the desired product as a light yellow solid (0.4 g, 49%); 1H NMR (DMSO-d6, 400 MHz) 5 9.25 (s, 1H), 8.23 - 8.21 (m, 1H), 8.13 - 7.11 (m, 1H), 7.99 - 7.95 (m, 2H). c) 2-(l,2,4-oxadiazolyl)aniline o2n h2n 0 nN 0 nN To a on of 5-(2-nitrophenyl)-l,2,4-oxadiazole (0.3 g, 1.57 mmol, 1.0 equiv.) in ethanol (5 mL) was added tin(II) chloride dihydrate (1.42 g, 6.28 mmol, 4.0 equiv.) and the e was d at 90°C for 12 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (10 mL) and washed with saturated aqueous sodium bicarbonate (5 mL) and brine (5 mL). The organic layer was dried and concentrated under reduced pressure and the residue was ed by silica gel chromatography (petroleum ethenethyl e 1:1 to ethyl acetate) to give the desired t as a light yellow solid (0.1 g, %); lR NMR (DMSO-d6, 400 MHz) 5 10.96 (s, 1H), 7.88 - 7.86 (m, 1H), 7.57 - 7.53 (m, 1H), 7.19 (d, /= 8.0 Hz, 1H), 7.11 - 7.07 (m, 1H), 6.37 (br. s., 2H); MS (ESI+) m/z 162.1 (M+H)+. d) (E)-N-(2-(l,2,4-oxadiazolyl)phenyl)(3-methoxy(propyn-l- yloxy)phenyl)acrylamide o o .0. .0.
"OH h2n N #^0 0 XN 0 To a solution of -(3-methoxypropynoxy-phenyl)propenoic acid (0.056 g, 0.242 mmol, 1.0 equiv.) and 2-(l,2,4-oxadiazolyl)aniline (0.039 g, 0.242 mmol, 1.0 equiv.) in pyridine (2 mL) was added phosphorus oxychloride (0.037 g, 0.242 mmol, 1.0 equiv.) at 0°C and the mixture was stirred at 20°C for 12 hours. The mixture was quenched with water (1 mL), diluted with ethyl acetate (20 mL) and washed with IN hydrochloric acid (20 mL) and then saturated aqueous sodium bicarbonate (5 mL). The organic layer was dried and concentrated under reduced pressure to give a residue, which was triturated in methanol (3 mL) and the solid collected by filtration to give the desired product as a light yellow solid (4 mg, 5%); iH NMR (DMSO-de, 400 MHz) 5 12.23 (s, 1H), 11.69 (s, 1H), 8.06 (d, /= 7.6 Hz, 1H), 7.79 - 7.72 (m, 2H), 7.51 (d, /= 8.0 Hz, 1H), 7.40 (t, /= 8.0 Hz, 1H), 7.27 - 7.25 (m, 2H), 7.12 (d, / = 8.0 Hz, 1H), 6.86 (d, / = 16.0 Hz, 1H), 4.86 (d, / = 2.0 Hz, 2H), 3.83 (s, 3H), 3.61 (t, / = 2.0 Hz, 1H); MS (ESI+) m/z 376.3 (M+H)+; 100% purity, RT 1.97 min (Method 10).
Ex Structure Data Method 21 o iH NMR (DMSO-d6, 400 MHz) 5 Prepared according N 10.71 (s, 1H), 9.44 (s, 1H), 8.47 (d, to the method for ^'o N'' 0 / = 8.0 Hz, 1H), 7.98 (d, / = 8.0 Hz, 20 (step d) ng N=^ 1H), 7.66 (d, /= 8.0 Hz, 1H), 7.61 from 2-(l,3,4- (E)-N-(2-( 1,3,4-oxadiazol (d, J= 16.0 Hz, 1H), 7.39 (d, J= 2.4 oxadiazol yl)phenyl)(3-methoxy(prop- Hz, 1H), 7.36 - 7.32 (m, 1H), 7.27 yl)aniline and (£)- 2-yn-1 -yloxy)phenyl)acrylamide (d, /= 8.0 Hz, 1H), 7.08 (d, /= 8.0 3-(3-methoxy Hz, 1H), 6.63 (d, / = 16.0 Hz, 1H), propynoxy- 4.86 (d, /= 2.0 Hz, 2H), 3.86 (s, phenyl)prop 3H), 3.60 (t, J = 2.0 Hz, 1H); MS enoic acid (ESI+) m/z 398.1 (M+Na)+; 98.9% purity, RT 2.71 min (Method 8) (/?)(3-methoxy(propyn-l-yloxy)phenyl)-/V-(2-(l-methyl-lH-pyrazolyl)phenyl)- acrylamide (22) a) (E)(4-hydroxymethoxyphenyl)-N-(2-(l-methyl-lH-pyrazolyl)phenyl)acrylamide O B" .0. .0. N N H Br // HO' // A e of (£’)-A/-(2-bromophenyl)(3-methoxypropynoxy-phenyl)prop enamide (0.16 g, 0.414 mmol, 1.0 equiv.) (4), (l-methylpyrazolyl)boronic acid (0.104 g, 0.828 mmol, 2.0 equiv.), [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.03 g, 0.041 mmol, 0.1 equiv.) and sodium ate (0.131 g, 1.24 mmol, 3.0 equiv.) in dioxane (6 mL) and water (1 mL) was stirred at 80 °C for 24 hours under nitrogen. The mixture was concentrated under reduced re to give a residue which was ed by silica gel chromatography (petroleum ether:ethyl acetate 1:1) to give the title compound as light yellow gum (0.1 g, 19%); MS (ESI+) m/z 350.2 (M+H)+. b) (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(l-methyl-lH-pyrazol yl)phenyl)acryl-amide o o .0. .0.
N N H H HO' // y' N-N N-N / / A mixture of (£)(4-hydroxymcthoxy-phcnyl)-A/-[2-(l-mcthylpyrazol yl)phenyl]propenamide (0.1 g, 0.286 mmol, 1.0 ), 3-bromoprop-l-yne (0.068 g, 0.572 mmol, 2.0 equiv.) and ium carbonate (0.119 g, 0.858 mmol, 3.0 equiv.) in acetone (5 mL) was stirred at 20 °C for 12 hours. The mixture was filtered and the te was concentrated under reduced pressure to give a residue which was purified by preparative HPLC to give the desired product as a light yellow solid (7 mg, 6%); ^ NMR (CDCI3, 400 MHz) 8 8.36 (hr. s., 1H), 7.71 - 7.68 (m, 2H), 7.54 (s, 1H), 7.45 (s, 1H), 7.39 - 7.34 (m, 1H), 7.29 - 7.28 (m, 1H), 7.19 - 7.17 (m, 1H), 7.13 - 7.11 (m, 1H), 7.08 - 7.06 (m, 1H), 7.03 (d, /= 8.0 Hz, 1H), 6.32 (d, J = 16.0 Hz, 1H), 4.82 (d, / = 2.4 Hz, 2H), 4.02 (s, 3H), 3.93 (s, 3H), 2.54 (t, / = 2.4 Hz, 1H); MS (ESI+) m/z 388.1 (M+H)+; 95.1% purity, RT 2.88 min (Method 11). (/?)(3-methoxy(propyn-l-yloxy)phenyl)-/V-(2-(3-methyl-lH-l,2,4-triazol-lyl )phenyl)acryl-amide (23) o H .0.
•O. .NU N H <\ P H A Br N i ;,n A mixture of (£’)-A-(2-bromophenyl)(3-methoxypropynoxy-phenyl)prop enamide (0.2 g, 0.517 mmol, 1.0 equiv.) (4), 3-methyl1,2,4-triazole (0.258 g, 3.11 mmol, 6.0 equiv.), cuprous iodide (0.049 g, 0.258 mmol, 0.5 equiv.) and cesium carbonate (0.506 g, 1.55 mmol, 3.0 equiv.) in dimethyl sulfoxide (2 mL) was stirred at 100 °C under nitrogen in ave for 3 hours. The mixture was cooled to 25°C, diluted with ethyl acetate (20 mL) and ed. The filtrate was concentrated under reduced pressure to give a residue which was purified by ative HPLC to give the desired product as a light yellow solid (5 mg, 2%); ^ NMR (CDCI3, 400 MHz) 5 9.89 (s, 1H), 8.63 (d, /= 8.0 Hz, 1H), 8.37 (s, 1H), 7.64 (d, /= 16.0 Hz, 1H), 7.46 (t, /= 8.0 Hz, 1H), 7.35 (d, /= 8.0 Hz, 1H), 7.21 (t, /= 8.0 Hz, 1H), 7.15 (d, / = 8.0 Hz, 1H), 7.08 - 7.05 (m, 2H), 6.36 (d, /= 16.0 Hz, 1H), 4.82 (d, /= 2.0 Hz, 2H), 3.94 (s, 3H), 2.60 (s, 3H), 2.55 (t, / = 2.0 Hz, 1H); MS (ESI+) m/z 389.1 (M+H)+; 99% purity, RT 2.34 min (Method 8).
(/?)-/V-(2-(lH-pyrazolyl)phenyl)(3-methoxy(propyn-l-yloxy)phenyl)acrylamide ^0 IP // a) 5-tetramethyl(2-nitrophenyl)-l,3,2-dioxaborolane o2n o' 'o A mixture of l-bromonitro-benzene (10.0 g, 49.5 mmol, 1.0 equiv.), 4,4,5,5- tetramethyl(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)-l,3,2-dioxaborolane (15.08 g, 59.4 mmol, 1.2 equiv.), potassium acetate (14.57 g, 148 mmol, 3.0 equiv.) and [1,1'- phenylphosphino)ferrocene]dichloropalladium(II) (1.09 g, 1.49 mmol, 0.03 equiv.) in dioxane (180 mL) was stirred at 80 °C for 12 hours under nitrogen. The mixture was concentrated under reduced pressure to give a residue which was purified by silica gel tography (petroleum ether: ethyl acetate 100:1 to 80:1) to give the desired product as yellow oil (12.0 g, 97%); NMR (DMSO-d6, 400 MHz) 5 8.17 (d, /= 8.0 Hz, 1H), 7.67 - 7.65 (m, 1H), 7.58 - 7.54 (m, 2H), 1.44 (s, 12H). b) 4-(2-nitrophenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole o2n o2n o' "o II SEIvf A mixture of 2-[(4-bromopyrazol-l-yl)methoxy]ethyl-trimethylsilane (0.8 g, 2.89 mmol, 1.0 equiv.), 5-tetramethyl(2-nitrophenyl)-l,3,2-dioxaborolane (2.16 g, 8.67 mmol, 3.0 equiv.), [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.211 g, 0.289 mmol, 0.1 equiv.) and potassium phosphate ic (1.84 g, 8.67 mmol, 3.0 equiv.) in dioxane (20 mL) and water (2 mL) was stirred at 100 °C for 12 hours under nitrogen. The mixture was concentrated under d pressure to give a residue which was purified by silica gel chromatography (petroleum ether: ethyl acetate 30:1 to 15:1) to give the desired product as light yellow gum (0.16 g, 16%); NMR (CDC13, 400 MHz) 5 7.76 - 7.74 (m, 2H), 7.67 (s, 1H), 7.60 - 7.56 (m, 1H), 7.52 - 7.49 (m, 1H), 7.44 - 7.40 (m, 1H), 5.46 (s, 2H), 3.61 (t,J= 8.0 Hz, 2H), 0.94 (t, J = 8.0 Hz, 2H), 0.00 (s, 9H). c) 2-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazolyl)aniline o2n h2n II // N-N N-N SEWf SEWf To a solution of trimethyl-[2-[[4-(2-nitrophenyl)pyrazol-l-yl]methoxy] ethyl] silane (0.16 g, 0.500 mmol, 1.0 ) in methanol (10 mL) was added Pd/C (0.05 g, 5% purity) and the mixture was stirred at 20 °C under a hydrogen atmosphere for 1.5 hours. The mixture was filtered and the filtrate was concentrated under reduced re to give the desired product as light yellow gum, which was used directly without r purification (0.15 g); MS (ESI+) m/z 290.1 (M+H)+. d) (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazolyl)phenyl)acrylamide O .0.
O H2N N 'OH H ‘7’ H S’ H N-N N-N SEIvf SEIvf The title compound was prepared according to the procedure described for the synthesis of (1) starting from (E)(3-methoxypropynoxy-phenyl)propenoic acid and 2- -(trimethylsilyl)ethoxy)methyl)-lH-pyrazolyl)aniline. MS (ESI+) m/z 504.2 (M+H)+. e) (E)-N-(2-(lH-pyrazolyl)phenyl)(3-methoxy(propyn-l- yloxy)phenyl)acrylamide N .o.
H N N-N H SEWf HN-N To a solution of (£,)(3-methoxypropynoxy-phenyl)-/V-[2-[l-(2- trimethylsilylethoxymethyl)pyrazolyl]phenyl]propenamide (0.09 g, 0.178 mmol, 1.0 equiv.) in methanol (2 mL) was added 4M hydrogen de in methanol (6 mL) solution and the mixture was stirred at 20 °C for 5 hours. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC to give the desired product as an off-white solid (8 mg, 12%); NMR (CDC13, 400 MHz) 5 8.40 (hr. s., 1H), 7.80 (s, 2H), 8.69 (d, /= 16.0 Hz, 1H), 7.40 - 7.32 (m, 3H), 7.21 - 7.18 (m, 1H), 7.13 - 7.10 (m, 1H), 7.08 - 7.06 (m, 1H), 7.03 (d, /= 8.0 Hz, 1H), 6.30 (d, /= 16.0 Hz, 1H), 4.81 (d, /= 4.0 Hz, 2H), 3.93 (s, 3H), 2.54 (t, / = 2.0 Hz, 1H); MS (ESI+) m/z 374.1 (M+H)+; 98.7% purity, RT 2.28 min (Method 8).
Ex Structure Data Method o iH NMR dg, 400 MHz) 5 Prepared according s°- NH 12.83 (s, 1H), 12.59 (hr. s„ 1H), to the method for <0^0 ^ N 8.57 (d, /= 8.0 Hz, 1H), 8.01 (s, 24 starting from 4- NHJ 1H), 7.79 - 7.74 (m, 2H), 7.58 (d, J bromo-l-((2- (E)-N-(2-( 1 H-imidazol = 8.0 Hz, 1H), 7.35 (s, 1H), 7.27 - (trimethylsilyl)etho yl)phenyl)(3-methoxy(prop- 7.19 (m, 2H), 7.08 - 7.05 (m, 2H), xy)methyl)-lH- 2-yn-1 -yloxy)phenyl)acrylamide 6.68 (d, J= 16.0 Hz, 1H), 4.85 (d, J i midazole = 2.4 Hz, 2H), 3.85 (s, 3H), 3.59 (t, J= 2.4 Hz, 1H); MS (ESI+) m/z 374.1 (M+H)+; 93.6% purity, RT 2.48 min (Method 8) 26 o 1H NMR (DMSO-d6, 400 MHz) 5 Prepared according NH 12.64 (s, 1H), 8.56 (d, J = 8.0 Hz, to the method for #^0' ^ N 1H), 7.94 (s, 1H), 7.76 (s, 1H), 7.67 24 starting from 4- / (d, /= 8.0 Hz, 1H), 7.57 (d,/= 16.0 bromo-1 l- (E)(3-methoxy(propyn- Hz, 1H), 7.35 (s, 1H), 7.26 - 7.20 dazole 1 -yloxy)phenyl)-/V-(2-( 1 -methyl- (m, 2H), 7.09 - 7.05 (m, 2H), 6.68 lH-imidazol (d, /= 16.0 Hz, 1H), 4.84 (d,/=2.0 yl)phenyl)acrylamide Hz, 2H), 3.86 (s, 3H), 3.76 (s, 3H), 3.58 (t, /= 2.0 Hz, 1H); MS (ESI+) m/z 388.1 (M+H)+; 95.5% purity, RT 2.72 min (Method 8) (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N- (methylsulfonyl)benzamide (27) 0 .0. .0. N N H H O NH ^^0 O OH 0s,k To a solution of )(3-methoxypropynoxy-phenyl)prop enoyl]amino]benzoic acid (0.08 g, 0.227 mmol, 1.0 equiv.) in tetrahydrofuran (5 mL) was added IJ'-carbonyldiimidazole (0.074 g, 0.455 mmol, 2.0 equiv.). The mixture was stirred at 50°C for 1 hour and then a on of methanesulfonamide (0.043 g, 0.455 mmol, 2.0 equiv.) and 1,8- diazabicyclo[5.4.0]undecene (0.103 g, 0.683 mmol, 3.0 equiv.) in tetrahydrofuran (5 mL) was slowly added. The on was stirred for another 5 hours at 20°C. The reaction mixture was diluted with ethyl acetate (5 mL) and washed with water (5 mL x 3). The organic layers were dried and concentrated under reduced pressure to give a residue which was purified by preparative HPLC to give the desired product as a white solid (20 mg, 21%); 1H NMR (DMSO- d6, 400 MHz) 5 10.74 (br. s., 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.58 - 7.56 (m, 2H), 7.33 (s, 1H), 7.22 - 7.21 (m, 2H), 7.08 - 7.06 (m, 1H), 6.77 (d, J = 16.0 Hz, 1H), 4.84 (d, J = 2.0 Hz, 2H), 3.84 (s, 3H), 3.59 (t, J = 2.0 Hz, 1H), 3.32 (s, 3H); MS (ESI+) m/z 451.1 (M+Na)+; 98% purity, RT 2.81 min (Method 11).
(E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(3-methyl-l,2,4-oxadiazol yl)phenyl)acryl-amide (28) a) N-((E)-l-(hydroxyimino)ethyl)((E)(3-methoxy(propyn-l- yloxy)phenyl)acrylamido)-benzamide o o o o N N H H Xnoh ^0 O' OH O' NH To a solution of )(3-methoxypropynoxy-phenyl)prop enoyl]amino]benzoic acid (0.1 g, 0.284 mmol, 1.0 equiv.) in N,N-dimethylformamide (5 mL) was added HATU (0.129 g, 341 umol, 1.2 equiv.), N,N-diisopropylethylamine (0.110 g, 0.853 mmol, 3.0 equiv.) and N-hydroxyacetamidine (0.042 g, 0.569 mmol, 2.0 ) and the mixture stirred for 12 hours at 25 °C. The reaction mixture was filtered and concentrated to give a residue which was purified by silica gel chromatography (petroleum ether: ethyl acetate 5:1 to ethyl acetate) to give the desired product as a light yellow solid and used t further purification (0.15 g crude); 1H NMR (CDC13, 400 MHz) 5 11.33 (s, 1H), 8.86 (d, J = 8.4 Hz, 1H), 7.99- 7.96 (m, 1H), 7.66 (d, J = 15.2 Hz, 1H), 7.59 - 7.58 (m, 1H), 7.12 - 7.07 (m, 3H), 7.03 (d, J = 8.8 Hz, 1H), 6.49 (d, J = 15.2 Hz, 1H), 4.81 (d, J = 2.0 Hz, 2H), 3.95 (s, 3H), 2.54 (t, J = 2.0 Hz, 1H), 2.15 (s, 3H). b) (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(3-methyl-l,2,4-oxadiazol yl)pheny 1) -acrylamide o o .0. N N Xnoh H CT NH A on of N-((E)-l-(hydroxyimino)ethyl)((E)(3-methoxy(propyn-l- yloxy)phenyl)-acrylamido)benzamide (0.15 g, 0.368 mmol, 1.0 equiv.) in N,N- ylformamide (3 mL) was heated to 110 °C for 10 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC to give the desired product as a light yellow solid (10 mg, 21%); 1H NMR (DMSO-d6, 400 MHz) 5 11.39 (s, 1H), 8.97 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 15.6 Hz, 1H), 7.63 (t, J = 8.4 Hz, 1H), 7.26 - 7.25 (m, 2H), 7.14 (s, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.53 (d, J = 15.6 Hz, 1H), 4.83 (d, J = 2.0 Hz, 2H), 3.96 (s, 3H), 2.58 (s, 3 H), 2.56 (t, J = 2.0 Hz, 1H); MS (ESI+) m/z 412.1 (M+Na)+; 93% purity, RT 3.33 min (Method 11). (/?)(3-methoxy(propyn-l-yloxy)phenyl)-/V-(2-(5-methyl-l,3,4-oxadiazol nyl)-acrylamide (29) /O. N N H H Nr 'o To a solution of 2-[[(£’)(3-methoxypropynoxy-phenyl)prop enoyl]amino]benzoic acid (0.5 g, 1.42 mmol, 1.0 ) in acetonitrile (30 mL) was added acetohydrazide (0.126 g, 1.70 mmol, 1.2 ) and phosphorus oxychloride (1.09 g, 7.10 mmol, .0 equiv.). The reaction mixture was stirred at 106°C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC to afford the desired product as a yellow solid (28 mg, 5%); ^ NMR (DMSO-Je, 400 MHz) 8 11.04 (s, 1H), 8.12 (d, 7=8.0 Hz, 1H), 7.97 (d,/= 16.0 Hz, 1H), 7.88 - 7.86 (m, 1H), 7.73 ( d, / = 8.0 Hz, 1H), 7.53 (t, / = 8.0 Hz, 1H), 7.37 - 7.36 (m, 2H), 7.14 - 7.10 (m, 2H), 4.87 (d, / = 2.0 Hz, 2H), 3.86 (s, 3H), 3.34 (t, / = 2.0 Hz, 1H), 2.19 (s, 3 H); MS (ESI+) m/z 390.1 (M+H)+; 95.5% purity, RT 1.77 min (Method 10).
(/?)-/V-(2-(dimethylamino)ethyl)(3-(3-methoxy(propyn lyloxy) ) acrylamido) benzamide (30) o o .0. .0.
N N H H O' O OH O' To a solution of A/',A/'-dimethylethane-1,2-diamine (42.9 mg, 0.487 mmol, 1.5 equiv.) in dichloromethane (5 mL) was added 2-[[(£’)(3-methoxypropynoxy-phenyl)prop enoyl]amino]benzoyl chloride (120 mg, 0.325 mmol, 1.0 equiv.) (prepared from 2-[[(£’)(3- methoxypropynoxy-phenyl)propenoyl]amino]benzoic acid and thionyl chloride) and triethylamine (99 mg, 0.974 mmol, 3.0 equiv.) and the resulting mixture was stirred at 20°C for 12 hrs. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC to afford the title compound as a light yellow solid as the trifluoroacetic acid salt (27.8 mg, 19%); H NMR (CDCI3, 400 MHz) 12.45 (br. s., 1H), 11.63 (s, 1H), 8.87 (br. s., 1H), 8.76 (d, /= 8.4 Hz, 1H), 8.02 (d, /= 8.0 Hz, 1H), 7.68 (d, /= 15.6 Hz, 1H), 7.52 (t, /= 8.4 Hz, 1H), 7.18-7.12 (m, 3H), 7.02 (d, /= 8.4 Hz, 1H), 6.50 (d, /= 16.0 Hz, 1H), 4.82 (s, 2H), 3.95 (s, 3H), 3.91 (br. s., 2H), 3.31 (br. s., 2H) 2.91 (s, 6H), 2.55 (s, 1H); MS (ESI+) m/z 422.2 (M+H)+; 93.7% purity, RT 2.46 min (Method 11).
Ex Structure Data Method 31 fi' 1H NMR d6, 400 MHz) 5 0 Prepared N 16.00 (br. s. 1H), 12.45 (br. s., 1H), ing to the O' NH 10.37 (s, 1H), 7.90 (d, J = 6.4 Hz, method for 1 N^N 1H), 7.78 (d, / = 6.4 Hz, 1H), 7.59 t u starting from 2- HN-N (t, J= 7.6 Hz, 1H), 7.52 (d, /= 15.6 (3-(3-mcthoxy(propyn- amino-/V-(2HHz , 1H), 7.28 - 7.26 (m, 2H), 7.19 yloxy)phenyl)acrylamido)-/V- tetrazol 7.18 (m, 1H), 7.07 (d, /= 18.4 Hz, trazolyl)benzamide yl)benzamide (J. 1H), 6.72 (d, /= 15.6 Hz, 1H), 4.84 Med. Chem. (d, J = 2.0 Hz, 2H), 3.83 (s, 3H), 1986,29, 2403) 3.34 (t, /= 2.0 Hz, 1H); MS (ESI+) m/z 419.0 (M+H)+; 97% purity, RT 2.73 min (Method 11) 32 o iH NMR (CDC13, 400 MHz) 5 Prepared N 12.73 (br. s„ 1H), 11.68 (s, 1H), according to the O' O' N N 8.76 (d, /= 8.4 Hz, 1H), 8.07 (br. method for 30 H I s„ 1H), 7.80 (d, J= 8.0 Hz, 1H), starting from N,N- /V-(3-(dimethylamino)propyl)(3- 7.69 (d, /= 15.6 Hz, 1H), 7.53 - dimethylpropane- (3-methoxy(propyn-1 - 7.52 (m, 1H), 7.16 - 7.13 (m, 3H), 1,3-diamine yloxy)phenyl)acrylamido) 7.03 (d, /= 8.0 Hz, 1H), 6.50 (d, J benzamide trifluoroacetic acid salt = 15.6 Hz, 1H), 4.81 (s, 2H), 3.95 (s, 3H), 3.59 (d, J= 5.6 Hz, 2H), 3.17 (t, J= 6.8 Hz, 2H), 2.85 (s, 6H), 2.55 (s, 1H), 2.19 (t, J= 6.0 Hz, 2H); MS (ESI+) m/z 436.2 (M+H)+; 96.4% , RT 2.45 min (Method 11) 33 o 1 H NMR (DMSO, 400 MHz) ed N 511.46 (s, 1H), 8.81 (d, 7=5.2 Hz, according to the O' O' N 1H), 8.54 (d, 7= 8.4 Hz, 1H), 7.75 method for 30 H (d, 7 =8.4 Hz, 1H), 7.56-7.51 (m, starting from 2- (£T)(3-(3-methoxy(propyn- 2H), 7.41 (d, 7=1.2 Hz, 1H), 7.24 methoxyethanamin l-yloxy)phenyl)acrylamido)-/V-(2- (d, 7= 8.8 Hz, 1H), 7.17 - 7.15 (m, e methoxyethyl)benzamide 1H), 7.05 (d, 7= 8.4 Hz, 1H), 6.78 (d, 7= 15.6 Hz, 1H), 4.84 (s, 2H), 3.85 (s, 3H), 3.59 (s, 1H), 3.50- 3.40 (m, 4H), 3.28 (s, 3H); MS (ESI+) m/z 409.2 ; 96.9% purity, RT 2.93 min (Method 11) 34 1H NMR (DMSO-d6, 400 MHz) 5 0 Prepared N 11.34 (s, 1H), 8.81 (br. s, 1H), 8.49 according to the H r? O' O' N (d, 7= 8.4 Hz, 1H), 7.75 (d, 7= 7.2 method for 30 H Hz, 1H), 7.57 - 7.52 (m, 2H), 7.40 ng from 2-(4- (s, 1H), 7.24 (d, 7= 8.0 Hz, 1H), (£T)(3-(3-methoxy(propyn- methylpiperazin-1 - 7.18 (t, 7= 8.0 Hz, 1H), 7.06 (d, 7 = l-yloxy)phenyl)acrylamido)-/V-(2- yl)ethanamine 8.4 Hz, 1H), 6.77 (d, 7= 15.6 Hz, (4-methylpiperazin-1 - 1H), 5.40-4.20 (m, 6H), 3.85 (s, yl)ethyl)benzamide trifluoroacetic 3H), 3.59 (s, 1H), 3.54-3.52 (m, acid salt 2H), 3.50 - 2.99 (m, 4H), 2.94 - 2.92 (m, 2H), 2.76 (s, 3H); MS (ESI+) m/z 477.2 (M+H)+; 97% , RT 2.38 min (Method 11) o 1H NMR (CDCI3, 400 MHz) 5 Prepared N r? 11.56 (s„ 1H), 8.76 (d, 7= 8.0 Hz, according to the H o^n^n^ O' 1H), 8.55 (br. s, 1H), 8.71 - 7.67 method for 30 H (m, 2H), 7.52 (t, 7= 4.0 Hz, 1H), starting from 2- (£T)(3-(3-methoxy(propyn- 7.15 - 7.12 (m, 3H), 7.04 (d, 7= 8.0 morpholinoethana l-yloxy)phenyl)acrylamido)-/V-(2- Hz, 1H), 6.48 (d, 7= 15.2 Hz, 1H), mine morpholino ethyl)benzamide 4.82 (d, 7 = 2.0 Hz, 2H), 4.02 - 4.01 trifluoroacetic acid salt (m, 4H), 3.95 (s„ 3H), 3.91 (d, 7 = 4.8 Hz, 2H), 3.70 - 3.50 (m, 2H), 3.36 (d, 7=4.8 Hz, 2H), 3.10 - 2.80 (m, 2H), 2.55 (s, 1H). MS (ESI+) m/z 464.2 (M+H)+; 94.2% purity, RT 2.47 min (Method 11) 36 iH NMR d6, 400 MHz) 5 Prepared 11.21 (s, 1H), 9.56 (br. s, 1H), 8.75 according to the (d, J= 7.2 Hz, 1H), 8.45 (d, J= 8.0 method for 30 H Hz, 1H), 7.75 (d, J= 7.6 Hz, 1H), starting from 1- (£T)(3-(3-methoxy(propyn- 7.56 - 7.52 (m, 2H), 7.39 (s„ 1H), methylpiperidin 1-yloxy)phenyl)acrylamido)-/V-( 1 - 7.23 (d, /= 8.0 Hz, 1H), 7.18 (t, / = amine methylpiperidinyl)benzamide 8.0 Hz, 1H), 7.06 (d, J= 8.4 Hz, trifluoroacetic acid salt 1H), 6.76 (d, /= 15.6 Hz, 1H), 4.85 (s, 2H), 4.05 - 4.02 (m, 1H), 3.85 (s, 3H), 3.69 (s, 1H), 3.60-3.58 (m, 2H), 3.12 - 3.07 (m, 2H), 2.78 (d, J= 3.6 Hz, 3H), 2.08 - 2.05 (m, 2H), 1.80- 1.74 (m, 2H); MS (ESI+) m/z 448.2 (M+H)+; 99% purity, RT 2.47 min (Method 11) 37 o iH NMR (DMSO-d6, 400 MHz) 5 Prepared N 11.39 (s, 1H), 9.46 (br. s, 1H), 8.87 according to the O' H O (t, 7=5.2 Hz, 1H), 8.51 (d, 7=8.0 method for 30 Hz, 1H), 7.77 (d, 7= 7.2 Hz, 1H), starting from (1- -(3-(3-methoxy(propyn- 7.56 - 7.52 (m, 2H), 7.41 (s, 1H), methylpiperidin 1 -yloxy)phenyl)acrylamido)-/V-(( 1 - 7.24 (d, 7= 8.0 Hz, 1H), 7.19 (t, 7 = yl)methanamine methylpiperidin 7.6 Hz, 1H), 7.06 (d, 7= 8.4 Hz, yl)methyl)benzamide 1H), 6.77 (d, 7= 15.6 Hz, 1H), 4.85 trifluoroacetic acid salt (s, 2H), 3.85 (s, 3H), 3.59 (s, 1H), 3.44- 3.41 (m, 2H), 3.21 (t, 7= 5.6 Hz, 2H), 2.94 - 2.85 (m, 2H), 2.74 (d, 7= 4.4 Hz, 3H), 1.90 (d,7 = 14.4 Hz, 2H), 1.87-1.82 (m, 1H), 1.44- 1.38 (m, 2H); MS (ESI+) m/z 462.2 (M+H)+; 98.9% purity, RT 2.49 min d 11) 38 o iH NMR (DMSO-d6, 400 MHz) 5 Prepared /O' N I X? 11.21 (s, 1H), 9.38 (d, 7= 6.4 H, according to the O' 1H), 8.50 (d, 7= 7.6 Hz, 1H), 7.83 method for 30 H (d, 7= 1.2 Hz. 1H), 7.55-7.51 (m, starting from (£T)(3-(3-methoxy(propyn- 2H), 7.40 (d, 7= 2.0 Hz, 1H), 7.23 oxetanamine 1 )phenyl)acrylamido)-/V- -7.19 (m, 2H), 7.05 (d, 7 = 8.4 Hz, (oxetan-3 -yl)benzamide 1H), 6.78 (d, 7= 15.6 Hz, 1H), 5.05 - 5.02 (m, 1H), 4.84 (d, 7 = 2.4 Hz, 2H), 4.78 (t, 7 = 6.8 Hz, 2H), 4.63 (d, 7= 6.4 Hz, 2H), 3.85 (s, 3H), 3.59 (t, 7= 2.4 Hz, 1H); MS (ESI+) m/z 407.2 (M+H)+; 98.4% purity, RT 1.82 min (Method 10) 39 o iH NMR (DMSO-dg, 400 MHz) 5 Prepared NH’ 11.30 (s, 1H), 8.75 (d, 7= 8.4 Hz, according to the 0‘ O' NH 1H), 7.77 (d, 7= 15.2 Hz, 1H), 7.55 method for 30 - 7.45 (m, 2H), 7.14 - 7.09 (m, 3H), starting from ^-o 7.03 (d, 7= 8.8 Hz, 1H), 6.58 (br. s, (tetrahydrofuran- (£T)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-/V- 1H), 6.49 (d, /= 15.6 Hz, 1H), 4.81 3-yl)methanamine ((tetr ahydrofuran-3 - (d, /= 2.4 Hz, 2H), 4.00-3.95 (m, yl)methyl)benzamide 4H), 3.85-3.78 (m, 1H), 3.80-3.74 (m, 1H), 3.70-3.67 (d, /= 4.4 Hz, 1H), 3.55 - 3.44 (m, 2H), 2.70-2.60 (m, 1H), 2.54 (t, /= 2.4 Hz, 1H), 2.17 - 2.12 (m, 1H), 1.73 - 1.70 (m, 1H); MS (ESI+) m/z 435.3 (M+H)+; 99.2% purity, RT 1.92 min (Method 10)_______________ 40 iH NMR (DMSO-d6, 400 MHz) 5 Prepared NH / 11.11 (s, 1H), 9.23 (t, 7=5.2 Hz, according to the 0' 0 1H), 9.01 (s, 1H), 8.38 (d, 7= 7.6 method for 30 & ^-N Hz, 1H), 7.75 (d, 7= 8.0 Hz, 1H), starting from (1- (£T)(3-(3-methoxy(propyn- 7.65 (s, 1H), 7.54 - 7.50 (m, 2H), methyl-lHyloxy)phenyl)acrylamido)-/V-(( 1 - 7.37 (d, 7=2.0 Hz, 1H), .19 imidazol methyl-1 H-imidazol-5 - (m, 2H), 7.07 (d, 7= 8.4 Hz, 1H), yl)methanamine yl)methyl)benzamide 6.75 (d, 7=15.6 Hz, 1H), 4.85 (d, 7 trifluoroacetic acid salt = 2.4 Hz, 2H), 4.59 (d, 7= 2.0 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 3H) 3.60 (t, 7= 2.4 Hz, 1H); MS (ESI+) m/z 445.3 (M+H)+; 96.3% purity, RT 1.54 min (Method 10) 41 o iH NMR (DMSO-d6, 400 MHz) 5 ed .0. 11.35 (s, 1H), 9.39 (d, 7= 6.0 Hz, according to the O' 0 1H), 8.59 (hr. s, 1H), 8.52 (d,7 = method for 30 8.4 Hz, 1H), .87 (m, 2H), starting from (£T)(3-(3-methoxy(propyn- 7.55-7.51 (m, 3H), 7.38-7.37 (m, pyridin 1 )phenyl)acrylamido)-/V- 2H), 7.21 (d, 7= 8.4 Hz, 2H), 7.04 ylmethanamine (pyridinylmethyl)benzamide (d, 7= 8.4 Hz, 1H), 6.75 (d,7 = .6 Hz, 1H), 4.83 (d, 7= 2.4 Hz, 2H), 4.65 (d, 7= 5.6 Hz, 2H), 3.83 (s, 3H), 3.57 (t, 7= 2.4 Hz, 1H); MS (ESI+) m/z 442.2 (M+H)+; 97.6% purity, RT 1.59 min (Method 10) 42 iH NMR (CDC13, 400 MHz) 5 0 ed .0. % 11.59 (s, 1H), 8.78 (d, 7= 8.4 Hz, according to the O’ 0 ff Sj 1H), 8.60 (s, 1H), 8.00 (hr. s, 1H), method for 30 7.70 - 7.67 (m, 2H), 7.65 - 7.53 (m, starting from 2- (£T)(3-(3-methoxy(propyn- 2H), 7.24 - 7.22 (m, 2H), 7.17 - (pyridin l-yloxy)phenyl)acrylamido)-/V-(2- 7.10 (m, 3H), 7.03 (d, 7= 8.4 Hz, yl)ethanamine (pyridinyl)ethyl)benzamide 1H), 6.51 (d, 7= 15.6 Hz, 1H), 4.81 (d, 7= 1.6 Hz, 2H), 3.96 (s, 3H), 3.89 - 3.85 (m, 2H), 3.13 (t, 7= 6.0 Hz, 2H), 2.55 (t, 7= 2.4 Hz, 1H); MS (ESI+) m/z 456.2 (M+H)+; 98.2% purity, RT 2.86 min (Method 13) WO 44620 43 0 iH NMR (DMSO-d6, 400 MHz) 5 ed .0. 11.27 (s, 1H), 9.42 (br. s, 1H), 8.81 according to the a 0 "'"O (br. s, 1H), 8.69 (br. s, 1H), 8.46 (d, method for 30 J = 8.4 Hz, 1H), 8.24 (br. s, 1H), starting from (£T)(3-(3-methoxy(propyn- 7.84 (d, /= 7.6 Hz, 1H), 7.55 (br. s, n 1 -yloxy)phenyl)acrylamido)-/V- 1H), 7.55 - 7.50 (m, 2H), 7.39 (s, ylmethanamine (pyridinylmethyl)benzamide 1H), 7.23 - 7.21 (m, 2H), 7.06 (d, J trifluoroacetic acid salt = 8.4 Hz, 1H), 6.76 (d, J= 15.6 Hz, 1H), 4.85 (d, /= 2.4 Hz, 2H), 4.63 (d, J= 4.0 Hz, 2H), 3.85 (s, 3H), 3.60 (t, J= 2.4 Hz, 1H); MS (ESI+) m/z 442.1 (M+H)+; 99.2% purity, RT 1.49 min (Method 10) 44 iH NMR (CDC13, 400 MHz) 5 ed .62 (s, 1H), 9.09 (s, 1H), 8.64 (d, according to the /= 6.4 Hz, 2H), 8.46 -8.45 (m, 1H), method for 30 7.78 - 7.73 (m, 3H), 7.56 - 7.55 (m, starting from -(3-(3-methoxy(propyn- 1H), 7.36 - 7.35 (m, 1H), 7.25 - pyridinamine 1 -yloxy)phenyl)acrylamido)-/V- 7.24 (m, 1H), 7.20 (s, 1H), 7.15 (s, (pyridinyl)benzamide 1H), 7.09 - 7.01 (m, 1H), 6.45 (d, J = 15.6 Hz, 1H), 4.83 (d, J= 2.4 Hz, 2H), 3.98 (s, 3H), 2.56 (t, J= 2.4 Hz, 1H); MS (ESI+) m/z 428.1 (M+H)+; 96.3% purity, RT 2.44 min (Method 8) 45 1H NMR (DMSO-d6, 400 MHz) 5 0 Prepared N H u 11.24 (s, 1H), 9.48 (t, 7=6.0 Hz, according to the O' 1H), 8.72 (d, 7= 6.0 Hz, 2H), 8.46 method for 30 (d, 7= 8.0 Hz, 1H), 7.89 (d, 7= 6.8 starting from (£T)(3-(3-methoxy(propyn- Hz, 1H), 7.76 (d, J = 6.0, 2H), 7.55 pyridin 1 -yloxy)phenyl)acrylamido)-/V- - 7.51 (m, 2H), 7.37 (d, 7= 1.6 Hz, ylmethanamine (pyridinylmethyl)benzamide 1H), 7.23 - 7.20 (m, 2H), 7.04 (d, 7 trifuoroacetic acid salt = 8.4 Hz, 1H), 6.74 (d, 7= 15.6 Hz, 1H), 4.83 (d, 7= 2.4 Hz, 2H), 4.68 (d, 7= 5.6 Hz, 2H), 3.83 (s, 3H), 3.59 (t, 7 = 2.4 Hz, 1H); MS (ESI+) m/z 442.1 (M+H)+; 98.7% purity, RT 2.5 min (Method 11) 46 1H NMR (DMS0-<4 400 MHz) 5 0 Prepared N 11.31 (s, 1H), 8.94-8.93 (m, 1H), according to the O' O' 8.81 (d, 7= 6.4 Hz, 2H), 8.54 (d, 7 method for 30 = 8.0 Hz, 1H), 7.89 (d, 7= 6.4 Hz, starting from 2- (£T)(3-(3-methoxy(propyn- 2H), 7.72 (d, 7= 7.6 Hz, 1H), 7.62- (pyridin l-yloxy)phenyl)acrylamido)-/V-(2- 7.58 (m, 2H), 7.47 (d, 7= 1.2 Hz, yl)ethanamine (pyridinyl)ethyl)benzamide 1H), 7.37-7.33 (m, 1H), 7.24-7.21 (m, 1H), 7.12 (d, 7= 8.4 Hz, 1H), 6.81 (d, 7= 15.6 Hz, 1H), 4.90 (d, 7 = 2.0 Hz, 2H), 3.92 (s, 3H), 3.76- 3.70 (m, 2H), 3.65 (s, 1H), 3.18 (t, 7 = 6.4 Hz, 2H); MS (ESI+) m/z 456.2 (M+H)+; 95.1% purity, RT 1.54 min d 10) 47 o iH NMR (DMSO-<4, 400 MHz) 5 ed .0. 11.07 (s, 1H), 10.67 (s, 1H), 8.47 according to the O' W" (d, J= 7.2 Hz, 1H), 8.04 (s, 1H), method for 30 H 7.82 (d, /= 6.8 Hz, 1H), 7.62 (s, starting from 1- (£T)(3-(3-methoxy(propyn- 1H), 7.60 - 7.52 (m, 2H), 7.39 (d, J methyl-lH- 1-yloxy)phenyl)acrylamido)-/V-( 1 - = 2.0 Hz , 1H), 7.24 - 7.23 (m, 2H), pyrazolamine methyl-1 H-pyrazolyl)benzamide 7.06 (d, /= 8.0 Hz, 1H), 6.79 (d, J = 15.6 Hz, 1H), 4.84 (d, J= 2.4 Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.59 (t, J= 2.4 Hz, 1H); MS (ESI+) m/z 431.1 ; 96.3% purity, RT 2.62 min (Method 12) 48 o iH NMR dg, 400 MHz) 5 Prepared N T l==\ H 1 L N 10.98 (s, 1H), 10.93 (s, 1H), 8.42 according to the O' o^n-^n (d, 7=8.0 Hz, 1H), 7.86 (d, 7=8.0 method for 30 H Hz, 1H), 7.64 (d, 7= 2.0 Hz, 1H), starting from 1- (£T)(3-(3-methoxy(propyn- 7.56 - 7.52 (m , 2H), 7.40 (s, 1H), methyl-lHyloxy)phcnyl)acrylamido)-/V-( 1 - 7.23 - 7.18 (m, 2H), 7.05 (d, 7= 8.4 pyrazolamine methyl-1 H-pyrazol-3 nzamide Hz, 1H), 6.83 (d, 7=15.6 Hz, 1H), 6.60 (s, 1H), 4.84 (s, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 3.58 (s, 1H); MS (ESI+) m/z 431.2 (M+H)+; 94% purity, RT 1.93 min (Method 10) (/?)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-/V-(piperidinyl)benzamide N NH O' OH To a solution of 2-[[(£’)(3-methoxypropynoxy-phenyl)prop enoyl]amino]benzoic acid (100 mg, 0.285 mmol, 1.0 equiv.), / O. N N H H OH HO' O^ OH HN5X° A mixture of 2-[[(T)(4-hydroxymcthoxy-phcnyl)propcnoyl]amino]benzoic acid (150 mg, 0.479 mmol, 1.0 equiv. Bioorg. Med. Chem. Lett. 2009, 19, 7003-7006), tertbutyl 4-(p-tolylsulfonyloxymethyl)piperidine-l-carboxylate (265 mg, 0.718 mmol, 1.5 equiv.) and potassium hydroxide (0.5 M, 3.8 mL, 4.0 equiv.) in acetone (3 mL) was stirred at 80°C for 16 hours. The mixture was concentrated under reduced pressure and the e stirred in 4M hydrogen chloride in dioxane (10 mL). The solvent was removed in vacuo and the residue purified by preparative HPLC to give the desired product as a yellow solid as the oroacetic acid salt (60.5 mg, 26.6%); ^ NMR (DMSO-d6, 400 MHz) 6 11.32 (s, 1H), 8.65-8.60 (m, 2H), 8.32 (br. s, 1H), 8.02 (dd, /= 8.0 Hz, /= 1.2 Hz, 1H), 7.62 (t, /= 8.0 Hz, 1H), 7.57(d, /= 15.6 Hz, 1H), 7.40 (d, /= 1.6 Hz, 1H), 7.25 (d, /= 8.0 Hz, 1H), 7.18 (t, /= 8.0 Hz, 1H), 7.03 (d, / = 8.4 Hz, 1H), 6.81 (d, /= 15.6 Hz, 1H), 3.92 (d, /= 6.4 Hz, 2H), 3.88 (s, 3H), 3.20 - 3.35 (m, 2H), 2.85 - 3.00 (m, 2H), 2.00 - 2.20 (m, 1H), 1.80 - 2.00 (m, 2H), 1.40 - 1.55 (m, 2H); MS (ESI+) m/z 411.2 (M+H)+; 90.3% purity, RT 2.16 min (Method 11). (/?)(3-(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)acrylamido)benzoic acid I o 'O' 0 OH a) l-methylpyrrolidinyl 4-methylbenzenesulfonate Crm %rCr / O'0* To the solution of l-methylpyrrolidinol (300 mg, 2.97 mmol, 1.00 equiv) and potassium hydroxide (666 mg, 11.86 mmol, 4.00 equiv) in tetrahydrofuran (5 mL) was added 4-methylbenzenesulfonyl chloride (848 mg, 4.45 mmol, 1.50 equiv) portion-wise ining the temperature at 0 °C and the resultant yellow slurry was stirred at 25°C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford the desired product as yellow oil (523 mg, 65%) which was used t further purification; MS (ESI+) m/z 256.1 (M+H)+. b) (E)(3-(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)acrylamido)benzoic acid A. o A. 0 N N O' OH HO' O^ OH A mixture of 2-[[(T)(4-hydroxymcthoxy-phcnyl)propcnoyl]amino]benzoic acid (100 mg, 0.32 mmol, 1.00 , (l-methylpyrrolidinyl) 4-methylbenzenesulfonate (130 mg, 0.48 mmol, 1.50 equiv) and ium ide (0.5 M, 2.55 mL, 4.00 equiv) in acetone (3 mL) was stirred at 60°C for 16 hours. The reaction mixture was concentrated in vacuo and the residue purified by preparative HPLC to afford the desired product as a light yellow solid (72 mg, 44 %) as a trifluoroacetate salt; NMR (CDCI3, 400 MHz) 5 11.48 (s, 1H), 8.87 (d, /= 8.8 Hz, 1H), 8.18 (dd, 7=8.0 Hz,/= 1.2 Hz, 1H), 7.61 -7.65 (m, 2H), 7.16 (t,/= 8.0 Hz, 1H), 7.02- 7.07 (m, 2H), 6.83 (d, /= 8.0 Hz, 1H), 6.42 (d, /= 15.6 Hz, 1H), 5.17 (s, 1H), 4.10 - 4.40 (m, 1H), 3.90 - 4.00 (m, 1H), 3.86 (s, 3H), 3.20 - 3.40 (m, 2H), 3.07 (s, 3H), 2.40 - 2.55 (m, 2H); MS (ESI+) m/z 397.3 (M+H)+; 98.8% purity; RT = 1.93 min (Method 10). (/?)(3-(4-((3,5-dimethylisoxazolyl)methoxy)methoxyphenyl)acrylamido)benzoic acid o o O N N n/J Cl H O OH HO" O"^ OH 0 A solution of 2-[[(£)(4-hydroxymethoxy-phenyl)propenoyl] ami no] benzoic acid (100 mg, 0.32 mmol, 1.00 equiv.), 4-(chloromethyl)-3,5-dimethyl-isoxazole (87 mg, 0.48 mmol, 1.50 equiv.) and potassium hydroxide (0.5 M, 2.6 mL, 4.00 equiv.) in acetone (2 mL) was stirred at 60°C for 16 hours. The on mixture was concentrated in vacuo and the residue was ed by preparative HPLC to afford the desired t as a light yellow solid (65 mg, 47%); i H NMR (DMSO-de, 400 MHz) 5 11.28 (s, 1H), 8.62 (d, /= 8.4 Hz, 1H), 8.01 (d, /= 8.0 Hz, 1H), 7.62 (t, / = 8.0 Hz, 1H), 7.57 (d, / = 15.2 Hz, 1H), 7.39 (s, 1H), 7.28 (d, / = 8.0 Hz, 1H), 7.17 (t, 7 = 7.6 Hz, 1H), 7.12 (d, 7=8.4 Hz, 1H), 6.81 (d, 7 =15.6 Hz, 1H), 4.95 (s, 2H), 3.83 (s, 3H), 2.39 (s, 3H), 2.21 (s, 3H); MS (ESI+) m/z 423.1 (M+H)+; 98.2% purity; RT = 1.49 min (Method 1). (/?)(3-(3-methoxy((l-methyl-l//-pyrazolyl)methoxy)phenyl)acrylamido)benzoic add (53) NfjP° cr oh a) 3-methoxy((l-methyl-lH-pyrazolyl)methoxy)benzaldehyde ;xr° Ex Structure Data Method 54 iH NMR (DMSO-d6, 400 MHz) 5 I o ed H 11.29 (s, 1H), 8.63 (d, /= 8.4 Hz, according to the O^OH 1H), 8.01 (d, /= 6.4 Hz, 1H), 7.61 method for 51 (E)(3-(3 -methoxy(oxetan-3 - (t,/= 10.0 Hz, 1H), 7.57 (d, / = starting from 2- ylmethoxy)phenyl)acrylamido)ben 15.6 Hz, 1H), 7.38 (d, J= 2.0 Hz, [[(£)(4- zoic acid 1H), 7.25 (d, /= 8.4 Hz, 1H), 7.17 hydroxy (t, / = 8.0 Hz, 1H), 7.05 (d, / = 8.4 methoxy- Hz, 1H), 6.80 (d, J= 15.6 Hz, 1H), phenyl)prop 4.71 (dd, J= 8.0 Hz, J= 6.0 Hz, enoyl] amino] benz 2H), 4.41 (t, J= 6.0 Hz, 2H), 4.24 oic acid and (d, J= 6.8 Hz, 2H), 3.84 (s, 3H), 3.30 - 3.40 (m, 1H); MS (ESI+) m/z ylmethanol 384.1 (M+H)+; 97.7% purity, RT 2.86 min (Method 12) 55 1H NMR (DMSO-d6, 400 MHz) 5 I o Prepared (X0- H 11.19 (s, 1H), 8.62 (d, /= 8.4 Hz, according to the O-'tDH 1H), 8.58 (d, /= 4.4 Hz, 1H), 8.00 method for 51 (dd, J= 7.2 Hz, J = 2.0 Hz, 1H), starting from 2- (£T)(3-(3-methoxy(pyridin 7.85 (t, J= 7.6 Hz, 1H), 7.61 (t, / = ylmethoxy)phenyl)acrylamido)ben [[(£)(4- 7.6 Hz, 1H), 7.56 (d, J= 15.6 Hz, zoic acid hydrochloric acid salt y 1H), 7.52 (d, /= 7.6 Hz, 1H), 7.42 methoxy-_____ (d, /= 2.0 Hz, 1H), 7.36 (dd, J= phenyl)prop 7.2 Hz, J = 4.2 Hz, 1H), 7.23 (dd, J enoyl] amino] benz = 8.4 Hz, /= 1.2 Hz, 1H), 7.17 (t,/ oic acid and = 8.0 Hz, 1H), 7.07 (d, J= 8.4 Hz, ne 1H), 6.80 (d, /= 15.6 Hz, 1H), 5.22 anol (s, 2H), 3.88 (s, 3H); MS (ESI+) m/z 405.1 ; 95.8% purity, RT 2.63 min (Method 11)_________ 56 I o iH NMR (DMSO-dg, 400 MHz) 5 Prepared 0 % N 11.28 (s, 1H), 8.62 (d, /= 8.0 Hz, according to the Sr H "O' O^OH 1H), 8.55 (d, /= 3.6 Hz, 1H), 8.00 method for 51 (£T)(3-(3-methoxy(2-(pyridin- (dd, 7=7.6 Hz,/= 1.2 Hz, 1H), starting from 2- 2- 7.81 (t, 7= 7.2 Hz, 1H), 7.61 (t, 7 = [[(£)(4- yl)ethoxy)phenyl)acrylamido)benz 8.0 Hz, 1H), 7.56 (d, 7= 15.6 Hz, hydroxy oic acid trifluoroacetic acid salt 1H), 7.45 (d, 7= 7.6 Hz, 1H), 7.37 methoxy- (d, 7= 1.2 Hz, 1H), 7.31(dd, 7= 6.4 phenyl)prop Hz, 7= 5.2 Hz, 1H), 7.24 (dd, 7= enoyl] amino] benz 8.8 Hz, 7= 1.2 Hz, 1H), 7.17 (t, 7 = oic acid and 2- 7.6 Hz, 1H), 7.05 (d, 7= 8.4 Hz, (pyridin 1H), 6.79 (d, 7= 15.6 Hz, 1H), 4.40 yl)ethan-l-ol (t, 7= 6.8 Hz, 2H), 3.80 (s, 3H), 3.24 (t, 7= 6.8 Hz, 2H); MS (ESI+) m/z 419.1 (M+H)+; 93.9% purity, RT 2.49 min (Method 11) 57 I o iH NMR (DMSO-dg, 400 MHz) 5 Prepared 0 % 11.28 (s, 1H), 8.64 - 8.60 (m, 2H), according to the 'O' O-'XJH 8.52 (d, 7= 4.0 Hz, 1H), 8.00 (dd, 7 method for 51 (£T)(3-(3-methoxy(2-(pyridin- = 7.6 Hz, 7= 1.2 Hz, 1H), 7.94 (d, starting from 2- 3- 7= 7.6 Hz, 1H), 7.61 (t, 7= 8.4 Hz, [[(£)(4- yl)ethoxy)phenyl)acrylamido)benz 1H), 7.56 (d, 7= 15.6 Hz, 1H), 7.49 hydroxy oic acid trifluoroacetic acid salt (dd, 7= 7.6 Hz, 7= 4.8 Hz, 1H), methoxy- 7.38 (d, 7= 2.0 Hz, 1H), d, 7 phenyl)prop = 8.0 Hz, 7= 2.0 Hz, 1H), 7.17 (t, 7 enoyl] amino] benz = 7.6 Hz, 1H), 7.03 (d, 7= 8.8 Hz, oic acid and 2- 1H), 6.80 (d, 7= 15.6 Hz, 1H), 4.27 (pyridin (t, 7= 6.8 Hz, 2H), 3.82 (s, 3H), yl)ethan-l-ol 3.12 (t, 7= 6.8 Hz, 2H); MS (ESI+) m/z 419.3 (M+H)+; 99.1% purity, RT 1.61 min (Method 10) 58 o i H NMR (DMSO-dg, 400 Prepared MHz) 5 11.30 (s, 1H), 8.75 (d, 7 = according to the O^OH 6.4 Hz, 2H), 8.64 (d, 7= 7.6 Hz, method for 51 1H), 8.02 (d, 7= 6.4 Hz, 1H), 7.71 starting from 2- (£T)(3-(3-methoxy(pyridin (d, 7= 6.4 Hz, 2H), 7.62 (t, 7= 8.4 [[(£)(4- ylmethoxy)phenyl)acrylamido)ben Hz, 1H), 7.57 (d, 7= 15.6 Hz, 1H), hydroxy zoic acid trifluoroacetic acid salt 7.46 (d, 7= 1.2 Hz, 1H), 7.25 (d, 7 methoxy- = 8.4 Hz, 1H), 7.17 (t, 7= 7.6 Hz, phenyl)prop 1H), 7.06 (d, 7= 8.4 Hz, 1H), 6.83 enoyl] amino] benz (d, 7= 15.6 Hz, 1H), 5.38 (s, 2H), oic acid and 3.91 (s, 3H); MS (ESI+) m/z 405.3 pyridin (M+H)+; 99.6% purity, RT 1.99 min (Method 10) ylmethanol 59 I o iH NMR (DMSO-d6, 400 MHz) 5 ed 0 % 11.28 (s, 1H), 8.78 (d, /= 6.4 Hz, according to the 0 O^OH 2H), 8.63 (d, /= 8.0 Hz, 1H), 8.01 method for 51 (£T)(3-(3-methoxy(2-(pyridin- (d, J= 8.0 Hz, 1H), 7.89 (d, J = 6.4 starting from 2- 4- Hz, 2H), 7.62 (t, J= 8.0 Hz, 1H), [[(£)(4- yl)ethoxy)phenyl)acrylamido)benz 7.56 (d, /= 15.6 Hz, 1H), 7.39 (d, J hydroxy oic acid trifluoroacetic acid salt = 1.2 Hz, 1H), 7.25 (d, J = 8.4 Hz, methoxy- 1H), 7.17 (t, / = 7.6 Hz, 1H), 7.06 phenyl)prop (d, 7=8.4 Hz, 1H), 6.80 (d,/ = enoyl] amino] benz .6 Hz, 1H), 4.38 (t, 7= 6.4 Hz, oic acid and 2- 2H), 3.82 (s, 3H), 3.32 (t, 7= 6.0 (pyridin Hz, 2H); MS (ESI+) m/z 419.1 yl)ethan-l-ol (M+H)+; 98.8% purity, RT 2.49 min (Method 11) 60 iH NMR (DMSO-dg, 400 MHz) 5 Prepared 11.74 (hr. s, 1H), 8.64 (d,7=9.2 according to the cr° Cr OH Hz, 1H), 8.02 (d, 7= 7.2 Hz, 1H), method for 52 N'N 7.55-7.59 (m, 2H), 7.38-7.41 (m, starting from 2- (£)(3-(3 -methoxy(( 1 l- 2H), 7.24 - 7.27 (m, 1H), 7.15-7.18 [[(£)(4- lH-pyrazol (m, 2H), 6.80 (d, 7= 15.2 Hz, 1H), hydroxy hoxy)phenyl)acrylamido)ben 6.38 (s, 1H), 5.21 (s, 2H), 3.85 (s, methoxyzoic 3H); MS (ESI+) m/z 408.3 )prop (M+H)+; 95.9% , RT 1.94 enoyl] amino] benz min (Method 10) oic acid and 5- omethyl) -1 - methyl-1H- pyrazole________ 61 iH NMR (CDC13, 400 MHz) 5 Prepared v. 11.23 (s, 1H), 8.86 (d, 7= 8.4 Hz, according to the ‘OH 1H), 8.13 (d, 7= 8.0 Hz, 1H), 7.67 method for 52 (£)(3-(4-mcthoxy(2- (d, 7= 15.6 Hz, 1H), 7.63 (t, 7= 7.6 starting from (E)- methoxy ethoxy )phenyl) acrylamide Hz, 1H), 7.16 - 7.10 (m, 3H), 6.83 2-(3-(3-hydroxy )benzoic acid (d, 7= 8.4 Hz, 1H), 6.41 (d, 7 = methoxyphenyl) ac .2 Hz, 1H), 4.25 (t, 7= 4.4 Hz, rylamido)benzoic 2H), 3.87 (t, 7= 4.8 Hz, 2H), 3.82 acid and 1-bromo- (s, 3H), 3.51 (s, 3H); MS (ESI+) 2-methoxyethane m/z 372.1 (M+H)+; 99% purity, RT 2.9 min (Method 11) 62 1H NMR (CD3OD, 400 MHz) 5 0 Prepared N 8.74 (d, 7= 5.2 Hz, 1H), 8.69 (d, 7 according to the 'O' 0^ OH = 8.4 Hz, 1H), 8.44 (t, 7= 8.0 Hz, method for 51 (E)(3 -(4-methoxy-3 -(2-(pyridin- 1H), 8.12 (d, 7= 7.6 Hz, 1H), 8.03 starting from 2- 2- (d, 7= 8.0 Hz, 1H), 7.86 (t, 7 = 6.4 [[(E)- (£)(3-(3- yl)ethoxy)phenyl)acrylamido)benz Hz, 1H), 7.62 - 7.56 (m, 2H), 7.27 - hydroxy oic acid trifluoroacetic acid salt 7.24 (m, 2H), 7.17 (t, 7= 7.6 Hz, methoxyphenyl) ac 1H), 6.98 (d, 7= 8.0 Hz, 1H), 6.60 rylamido)benzoic (d, 7= 15.6 Hz, 1H), 4.48 (t, 7= 5.2 acid and 2- Hz, 2H), 3.81 (s, 3H), 3.52 (t, 7 = (pyridin 4.8 Hz, 2H); MS (ESI+) m/z 419.2 yl)ethan-l-ol_____ WO 44620 2018/016272 (M+H)+; 95.1% purity, RT 2.52 min (Method 11)____________ 63 i nO^Q- 0 H NMR (CD3OD, 400 MHz) 5 Prepared N 8.95 (s, 1H), 8.78 (d,/=5.6Hz, according to the 'O' 0"X)H 1H), 8.71 (d, /= 8.4 Hz, 1H), 8.61 method for 51 (E)(3-(4-methoxy(pyridin (d, J= 8.0 Hz, 1H), 8.13 (d, J= 6.6 starting from 2- ylmethoxy)phenyl)acrylamido)ben Hz, 1H), 7.98 - 8.02 (m, 1H), 7.65 - [[(E)- (£)(3-(3- zoic acid trifluoroacetic acid salt 7.59 (m, 2H), 7.44 (d, J= 1.2 Hz, hydroxy 1H), 7.33 (d, /= 4.8 Hz, 1H), 7.17 methoxyphenyl) ac (t, J= 7.6 Hz, 1H), 7.09 (d, /= 8.4 rylamido)benzoic Hz, 1H), 6.66 (d, J= 15.6 Hz, 1H), acid and pyridin .39 (s, 2H), 3.92 (s, 3H); MS ylmethanol (ESI+) m/z 405.1 (M+H)+; 93.4% purity, RT 1.54 min (Method 10) 64 1H NMR (CD3OD, 400 MHz) 5 ed 8.91 (s, 1H), 8.74 (d, J = 5.2 Hz, according to the 1H), 8.67 - 8.63 (m, 2H), 8.09 (dd, method for 51 (E)(3 -(4-methoxy-3 -(2-(pyridin- J= 8.0 Hz, /= 1.2 Hz, 1H), 8.02 starting from 2- 3- (dd, J= 7.6 Hz, /= 6.0 Hz, 1H), [[(E)- (E)(3-(3- yl)ethoxy)phenyl)acrylamido)benz 7.58 - 7.52 (m, 2H), 7.23 - 7.12 (m, y oic acid trifluoroacetic acid salt 3H), 6.95 (d, /= 8.4 Hz, 1H), 6.56 methoxyphenyl) ac (d, J= 15.6 Hz, 1H), 4.36 (t, J= 4.8 rylamido)benzoic Hz, 2H), 3.83 (s, 3H), 3.36 (t, J = acid and 2- 4.8 Hz, 2H); MS (ESI+) m/z 419.2 (pyridin (M+H)+; 95.3% purity, RT 2.54 yl)ethan-l-ol min (Method 12) 65 1H NMR , 400 MHz) 5 0 Prepared fi N 8.76 (d, /= 8.0 Hz, 2H), 8.70 (d, J according to the 'O' O^OH = 11.2 Hz, 1H), 8.15 - 8.05 (m, method for 51 (E)(3 -(4-methoxy-3 -(2-(pyridin- 3H), 7.63 - 7.56 (m, 2H), 7.29 (s, starting from 2- 4- 1H), 7.26 (d,/= 11.2 Hz, 1H), 7.17 [[(E)- (3-(3- yl)ethoxy)phenyl)acrylamido)benz (t, J= 7.6 Hz, 1H), 7.00 (d, / = 11.2 hydroxy oic acid oroacetic acid salt Hz, 1H), 6.63 (d, J= 16.8 Hz, 1H), methoxyphenyl) ac 4.46 (t, J= 7.6 Hz, 2H), 3.84 (s, rylamido)benzoic 3H), 3.45 (t, J = 7.2 Hz, 2H); MS acid and 2- (ESI+) m/z 419.1 (M+H)+; 96.1% (pyridin purity, RT 2.52 min (Method 12) yl)ethan-l-ol 66 "Xo. o 1 H NMR (DMSO-d6, 400 MHz) 5 Prepared N 11.60 (hr. s, 1H), 8.63 (d,/= 8.4 according to the o OH Hz, 1H), 8.01 (d, J= 7.2 Hz, 1H), method for 53 (E)(3-(4-methoxy((l-methyl- 7.81 (s, 1H), 7.64 - 7.40 (m, 4H), starting from 3- lH-pyrazol 7.24 (t, J= 8.4 Hz, 1H), 7.15 (t, / = hydroxy yl)methoxy)phenyl)acrylamido)ben 7.6 Hz, 1H), 6.99 (t, 7=8.0 Hz, methoxybenzaldeh zoic acid 1H), 6.79 (d, 7= 15.6 Hz, 1H), 5.01 yde (s, 2H), 3.83 (s, 3H), 3.78 (s, 3H); MS (ESI+) m/z 408.2 (M+H)+; 96.8% purity, RT 1.94 min (Method 10) WO 44620 67 o iH NMR (CD3OD, 400 MHz) 5 Prepared % 8.70 (d, / = 11.2 Hz, 1H), 8.12 (d, J according to the / H "O' cr oh = 9.6 Hz, 1H), 7.66 - 7.50 (m, 2H), method for 52 (£)(3-(4-mcthoxy(( 1 -methyl- 7.45 - 7.39 (m, 2H), 7.27 (d, / = starting from 2- lH-pyrazol 10.8 Hz, 1H), 7.16 (t, /= 10.4 Hz, [[(E)- (E)(3-(3- hoxy)phenyl)acrylamido)ben 1H), 7.03 (d,/= 11.2 Hz, 1H), 6.63 hydroxy zoic acid (d, J= 16.8 Hz, 1H), 6.40 (s, 1H), methoxyphenyl) ac .22 (s, 2H), 3.95 (s, 3H), 3.87 (s, rylamido)benzoic 3H); MS (ESI+)m/z 408.1 acid and 5- (M+H)+; 97.4% purity, RT 2.95 (chloromethyl) -1 - min (Method 12) methyl-1H- pyrazole________ -(3-(3-methoxy((4-methylpiperazin-l-yl)methyl)phenyl)acrylamido)benzoic acid 1 0 G N a) l-(4-bromomethoxybenzyl)methylpiperazine I I L^nh ■OCT OXr To a on of 4-bromomethoxy-benzaldehyde (500 mg, 2.3 mmol, 1.0 equiv.), 1- methylpiperazine (389 pL, 3.5 mmol, 1.5 equiv.) and acetic acid (40 pL, 0.699 mmol, 0.3 equiv.) in 1,2-dichloroethane (10 mL) was added sodium triacetoxyborohydride (741 mg, 3.5 mmol, 1.5 equiv.) portion-wise maintaining the temperature at 0°C. The mixture was stirred at 25°C for 3 hours and was then quenched with saturated aqueous sodium bicarbonate solution (20 mL).
Then the mixture was extracted with dichloromethane (20 mL x3) and the combined c layer washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to give the desired product as yellow oil (560 mg, crude) which was used without further purification; ^ NMR (CDCI3, 400 MHz) 5 7.23 (d, J = 8.0 Hz, 1H), 7.07 (dd, J = 8.0 Hz, J2 = 2.0 Hz 1H), 6.99 (d, J = 1.6 Hz, 1H), 3.81 (s, 3H), 3.50 (s, 2H), 2.60 - 2.35 (m, 8H), 2.29 (s, 3H). b) 3-methoxy((4-methylpiperazin-l-yl)methyl)benzaldehydeoar I oxoI \ To a solution of romomethoxybenzyl)methylpiperazine (250 mg, 0.836 mmol, 1.0 equiv.) in anhydrous tetrahydrofuran (10 mL) at -78°C under a nitrogen atmosphere was added n-bulyllilhium (2.5 M in hexane, 1.00 mL, 3.0 ) via syringe drop-wise over a period of 10 minutes. The resulting solution was stirred at -78°C for 10 minutes and then N,N- dimethylformamide (644 pL, 8.4 mmol, 10.0 equiv.) was added at -78°C over 10 minutes. The e was then stirred at 25 °C for 1 hour. The reaction was ed with saturated ammonium chloride aqueous solution (10 mL) and the resultant mixture was extracted with ethyl e (20 mL x3). The combined organic layer was washed with brine (20 mL), dried over sulfate , filtered and concentrated to give the desired product as yellow oil (225 mg, crude) which was used without further purification; MS (ESI+) m/z 249.1 (M+H)+. c) (E)(3-(3-methoxy((4-methylpiperazin-l-yl)methyl)phenyl)acrylamido)benzoic acid oxr°I 0 0 uI 0 HO N H H 0 OH 0 OH To a solution of carboxyacetyl)amino]benzoic acid (100 mg, 0.448 mmol, 1.0 equiv.) and 3-methoxy((4-methylpiperazin-l-yl)methyl)benzaldehyde (223 mg, 0.896 mmol, 2.0 equiv.) in toluene (5 mL) was added piperidine (44 pL, 0.448 mmol, 1.0 equiv.) and the on mixture stirred at 110°C for 16 hours. The mixture was concentrated in vacuo and the residue purified by preparative HPLC to give the desired product as a white solid (15 mg, 8%) as the trifluoroacetic acid salt; NMR , 400 MHz) 5 8.71 (d, /= 8.0 Hz, 1H), 8.14 (d, / = 6.4 Hz, 1H), 7.69 (d, /= 15.6 Hz, 1H), 7.61 (t, /= 7.2 Hz, 1H), 7.43 (d, /= 7.6 Hz, 1H), 7.34 (s, 1H), 7.29 (d, / = 8.0 Hz, 1H), 7.19 (t, / = 8.0 Hz, 1H), 6.84 (d, / = 16.0 Hz, 1H), 3.97 (s, 2H), 3.95 (s, 3H), 3.30 - 3.20 (m, 4H), 3.10 - 2.90 (m, 4H), 2.85 (s, 3H). MS (ESI+) m/z 410.2 (M+H)+; 96.5% purity, RT 1.89 min (Method 11).
Ex Structure Data Method 69 iH NMR (DMSO - d6, 400 MHz) 5 Prepared 11.23 (s, 1H), 8.59 (d, /= 8.0 Hz, according to the 'OH 1H), 8.03 (dd, / = 8.0 Hz, / = 2.0 method for 68 (£)(3-(3-mcthoxy Hz, 1H), 7.67 - 7.55 (m, 2H), 7.52 - starting from 4- (morpholinomethyl)phenyl)acryla 7.43 (m, 2H), 7.36 (d, J= 7.6 Hz, bromomethoxymido )benzoic acid trifluoroacetic 1H), 7.19 (t, / = 8.0 Hz, 1H), 6.93 benzaldehyde and acid salt (d, /= 16.0 Hz, 1H), 4.22 (s, 2H), morpholine 3.96 (s, 3H), 3.81 (br. s, 4H), 3.11 (br. s, 4H). MS (ESI+) m/z 397.1 (M+H)+; 95.1% purity, RT 5.41 min (Method 4) (/?)(3-(4-methoxy(((l-methylpiperidinyl)oxy)methyl)phenyl)acrylamido)benzoic add (70) O, o O OH a) 4-bromo(chloromethyl)-l-methoxybenzeneoa HO cica I I To the solution of (4-bromomethoxy-phenyl)methanol (2.9 g, 13.4 mmol, 1.0 equiv.) and A/.iV-dimethylformamidc (51 pL, 0.668 mmol, 0.05 equiv.) in dichloromethane (30 mL) was added l chloride (1.5 mL, 20 mmol, 1.5 equiv.) drop-wise ining the temperature at 0°C. The reaction mixture was then stirred at 40°C for 2 hours, cooled to room temperature and trated in vacuo. The residue was diluted with dichloromethane (30 mL) and the resulting solution washed with saturated s sodium bicarbonate (10 mL) and brine (10 mL), dried over sulfate sodium, filtered and concentrated to give the desired product as a light yellow solid (1.2 g) which was used without further purification; ^ NMR (CDCI3, 400 MHz) 5 7.49 (d, J = 2.4 Hz, 1H), 7.41 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 4.60 (s, 2H), 3.87 (s, 3H). b) 4-((5-bromomethoxybenzyl)oxy)-l-methylpiperidine c'COr Cl 1 'XT To a solution of l-methylpiperidinol (178 pL, 1.5 mmol, 1.2 equiv.) in tetrahydrofuran (5 mL) was added sodium hydride (76.4 mg, 1.9 mmol, 60% purity in mineral oil, 1.5 ) at 0°C. The mixture was stirred at 25°C for 1 hour. 4-Bromo (chloromethyl)-l-methoxybenzene (300 mg, 1.3 mmol, 1.0 equiv.) was then added and the mixture stirred for 11 hours at 60°C. The reaction was quenched by saturated aqueous ammonium chloride (10 mL) under stirring and extracted with ethyl acetate (5 mL x 3). The combined organic layer was washed with brine (10 mL), dried over sulfate , filtered and concentrated to give a residue which was ed by column chromatography (silica gel, dichloromethane: methanol = 100: 1 to 10: 1) to give the desired product as light yellow oil (270 mg); NMR (CDCI3, 400 MHz) 5 7.53 (d, / = 3.2 Hz, 1H), 7.34 (dd, / = 7.6 Hz, / = 3.2 Hz, 1H), 6.71 (d, /= 13.6 Hz, 1H), 4.52 (s, 2H), 3.80 (s, 3H), 3.40 - 3.50 (m, 1H), 2.80 - 2.65 (m, 2H), 2.30 (s, 3H), 2.30 - 2.10 (m, 2H), 2.05 - 1.90 (m, 2H), 1.85 - 1.65 (m, 2H). c) 4-methoxy(((l-methylpiperidinyl)oxy)methyl)benzaldehyde Ol'Xf 'O I I The title compound was prepared according to the procedure described for the synthesis of 3-methoxy((4-methylpiperazin-l-yl)methyl)benzaldehyde starting from 4-((5- 2-methoxybenzyl)oxy)-l-methylpiperidine. MS (ESI+) m/z 264.1 (M+H)+. d) (E)(3-(4-methoxy(((l-methylpiperidinyl)oxy)methyl)phenyl)acrylamido)benzoic Cl ■N^kA0. o o O XT' N HO H O O OH I O OH I The title compound was prepared as the trifluoroacetic acid salt according to the procedure described for the synthesis of (£’)(3-(3-methoxy((4-methylpiperazin-lyl )methyl)phenyl)acrylamido)benzoic acid (68) starting from 2-[(2-carboxyacetyl)amino]benzoic acid and 4-methoxy(((l-methylpiperidinyl)oxy)methyl)benzaldehyde (11%); H NMR de, 400 MHz, performed at 80°C) 5 11.17 (br. s, 1H), 8.58 (d, /= 10.8 Hz, 1H), 8.02 (d, /= 8.4 Hz, 1H), 7.70 - 7.55 (m, 4H), 7.18 - 7.05 (m, 2H), 6.65 (d, 7 = 20.8 Hz, 1H), 4.57 (s, 2H), 3.88 (s, 3H), 3.75 (br.s , 1H, partially obscured by water signal), 3.25 - 3.10 (m, 4H, partially obscured by water signal), 2.80 (s, 3H), 2.10 - 1.80 (m, 4H); MS (ESI+) m/z 425.2 (M+H)+; 98% purity, RT 2.52 min (Method 11).
Ex Structure Data Method 71 o iH NMR (CD3OD, 400 MHz) 5 8.70 Prepared according % N (d, /= 8.0 Hz, 1H), 8.12 (d, /= 7.2 to the method for 0 Cr OH Hz, 1H), 7.68 - 7.55 (m, 4H), 7.16 70 starting from 4- (£)(3 -(4-methoxy-3 -((prop (t, J= 7.6 Hz, 1H), 7.03 (d, J= 7.6 bromo yn Hz, 1H), 6.61 (d, / = 16.0 Hz, 1H), omethyl)-1 - yloxy)methyl)phenyl)acrylamido) 4.64 (s, 2H), 4.26 (d, J= 2.0 Hz, methoxybenzene benzoic acid 2H), 3.89 (s, 3H), 2.91 (t, 7=2.0 and propyn-l-ol Hz, 1H); MS (ESI+) m/z 388.1 (M+Na)+; 99% , RT 2.13 min (Method 10) WO 44620 2018/016272 72 I o iH NMR (DMSO-4, 400 Prepared according N MHz) 5 11.45 (br. s, 1H), 8.61 (d, J to the method for 0 OH = 8.4 Hz, 1H), 8.01 (d, J= 8.0 Hz, 70 starting from 4- (£T)(3-(3-methoxy((prop 1H), 7.64 - 7.56 (m, 2H), 7.39 (s, bromo yn 1H), 7.35 - 7.30 (m, 2H), 7.18 (t, / = (chloromethyl) yloxy)methyl)phenyl)acrylamido) 7.6 Hz, 1H), 6.94 (d, /= 15.6 Hz, methoxybenzene benzoic acid 1H), 4.54 (s, 2H), 4.23 (d, J= 2.4 and propyn-l-ol Hz, 2H), 3.88 (s, 3H), 3.48 (t, J = 2.0 Hz, 1H); MS (ESI+) m/z 366.2 (M+H)+; 97.8% purity, RT 2.18 min (Method 10) (/?)(3-(4-methoxy(methoxymethyl)phenyl)acrylamido)benzoic acid (73) 'O' N 'O' 0^ OH a) 4-bromo-l-methoxy(methoxymethyl)benzeneci^a i i To a solution of 4-bromo(chloromethyl)-l-methoxy-benzene (600 mg, 2.6 mmol, 1.0 equiv.) in tetrahydrofuran (5 mL) was added sodium methoxide (165 mg, 3.1 mmol, 1.2 ) and the resultant mixture stirred under reflux for 12 hours. The reaction mixture was concentrated under vacuum to give a residue which was diluted with ethyl acetate (10 mL) and washed with water (10 mL x 3). The combined organic layer was washed with brine (10 mL x 2), dried over sodium sulfate, filtered and concentrated to give the desired t as yellow oil (430 mg) which was used without further purification; ^ NMR (CDCI3, 400 MHz) 8 7.49 (d, J = 2.0 Hz, 1H), 7.36 (dd, / = 8.8 Hz, / = 2.4 Hz, 1H), 6.74 (d, / = 7.6 Hz, 1H), 4.46 (s, 2H), 3.82 (s, 3H), 3.44 (s, 3H). b) 4-methoxy(methoxymethyl)benzaldehyde OX "O' o I I The title material was ed according to the procedure described for the synthesis of 4-methoxy((4-methylpiperazin-l-yl)methyl)benzaldehyde starting from 4-bromo-l- methoxy(methoxymethyl)benzene. ^ NMR (CDCI3, 400 MHz) 8 9.91 (s, 1H), 7.92 (s, 1H), 7.84 (dd, / = 8.4 Hz, / = 2.0 Hz, 1H), 6.99 (d, / = 8.4 Hz, 1H), 4.53 (s, 2H), 3.94 (s, 3H), 3.47 (s, c) (E)(3-(4-methoxy(methoxymethyl)phenyl)acrylamido)benzoic acid 'O' N O O' OH OH I The title compound was prepared according to the procedure described for the synthesis of (£’)(3-(3-methoxy((4-methylpiperazin-l-yl)methyl)phenyl)acrylamido)benzoic acid (68) starting from 2-[(2-carboxyacetyl)amino]benzoic acid and 4-methoxy (methoxymethyl)benzaldehyde (25 %); 'H NMR (CD3OD, 400 MHz) 5 8.69 (d, 7= 8.0 Hz, 1H), 8.11 (d, 7 = 7.2 Hz, 1H), 7.65 -7.54 (m, 4H), 7.15 (t, 7=7.6 Hz, 1H), 7.02 (d,7= 8.8 Hz, 1H), 6.60 (d, 7= 15.6 Hz, 1H), 4.50 (s, 2H), 3.88 (s, 3H), 3.43 (s, 3H); MS (ESI+) mJz 342.1 (M+H)+; 99.2% purity, RT 2.94 min (Method 11). (/?)(3-(4-methoxy((propyn- l-ylamino)methyl)phenyl)acrylamido)benzoic acid (74) a) N-(5-bromomethoxybenzyl)propyn-l-amine CerBr* ^^nh2 ^oaBr A e of 5-bromomethoxybenzaldehyde (1.00 g, 4.65 mmol, 1.00 equiv.) and propyn-l-amine (298 uL, 4.65 mmol, 1.00 equiv.) in 1,2-dichloroethane (15.00 mL) was stirred for 0.5 hours at 25°C. Sodium triacetoxyborohydride (1.48 g, 6.98 mmol, 1.50 equiv.) and acetic acid (28 mg, 0.46 mmol, 0.10 equiv.) were then added at 0°C and the ing reaction stirred for 11.5 hours at 25 °C. The reaction mixture was quenched with 1 N hydrochloric acid (10 mL) and the solvent was removed under d pressure. The residue was diluted with dichloromethane (30 mL) and washed with saturated sodium bicarbonate aqueous (10 mL), water (10 mL x3) and brine (10 mL). The organic layer was dried over sodium sulfate and trated under reduced pressure. The residue was ed by silica gel column chromatography (petroleum ether: ethyl acetate 1:0 to 10:1) to afford the desired product as colourless oil (1.10 g, 58%); 1H NMR (CDC13, 400 MHz) 5 7.39 (d, 7 = 2.0 Hz, 1H), 7.36 (dd, 7 = 8.8 Hz, J= 2.4 Hz. 1H), 6.75 (d, / = 8.4 Hz, 1H), 3.84 (s, 2H), 3.82 (s, 3H), 3.43 (d, / = 2.4 Hz, 2H), 2.26 (1,7 =2.4 Hz, 1H). b) tert-butyl 5-bromomethoxybenzyl(propyn-l-yl)carbamate To the mixture of A/-(5-bromomcthoxybenzyl)propyn-l -amine (0.500 g, 1.97 mmol, 1.00 equiv.), di-/er/-butyl dicarbonate (1.29 g, 5.91 mmol, 3.00 equiv.) and 4- (dimethylamino)pyridine (0.024 g, 0.19 mmol, 0.10 equiv.) in methanol (10 mL) was added triethylamine (199.34 mg, 1.97 mmol, 1.00 equiv.) and the resulting reaction mixture was stirred for 6 hours at 25°C. The reaction mixture was trated under reduced pressure to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate= 50:1 to 20:1) to afford the desired product as colourless oil (0.41 g) which was used without further purification; 1H NMR (CDCI3, 400 MHz) 5 7.34 (dd, 7 = 8.8 Hz, 7 = 2.4 Hz, 1H), 7.31 (d, 7 = 2.0 Hz, 1H), 6.73 (d, 7= 8.4 Hz, 1H), 4.60 - 4.45 (m, 2H), 4.20 - 3.90 (m, 2H), 3.82 (s, 3H), 2.30 - 2.15 (m, 1H), 1.70 - 1.40 (m, 9H). c) tert-butyl 5-formylmethoxybenzyl(propyn-l-yl)carbamate O O I I ] To a solution of tert-butyl 5-bromomethoxybenzyl(propyn-l-yl)carbamate (0.300 g, 0.85 mmol, 1.00 equiv.) in ydrofuran (5 mL) at -78°C under a nitrogen atmosphere was added n-BuLi (2.5 M, 0.68 mL, 2.00 ) slowly and the reaction stirred for 10 minutes at -78°C. Dimethyl formamide (619 mg, 8.47 mmol, 10.00 ) was then added and the resulting solution d for 30 minutes at -78°C. The reaction mixture was warmed to 20°C, quenched by the addition of aqueous saturated ammonium chloride (5 mL) and ted with ethyl acetate (5 mL x3). The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give a e which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 20:1 to 5:1) to afford the desired product as yellow oil (0.150 g) which was used without further cation; MS (ESI+) m/z 326.0 (M+Na)+. d) (E)(3-(3-(((tert-butoxycarbonyl)(propyn-l-yl)amino)methyl)methoxyphenyl)- acrylamido)benzoic acid o o o O^N O^N O HOAAn N H H O OH O O^ OH I I To a solution of 2-[(2-carboxyacetyl)amino]benzoic acid (100 mg, 0.45 mmol, 1.00 equiv.) and tert-butyl 5-formylmethoxybenzyl(propyn-l-yl)carbamate (136 mg, 0.45 mmol, 1.00 ) in chloroform (5 mL) was added dine (4 mg, 0.04 mmol, 0.10 equiv.) and the resulting mixture stirred at 60°C for 12 hours. The reaction was concentrated under reduced pressure to afford the d product as light yellow oil, which was used in the next step without further purification (250 mg); MS (ESI+) m/z 487.1 (M+Na)+. e) (E)(3-(4-methoxy((propyn-l-ylamino)methyl)phenyl)acrylamido)benzoic acid O OH I To a solution of (£,)(3-(3-(((/er/-butoxycarbonyl)(propyn-l-yl)amino)methyl) methoxyphenyl)-acrylamido)benzoic acid (250 mg, crude) in dioxane (5 mL) was added 4M hydrochloric acid in dioxane (3 mL) and the mixture stirred at 25°C for 3 hours. The mixture was concentrated under reduced re and the residue was washed with methanol (5 mL x3) to afford the d product as a yellow solid (56.2 mg, 24.6%) as the hydrochloride salt; ^ NMR (DMSO-de, 400 MHz) 5 12.77 (hr. s, 1H), 8.60 (d, /= 8.0 Hz, 1H), 8.00 (d, /= 6.8 Hz, 1H), 7.74 (s, 1H), 7.62 (d, / = 8.4 Hz, 1H), 7.54 (d, / = 15.2 Hz, 1H), 7.47 (t, / = 7.2 Hz, 1H), 7.10 - 7.05 (m, 2H), 6.62 (d, /= 15.6 Hz, 1H), 3.94 (s, 2H), 3.85 (s, 3H), 3.62 (s, 2H), 3.37 (s, 1H); MS (ESI+) m/z 365.3 (M+H)+; 94.4% purity; RT = 1.54 min (Method 10).
Ex Structure Data Method iH NMR (DMSO-d6, 400 I o Prepared according 75 N MHz) 5 11.37 (s, 1H), 9.47 (hr. s, to the method for OH 1H), 8.61 (d, /= 8.4 Hz, 1H), 8.02 74 starting from 4- (E)(3-(3-methoxy((propyn- (d, /= 6.4 Hz, 1H), 7.66 - 7.60 (m, bromomethoxy- 1- 2H), 7.49 - 7.45 (m, 2H), 7.37 (d, J benzaldehyde and ylamino)methyl)phenyl)acrylamid = 7.6 Hz, 1H), 7.18 (t, /= 7.6 Hz, propyn-1 -amine o)benzoic acid 1H), 7.02 (d, /= 15.6 Hz, 1H), 4.18 (s, 2H), 3.93 - 3.90 (m, 5H), 3.75 (t, /= 2.4 Hz, 1H); MS (ESI+) m/z 365.2 (M+H)+; 99.6% purity, RT 1.57 min (Method 10)___________ V-(3-cyanophenyl)[2-[2-(dimethylamino)ethoxy]methoxypropynoxyphenyl ]propenamide (76) a) 6-formylmethoxy(propyn-l-yloxy)phenyl acetate Ao Ao o /O. A To a solution of (6-formylhydroxymethoxyphenyl)acetate (0.38 g, 1.81 mmol 1.0 equiv., J. Med. Chem. 2000, 43, 1550-1562) and 3-bromoprop-l-yne (1.26 g, 9.03 mmol, 5.0 equiv.) in acetone (10 mL) was added potassium carbonate (1.50 g, 10.8 mmol, 6.0 equiv.) and the mixture d at 20°C for 12 hours. The mixture was filtered and the filtrate trated in vacuo to give a residue which was purified by silica gel chromatography (petroleum ether: ethyl acetate 10:1 to 5:1) to give the desired t as light yellow gum (0.2 g) which was used without further purification; NMR (CDC13,400 MHz) 5 9.96 (s, 1H), 7.61 (d, / = 8.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 4.85 (d, / = 2.4 Hz, 2H), 3.88 (s, 3H), 2.59 (t, / = 2.4 Hz, 1H), 2.43 (s, b) oxymethoxypropynoxy-benzaldehyde Ao OH To a solution of (6-formylmethoxypropynoxyphenyl) acetate (2.10 g, 8.46 mmol, 1.0 equiv.) in water (10 mL) and tetrahydrofuran (10 mL) was added lithium hydroxide (0.79 g, 16.9 mmol, 2.0 equiv.) and the reaction stirred at 20°C for 1 hour. The mixture was WO 44620 concentrated under reduced pressure to remove the tetrahydrofuran and the aqueous mixture was extracted with ethyl acetate (10 mL x 2). The organic layer was concentrated under d pressure to give a residue, which was ed by silica gel chromatography (petroleum ether: ethyl acetate = 15:1 to 10:1) to give the desired product as a light yellow solid (1.50 g, 86%); ^ NMR (CDCI3,400 MHz) 5 11.22 (s, 1H), 9.78 (s, 1H), 7.31 (d,J= 8.8 Hz, 1H), 6.75 (d,/= 8.8 Hz, 1H), 4.86 (s, 2H), 3.93 (s, 3H), 2.58 (t, / = 2.4 Hz, 1H). c) 2-[2-(dimethylamino)ethoxy]methoxypropynoxybenzaldehyde OH \ To a solution of oxymethoxypropynoxybenzaldehyde (0.33 g, 1.60 mmol, 1.0 equiv.) in itrile (8 mL) was added 2-chloro-/V,/V-dimethylethanamine (0.35 g, 2.40 mmol, 1.5 equiv.), sodium iodide (0.048 g, 320 umol, 0.2 equiv.) and caesium carbonate (1.30 g, 4.00 mmol, 2.5 equiv.) and the reaction stirred at 90°C for 3 hours. The mixture was then cooled to 20°C, diluted with ethyl acetate (20 mL) and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (petroleum ether: ethyl acetate 5:1 to 1:1) to give the desired product as light yellow gum (0.3 g, 68%); NMR (CDC13,400 MHz) 5 10.33 (s, 1H), 7.62 (d, /= 8.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 4.83 (d, J = 2.0 Hz, 2H), 4.29 (t, J = 5.6 Hz, 2H), 3.91 (s, 3H), 2.71 (t, J = 5.6 Hz, 2H), 2.57 (t, / = 2.4 Hz, 1H), 2.32 (s, 6H). d) (E)[2-[2-(dimethylamino)ethoxy]methoxypropynoxy-phenyl]propenoic I I /O. /O' 'OH To a on of 2-[2-(dimethylamino)ethoxy]methoxyprop ynoxybenzaldehyde (0.22 g, 0.793 mmol, 1.0 equiv.) and malonic acid (0.165 g, 1.59 mmol, 2.0 ) in pyridine (5 mL) was added piperidine (10.1 mg, 0.119 mmol, 0.15 equiv.) and the reaction stirred at 100°C for 1 hour. The mixture was cooled and concentrated under reduced pressure. The residue was diluted with water (5 mL) and the pH adjusted to 9 by the addition of saturated sodium carbonate solution. The aqueous mixture was extracted with ethyl acetate (5 mL x4), filtered and concentrated to give a crude product as a light yellow solid (0.25 g) as the sodium salt which was used without further purification; ^ NMR (DMSO-Je, 400 MHz) 8 7.74 (d, / = 16.0 Hz, 1H), 7.53 (d, / = 9.2 Hz, 1H), 6.97 (d, / = 9.2 Hz, 1H), 6.47 (d, / = 16.4 Hz, 1H), 4.92 (d, / = 2.0 Hz, 2H), 4.20 (t, /= 5.2 Hz, 2H), 3.80 (s, 3H), 3.66 (t, / = 2.4 Hz, 1H), 3.19 - 3.17 (m, 2H), 2.65 (s, 6H). e) (E)-N-(3-cyanophenyl)[2-[2-(dimethylamino)ethoxy]methoxypropynoxy- phenyl]propenamide I I \ \ .0. .0.
'OH LXXCN ] To a solution of (T)[ 2-[2-(di methyl ami no)cthoxy]mcthoxypropynoxy- phenyl]propenoic acid (0.1 g, 0.313 mmol, 1.0 equiv.) and 3-aminobenzonitrile (0.037 g, 0.313 mmol, 1.0 equiv.) in pyridine (2 mL) was added phosphoryl chloride (29.10 pL, 0.313 mmol, 1.0 equiv.) at 0°C and the e was stirred at 0°C for 15 minutes. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC to afford the desired compound as a light yellow solid (12 mg, 9%); 1H NMR (DMSO-Je, 400 MHz) 8 10.49 (s, 1H), 8.23 (s, 1H), 7.88-7.83 (m, 2H), 7.56-7.52 (m, 2H), 7.38 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.73 (d, / = 16.0 Hz, 1H), 4.91 (d, / = 2.4 Hz, 2H), 4.06 (t, / = 5.8 Hz, 2H), 3.78 (s, 3H), 3.65 (t, / = 2.2 Hz, 1H), 2.63 (t, / = 5.8 Hz, 2H), 2.22 (s, 6H); MS (ESI+) m/z 420.2 (M+H)+; 99.1% purity, RT 2.79 min d 8).
Ex Structure Data Method 77 I iH NMR (DMSO-d6,400 MHz) 5 Prepared according .29 (s, 1H), 7.88 - 7.82 (m, 2H), to the method for 0 1^ .0. 7.75 - 7.72 (m, 2H), 7.41 (d, J= 8.4 76 final step Hz, 1H), 7.38 - 7.33 (m, 1H), 6.99 starting from (£) (d, /= 8.8 Hz, 1H), 6.88 (d, /= 15.6 [2-[2- ((£’)-/V-(2-cyanophcnyl)(2-(2- Hz, 1H), 4.91 (d, /= 2.4 Hz, 2H), (dimethylamino)- (dimethylamino)ethoxy) -3 - 4.06 (t,/=5.8Hz, 2H), 3.78 (s, ethoxy ] -3 xymethoxy 2-yn-l - 3H), 3.65 (t, J= 2.4 Hz, 1H), 2.63 4-propynoxyyloxy )phenyl)acrylamide (t, J= 5.8 Hz, 2H), 2.22 (s, 6H); MS phenyl]prop (ESI+) m/z 420.2 (M+H)+; 99% enoic acid and 2- purity, RT 2.66 min (Method 8) aminobenzonitrile WO 44620 (/?)(3-(2-(2-(dimethylamino)ethoxy)methoxy(propyn-lyloxy )phenyl)acrylamido)-benzoic acid (78) I I \ o o \ o o o /O. H .0.
O N OH H A mixture of 2-[2-(dimethylamino)ethoxy]methoxypropynoxybenzaldehyde (0.125 g, 0.45 mmol, 1.0 equiv.), arboxyacetamido)benzoic acid (0.111 g, 0.50 mmol, 1.1 equiv.) and piperidine (51 pL, 0.50 mmol, 1.1 equiv.) in anhydrous toluene was stirred under reflux for 4 hours. The reaction was then cooled to room temperature and the solvent removed in vacuo. The residue was purified by preparative HPLC to provide the title compound (14 mg, 7 %); ‘H NMR (400 MHz, DMSO) 5 14.33 (s, 1H), 8.63 - 8.60 (m, 1H), 8.10 (dd, / = 7.8 Hz, J = 1.8 Hz, 1H), 7.96 (d, / = 17.4 Hz, 1H), 7.66 (d, 7=8.8 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.09- 7.03 (m, 2H), 6.59 (d, /= 16.5 Hz, 1H), 4.98 (d, /= 2.3 Hz, 2H), 4.39 (t, /= 4.5 Hz, 2H), 3.86 (s, 3H), 3.68 (t, J=2.4 Hz, 1H), 3.65 - 3.59 (m, 2H), 2.98 (s, 6H); MS (ESI+) m/z 439.7 (M+H)+; 98% purity, RT 2.66 min (Method 2).
V-(2-cyanophenyl)[3-methoxy(l-methylazetidinyl)oxypropynoxyphenyl ]propenamide (79) "A0 o a) tert-butyl(6-formylmethoxypropynoxy-phenoxy)azetidine-l-carboxylate Boc^NA0 /O. O .o.
To a solution of 2-hydroxymethoxypropynoxybenzaldehyde (0.160 g, 0.77 mmol, 1.0 equiv.) in A^AAlimethylformamidc (3 mL) was added potassium carbonate (0.322 g, 2.33 mmol, 3.0 equiv.) and / O H 'N CN H #^o #^0 CN The title compound was prepared according to the procedure described for the synthesis of (£’)(3-(2-(2-(dimethylamino)ethoxy)methoxy(propyn-lyloxy )phenyl)acrylamido)benzoic acid (78) starting from /er/-butyl(6-formylmethoxy -ynoxy-phenoxy)azetidine-l-carboxylate and 3-(2-cyanoanilino)oxo-propanoic acid (42 %); MS (ESI+) m/z 526.2 (M+Na)+. c) (E)[2-(azetidinyloxy)methoxypropynoxyphenyl]-N-(2-cyanophenyl)prop enamide Boc'n^0 HN^0 O O o /O.
N N H H CN ^o CN To a solution of /er/-butyl[6-[(£,)(2-cyanoanilino)oxo-prop-l-enyl] ypropynoxy-phenoxy]azetidine-l-carboxylate (0.190 g, 0.37 mmol, 1.0 equiv.) in dichloromethane (6 mL) was added zinc bromide (0.850 g, 3.77 mmol, 10.0 ) and the reaction mixture stirred at 25 °C for 4 hours. The mixture was concentrated and the residue added into saturated aqueous sodium bicarbonate on (15 mL). The s mixture was ted with ethyl acetate (10 mL x3) and the combined organic phase was concentrated in WO 44620 vacuo to give the title compound as yellow oil (100 mg) which was used without further purification; MS (ESI+) m/z 403.9 (M+H)+. d) (E)-N-(2-cyanophenyl)[3-methoxy(l-methylazetidinyl)oxypropynoxy- phenyl]propenamide O O .0. .0.
N N CN H To a solution of (£,)[2-(azetidinyloxy)methoxypropynoxyphenyl]-/V-(2- cyanophenyl)propenamide (100 mg, 0.24 mmol, 1.00 ) in methanol (5 mL) was added sodium bicarbonate (42 mg, 0.49 mmol, 2.00 equiv.) and aqueous formaldehyde (40 mg, 0.49 mmol, 37%, 2.00 equiv.) and the resulting mixture stirred at 25°C for 0.3 hours. Sodium cyanoborohydride (31 mg, 0.49 mmol, 2.00 equiv.) was added and stirring continued at 25°C for 1 hour. The mixture was ed and the filtrate concentrated under vacuum to afford a residue which was purified by preparative HPLC to provide the desired product as a white solid (12.0 mg, 11%); ^NMR (CD3OD,400 MHz) 5 7.93 (d,/= 15.6 Hz, 1H), 7.81 (d, 7=8.4 Hz, 1H), 7.74 (d, / = 8.0 Hz, 1H), 7.70 (t, / = 8.0 Hz, 1H), 7.40 (d, / = 9.2 Hz, 1H), 7.37 (t, / = 7.6 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 16.0 Hz, 1H), 4.72 - 4.68 (m, 1H), 3.82 (s, 3H), 3.80 - 3.76 (m, 2H), 3.42 - 3.34 (m, 2H), 3.01 (t, / = 2.4 Hz, 1H), 2.43 (s, 3H), propargyl CH2masked by residual water signal; LCMS: m/z 418.1 [M+H]+; 95.1% purity; RT = 2.55 min (Method 12). ?)(3-methoxypropynoxypyrrolidinyloxyphenyl)prop enoyl]amino]benzoic acid (80) HN—.a0 a) tert-butyl 3-(6-formylmethoxypropynoxyphenoxy)pyrrolidine-l-carboxylate •O. 0 The title compound was prepared according to the procedure described for the synthesis of /er/-butyl(6-formylmethoxypropynoxyphenoxy)azetidine- 1-carboxylate starting from oxymethoxypropynoxybenzaldehyde and / 'OH ON To a solution of (T)[ 2-[2-(di methyl ami no)cthoxy]mcthoxyphcnyl]propcnoic acid (0.52 g, 0.471 mmol, 1.0 equiv.) in romethane (5 mL) was added diisopropylethylamine (0.183 g, 1.41 mmol, 3.0 equiv.) and HATU (0.215 g, 0.565 mmol, 1.2 equiv.). The reaction was stirred at 20°C for 30 minutes, 3-aminobenzonitrile (0.084 g, 0.707 mmol, 1.5 eqwz'v.) was added and the resulting mixture stirred for 2 hours at 20°C. The reaction was washed with water (5mL x 3) and the organic phase was dried over anhydrous sodium sulfate, filtered and trated in vacuo. The residue was ed by preparative HPLC to afford the desired compound as a light yellow solid (40 mg, 23%); ^ NMR (DMSO-Je, 400 MHz) 5 10.53 (s, 1H), 8.23 (s, 1H), 7.96 (d, 7 = 16.0 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.56 - 7.53 (m, 2H), 7.22 - 7.20 (m, 1H), 7.14-7.11 (m, 2H), 6.80 (d, /= 15.6 Hz, 1H), 4.01 (t, /= 5.6 Hz, 2H), 3.83 (s, 3H), 2.60 (t, /= 6.0 Hz, 2H), 2.21 (s, 6H); MS (ESI+) m/z 366.2 (M+H)+; 100% purity, RT 2.71 min (Method 8).
Ex Stmcture Data Method I iH NMR (DMSO-cfg, 400 MHz) 5 Prepared according 92 \ 10.32 (s, 1H), 7.97 (d, J= 16.0 Hz, to the method for 0 o 1H), 7.84 (d, /= 8.0 Hz, 1H), 7.74 - 91 step c starting N 7.70 (m, 2H), 7.38 - 7.33 (m, 1H), from (£T)[2-[2- CN 7.25 - 7.23 (m, 1H), 7.16 - 7.12 (m, (dimethylamino)eth (£0-A^-(2-cyanophenyl)(2-(2- 2H), 6.94 (d, /= 16.0 Hz, 1H), 4.01 oxy]methoxy- (dimethylamino)ethoxy) (t, 7=5.6 Hz, 2H), 3.83 (s, 3H), phenyl]prop methoxyphenyl) acrylamide 2.59 (t, 7= 6.0 Hz, 2H), 2.20 (s, enoic acid and 2- 6H); MS (ESI+) m/z 366.1 (M+H)+; aminobenzonitrile 98.9% purity, RT 2.29 min (Method (/?)-/V-(3-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide a) 2-[2-(dimethylamino)ethoxy]methoxybenzaldehyde OH \ The title nd was prepared according to the procedure described for the synthesis of 2-[2-(dimethylamino)ethoxy]methoxypropynoxybenzaldehyde starting from 2-hydroxymethoxybenzaldehyde and 2-ch 1 ,iV-dimcthy 1 cthanaminc (27% yield); 'H NMR (CDCI3,400 MHz) 5 10.33 (s, 1H), 7.83 (d, 7 = 8.4 Hz, 1H), 6.56 (d, 7 = 8.8 Hz, 1H), 6.46 (s, 1H), 4.17 (t, 7 = 5.8 Hz, 2H), 3.88 (s, 3H), 2.82 (t, 7= 5.6 Hz, 2H), 2.38 (s, 6H); MS (ESI+) m/z 224.0 (M+H)+. b) (E)[2-[2-(dimethylamino)ethoxy]methoxyphenyl]propenoic acid I I \ \ x) "OH "O' •O' The title compound was prepared according to the ure bed for the synthesis of (£’)[2-[2-(dimethylamino)ethoxy]methoxypropynoxyphenyl]prop enoic acid starting from 2-(2-(dimethylamino)ethoxy)methoxybenzaldehyde and malonic acid (83% yield); ^ NMR (CD3OD,400 MHz) 5 8.01 (d, / = 21.6 Hz, 1H), 7.63 (d, /= 11.2 Hz, 1H), 6.68 - 6.45 (m, 2H), 6.38 (d, 7=21.2 Hz, 1H), 4.47 (t, 7=6.4 Hz, 2H), 3.86 (s, 3H), 3.71 (t,7 = 6.6 Hz, 2H), 3.04 (s, 6H); MS (ESI+) m/z 266.3 . c) (E)-N-(3-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide I I \ \ 'OH ^1 iHxXCN \ H O o The title compound was prepared as the trifluoroacetic acid salt according to the procedure described for the synthesis of (T)-A/-(3-cyanophcnyl)[2-[2- (dimethylamino)ethoxy]methoxypropynoxy-phenyl]propenamide (76) starting from (£’)[2-[2-(dimethylamino)-ethoxy]methoxyphenyl]propenoic acid and 3- aminobenzonitrile (26% yield); NMR (CDC13,400 MHz) 5 8.31 (s, 1H), 8.04 (s, 1H), 7.92 - 7.88 (m, 2H), 7.45 - 7.36 (m, 3H), 6.76 (d, 7= 15.6 Hz, 1H), 6.53 (d, 7= 6.0 Hz, 1H), 6.48 (d, 7 = 2.0 Hz, 1H), 4.15 (t, 7 = 5.6 Hz, 2H), 3.85 (s, 3H), 2.85 (t, 7= 5.6 Hz, 2H), 2.40 (s, 6H); MS (ESI+) m/z 366 ; 95.3% purity, RT 2.06 min (Method 5).
Ex Structure Data Method 94 I iH NMR (CD3OD, 400 MHz) 5 8.11 Prepared according \ (d, 7 = 16.0 Hz, 1H), 7.78 - 7.75 (d, to the method for o 0 7= 8.0 Hz, 2H), 7.72 - 7.68 (m, 93 step c starting H 2H), 7.38 (t, 7= 8.0 Hz, 1H), 6.76 - from (£T)[2-[2- 'O' 6.68 (m, 3H), 4.45 (t, 7= 4.6 Hz, (dimethylamino)eth (E) -/V-(2-cy anophenyl) -3 - [2- [2- 2H), 3.88 (s, 3H), 3.71 (t, 7=4.6 oxy] methoxy- (dimethylamino)ethoxy] Hz, 2H), 3.05 (s, 6H); MS (ESI+) ]prop methoxy-phenyl]propenamide m/z 366.1 (M+H)+; 94% purity, RT enoic acid and 2- trifluoroacetic acid salt 2.91 min (Method 11) aminobenzonitrile -(3-(3,4-dimethoxy(propyn- l-yloxy)phenyl)acrylamido)benzoic acid (95) ■0 o O OH a) 3,4-dimethoxy(propyn-l-yloxy)benzaldehyde WO 44620 .0. '0 To a solution of 2-hydroxy-3,4-dimethoxybenzaldehyde (0.200 g, 1.09 mmol, 1 equiv., Inorganic Chemistry, 2004, 43, 4743-4750) in acetone (1.7 mL) was added potassium carbonate (0.300 g, 2.17 mmol, 2 equiv.) and propargyl bromide (0.19 mL, 1.28 mmol, 1.2 mmol, 80 wt % in toluene) and the resulting suspension stirred at 60 °C overnight. The on was cooled to room temperature and the solid removed by filtration and washed with acetone. The combined filtrate was concentrated in vacuo and the residue was partitioned n ethyl acetate and water. The organic phase was washed with water, dried over MgSCL and the solvent removed in vacuo. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate 1:0 to 2:1) to afford the title compound as a white solid (0.133 g, 54 %); ^ NMR (400 MHz, CDCI3) 5 10.32 (s, 1H), 7.65 (d, 7=8.8 Hz, 1H), 6.81 (d, 7=8.8 Hz, 1H), 4.92 (d, 7 = 2.5 Hz, 2H), 3.94 (s, 3H), 3.90 (s, 3H), 2.49 (t, 7= 2.4 Hz, 1H). b) (E)(3-(3,4-dimethoxy(propyn-l-yloxy)phenyl)acrylamido)benzoic acid "o "o o .0. H .0. ■o N OH H O o O^ OH The title compound was ed according to the ure described for the synthesis of (£,)(3-(2-(2-(dimethylamino)ethoxy)methoxy(propyn-l- yloxy)phenyl)acrylamido)benzoic acid (78) starting from methoxy(propyn-lyloxy )benzaldehyde and 2-(2-carboxyacetamido)benzoic acid (16 % yield); ^ NMR (400 MHz, DMSO) 5 11.72 (s, 1H), 8.68 (d, 7 = 7.6 Hz, 1H), 8.06 (dd, 7= 8.0 Hz, 7= 1.6 Hz, 1H), 7.89 (d, 7= 16.0 Hz, 1H), 7.67 - 7.60 (m, 2H), 7.23 - 7.18 (m, 1H), 6.98 (d, 7= 8.8 Hz, 1H), 6.81 (d, 7 = 16.0 Hz, 1H), 4.88 (d, 7 = 2.5 Hz, 2H), 3.92 (s, 3H), 3.83 (s, 3H), 3.59 (t, 7 = 2.4 Hz, 1H); MS (ESI-) m/z 380.1 (M-H)-; 96.7% purity, RT 2.62 min (Method 3). (/?)(3-(3,4-dimethoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (96) o o O OH a) 3,4-dimethoxy(pyridinylmethoxy)benzaldehyde .0. ‘O To a solution of 2-hydroxy-3,4-dimethoxybenzaldehyde (0.240 g, 1.32 mmol, 1 equiv., Inorganic Chemistry, 2004, 43, 4743-4750) in acetonitrile (10.5 mL) was added potassium carbonate (0.546 g, 3.95 mmol, 3 equiv.), 3-picolyl chloride hloride (0.216 g, 1.32 mmol) and sodium iodide (0.02 g, 0.13 mmol, 0.1 equiv.) and the resulting mixture stirred at 95 °C for 16 hours. The reaction was cooled to room ature and poured into saturated potassium carbonate solution. The itrile was removed in vacuo and the aqueous phase ted with ethyl acetate (x2). The combined organic phase was washed with saturated ium carbonate solution, dried over MgS04 and the solvent removed in vacuo. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate 1:0 to 0:1) to afford the title compound as a white solid (0.182 g, 50%); ‘H NMR (400 MHz, CDC13) 5 10.14 (s, 1H), 8.67 (d,/= 1.8 Hz, 1H), 8.61 (dd, 7 = 4.8,/= 1.5 Hz, 1H), 7.82 - 7.77 (m, 1H), 7.60 (d,/= 8.8 Hz, 1H), 7.33 (dd, J = 7.8, 4.8 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 5.24 (s, 2H), 3.96 (s, 3H), 3.90 (s, 3H). b) (E)(3-(3,4-dimethoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid [1 [1 0 0 "O "O 0 .0. H .0.
O N OH H 'O' ‘O' O^ OH The title compound was prepared according to the procedure bed for the synthesis of (£,)(3-(2-(2-(dimethylamino)ethoxy)methoxy(propyn-lyloxy )phenyl)acrylamido)benzoic acid (78) starting from 3,4-dimethoxy(pyridin ylmethoxy)benzaldehyde and 2-(2-carboxyacetamido)benzoic acid (12 % yield); ^ NMR (400 MHz, DMSO) 5 11.78 (s, 1H), 8.71 (d,/= 1.8 Hz, 1H), 8.66 (d,/ = 7.6 Hz, 1H), 8.61 (dd,/ = 4.8 Hz, / = 1.5 Hz, 1H), 8.06 (dd, / = 7.8 Hz, 7 = 1.5, Hz, 1H), 7.99 - 7.94 (m, 1H), 7.78 (d, / = .8 Hz, 1H), 7.66 - 7.58 (m, 2H), 7.50 (dd, J = 7.7 Hz, J = 4.9, Hz, 1H), 123 - 1X1 (m, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 15.7 Hz, 1H), 5.16 (s, 2H), 3.93 (s, 3H), 3.86 (s, 3H); MS (ESI+) m/z 435.3 (M+H)+; 98.6% purity, RT 2.91 min (Method 2).
(E)(3-(3-methoxy(4-methylpiperazin-l-yl)phenyl)acrylamido)benzoic acid r? H a) (E)(3-(4-bromomethoxyphenyl)acrylamido)benzoic acid XT0I o o o HO N H H O^TIH Br 0^ OH To a mixture of carboxyacetyl)amino]benzoic acid (500 mg, 2.24 mmol, 1.0 equiv.) and 4-bromomethoxy-benzaldehyde (530 mg, 2.46 mmol, 1.1 equiv.) in toluene (5 mL) was added piperidine (19 mg, 0.224 mmol, 0.1 equiv.)- The mixture was stirred at 110°C for 10 hours. The precipitated solid was collected by filtration and suspended in IN hloric acid (20 mL) and d at 20°C for 2 hours. The mixture was filtered and the collected solid dried under vacuum to afford the desired product as a yellow solid (400 mg, 47%). ^ NMR (400 MHz, DMSO-d6) 5 11.34 (s, 1H), 8.61 ((d, /= 8.0 Hz, 1H), 8.02 (dd, J 1.2 Hz, 7.6 Hz, 1H), 7.63 - 7.59 (m, 3H), 7.50 (s, 1H), 7.27 (d, / = 8.0 Hz, 1H), 7.19 (t, / = 8.0 Hz, 1H), 7.02 (d, / = 8.0 Hz, 1H), 3.93 (s, 3H). b) (E)(3-(3-methoxy(4-methylpiperazin-l-yl)phenyl)acrylamido)benzoic acid I o I o o o N N r?A H 0^ OH Br 0^ OH O ] A mixture of (£’)(3-(4-bromomethoxyphenyl)acrylamido)benzoic acid (100 mg, 0.266 mmol, 1.0 equiv.), 1-methylpiperazine (40 mg, 0.40 mmol, 1.5 equiv.), t-BuOK (90 mg, 0.799mmol, 3.0 ) and tBuXPhos Pd G1 (18 mg, 0.027 mmol, 0.1 equiv.) in tetrahydrofuran (3 mL) was de-gassed and then heated to 80°C for 2 hours under a nitrogen atmosphere. The mixture was filtered and concentrated to dryness under vacuum. The residue was purified by ative HPLC to afford the desired product as a yellow solid (16 mg, 12%) as the trifluoroacetic acid salt. ^ NMR (400 MHz, DMSO-d6) 5 11.36 (s, 1H), 8.62 ((d, /= 8.0 Hz, 1H), 8.02 (dd, / 1.2 Hz, 7.6 Hz, 1H), 7.62 - 7.56 (m, 2H), 7.38 (d, / = 1.2 Hz, 1H), 7.25 (d, / = 8.0 Hz, 1H), 7.18 (t, 7=8.4 Hz, 1H), 6.98 (d, 7=8.0 Hz, 1H), 6.83 (d, 7 =15.6 Hz, 1H), 3.89 (s, 3H), 2.87 (s, 3H) piperazine signals obscured under water signal; MS (ESI+) m/z 396.2 (M+H)+; 97.9% purity, RT 2.39 min d 11). (/?)(3-(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)acrylamido)benzoic acid o o. o. N N H H O OH Br' O OH A mixture of 2-[[(Tf)(4-bromomcthoxy-phcnyl)propcnoyl] ami no] benzoic acid (150 mg, 0.399 mmol, 1.0 equiv.), tert-butyX 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)-3,6- dihydro-2H-pyridine-l-carboxylate (1240 mg, 0.399 mmol, 1.0 equiv.), potassium ate (165 mg, 1.2 mmol, 3.0 equiv.) and Pd(dppf)Cl2 (29 mg, 0.040 mmol, 1.0 equiv.) in N,N- dimethylformamide (1.5 mL) and water (0.3 mL) was de-gassed and then heated to 100°C for 3 hours under a nitrogen atmosphere. After cooling to room temperature the mixture was diluted with dichloromethane: methanol (10: 1), filtered through a silica pad and concentrated in vacuo.
The residue was then stirred at 25°C hydrochloric acid/methanol (2 mL, 8 mmol) for 30 minutes and concentrated under vacuum to give the desired product as a yellow solid (180 mg, 75%) as a hydrochloric acid salt. NMR (CD3OD, 400 MHz) 5 8.69 (d, 7 = 8.4 Hz, 1H), 8.14 (d, 7 = 6.4 Hz, 1H), 7.67 (d, 7= 15.6 Hz, 1H), 7.55 (t, 7 = 7.6 Hz, 1H), 7.27 (d, 7= 14.4 Hz, 3H), 7.17 (t, 7 = 7.2 Hz, 1H), 6.80 (d, 7 = 15.6 Hz, 1H), 5.91 (s, 1H), 3.92 (s, 3H), 3.90 - 3.81 (m, 2H), 3.44 (t, 7 = 6.0 Hz, 2H), 2.85 - 2.72 (m, 2H); MS (ESI+) m/z 379.1 ; 100% purity, RT 1.54 min (Method 10). (/?)(3-(3-methoxy(l-methyl-l,2,3,6-tetrahydropyridinyl)phenyl)acrylamido)benzoic add (99) I o I o o o N N H H CT OH OH HN. .N.
To a mixture of 2-[[(£,)[3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl]prop- 2-enoyl]amino]benzoic acid (180 mg, 0.476 mmol, 1.0 equiv.) (98) in ol (3 mL) was added formaldehyde (1 mL, 37% aqueous). After stirring at 25°C for 30 minutes sodium triacetoxyborohydride (302 mg, 1.43 mmol, 3.0 equiv.) was added and the mixture stirred for 2 hours. The reaction was then concentrated in vacuo and the residue ved in dichloromethane: methanol (10:1) and filtered. The filtrate was concentrated in vacuo and the residue purified by ative HPLC to give the desired product as a yellow solid (41 mg, 22%) as the trifluoroacetic acid salt; 'H NMR (CD3OD, 400 MHz) 5 8.72 (d, J = 8.4 Hz, 1H), 8.13 (dd, J= 8.0 Hz, 7= 1.6 Hz, 1H), 7.66 (d, /= 14.2 Hz, 1H), 7.62 (d, /= 7.2 Hz, 1H), 7.29 (d, /= 16.8 Hz, 3H), 7.21 (t, /= 6.8 Hz, 1H), 6.83 (d, /= 15.6 Hz, 1H), 5.90 (s, 1H), 4.11 - 4.04 (m, 1H), 3.93 (s, 3H), 3.84 - 3.66 (m, 2H), 3.39 - 3.33 (m, 1H), 3.02 (s, 3H), 2.89 - 2.83 (m, 2H); MS (ESI+) m/z 393.1 (M+H)+; 95.3 % purity, RT 1.61 min (Method 11). (/?)(3-(4-ethylmethoxyphenyl)acrylamido)benzoic acid (100) I o I o 0 0 N N H H Br' OH OH A mixture of 2-[[(L)(4-bromomcthoxy-phcnyl)propcnoyl]amino]benzoic acid (150 mg, 0.399 mmol, 1.0 equiv.), ethylboronic acid (35.4 mg, 0.478 mmol, 1.2 equiv.), cesium carbonate (390 mg, 1.20 mmol, 3.0 equiv.) and P Biphenyl (26.7 mg, 0.04 mmol, 0.1 equiv.) in ylbutanol (1 mL) was de-gassed and then heated to 90°C for 2 hours under a nitrogen atmosphere. The cooled mixture was diluted with ethyl acetate (20 mL), washed with brine (2x5 mL) and the organic phase concentrated to dryness in vacuo and the residue purified by preparative HPLC to afford the desired product as a yellow solid (43.0 mg, 32%); ^ NMR (CD3OD, 400 MHz) 5 8.72 (d, /= 8.0 Hz, 1H), 8.14 (dd, 7= 1.6 Hz, 7= 9.6 Hz, 1H), 7.68 (d, 7 = 16.0 Hz, 1H), 7.64 - 7.59 (m, 1H), 7.21 - 7.17 (m, 4H), 6.74 (d, 7= 15.6 Hz, 1H), 3.92 (s, 3H), 2.66 (q, 7 = 7.2 Hz, 2H), 1.20 (t, 7 = 7.6 Hz, 3H); MS (ESI-) m/z 324.1 (M-H)-. 97.9 % purity, RT 1.61 min (Method 8). (/?)(3-(4-methoxymorpholinophenyl)acrylamido)benzoic acid (101) O Cr OH a) (E)(3-(3-bromomethoxyphenyl)acrylamido)benzoic acid ocr o o o HO N H H 0^ OH 0 O^ OH To a solution of 2-[(2-carboxyacetyl)amino]benzoic acid (500 mg, 2.24 mmol, 1.0 equiv.) in toluene (20 mL) was added 3-bromomethoxybenzaldehyde (506 mg, 2.35 mmol, 1.05 equiv.) and piperidine (95.4 mg, 1.12 mmol, 0.5 equiv.) and the resulting mixture stirred at 110 °C for 16 hours. The reaction was cooled to room temperature, IN hloric acid (2 mL) was added and the mixture was extracted with ethyl acetate (100 mL x2). The combined c phase was concentrated under reduced pressure to afford the desired product as a white solid (300 mg, 36%) which was used without further purification; MS (ESI+) m/z 376.0 / 378.0 (M+H)+. b) (E)(3-(4-methoxymorpholinophenyl)acrylamido)benzoic acid 0 0 N N H H O O OH OH ] The title compound was prepared as the trifluoroacetic acid salt according to the procedure described for the synthesis of (L)(3-(3-mcthoxy(4-mcthylpipcrazin-l - nyl)acrylamido)benzoic acid (97) starting from (L)(3-(3-hroino methoxyphenyl)acrylamido)benzoic acid and morpholine (14%); 'fi NMR (DMSO-de, 400 MHz) 5 11.24 (s, 1H), 8.60 (d, 7=8.4 Hz, 1H), 8.01 (d, 7 = 7.2 Hz, 1H), 7.65 - 7.50 (m, 2H), 7.35 (d, 7 =8.0 Hz, 1H), 7.27 (s, 1H), 7.18 (t,7 = 7.6 Hz, 1H), 7.01 (d, 7= 8.4 Hz, 1H), 6.75 (d, 7= 15.6 Hz, 1H), 3.84 (s, 3H), 3.78 - 3.67 (m, 4H), 3.05 - 2.94 (m, 4H); MS (ESI+) m/z 383.1 (M+H)+; 98.4% , RT 2.69 min (Method 11). 2-[[(/?)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid (102) O^ OH WO 44620 a) methyl 4-allylmethoxybenzoate o o .0. .0.
"O' o To a solution of methyl omethoxybenzoate (28.00 g, 114.25 mmol, 1.00 equiv.) in A/.iV-dimethylformamidc (400 mL) was added allyl(tributyl)stannane (38.53 mL, 125.68 mmol, 1.10 equiv.) and Pd(PPli3)4 (13.20 g, 11.43 mmol, 0.10 equiv.). The mixture was degassed under vacuum and purged with nitrogen 3 times and the resulting e stirred at 80°C for 4 hours under a nitrogen atmosphere. Water (25 mL) and sodium fluoride (5 g) were added, the resultant mixture was stirred at 25°C for 30 minutes and then filtered. The filter cake was washed with ethyl acetate (20 mL x2). The combined filtrate was extracted with ethyl acetate (250 ml x3). The organic phase was combined and washed with brine (100 mL x2), dried over sodium e, filtered and concentrated in vacuo. The residue was ed by silica gel column chromatography (petroleum ethenethyl acetate 1000:1 to 800:1) to give the desired product as colourless oil (21.2 g, 90%); NMR (DMSO, 400 MHz) 5 7.51 (dd, /= 8.0 Hz, / = 1.6 Hz, 1H), 7.45 (s, 1H), 7.21 (d, / = 7.6 Hz, 1H), 5.96 - 5.89 (m, 1H), 5.06 - 5.01 (m, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 3.36 (s, 2H). b) methyl 4-(cyclopropylmethyl)methoxybenzoate o o .0. .0.
"O' "O' A solution of diethlyzinc in toluene (1 M, 155.16 mL, 4.00 equiv.) was added to dichloromethane (100 mL) under a nitrogen atmosphere. The solution was cooled in an ice bath, a solution of trifluoroacetic acid (12.35 mL, 166.80 mmol, 4.30 equiv.) in dichloromethane (100 mL) was added drop-wise and the on mixture stirred for 20 minutes at 0°C. A solution of diiodomethane (12.52 mL, 155.16 mmol, 4.00 equiv.) in dichloromethane (100 mL) was added and the reaction stirred for 20 minutes. Methyl lmethoxybenzoate (8.00 g, 38.79 mmol, 1.00 ) was then added and the resulting mixture stirred for 48 hours at 20°C. The mixture was poured into water (300 mL) and extracted with dichloromethane (200 mL x3). The combined organic phase was washed with brine (200 mL), dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by preparative HPLC to provide the desired product as a yellow liquid (3.5 g, 41%); NMR (CDCI3, 400 MHz) 5 7.61 (dd, / = 7.6 Hz, / = 1.6 Hz, 1H), 7.51 (s, 1H), 7.36 (d, / = 7.6 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 2.58 (d,/= 6.8 Hz, 2H), 1.05 - 1.01 (m, 1H), 0.52 - 0.50 (m, 2H), 0.20 - 0.18 (m, 2H). c) [4-(cyclopropylmethyl)methoxy-phenyl]methanol /O. OH To a solution of methyl 4-(cyclopropylmethyl)methoxybenzoate (3.50 g, 15.89 mmol, 1.00 equiv.) in tetrahydrofuran (50 mL) was added DIBAL-H (1 M, 47.7 mL, 3.00 equiv.) at 0°C and the reaction was stirred at 25 °C for 1 hour. The mixture was quenched with water (100 mL) and acidified with 6 N hloric acid until the pH was 6~7. The mixture was extracted with ethyl acetate (100 mL x3). The combined organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered and trated in vacuo to afford the desired product as a yellow liquid (3.4 g) which was used without further purification; 1H NMR (CDCI3, 400 MHz) 5 7.29 (d, J = 8.0 Hz, 1H), 6.92 - 6.90 (m, 2H), 4.69 (s, 2H), 3.88 (s, 3H), 2.55 (d, J = 6.8 Hz, 2H), 1.06 -1.02 (m, 1H), 0.51 - 0.48 (m, 2H), 0.21 - 0.18 (m, 2H). d) 4-(cyclopropylmethyl)methoxy-benzaldehyde To a solution of [4-(cyclopropylmethyl)methoxyphenyl]methanol (3.40 g, 17.69 mmol, 1.00 equiv.) in dichloromethane (30 mL) was added artin inane (26.26 g, 61.92 mmol, 19.17 mL, 3.50 equiv.) at 0°C and the reaction was stirred at 25°C for 1 hour. The reaction was quenched with saturated aqueous sodium sulphite (80 mL) and ted aqueous sodium carbonate (50 mL) at 0°C and the resulting mixture extracted with ethyl acetate (100 mL x4). The combined organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ethenethyl acetate 20:1) to provide the desired product as a colourless liquid (2.6 g, 77%); NMR (CDCR, 400 MHz) 5 9.95 (s, 1H), 7.48 (d, /= 7.6 Hz, 1H), 7.43 (d, / = 7.6 Hz, 1H), 7.37 (s, 1H), 3.90 (s, 3H), 2.61 (d, / = 6.8 Hz, 2H), 1.09 - 1.04 (m, 1H), 0.56 - 0.51 (m, 2H), 0.21 - 0.20 (m, 2H). e) 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid 0 0 0 HO N H H OH OH To a solution of 4-(cyclopropylmethyl)methoxybenzaldehyde (2.30 g, 12.09 mmol, 1.00 equiv.) in toluene (50 mL) was added 2-[(2-carboxyacetyl)amino]benzoic acid (2.97 g, 13.30 mmol, 1.10 ) and piperidine (120 pL, 1.21 mmol, 0.10 equiv.) and the mixture d at 130°C for 6 hours. The mixture was concentrated in vacuo and the residue purified by preparative HPLC to provide the title compound as a white solid (2.0 g, 47%); ^ NMR (CD3OD, 400 MHz) 5 8.72 (d, /= 8.4 Hz, 1H), 8.13 (dd, /= 8.0 Hz, 7= 1.6 Hz, 1H), 7.65 (d, / = .6 Hz, 1H), 7.59 (t, / = 6.8 Hz, 1H), 7.29 (d, / = 7.6 Hz, 1H), 7.20 - 7.15 (m, 3H), 6.75 (d, / = .6 Hz, 1H), 3.90 (s, 3H), 2.55 (d, / = 6.8 Hz, 2H), 1.05 -1.01 (m, 1H), 0.50 - 0.47 (m, 2H), 0.19-0.18 (m, 2H); MS (ESI+) m/z 352.1 [M+H]+; 100% purity, RT 2.90 min (Method 9).
Ex Structure Data Method 103 1 I 0 H NMR (DMSO-d6, 400 MHz) Prepared according N 511.29 (s, 1H), 8.62 (d, /= 8.4 Hz, to the method for 0 OH 1H), 8.01 (dd, / = 1.2 Hz, 9.2 Hz, 97 starting from 4- 0^r? 1H), 7.62 - 7.55 (m, 2H), 7.34 (s, bromo-3 -methoxy- (£)(3-(3-mcthoxy 1H), 7.24 (d, /= 8.4 Hz, 1H), 7.18 benzaldehyde, 2- morpholinophenyl)acrylamido)b (t, J= 4.0 Hz, 1H), 6.90 (d, J= 8.4 1(2- enzoic acid trifluoroacetic acid Hz, 1H), 6.79 (d, /= 15.6 Hz, 1H), carboxyacetyl)amin salt 3.88 (s, 3H), 3.75 - 3.72 (m, 4H), o] benzoic acid and 3.05 - 3.03 (m 4H); MS (ESI+) m/z morpholine 383.1 ; 99.5% purity, RT 2.76 min (Method 11) 104 1H NMR (CD3OD, 400 MHz) 5 8.71 N O Prepared according N (d, /= 8.4 Hz, 1H), 8.14 (dd, /= 1.2 to the method for 'O' OH Hz, 7.6 Hz, 1H), 7.68 - 7.64 (m, 98 and then 99 (£)(3-(4-mcthoxy( 1 - 2H), 7.62 (t, J= 2.4 Hz, 1H), 7.51 starting from {E) methyl-1,2,3,6- (d, /= 2.4 Hz, 1H), 7.19 (t, J= 7.6 (3-(3-bromo tetrahydropyridin Hz, 1H), 7.10 (d, /= 8.8 Hz, 1H), methoxyphenyl)acr yl)phenyl) acrylamido)benzoic 6.66 (d, J= 15.6 Hz, 1H), 5.88 (s, ylamido)benzoic acid oroacetic acid salt 1H), 4.11 - 3.41 (m, 6H), 3.10 - 2.76 acid (m, 6H); MS (ESI+) m/z 393.2 (M+H)+; 99.0% purity, RT 2.48 min (Method 11) 105 o 1H NMR (DMSO-dg, 400 MHz) 5 Prepared according N 11.30 (s, 1H), 8.62 (d, J= 7.6 Hz, to the method for 0 0^ OH 1H), 8.01 (dd, / = 1.6 Hz, 8.0 Hz, 100 starting from I 1H), 7.64 - 7.45 (m, 4H), 7.17 (t, J = (E)(3-(3-bromo- (£)(3-(3-ethyl 8.0 Hz, 1H), 7.01 (d, J = 8.4 Hz, 4- methoxyphenyl)acrylamido)benz 1H), 6.73 (d, /= 15.6 Hz, 1H), 3.84 yphenyl)acr oic acid (s, 3H), 2.60 (q, J= 7.6 Hz, 2H), ylamido)benzoic 1.16 (t, J= 7.6 Hz, 3H); MS (ESI+) acid m/z 348.1 (M+Na)+; 95.9% purity, RT 3.16 min (Method 11) 106 iH NMR (CDC13, 400 MHz) 511.18 0 Prepared according N (s, 1H), 8.92 (d, /= 8.8 Hz, 1H), to the method for 'O' 0 OH 8.15 (dd, J= 1.6 Hz, 9.6 Hz, 1H), 102 starting from (£)(3-(3- 7.74 (d, J= 15.6 Hz, 1H), 7.67 - methyl o (cyclopropylmethyl) 7.62 (m, 1H), 7.54 (d, J= 4.0 Hz, methoxybenzoate methoxyphenyl)acrylamido)benz 1H), 7.44 (dd, J = 2.4 Hz, 10.8 Hz, oic acid 1H), 7.15 - 7.12 (m, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.49 (d, J= 15.2 Hz, 1H), 3.87 (s, 3H), 2.55 (d, J= 6.8 Hz, 2H), 1.08 - 1.05 (m, 1H), 0.55 - 0.52 (m, 2H), 0.24 - 0.20 (m, 2H); MS (ESI+) m/z 352.0 (M+H)+; 96.9% purity, RT 2.97 min (Method 2-[[(£T)(4-methyl-2,3-dihydro-l,4-benzoxazinyl)propenoyl]amino]benzoic acid (107) I 0 'O' OH a) ethyl 2-(4-formylnitrophenoxy)acetate rxr* o2n To a solution of 4-hydroxynitrobenzaldehyde (40.00 g, 239.35 mmol, 1.00 equiv.) in acetonitrile (100 mL) was added ethyl 2-chloroacetate (44.00 g, 359.03 mmol, 38.26 mL, 1.50 equiv.), sodium iodide (17.94 g, 119.68 mmol, 0.50 equiv.) and potassium carbonate (99.24 g, 718.05 mmol, 3.00 equiv.) and the resultant mixture stirred at 80°C for 4 hours. The reaction e was cooled to 25 °C and filtered. The solid was washed with ethyl acetate (100 mL) and the combined filtrate was washed with brine (50 mL x2). The combined organic layers were dried over sodium sulfate, trated under reduced pressure and the residue purified by silica gel column chromatography leum ethenethyl acetate 10:1 to 3:1) to give the desired product as a yellow solid (15.50 g, 26%); NMR (DMSO-d6, 400 MHz) 5 9.95 (s, 1H), 8.44 (d, 7=2.0 Hz, 1H), 8.16 (dd, 7=8.8 Hz, 7 = 2.4 Hz, 1H), 7.51 (d, 7= 8.8 Hz, 1H), 5.17 (s, 2H), 4.19 (q, 7= 6.8 Hz, 2H), 1.21 (t, 7= 6.8 Hz, 3H). b) 3-oxo-4H-l,4-benzoxazinecarbaldehyde o2nxr° r °XHJT° To a solution of ethyl 2-(4-formylnitrophenoxy)acetate (9.30 g, 36.73 mmol, 1.00 equiv.) in acetic acid (20.00 mL) was added iron powder (12.31 g, 220.37 mmol, 6.00 equiv.) and the mixture stirred at 60°C for 16 hours. The reaction mixture was diluted with dichloromethane (50 mL) and methanol (50 mL), stirred at 25 °C for 1 hour and then filtered. The filtrate was trated in vacuo to give the desired product as a yellow solid which was used t further cation (4.40 g, 67%); NMR (DMSO-d6, 400 MHz) 5 10.99 (hr. s, 1H), 9.84 (s, 1H), 7.54 (dd, J= 8.0 Hz, J= 1.6 Hz, 1H), 7.38 (d,J= 1.2 Hz, 1H), 7.15 (d,J= 8.4 Hz, 1H), 4.72 (s, 2H). c) 4-methyloxo-l,4-benzoxazinecarbaldehyde To a mixture of 3-oxo-47/-l,4-benzoxazinecarbaldehyde (3.27 g, 18.46 mmol, 1.00 equiv.) and m carbonate (18.04 g, 55.38 mmol, 3.00 equiv.) in acetonitrile (20.00 mL) was added methyl iodide (2.30 mL, 36.92 mmol, 2.00 equiv.) and the mixture stirred at 80 °C for 2 hours. The reaction was cooled to 25 °C and diluted with ethyl acetate (30 mL). The resultant mixture was filtered and the filtrate trated under reduced pressure to give the desired product which was used without further purification (3.50 g, 99%); ^ NMR (DMSO-Je, 400 MHz) 5 9.91 (s, 1H), 7.63-7.60 (m, 2H), 7.20 (d, /= 8.8 Hz, 1H), 4.79 (s, 2H), 3.34 (s, 3H). d) (4-methyl-2,3-dihydro-l,4-benzoxazinyl)methanol TlX0 —^ CO^HI I To a solution of 4-methyloxo-l,4-benzoxazinecarbaldehyde (5.90 g, 30.86 mmol, 1.00 equiv.) in tetrahydrofuran (100 mL) was added BHrMciS (10 M, 30.86 mL, 10.00 equiv.) drop-wise at 0°C and the resultant e d at 60°C for 2 hours. The reaction was quenched with methanol (100 mL) at 25 °C and concentrated in vacuo. The residue was dissolved in methanol (100 mL) and stirred at 60°C for 2 hr. The solvent was removed under reduce pressure to give the crude product, which used directly in the next step (7.0 g); MS (ESI+) m/z 180.1 (M+H)+. e) 4-methyl-2,3-dihydro-l,4-benzoxazinecarbaldehyde CO'0" (XT0I To a solution of (4-methyl-2,3-dihydro-l,4-benzoxazinyl)methanol (7.00 g, 39.06 mmol, 1.00 equiv.) in dichloromethane (30.00 mL) was added Dess-Martin periodinane (24.85 g, 58.59 mmol, 18.14 mL, 1.50 equiv.) at 0 °C and the mixture stirred at 25 °C for 10 s. The reaction was quenched with saturated aqueous sodium thiosulfate (30 mL) and extracted with ethyl e (30 mL x 3). The organic layer was washed with saturated sodium bicarbonate (30 mL x2) and brine (30 mL x 2), dried over sodium e and the solvent removed in vacuo. The residue was purified by silica gel column chromatography (petroleum ethenethyl acetate 1:0 to :1) to give the desired product as a yellow oil (2.30 g, 33%); MS (ESI+) m/z 178.0 (M+H)+. f) 2-[[(E)(4-methyl-2,3-dihydro-l,4-benzoxazinyl)propenoyl]amino]benzoic acid ccr°I 0 0 5 I 0 HOAA N OH "O' 0^ OH To a solution of 4-methyl-2,3-dihydro-l,4-benzoxazinecarbaldehyde (2.46 g, 13.88 mmol, 1.00 equiv.) and carboxyacetyl)amino]benzoic acid (3.10 g, 13.88 mmol, 1.00 equiv.) in toluene (20 mL) was added piperidine (275 p,L, 2.78 mmol, 0.20 equiv.) and the mixture stirred at 110 °C for 16 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to provide the desired product as a yellow solid (3.26 g, 69%); ^ NMR (DMSO-d6, 400 MHz) 5 11.29 (s, 1H), 8.62 (d, /= 8.0 Hz, 1H), 8.00 (dd, / = 8.0 Hz,/= 1.6 Hz, 1H), 7.61 (t, 7=8.0 Hz, 1H), 7.53 (d,/= 15.2 Hz, 1H), 7.16 (t,/= 8.0 Hz, 1H), 7.06 (d, / = 2.0 Hz, 1H), 6.97 (d, / = 8.4 Hz, 1H), 6.72 - 6.68 (m, 2H), 4.27 (t, / = 4.4 Hz, 2H), 3.25 (t, /= 4.4 Hz, 2H), 2.90 (s, 3H). MS (ESI+) m/z 339.1 [M+H]+; 100% ; RT = 1.27 min (Method 6). (/?)(3-(2-methyloxoisoindolinyl)acrylamido)benzoic acid (108) o o —N H a) 6-vinylisoindolin-l-one o o HN HN A mixture of 6-iodoisoindolin-l-one (1.00 g, 3.86 mmol, 1.0 equiv.), 5- tetramethylvinyl-l,3,2-dioxaborolane (0.892 g, 5.79 mmol, 1.5 equiv.), tetrakis(triphenylphosphine)palladium(0) (0.446 g, 0.386 mmol, 0.1 equiv.) and potassium carbonate (1.07 g, 7.72 mmol, 2.0 ) in dioxane (15 mL) and water (3 mL) was degassed and purged with en 3 times and then stirred at 90°C for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue which was washed petroleum ether/ethyl acetate (10/1, 30 mL) and the solid collected by filtration to give the desired product as a yellow solid (0.6 g, 73%); MS (ESI+) m/z 160.3 (M+H)+. b) 2-methylvinylisoindolin-l-one o o HN —N To a suspension of 6-vinylisoindolin-l-one (0.160 g, 1.0 mmol, 1.00 equiv.) in acetonitrile (5 mL) was added m carbonate (0.823 g, 2.53 mmol, 2.5 equiv.) and methyl iodide (75 pL, 1.21 mmol, 1.20 equiv.) and the resultant e was stirred at 80°C for 1.5 hours. The mixture was cooled to 20°C, diluted with ethyl acetate (20 mL) and filtered. The filtrate was washed with brine (10 mL) and the organic phase was concentrated under reduced re to afford the desired product (0.180 g) as light yellow gum which was used without further purification; MS (ESI+) m/z 174.1 (M+H)+. c) yloxoisoindolinecarbaldehyde o o —N —N To a solution of 2-methylvinylisoindolin-l-one (0.160 g, 0.92 mmol, 1.00 equiv.) in dioxane (10 mL) and water (1 mL) was added 4-methylmorpholine /V-oxide monohydrate (146 pL, 1.39 mmol, 1.50 equiv.) and osmium(IV) oxide (0.070 g, 0.28 mmol, 0.30 equiv.) and mixture was stirred at 20°C for 10 minutes. Sodium periodate (0.800 g, 3.74 mmol, 4.05 ) was added and the resultant mixture was stirred at 20°C for an additional 1.5 hours. The mixture was diluted with ethyl acetate (30 mL) and filtered. The filtrate was washed with brine (10 mL) and the organic layer was trated under reduced pressure to afford the desired product (0.170 g) as light yellow gum which was used without r purification; MS (ESI+) m/z 176.1 (M+H)+. d) (E)(3-(2-methyloxoisoindolinyl)acrylamido)benzoic acid o o o o o O HO N —N H —N H O OH O OH To a e of 2-methyloxoisoindolinecarbaldehyde (0.080 g, 0.46 mmol, 1.00 equiv.) and 2-[(2-carboxyacetyl)amino]benzoic acid (0.102 g, 0.46 mmol, 1.00 equiv.) in toluene (3 mL) was added piperidine (7 pL, 0.07 mmol, 0.15 equiv.) and the mixture was stirred at 120°C for 2 hours. The on was concentrated under reduced pressure. The residue was triturated with methanol (5 mL) and IN hydrochloric acid (2 mL) and the solid collected by filtration to afford the desired product (0.021 g, 13% yield) as a grey solid; ^ NMR (DMSO-Je, 400 MHz) 5 11.40 (br. s., 1H), 8.60 (d, 7=8.4 Hz, 1H), 8.03 -7.94 (m, 2H), 7.93 (d,/= 1.6 Hz, 1H), 7.72 (d, / = 15.6 Hz, 1H), 7.65 - 7.62 (m, 2H), 7.03 - 7.02 (m, 1H), 7.10 (d, / = 15.6 Hz, 1H), 4.50 (s, 2H), 3.08 (s, 3H); MS (ESI+) m/z 337.1 (M+H)+; 95.8% purity, RT 1.66 min (Method 6). (/?)(3-(4-methyloxo-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (109) O' N CT OH a) (E)(3-(3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid Xcr° Xcr° H i To a mixture of 3-oxo-4H-l,4-benzoxazinecarbaldehyde (0.600 g, 3.39 mmol, 1.00 equiv.) and caesium ate (3.31 g, 10.17 mmol, 3.00 equiv.) in A/.N-di methyl form amide (6 mL) was added methyl iodide (0.42 mL, 6.78 mmol, 2.00 equiv.) and the mixture was stirred at WO 44620 90°C for 1 hour. The reaction was cooled to 20°C, diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic phase was dried over sodium e, filtered and concentrated under reduced pressure to give the title compound as a light yellow solid (0.600 g) which used without further cation; ^ NMR (CDCI3, 400 MHz) 8 9.90 (s, 1H), 7.60 (dd, J = 8.0 Hz, /= 1.6 Hz, 1H), 7.50 (d,/= 1.6 Hz, 1H), 7.12 (d,/= 8.0 Hz, 1H), 4.69 (s, 2H), 3.42 (s, b) (E)(3-(4-methyloxo-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic x:CL° -ax 0 XL /5s. 0 0 I O' N OH OH I To a mixture of 4-methyloxo-l,4-benzoxazinecarbaldehyde (0.060 g, 0.31 mmol, 1.00 equiv.) and carboxyacetyl)amino]benzoic acid (0.070 g, 0.31 mmol, 1.00 equiv.) in toluene (3 mL) was added piperidine (3 pL, 0.10 equiv.) and the resultant mixture stirred at 110°C for 12 hours. The reaction was cooled to 20°C and the resultant precipitate collected by filtration, washed with methanol (3 mL) and dried under vacuum to give the desired t as a light yellow solid (0.056 g, 48%); 56 mg (48%);^ NMR (DMSO-X 400 MHz) 8 13.61 (hr. s., 1H), 11.36 (s, 1H), 8.61 (d, 7=8.0 Hz, 1H), .99 (m, 1H), 7.64 - 7.54 (m, 2H), 7.47 - 7.43 (m, 2H), 7.21 - 7.15 (m, 2H), 6.86 (d, /= 16.0 Hz, 1H), 4.70 (s, 2H), 3.30 (s, 3H); MS (ESI+) m/z 353.1 (M+H)+; 95% purity, RT 1.76 min (Method 6).
Ex Structure Data Method 110 1H NMR (DMSO-d6, 400 MHz) 5 0 Prepared according N 11.30 (s, 1H), 8.61 (d, J = 8.0 Hz, to the method for N 0^ OH 1H), 8.00 - 7.98 (m, 1H), 7.61 - 7.57 108 (final step) I (m, 1H), 7.44 (d, J = 16.0 Hz, 1H), starting from 4- CE)(3-(4-methyl-3,4-dihydro- 7.16 - 7.12 (m, 2H), 7.08 - 7.07 (m, methyl-3,4- 2H-benzo[b] [ 1,4] oxazin-7 - 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.55 dihydro-2H- yl)acrylamido)benzoic acid (d, /= 16.0 Hz, 1H), 4.23 - 4.21 (m, benzofb] [1,4] oxazi 2H), 3.34 - 3.31 (m, 2H), 2.90 (s, necarbaldehyde 3H); MS (ESI+) m/z 339.1 (M+H)+; and 2-(2- 98.7% purity, RT 1.86 min (Method carboxyacetamido) 6) benzoic acid WO 44620 o iH NMR (DMSO-cfg, 400 MHz) 5 H Prepared according 111 N 13.60 (br. s„ 1H), 11.33 (s, 1H), to the method for "O' OH 10.80 (s, 1H), 8.58 (d, J = 8.0 Hz, 108 (final step) (£)(3-(3-oxo-3,4-dihydi'o-2H- 1H), 8.01 - 7.99 (m, 1H), 7.64 - 7.60 starting from 3- benzofb] [1,4] oxazin (m, 1H), 7.52 (d, J = 16.0 Hz, 1H), oxo-3,4-dihydroyl )acrylamido)benzoic acid 7.34 - 7.31 (m, 1H), 7.19 - 7.16 (m, 2H- 2H), 7.00 (d, J = 8.0 Hz, 1H), 6.63 benzofb] [1,4] oxazi (d, J = 16.0 Hz, 1H ), 4.64 (s, 2H); necarbaldehyde MS (ESI+) m/z 339.0 (M+H)+; and 2-(2- 95.2% purity, RT 1.67 min (Method carboxyacetamido) 6) benzoic acid o iH NMR (DMSO-dg, 400 MHz) 5 I Prepared according 112 N 11.37 (br. s„ 1H), 8.63 (d, J= 8.0 to the method for "O' OH Hz, 1H), 8.02 - 7.99 (m, 1H), 7.65 - 108 (final step) (3 -(4-methyl-3 -oxo-3,4- 7.58 (m, 3H), 7.42 - 7.40 (m, 1H), starting from 4- dihydro-2H-benzo[b] [1,4]oxazin- 7.19 - 7.15 (m, 1H), 7.04 (d, J= 8.0 methyloxo-l,4- 6-yl)acrylamido)benzoic acid Hz, 1H), 6.88 (d, / = 16.0 Hz, 1H), benzoxazine 4.71 (s, 2H), 3.35 (s, 3H); MS carbaldehyde and (ESI+) m/z 353.0 (M+H)+; 94% 2-(2- purity, RT 1.88 min (Method 6) carboxyacetamido) benzoic acid (/?)-l-(2H-benzo[b][l,4]oxazin-4(3H)-yl)(3-ethyl(propyn-l-yloxy)phenyl)propen- 1-one (113) a) (E)(3-ethyl(propyn-l-yloxy)phenyl)acrylic acid ] To a mixture of 3-ethylpropynoxybenzaldehyde (0.28 g, 1.49 mmol, 1.0 equiv.) and malonic acid (0.232 g, 2.23 mmol, 1.5 equiv.) in pyridine (5 mL) was added piperidine (0.013 g, 0.149 mmol, 0.1 equiv.) at 25°C and the resulting solution stirred at 120°C for 12 hours. The pH of the solution was adjusted to pH = 3 with IN hydrochloric acid and the resulting itate collected to afford the title nd as a yellow solid (0.32 g, 86%); lU NMR (CDC13, 400 MHz) 5 7.74 (d, / = 15.6 Hz, 1H), 7.39 (d, / = 7.2 Hz, 2H), 6.98 (d, /= 8.4 Hz, 1H), 6.34 (d, /= 16.0 Hz, 1H). 4.77 (d, /= 2.0 Hz, 2H), 2.67 (q, /= 7.6 Hz, 2H), 2.53 (t, / = 2.0 Hz, 1H), 1.22 (t, / = 7.6 Hz, 3H); MS (ESI+) m/z 231.1 (M+H)+. b) (E)-l-(2H-benzo[b][l,4]oxazin-4(3H)-yl)(3-ethyl(propyn-l-yloxy)phenyl)prop en-l-one o o o To a stirred solution of (£’)(3-ethyl(propyn-l-yloxy)phenyl)acrylic acid (0.28 g, 1.22 mmol, 1.0 equiv.) in dichloromethane (5 mL) at 0°C was added oxalyl chloride (0.463 g, 3.65 mmol, 3.0 ) and the mixture stirred at 25°C for 10 minutes. The reaction mixture was concentrated under reduced pressure to give a yellow solid and the residue was dissolved in dichloromethane (4 mL). 3,4-Dihydro-2/7-L4-bcnzoxazinc (0.197g, 1.46mmol, 1.2 equiv.), triethylamine (0.057 g, 0.563 mmol, 2.0 ) and dimethylaminopyridine (0.003 g, 0.028 mmol, 0.1 equiv.) were added at 25°C and the resultant mixture was stirred at 25°C for 12 hours. The reaction was diluted with water (30 mL) and extracted with dichloromethane (4 x 10 mL). The ed organic phase was dried over sodium e and concentrated under reduced re. The residue was ed by preparative HPLC to afford the desired product as a white solid (48 mg, 47%); NMR (CDCI3, 400 MHz) 5 7.74 (d, / = 15.6 Hz, 1H), 7.34 - 7.32 (m, 2H), 7.21 (d, /= 6.8 Hz, 1H), 7.14 - 7.10 (m, 1H), 6.98 - 6.92 (m, 4H), 4.75 (d, / = 2.4 Hz, 2H), 4.37 (t, / = 4.4 Hz, 2H), 4.08 (t, / = 4.8 Hz, 2H), 2.65 (q, / = 7.6 Hz, 2H), 2.52 (t, / = 2.4 Hz, 1H), 1.20 (t, /= 7.6 Hz, 3H); MS (ESI+) m/z 348.1 (M+H)+; 100% purity, RT 2.42 min (Method 10). (/?)(3-ethyl(propyn-l -yloxy)phenyl)-N-(2-(3-methyl-l H-1,2,4-triazol-l -yl)phenyl)- acrylamide (114) a) 3-methyl-l-(2-nitrophenyl)-lH-l,2,4-triazolecc* Ty- ocN°2 To a mixture of l-fluoronitrobenzene (1 mL, 12.8 mmol, 1.0 equiv.) and 3-methyl- 177-1,2,4-triazole (1.27 g, 15.3 mmol, 1.2 equiv.) in acetonitrile (20 mL) was added potassium carbonate (5.29 g, 38.3 mmol, 3.0 equiv.) and the mixture was d at 60°C for 12 hours. The mixture was cooled to 20°C, diluted with ethyl acetate (20 mL) and ed. The filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography leum ether: ethyl acetate 2:1 to 1:1) to give the desired product as a light yellow solid (1.20 g, 46%); ^ NMR d6, 400 MHz) 5 8.96 (s, 1H), 8.12 (d, /= 8.0 Hz, 1H), 7.90 - 7.88 (m, 1H), 7.86 - 7.84 (m, 1H), 7.60 (t,J= 8.0 Hz, 1H), 2.31 (s, 3H). b) 2-(3-methyl-lH-l,2,4-triazol-l-yl)aniline ocN°2 or To a solution of 3-methyl-l-(2-nitrophenyl)-l,2,4-triazole (1.20 g, 5.88 mmol, 1.0 equiv.) in methanol (16 mL) was added Pd/C (0.2 g, 5%) and the mixture was stirred at 20°C under a hydrogen atmosphere for 4 hours. The mixture was filtered and the filtrate concentrated under reduced pressure to give the desired product as light yellow gum which was used directly without further purification (1.00 g); 1H NMR (CDC13, 400 MHz) 5 8.24 (s, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.15 (d,/= 1.6 Hz, 1H), 6.85 (d, 7 = 2.8 Hz, 1H), 6.83 (d, 7 = 7.6 Hz, 1H), 4.54 (hr. s., 2H), 2.50 (s, 3H). c) (3-ethyl(propyn-l-yloxy)phenyl)-N-(2-(3-methyl-lH-l,2,4-triazol-l- yl)pheny 1) -acrylamide .Nk H Nij Prepared according to the procedure described for the synthesis of (£)-1 -(2H- benzo[b][l,4]oxazin-4(3H)-yl)(3-ethyl(propyn-l-yloxy)phenyl)propen-l-one (113) ng from (C)(3-cthyl(propyn-l-yloxy)phcnyl(acrylic acid and ethyl-lH-l,2,4- triazol-1 -yl)aniline (14%); ^ NMR (CDC13, 400 MHz) 5 9.80 (s, 1H), 8.62 (d, 7= 8.4 Hz, 1H), 8.41 (s, 1H), 7.65 (d, 7= 15.6 Hz, 1H), 7.50 - 7.40 (m, 1H), 7.39 - 7.34 (m, 3H), 7.28 - 7.20 (m, 1H), 6.98 (t, 7 = 9.2 Hz, 1H), 6.35 (d, 7 = 15.2 Hz, 1H), 4.76 (d, 7 = 2.4 Hz, 2H), 2.68 (q, 7 = 7.6 Hz, 2H), 2.62 (s, 3H), 2.52 (t, 7 = 2.4 Hz, 1H), 1.23 (t, 7 = 7.6 Hz, 3H); MS (ESI+) m/z 387.2 (M+H)+; 95.8% purity, RT 2.15 min (Method 10). (/?)-l-(2H-benzo[b][l,4]oxazin-4(3H)-yl)(2-(2-(dimethylamino)ethoxy)-3,4- dimethoxyphenyl)-propen-l-one (115) 'O o a) 2-(2-(dimethylamino)ethoxy)-3,4-dimethoxybenzaldehyde OH / ■0 o Y" 0 'O' '0 To a solution of 2-hydroxy-3,4-dimethoxybenzaldehyde (3.00 g, 16.5 mmol, 1.0 equiv.) and dimethylaminoethylchloride hydrochloride (2.38g, 16.5 mmol, 1.0 equiv.) in acetonitrile (50 mL) was added potassium carbonate (6.83 g, 49.4 mmol, 3.0 equiv.) and sodium iodide (0.247 g, 1.65 mmol, 0.1 equiv.) and the e stirred at 80 °C for 12 hours. The reaction mixture was filtered and the filtrate concentrated under reduced re. The residue was purified by silica gel column chromatography (dichloromethane: methanol 1:0 to 10:1) to provide the desired product as brown oil, (3.20 g) which was used without r purification; ^ NMR (CDCI3, 400 MHz) 8 10.30 (s, 1H), 7.61 (d, / = 8.4 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 4.27 (t, J = 5.6 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 2.69 (t, J = 5.6 Hz, 2H), 2.31 (s, 6H). b) (E)(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)acrylic acid I I 0 r 0 .0. .0. '0 'OH 0 0 The title compound was prepared according to the procedure described for the synthesis of (£’)(3-ethylpropynoxyphenyl)propenoic acid ng from 2-(2- (dimethylamino)ethoxy)-3,4-dimethoxybenzaldehyde and malonic acid; 'fi NMR (CD3OD, 400 MHz) 5 7.75 (d, /= 16.0 Hz, 1H), 7.42 (d, /= 8.8 Hz, 1H), 6.92 (d, /= 8.8 Hz, 1H), 6.44 (d, / = 16.0 Hz, 1H), 4.28 (t, /= 4.8 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.62 (t, /= 4.8 Hz, 2H), 3.07 (s, c) (2H-benzo[b][l,4]oxazin-4(3H)-yl)(2-(2-(dimethylamino)ethoxy)-3,4- dimethoxyphenyl) propen-l-one WO 44620 I I / \ o o 0 0 .0. .0.
'OH N T V "O' The title compound was prepared according to the procedure described for the synthesis of (£’)-l-(2//-benzo[b][l,4]oxazin-4(3//)-yl)(3-ethyl(propyn-l- yloxy)phenyl)propen-l-one (113) starting from (£’)(2-(2-(dimethylamino)ethoxy)-3,4- oxyphenyl)acrylic acid and 3,4-dihydro-2H-benzo[b][l,4]oxazine (11%); H NMR (CD3OD, 400 MHz) 5 7.91 (d,/= 15.6 Hz, 1H), 7.29 (d,/= 8.8 Hz, 2H), 7.15 - 7.12 (m, 2H), 6.95 - 6.93 (m, 2H), 6.83 (d, /= 8.8 Hz, 1H), 4.35 (t, /= 4.8 Hz, 2H), 4.13 (t, /= 5.6 Hz, 2H), 4.04 (t, J = 4.8 Hz, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 2.68 (t, J = 5.6 Hz, 2H), 2.32 (s, 6H). MS (ESI+) m/z 413.2 (M+H)+; 100% purity, RT 1.58 min (Method 10). (/?)(3-(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)acrylamido)benzoic acid (116) I I \ 0 o \ .0. H .0. 0 0^ OH N 'O' o O^ OH A mixture of 2-(2-(dimethylamino)ethoxy)-3,4-dimethoxybenzaldehyde (4.17 g, 16.4 mmol, 1.0 ), arboxyacetamido)benzoic acid (3.99 g, 18.0 mmol, 1.1 equiv.) and piperidine (1.78 mL, 18.0 mmol, 1.1 equiv.) in toluene (100 mL) was heated at 115 °C for 4 hours. The mixture was cooled to room temperature and the solvent removed in vacuo. The residue was dissolved in a minimal amount of methanol, allowed to stand overnight and the ing solid collected. The solid was washed with methanol, the washings concentrated in vacuo and the residue was purified by silica gel column chromatography (methanol/DCM 2% to %). The product from the column was then combined with the solid and recrystallized from methanol to afford the title compound as a white solid (4.07 g, 60%). ‘H NMR (400 MHz, DMSO) 5 14.27 (s, 1H), 8.62 - 8.60 (m, 1H), 8.10 (dd, /= 7.8 Hz, /= 1.5 Hz, 1H), 7.97 (d, J = 16.6 Hz, 1H), 7.67 (d, /= 8.8 Hz, 1H), 7.45 - 7.39 (m, 1H), 7.09 - 7.04 (m, 1H), 6.99 (d, /= 9.1 Hz, 1H), 6.56 (d, / = 17.0 Hz, 1H), 4.42 - 4.37 (m, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 3.66 (dd, / = 4.4 Hz , 7 = 4.4 Hz, 2H), 3.01 (s, 6H). MS (ESf) m/z 415.4 (M+H)+: 99.0 % , RT 2.60 min (Method 2). (/?)chloro(3-(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)acrylamido)benzoic add (117) o OH a) 2-(2-Carboxyacetamido)chlorobenzoic add Cl Cl H02C^hN O' o OH A mixture of methyl 2-aminochlorobenzoate (0.50 g, 2.69 mmol, 1.0 equiv.) and NaOH (0.14 g, 3.58 mmol, 1.3 equiv.) in ethanol (5 mL) and water (5 mL) was heated at reflux for 1.5 hours and then cooled to room temperature. The pH was adjusted to pH 1 with 2N hydrochloric acid and the resulting precipitate was isolated by filtration, washed with water then dried under suction and used without further purification.
] The solid (0.37 g, 2.16 mmol, 1.05 equiv.) was suspended in toluene (5 mL) and 2,2- dimethyl-l,3-dioxane-4,6-dione (0.295 g, 2.05 mmol, 1.0 equiv.) was added. The mixture was heated at reflux for 6 hours at which point a r portion of 2,2-dimethyl-l,3-dioxane-4,6- dione (0.016 g, 0.11 mmol) was added. After a further 30 minutes at reflux the mixture was cooled and the resulting precipitate was isolated by filtration, washed with toluene and dried under suction to give the title compound as a cream solid (0.49 g, 89%). ^ NMR (400 MHz, DMSO): 5, ppm 12.95 - 12.95 (m, 1H), 11.47 (s, 1H), 8.64 (d, 7= 2.3 Hz, 1H), 8.05 (d, 7= 8.6 Hz, 1H), 7.33 - 7.29 (m, 1H), 3.57 (s, 2H). MS (ESI+) m/z 258 (M+H)+. b) (E)chloro(3-(2-(2-(dimethylamino)ethoxy)-3,4- dimethoxyphenyl)acrylamido)benzoic acid Cl \ Cl H°2C^N 0 H N cr OH H 'O' O^ OH WO 44620 The title compound was prepared according to the procedure for (£’)(3-(2-(2- (dimethylamino)ethoxy)methoxy(propyn-l-yloxy)phenyl)acrylamido)-benzoic acid (78) starting from 2-(2-carboxyacetamido)chlorobenzoic acid and 2-(2-(dimethylamino)ethoxy)- 3,4-dimethoxybenzaldehyde (50%); ‘H NMR (400 MHz, CDC13): 5 ppm 7.51 (1H, d, J=15.4 Hz), 7.10 - 7.07 (1H, m), 7.06 - 7.02 (1H, m), 6.97 (1H, d, / = 8.3 Hz), 6.41 (1H, d, / = 14.9 Hz), 6.00 - 5.93 (1H, m), 4.78 (2H, d, /= 2.5 Hz), 3.89 (3H, s), 3.77 - 3.66 (1H, m), 2.68 - 2.59 (1H, m), 2.54 - 2.51 (1H, m), 2.01 - 1.96 (2H, m), 1.77 - 1.66 (2H, m), 1.33 - 1.19 (4H, m); MS: (ESI+) m/z 329.2(M+H)+99.01% purity, RT = 2.87min., (Method 3). (/?)-l-(2H-benzo[b][l,4]oxazin-4(3//)-yl)(3-methoxy((l-methylpyrrolidin yl)oxy)phenyl)propen- 1-one (118) a) (E)-methyl 3-(3-methoxy((l -methylpyrrolidinyl)oxy)phenyl)acrylate I o I o o 0 0 ■O' HO' 'O' To a solution of methyl (£’)(4-hydroxymethoxyphenyl)propenoate (2.00 g, 9.61 mmol, 1.0 ), l-methylpyrrolidinol (1.17 g, 11.5 mmol, 1.2 equiv.) and triphenylphosphine (3.02 g, 11.53 mmol, 1.20 equiv.) in tetrahydrofuran (10 mL) at 0°C was added diisopropylazodicarboxylate (2.33 g, 11.5 mmol, 1.2 equiv.) over 30 s. The reaction mixture was d with IN hydrochloric acid (50 mL) and extracted with ethyl acetate (3 x 50 mL), the s layer was adjusted to pH = 8 with IN sodium hydroxide solution and ted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo to give the desired product as a yellow oil (2.50 g, 89%) which was used without further purification; ^ NMR (CDCI3, 400 MHz) 8 7.62 (d, /= 16.0 Hz, 1H), 7.05 (d, /= 8.0 Hz, 1H), 7.04 (s, 1H), 7.76 (d, /= 8.0 Hz, 1H), 6.30 (d, J= 16.0 Hz, 1H), 4.89 - 4.85 (m, 1H), 3.87 (s, 3H), 3.79 (s, 3H), 2.95 - 2.92 (m, 1H), 2.80 - 2.76 (m, 2H), 2.55 - 2.53 (m, 1H), 2.39 (s, 3H), 2.38 - 2.35 (m, 1H), 2.05 - 2.01 (m, 1H). b) (E)(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)acrylic acid I o I 0 0 o 'O' 'OH —N. —N, 'O' 'O' To a mixture of (Lj-methyl 3-(3-methoxy((l-methylpyrrolidin yl)oxy)phenyl)acrylate (1.50 g, 5.15 mmol, 1.0 equiv.) in methanol (15 mL) and water (2 mL) was added lithium hydroxide (0.247 g, 10.3 mmol, 2.0 equiv.) and the mixture stirred at 25°C for 12 hours. The reaction e was concentrated under reduced pressure. The e was diluted with water (100 mL) and the e extracted with dichloromethane (30 mL x3). The aqueous phase was adjusted to pH=5 with IN hydrochloric acid and concentrated under d pressure to get the desired product as a brown oil, which was used directly without further purification (1.50 g); NMR (CD3OD, 400 MHz) 5 7.39 (d, /= 16.0 Hz, 1H), 7.19 (d, / = 2.0 Hz, 1H), 7.09 (dd, / = 8.0 Hz, / = 2.0 Hz, 1H), 6.97 (d, / = 8.0 Hz, 1H), 6.40 (d, / = 16.0 Hz, 1H), 5.14 - 5.12 (m, 1H), 3.88 (s, 3H), 3.53 - 3.49 (m, 3H), 3.31 - 3.30 (m, 1H), 2.90 (s, 3H), 2.47 - 2.43 (m, 1H), 2.54 - 2.27 (m, 1H). c) (E)-l-(2H-benzo[b][l,4]oxazin-4(3H)-yl)(3-methoxy((l-methylpyrrolidin yl)oxy)phenyl)-propen-l-one I o o 0 .0.
'O' N ‘O' o The title compound was prepared according to the procedure described for the synthesis of (£’)-l-(2H-benzo[b][l,4]oxazin-4(3H)-yl)(3-ethyl(propyn-l- yloxy)phenyl)propen-l-one (113) starting from (£)(3-methoxy((l-methylpyrrohdin yl)oxy)phenyl)acrylic acid and 3,4-dihydro-2H-benzo[b][l,4]oxazine (9%); H NMR (CDCI3, 400 MHz) 5 7.64 (d, / = 15.2 Hz, 1H), 7.13 (d, / = 2.0 Hz, 1H), 7.09 - 7.05 (m, 1H), 7.04 - 6.98 (m, 1H), 6.91 (d, /= 1.6 Hz, 1H), 6.88 (t, /= 6.8 Hz, 1H), 6.83 - 6.81 (m, 2H), 6.71 (d, /= 8.0 Hz, 1H), 4.80 - 4.80 (m, 1H), 4.29 (t, /= 4.8 Hz, 2H), 4.00 (t, /= 4.8 Hz, 2H), 3.78 (s, 3H), 2.89 - 2.87 (m, 1H), 2.77 - 2.74 (m, 2H), 2.52 - 2.47 (m, 1H), 2.35 (s, 3H), 2.27 - 2.23 (m, 1H), 1.99 - 1.96 (m, 1H); MS (ESI+) m/z 395.2 (M+H)+; 92.8% purity, RT 2.59 min (Method 8). (2//-benzo[b][l,4]oxazin-4(3//)-yl)(2-(3-methoxy(propyn-l-yloxy) ) cyclopropyl) methanone (119) a) methyl 2-(3-methoxy(propyn-l-yloxy)phenyl)cyclopropanecarboxylate 0 0 .0. .0.
‘O' 0 ] To a solution of hylsulfoxonium iodide (1.34 g, 6.09 mmol, 1.5 equiv.) in dimethylsulfoxide (10 ml) at 0°C was added sodium hydride (0.107 g, 4.47 mmol, 1.1 equiv.) and the mixture stirred at 25°C for 30 minutes. Methyl (£’)(3-methoxyprop ynoxy-phenyl)propenoate (1.00 g, 4.06 mmol, 1.0 equiv.) was then added and the reaction stirred at 25°C for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (5 x 10 mL). The combined organic phase was washed with water (5 x 30 ml), dried over sodium sulfate and concentrated under reduced pressure to give the desired product as a yellow oil (1.00 g) which was used without further purification; ^ NMR (CDCI3, 400 MHz) 8 6.95 (d, /= 8.1 Hz, 1H), 6.66 - 6.63 (m, 2H), 4.75 (d, 7= 2.4 Hz, 2H), 3.87 (s, 3H), 3.73 (s, 3H), 2.52 (d, 7 = 2.4 Hz, 1H), 2.51 -2.49 (m, 1H), 1.65 - 1.59 (m, 1H), 1.58 - 1.56 (m, 1H), 1.30- 1.27 (m, 1H). b) 2-(3-methoxy(propyn-l-yloxy)phenyl)cyclopropanecarboxylic acid 0 0 .0. o .0.
] To a e of methyl 2-(3-methoxy(propyn-l- yloxy)phenyl)cyclopropanecarboxylate (1.00 g, 3.86 mmol, 1.0 equiv.) in methanol (15 mL) and water (2 mL) was added lithium hydroxide (0.185 g, 7.72 mmol, 2.0 equiv.) and the reaction was stirred at 25°C for 12 hours. The reaction was concentrated under d pressure to give a residue which was diluted with water (100 mL) and the aqueous mixture extracted with dichloromethane (3 x 30 mL). The aqueous phase was adjusted to pH 5 with IN hydrochloric acid and trated under reduced pressure to get the d product as brown oil, which was used directly without further purification (0.4 g, 42%); ^ NMR (CDCI3, 400 MHz) 8 6.96 (d, 7 = 8.4 Hz, 1H), 6.69 (d, 7 = 2.4 Hz, 1H), 6.65 (dd, 7 = 8.4 Hz, 7 = 2.0 Hz, 1H), 4.74 (d, 7 = 2.4 Hz, 2H), 3.90 (s, 3H), 2.58 - 2.51 (m, 1H), 2.50 (t, 7= 2.4 Hz, 1H), 1.88 - 1.86 (m, 1H), 1.65 - 1.62 (m, 1H), 1.29 - 1.25 (m, 1H). c) (2H-benzo[b][l,4]oxazin-4(3H)-yl)(2-(3-methoxy(propyn-l-yloxy) phenyl) cyclopropyl) methanone o o .0. .0.
"OH N T ^0 k/O The title compound was prepared according to the ure described for the synthesis of (£,)-l-(2//-benzo[b][l,4]oxazin-4(3H)-yl)(3-ethyl(propyn-l- yloxy)phenyl)propen-l-one (113) starting from 2-(3-methoxy(propyn-lyloxy )phenyl)cyclopropanecarboxylic acid and 3,4-dihydro-2H-benzo[b][l,4]oxazine (9%); H NMR (CDCI3, 400 MHz) 5 7.27 - 7.26 (m, 1H), 7.04 - 7.02 (m, 1H), 6.96 - 6.91 (m, 2H), 6.75 - 6.70 (m, 1H), 6.64 - 6.63 (m, 1H), 6.62 - 6.61 (m, 1H), 4.74 (d, / = 2.4 Hz, 2H), 4.36 - 4.30 (m, 2H), 4.22 - 4.21 (m, 1H), 3.85 - 3.84 (m, 4H), 2.63 - 2.59 (m, 1H), 2.51 (t, / = 2.0 Hz, 1H), 2.40 - 2.39 (m, 1H), 1.83 - 1.79 (m, 1H), 1.33 - 1.30 (m, 1H); MS (ESI+) m/z 364.1 (M+H)+; 99.7% purity, RT 2.12 min (Method 9).
(/?)-/V-(4-fluorophenyl)(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)acrylamide (120) o K& a) (E)-tert-butyl 4-(2-methoxy(3-methoxyoxoprop-l-en-l-yl)phenyl)-5,6- dihydropyridine-1 (2H) -carboxylate o aO' .0. .0. 'O' "O' B'0 Br' .N Boc -N A mixture of methyl (£’)(4-bromomethoxyphenyl)propenoate (0.5 g, 1.84 mmol, 1.0 equiv.), / WO 44620 b) (E)(4-(l-(tert-butoxycarbonyl)-l,2,3,6-tetrahydropyridinyl) methoxyphenyl)acrylic acid o o o .0.
"O' "OH Boo"N Boc^ The title compound was prepared according to the procedure described for the synthesis of2-(3-methoxy(propyn-l-yloxy)phenyl)cyclopropanecarboxylic acid starting from (Tj-tcrt-hutyl 4-(2-methoxy(3-methoxyoxoprop-l-en-l-yl)phenyl)-5,6- dihydropyridine-1 (2H)-carboxylate; NMR (CD3OD, 400 MHz) 5 7.36 (d, / = 15.6 Hz, 1H), 7.13 - 7.06 (m, 3H), 6.49 (d,J= 16.0 Hz, 1H), 5.77 - 5.76 (m, 1H), 4.04 - 4.01 (m, 2H), 3.84 (s, 3H), 3.62 - 3.58 (m, 2H), 2.49 - 2.45 (m, 2H), 1.47 (s, 9H); MS (ESI+) m/z 382.1 +. c) (E)-N-(4-fluorophenyl)(3-methoxy(l,2,3,6-tetrahydropyridin yl)phenyl)acrylamide "OH .0. vOr Boc"N HN.
To a on of (£,)[4-(l-/er/-butoxycarbonyl-3,6-dihydro-27/-pyridinyl) methoxy-phenyl]propenoic acid (0.1 g, 0.278 mmol, 1.0 equiv.) in A/.iV-di methyl form amide (5 mL) was added HATU (0.159 g, 0.417 mmol, 1.5 equiv.) and diisopropylethylamine (0.108 g, 0.835 mmol, 3.0 ) and the resultant mixture was stirred at 20°C for 1 hour. Then 4- fluoroaniline (0.037 g, 0.334 mmol, 1.2 equiv.) was added and the mixture was stirred for 3 hours at 20°C. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with water (3x10 mL). The organic layer was dried over sodium sulfate and concentrated under d pressure. The resulting yellow oil was dissolved in dichloromethane (5 mL) and treated with trifluoroacetic acid (0.378 g, 3.31 mmol, 10.0 equiv.) and the resulting solution was stirred at 20°C for 2 hours. The e was concentrated under reduced pressure to give a residue which was purified by preparative HPLC to give the desired product as a yellow solid (0.042 g, 27%); 1H NMR (CD3OD, 400 MHz) 5 7.69 - 7.65 (m, 2H), 7.62 (s, 1H), 7.23 - 7.21 (m, 3H), 7.10 - 7.06 (m, 2H), 6.80 (d, /= 16.0 Hz, 1H), 5.88 - 5.87 (m, 1H), 3.89 (s, 3H), 3.83 (d, J = 2.4 Hz, 2H), 3.43 - 3.40 (m, 2H), 2.98 - 2.78 (m, 2H); MS (ESI+) m/z 353.1 (M+H)+; 98.3% purity, RT 2.47 min (Method 11).
WO 44620 /V-(4-cyanophenyl)(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)cyclopropane amide (121) wCN .0. a) methyl 2-(4-bromomethoxyphenyl)cyclopropanecarboxylate o o .0. .0. 0 ‘O' Br­ er ] The title compound was prepared according to the procedure described for the synthesis of methyl ethoxy(propyn-l-yloxy)phenyl)cyclopropanecarboxylate starting from (^-methyl 3-(4-bromomethoxyphenyl)acrylate; 'h NMR (CDCI3,400 MHz) 8 7.42 (d, J = 8.4 Hz, 1H), 6.67 (d, / = 8.4 Hz, 1H), 6.55 (dd, /= 8.4 Hz, / = 2.0 Hz, 1H), 3.89 (s, 3H), 3.73 (s, 3H), 2.52 - 2.48 (m, 1H), 1.91 - 1.89 (m, 1H), 1.63 - 1.59 (m, 1H), 1.33 - 1.31 (m, b) tert-butyl 4-(2-methoxy(2-(methoxycarbonyl)cyclopropyl)phenyl)-5,6- dihydropyridine-1 (2H) -carboxylate o .0. .0. "O' The title compound was prepared according to the procedure described for the synthesis of (i?)-tert-butyl 4-(2-methoxy(3-methoxyoxoprop-l-en-l-yl)phenyl)-5,6- dihydropyridinc-1 (2/7)-carboxylatc starting from methyl 2-(4-bromo methoxyphenyl)cyclopropanecarboxylate and / 'OH 0 'O' 'O' To a solution of (T)(2-(2-(di methyl ami no)ethoxy)-3,4-dimethoxyphenyl)acry lie acid (1.50 g, 5.08 mmol, 1.0 equiv.) in methanol (20 mL) was added copper sulfate (1.49 g, 15.2 mmol, 3.0 equiv.) at 0°C and the resultant mixture stirred at 20°C for 3 hours. The reaction mixture was adjusted to pH 7 with IN hydrochloric acid and concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 mL) and washed with water (20 mL x3).
The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the desired product as yellow oil (1.35 g) which was used without r purification; 1H NMR (CDCI3, 400 MHz) 5 7.96 (d, J = 16.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.68 (d /= 8.4 Hz, 1H), 6.40 (d, /= 16.4 Hz, 1H), 4.13 (t, /= 6.0 Hz, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.33 (s, 3H), 2.73 (t, /= 5.6 Hz, 2H), 2.35 (s, 6H). b) 2-(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)-N-(4-fluorophenyl)cyclopropane- 1-carboxamide I I /' \ •O. .0.
'O' w "O' o The title compound was ed as the trifluoroacetic acid salt according to the procedure described for the synthesis of (2/7-bcnzo[b][ azin-4(3/7)-yl)(2-(3-mcthoxy 2-yn-l-yloxy)phenyl) cyclopropyl)methanone (119) starting from (Lj-methyl 3-(2-(2- (dimethylamino)ethoxy)-3,4-dimethoxyphenyl)acrylate and 4-fluoroaniline; 'h NMR (CD3OD, 400 MHz) 5 7.59 - 7.56 (m, 2H), 7.06 (t, /= 8.8 Hz, 2H), 6.81 (d, /= 8.8 , 6.73 (d,/ = 8.4 Hz, 1H), 4.31 - 4.26 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.53 (t, /= 2.4 Hz, 2H), 3.00 (s, 6H), 2.67 - 2.65 (m, 1H), 1.90 - 1.88 (m, 1H), 1.55 - 1.53 (m, 1H), 1.40 - 1.38 (m, 1H); MS (ESI+) m/z 403.2 (M+H)+; 96.7% purity, RT 2.48 min (Method 11).
Ex Structure Data Method 123 1H NMR (CDCL, 400 MHz) 5 8.49 0 r Prepared according N (t, J= 3.2 Hz, 1H), 7.73 (d, J= 15.6 to the method for F Hz, 1H), 7.48 (s, 1H), 7.42 - 7.38 113 starting from 2- (£)(3-ethyl(propyn-l- (m, 2H), 7.17 - 7.15 (m, 1H), 7.12 - fluoroaniline yloxy)phenyl)-N-(2- 7.10 (m, 1H), 7.10 - 7.09 (m, 1H), fluorophenyl) acrylamide 6.98 (d, J = 8.4 Hz, 1H), 6.47 (d, J = .2 Hz, 1H), 4.77 (d, J= 2.4 Hz, 2H), 2.68 (q, /= 7.2 Hz, 2H), 2.53 (t, 7=2.4 Hz, 1H), 1.24 (t, 7=7.2 Hz, 3H); MS (ESI+) m/z 324.1 (M+H)+; 100% purity, RT 2.33 min w (Method 10)_____________________ 124 CN 1H NMR (CDC13, 400 MHz) 5 7.77 Prepared according - 7.73 (m, 3H), 7.64 (d, 7= 8.8 Hz, to the method for <0^0 2H), 7.44 - 7.38 (m, 3H), 6.98 (d, 7 113 starting from 4- = 8.0 Hz, 1H), 6.43 (d, 7= 15.6 Hz, aminobenzonitrile (£’)-/V-(4-cyanophcnyl)(3- 1H), 4.77 (d, 7= 2.4 Hz, 2H), 2.68 4-(propyn-1 - (q, 7= 6.8 Hz, 2H), 2.54 (t, 7= 2.4 yloxy)phenyl)acrylamide Hz, 1H), 1.23 (t, 7= 6.8 Hz, 3H); MS (ESI+) m/z 331.2 (M+H)+; 92% w purity, RT 2.33 min (Method 10) 125 1H NMR (CDCI3, 400 MHz) 5 7.71 Prepared according (d, 7= 15.2 Hz, 1H), 7.58 (s, 2H), to the method for I H 7.38 - 7.35 (m, 3H), 7.05 (t, 7= 8.4 113 starting from 4- Hz, 2H), 6.95 (d, 7= 8.4 Hz, 1H), fluoroaniline (£)(3-ethyl(propyn-l- 6.43 (d, 7= 15.6 Hz, 1H), 4.76 (d, 7 yloxy)phenyl)-N-(4- = 2.4Hz, 2H), 2.66 (q, 7= 7.6 Hz, fluorophenyl) mide 2H), 2.53 (t, 7= 2.4 Hz, 1H), 1.22 (t, 7= 7.6 Hz, 3H); MS (ESI+) m/z 324.1 (M+H)+; 96.5% purity, RT 2.32 min (Method _________ 126 o 1H NMR (CDCI3, 400 MHz) 5 7.96 Prepared according N Vi (d, 7= 16.0 Hz, 1H), 7.62 (d, 7= 8.0 to the method for <0^0 Nsa Hz, 1H), 7.48 - 7.46 (m, 3H), 7.41 113 starting from (£)(3-ethyl(propyn-l- (t, 7= 8.0 Hz, 1H), 7.24 (d, 7= 7.6 lH-indazolol yloxy)phenyl) -1 -(3 -hydroxy-1H- Hz, 1H), 7.01 (d, 7 = 8.0 Hz, 1H), l-1 -yl)propen-1 -one 6.65 (d, 7= 13.2 Hz, 1H), 4.79 (d, 7 = 2.4 Hz, 2H), 2.70 (q, 7= 7.6 Hz, 2.4 Hz, 2H), 2.55 (t, 7= 2.4 Hz, 1H), 1.25 (t, 7= 7.6 Hz, 3H); MS (ESI+) m/z 347.1 (M+H)+; 96.8% purity, RT 2.97 min (Method 12) 127 I 1H NMR (CD3OD, 400 MHz) 5 8.04 ed according - 8.03 (m, 1H), 7.94 (d, 7= 15.6 Hz, to the method for 0 1H), 7.42 (d, 7= 8.8 Hz, 1H), 7.24 - 118 starting from 2- N 7.13 (m, 3H), 6.89 (s, 1H), 6.85 (d, fluoroaniline ‘O' 7= 8.0 Hz, 1H), 4.16 (d, 7= 5.6 Hz, (£)(2-(2- 2H), 3.90 (s, 3H), 3.85 (s, 3H), 2.83 (dimethylamino)ethoxy)-3,4- (t, 7= 5.6 Hz, 2H), 2.38 (s, 6H); MS dimethoxyphenyl)-N-(2- (ESI+) m/z 389.2 ; 100% fluorophenyl) acrylamide purity, RT 1.44 min (Method 10) 128 I iH NMR (CD3OD, 400 MHz) 5 7.90 Prepared according \ (d, /= 15.6 Hz, 1H), 7.68 - 7.66 (m, to the method for 2H), 7.48 (d, /= 8.8 Hz, 1H), 7.08 115 starting from 4- /0. (t, / = 8.4 Hz, 2H), 6.95 (d, / = 8.8 fluoroaniline \ H O Hz, 1H), 6.72 (d, /= 15.6 Hz, 1H), (£)(2-(2- 4.30 (t, J= 4.8 Hz, 2H), 3.92 (s, (dimethylamino)ethoxy)-3,4- 3H), 3.91 (s, 3H), 3.65 (t, 7=5.2 dimethoxyphenyl)-/V-(4- Hz, 2H), 3.10 (s, 6H); MS (ESI+) fluorophenyl)acrylamide m/z 389.2 (M+H)+; 100% purity, trifluoroacetic acid salt RT 1.46 min (Method 10) 129 I 1H NMR (CD3OD, 400 MHz) 5 7.96 Prepared according \ (d, 7= 16.0 Hz, 1H), 7.88 (d, 7= 8.8 to the method for 115 starting from 4- Hz, 2H), 7.70 (d, 7= 8.8 Hz, 2H), /0. W H 7.50 (d, 7 = 8.8 Hz, 1H), 6.97 (d, 7 = aminobenzonitrile O 8.8 Hz, 1H), 6.74 (d, 7 = 16.0 Hz, (£’)-/V-(4-cyanophcnyl)(2-(2- 1H), 4.31 (t, 7= 4.8 Hz, 2H), 3.93 (dimethylamino)ethoxy)-3,4- (s, 3H), 3.91 (s, 3H), 3.66 (t, 7= 4.8 dimethoxyphenyl)acrylamide Hz, 2H), 3.10 (s, 6H); MS (ESI+) oroacetic acid salt m/z 396.2 (M+H)+; 97.5% purity, RT 1.44 min (Method 10) 130 1H NMR (CD3OD, 400 MHz) 5 8.11 0 Prepared according - 8.09 (m, 1H), 7.64 (d, 7= 15.6 Hz, fCXo N to the method for F 1H), 7.26 - 7.25 (m, 1H), 7.26 - 7.17 118 starting from 2- (£0-A^-(2-fluorophenyl)(3- (m, 4H), 6.96 (d, 7= 7.6 Hz, 1H), fluoroaniline methoxy(( 1 -methylpyrrolidin- 6.94 (d, 7= 15.6 Hz, 1H), 5.03 - 3-yl)oxy)phenyl)acrylamide 5.02 (m, 1H), 3.90 (s, 3H), 3.09 - 3.04 (m, 3H), 2.77 - 2.75 (m, 1H), 2.56 (s, 3H), 2.44 - 2.37 (m, 1H), 2.13-2.11 (m, 1H); MS (ESI+) m/z 371.2 ; 98.1% purity, RT ixr 2.48 min d 8) 131 iH NMR (CD3OD, 400 MHz) 5 7.96 Prepared according - 7.60 (m, 2H), 7.72 - 7.58 (m, 3H), to the method for .N 'O’ 7.28 (s, 1H), 7.21 (d, 7= 8.0 Hz, 118 starting from 4- (£0-A^-(4-cyanophenyl)(3- 1H), 7.04 (d, 7= 7.2 Hz, 1H), 6.71 aminobenzonitrile y(( 1 -methylpyrrolidin- (d, 7= 15.6 Hz, 1H), 5.30 - 5.16 (m, 3-yl)oxy)phenyl)acrylamide 1H), 3.95 - 3.70 (m, 5H), 3.48 - 3.31 trifluoroacetic acid salt (m, 1H), 3.30 - 3.17 (m, 1H), 3.01 (s, 3H), 2.65 - 2.21 (m, 2H); MS (ESI+) m/z 378.2 (M+H)+; 100% purity, RT 1.44 min (Method 10) 132 nXT iH NMR (CD3OD, 400 MHz) 5 7.70 Prepared according o - 7.65 (m, 2H), 7.59 (d, 7 = 15.6 Hz, to the method for N 1H), 7.26 - 7.25 (m, 1H), 7.10 - 7.09 118 starting from 4- (£’)-/V-(4-fluoi'ophcnyl)(3- (m, 1H), 7.07 - 7.04 (m, 3H), 6.72 fluoroaniline methoxy(( 1 lpyrrolidin- (d, 7= 15.6 Hz, 1H), 5.25 - 5.23 (m, 3-yl)oxy)phenyl)acrylamide 1H), 3.93 - 3.88 (m, 5H), 3.45 - 3.10 trifluoroacetic acid salt (m, 1H), 3.33 - 3.32 (m, 1H), 3.24 - 3.03 (m, 3H), 2.33 - 2.26 (m, 2H); MS (ESI+) m/z 371.2 (M+H)+; 100% purity, RT 1.45 min (Method 133 w 1H NMR (CDC13, 400 MHz) 5 7.58 Prepared according .0. (s, 1H), 7.52 - 7.48 (m, 2H), 7.01 (d, to the method for H J= 8.4 Hz, 2H), 6.94 (d, /= 8.0 Hz, 119 ng from 4- 1H), 6.65 (d, /= 8.4 Hz, 2H), 4.74 fluoroaniline /V-(4-fluorophenyl)(3- (d, /= 2.4 Hz, 2H), 3.82 (s, 3H), methoxy(propyn-1 - 2.55 - 2.53 (m, 1H), 2.50 (t, /= 2.4 yloxy)phenyl)cyclopropanecarbo Hz, 1H), 1.73 - 1.68 (m, 2H), 1.34 - xamide 1.31 (m, 1H); MS (ESI+) m/z 340.3 (M+H)+; 100% purity, RT 2.11 min (Method 10) 134 o 1H NMR (CDCI3, 400 MHz) 5 8.43 Prepared according (hr. s, 1H), 7.70 (d, /= 6.8 Hz, 1H), to the method for 7.62 (d, /= 8.0 Hz, 1H), 7.39 (d, / = 119 starting from (3 -hydroxy-1 H-indazol-1 -yl) (2- 7.2 Hz, 1H), 6.97 (d, /= 8.0 Hz, lH-indazolol (3-methoxy(propyn-1 - 1H), 6.79 - 6.77 (m, 2H), 4.74 (d, J yloxy)phenyl)cyclopropyl) = 2.4 Hz, 2H), 3.84 (s, 3H), 3.04 (s, methanone 1H), 2.82 - 2.77 (m, 1H), 2.48 (t, / = 2.4 H, 1H), 1.91 - 1.89 (m, 1H), 1.58 - 1.55 (m, 1H); MS (ESI+) m/z 363.1 (M+H)+; 385.1 (M+Na)+; 97.9% purity, RT 2.94 min (Method 135 CN 1H NMR , 400 MHz) 5 7.78 Prepared according 0 K& (s, 1H), 7.68 (d, /= 8.8 Hz, 2H), to the method for H 7.61 (d, / = 8.8 Hz, 2H), 6.97 (d, / = 119 starting from 4- 8.4 Hz, 1H), 6.65 - 6.64 (m, 2H), aminobenzonitrile /V-(4-cyanophenyl)(3 - 4.75 (d, /= 2.4 Hz, 2H), 3.82 (s, methoxy(propyn-1 - 3H), 2.63 - 2.50 (m, 1H), 2.49 (t, / = yloxy)phenyl)cyclopropanecarbo 2.4 Hz, 1H), 1.61-1.40 (m, 2H), xamide 1.45 - 1.34 (m, 1H); MS (ESI+) m/z 347.1 (M+H)+; 98.6% purity, RT 136 w 2.04 min (Method 9) 1H NMR (CDCI3, 400 MHz) 5 7.59 ed ing -7.51 (m, 3H), 7.02 (d, 7=8.8 Hz, to the method for H 2H), 6.76 (d, 7= 8.4 Hz, 1H), 6.70 119 ng from /N 'O' /V-(4-fluorophenyl)(3- (s, 1H), 6.63 (d, 7= 1.6 Hz, 1H), (Ej-mcthyl 3-(3- methoxy(( 1 -methylpyrrolidin- 4.89 - 4.85 (m, 1H), 3.84 (s, 3H), methoxy((l- 3-yl)oxy)phenyl)cyclopropane- 3.30 - 3.25 (m, 1H), 2.94 - 2.90 (m, methylpyrrolidin-3 - 1-carboxamide 3H), 2.60 - 2.53 (m, 4H), 2.31 - 2.28 yl)oxy)phenyl)acryl (m, 1H), 2.20 - 2.15 (m, 1H), 1.71 - ate and 4- 1.60 (m, 2H), 1.34 - 1.32 (m, 1H); fluoroaniline MS (ESI+) m/z 385.1 (M+H)+; 96.4% purity, RT 1.56 min (Method 137 CN 1H NMR (CD3OD, 400 MHz) 5 7.78 Prepared according .0. w (d, 7= 8.8 Hz, 2H), 7.70 - 7.65 (m, to the method for .N ‘0‘ 2H), 6.94 (d, 7= 8.0 Hz, 1H), 6.87 119 ng from A^-(4-cyanophenyl)(3- (s, 1H), 6.75 - 6.73 (m, 1H), 5.08 (s, (Ej-mcthyl 3-(3- methoxy(( 1 -methylpyrrolidin- 1H), 3.91 (d, J= 8.4 Hz 1H), 3.86 methoxy((l- 3-yl)oxy)phenyl)cyclopropane- (s, 3H), 3.43 - 3.40 (m, 1H), 3.25 - methylpyrrolidin-3 - 1-carboxamide 3.18 (m, 1H), 3.10-3.00 (m, 4H), yl)oxy)phenyl)acryl 2.50 - 2.48 (m, 1H), 2.35 -2.15 (m, ate and 4- 2H), 2.05 - 2.03 (m, 1H), 1.61 - 1.59 enzonitrile (m, 1H), 1.39- 1.30 (m, 1H) ; MS (ESI+) m/z 392.2 (M+H)+; 94.5% purity, RT 2.72 min d 12) 138 o iH NMR (CD3OD, 400 MHz) 5 7.94 Prepared according N - 7.92 (m, 1H), 7.17 - 7.14 (m, 3H), to the method for N "O' 6.94 (d, J= 7.2 Hz, 1H), 6.88 (s, 119 starting from /V-(2-fluorophenyl)(3- 1H), 6.75 (d, J= 8.0 Hz, 1H), 5.10 - (Ej-mcthyl 3-(3- methoxy(( 1 -methylpyrrolidin- 5.09 (m, 1H), 3.93 - 3.87 (m, 5H), methoxy((l- 3-yl)oxy)phenyl)cyclopropane 3.41 - 3.42 (m, 1H), 3.27 - 3.17 (m, methylpyrrolidin-3 - carboxamide 1H), 3.10 - 3.00 (m, 3H), 2.50 - 2.47 yl)oxy)phenyl)acryl (m, 2H), 2.30 - 2.19 (m, 2H), 1.60 - ate and 2- 1.57 (m, 1H), 1.37 - 1.33 (m, 1H) ; fluoroaniline MS (ESI+) m/z 385.2 (M+H)+; 96.5% , RT 2.4 min (Method 139 CN 1H NMR (CD3OD, 400 MHz) 5 Prepared according .0. w 7.88 - 7.86 (m, 2H), 7.71 - 7.67 (m, to the method for H 3H), 7.26 - 7.22 (m, 3H), 6.82 (d, J 120 starting from 4- HN = 15.6 Hz, 1H), 5.89 (s, 1H), 3.90 aminobenzonitrile.
(£’)-/V-(4-cyanophcnyl)(3- (s, 3H), 3.83 (d, J= 2.8 Hz, 2H), methoxy(l,2,3,6- 3.42 (t, J= 6.0 Hz, 2H), 2.86 - 2.79 tetrahydropyridin (m, 2H); MS (ESI+) m/z 360.3 yl)phenyl) acrylamide (M+H)+; 98.2% purity, RT 1.61 trifluoroacetic acid salt min (Method 9) 140 0 1H NMR (CD3OD, 400 MHz) 5 Prepared ing N 8.69 (s, 1H), 7.97 (d, J= 7.6 Hz, to the method for 1H), 7.61 - 7.53 (m, 3H), 7.39 - 7.38 120 starting from 2- HN (m, 1H), 7.22 - 7.18 (m, 3H), 6.75 (3-methyl-lH- (3-methoxy(l,2,3,6- (d, /= 15.6 Hz, 1H), 5.87 (t, /= 1.6 1,2,4-triazol-ltetrahydropyridinyl )phenyl)- Hz, 1H), 3.87 (s, 3H), 3.83 (d, / = yl) aniline. (3-methyl-1H-1,2,4-triazol- 2.8 Hz, 2H), 3.42 (t, /= 6.0 Hz, 1 -yl)phenyl) acrylamide 2H), 2.78 - 2.76 (m, 2H), 2.46 (s, trifluoroacetic acid salt 3H); MS (ESI+) m/z 416.3 (M+H)+; 100% purity, RT 2.26 min (Method 141 o 1H NMR (CD3OD, 400 MHz) 5 Prepared according N 8.09 (t, /= 1.2 Hz, 1H), 7.68 (d, J = to the method for F 15.6 Hz, 1H), 7.24 - 7.17 (m, 6H), 120 starting from 2- HN 6.67 (d, J= 15.6 Hz, 1H), 5.89 (s, fluoroaniline (£’)-/V-(2-fluoi'ophcnyl)(3- 1H), 3.90 (s, 3H), 3.84 (d, /= 2.0 methoxy(l,2,3,6- Hz, 2H), 3.43 (t, /= 6.0 Hz, 2H), tetrahydropyridin 2.80 - 2.78 (m, 2H); MS (ESI+) m/z yl)phenyl)acrylamide 353.2 (M+H)+; 100% , RT 2.52 min (Method 8)_____________ 142 o 1H NMR (CD3OD, 400 MHz) 5 Prepared according N KJ 8.44 (d, J= 8.4 Hz, 1H), 7.90 - 7.78 to the method for OH (m, 2H), 7.78 (d, J= 7.6 Hz, 1H), 120 ng 7.63 - 7.59 (m, 1H), 7.43 - 7.40 (m, fromlH-indazol (E)-1 -(3 -hydroxy-1 H-indazol-1 - 1H), 7.35 - 7.32 (m, 1H), 7.31 - 7.29 ol yl)(3-methoxy(l,2,3,6- (m, 1H), 7.29 - 7.27 (m, 1H), 5.91 ydropyridin (t, 7=2.0 Hz, 1H), 3.93 (s, 3H), yl)phenyl)propen-1 -one 3.84 (d, 7= 2.8 Hz, 2H), 3.43 (t, 7 = 6.0 Hz, 2H), 2.82 - 2.80 (m, 2H); MS (ESI+) m/z 376.2 (M+H)+; 91.6% purity, RT 1.6 min (Method Ur 10) 143 1H NMR (CD3OD, 400 MHz) 5 7.57 Prepared according .0. - 7.54 (m, 2H), 7.09 (d, 7= 8.0 Hz, to the method for H 1H), 7.06 - 7.02 (m, 2H), 6.82 (s, 121 starting from 4- HN 1H), 6.74 (d, 7= 6.8 Hz, 1H), 5.79 - fluoroaniline.
/V-(4-fluorophenyl)(3- 5.78 (m, 1H), 3.83 (s, 3H), 3.80 (t, 7 methoxy(l,2,3,6- = 2.4 Hz, 2H), 3.40 (t, 7 = 6.0 Hz, tetrahydropyridin 2H), 2.77 - 2.73 (m, 2H), 2.49 - 2.47 yl)phenyl)cyclopropane (m, 1H), 2.07 - 2.05 (m, 1H), 1.62 - carboxamide trifluoroacetic acid 1.59 (m, 1H), 1.39- 1.38 (m, 1H); salt MS (ESI+) m/z 367.1 (M+H)+; 97.6% purity, RT 2.47 min (Method 144 1H NMR (CD3OD, 400 MHz) 5 8.66 0 Prepared according N (s, 1H), 7.79 (d, 7= 8.0 Hz, 1H), to the method for H ^ 7.52 - 7.49 (m, 2H), 7.39 (t, 7= 7.6 121 starting from 2- N.v /7 HN Hz, 1H), 7.09 (d, 7= 7.6 Hz, 1H), (3-methyl-lH- 2-(3-methoxy( 1,2,3,6- 6.79 (s, 1H), 6.72 (d, 7= 8.0 Hz, 1,2,4-triazol-ltetrahydropyridinyl l)- 1H), 5.78 - 5.77 (m, 1H), 3.82 (s, yl) aniline /V-(2-(3-methyl-1H-1,2,4-triazol- 3H), 3.80 (d, 7= 2.0 Hz, 2H), 3.40 1- (t, 7= 6.0 Hz, 2H), 2.75 (d, 7= 2.0 yl)phenyl)cyclopropanecarboxa Hz, 2H), 2.40 (s, 3H), 2.37 - 2.35 mide trifluoroacetic acid salt (m, 1H), 2.02 - 2.00 (m, 1H), 1.53 - 1.50 (m, 1H), 1.36- 1.29 (m, 1H); MS (ESI+) m/z 430.2 ; 98.1% purity, RT 2.33 min (Method 145 1H NMR (CD3OD, 400 MHz) 5 7.93 0 Prepared according N (d, 7 = 8.4 Hz, 1H), 7.16 - 7.10 (m, to the method for F 4H), 6.83 (s, 1H), 6.76 (d, 7 = 7.6 121 starting from 2- HN. Hz, 1H), 5.80 (s, 1H), 3.84 (s, 3H), fluoroaniline /V-(2-fluorophenyl)(3- 3.81 (d, 7 =2.4 Hz, 2H), 3.40 (t, 7 = methoxy(l,2,3,6- 6.0 Hz, 2H), 2.76 (d, 7 = 2.0 Hz, tetrahydropyridin 2H), 2.53 - 2.51 (m, 1H), 2. 62 - yl)phenyl)cyclopropane 2.25 (m, 1H), 1.63 - 1.60 (m, 1H), carboxamide oroacetic acid 1.40 - 1.38 (m, 1H); MS (ESI+) m/z 367.2 (M+H)+; 97.8% purity, RT 2.44 min (Method 11) 146 o iH NMR (CD3OD, 400 MHz) 5 8.33 Prepared according N (d, J= 8.4 Hz, 1H), 7.73 (d, /= 7.6 to the method for Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 121 starting from HN. 7.36 (d, /= 7.6 Hz, 1H), 7.10 (d, J = lH-indazolol (3 -hydroxy-1 H-indazol-1 -yl) (2- 8.0 Hz, 1H), 6.87 (s, 1H), 6.79 (d, J (3-methoxy( 1,2,3,6- = 7.6 Hz, 1H), 5.80 - 5.79 (m, 1H), tetrahydropyridinyl)phenyl) 3.92 (s, 3H), 3.83 - 3.81 (m, 2H), cyclopropyl)methanone 3.40 (t, J = 6.0 Hz, 2H), 3.31 (s, trifluoroacetic acid salt 1H), 2.85 - 2.70 (m 2H), 2.68 - 2.66 (m, 1H), 1.82 - 1.80 (m, 1H), 1.59 - 1.58 (m, 1H); MS (ESI+) m/z 390.1 (M+H)+; 96.8% purity, RT 2.52 min d 11) (£)-/V-(3-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide (147) oO^°' a) ethyl (E)(3-methoxy(oxetanylmethoxy)phenyl)acrylate o o .0. .0.
HO" £T0' To a stirred solution of ethyl (T)(4-hydroxymcthoxyphcnyl(acrylate (1.0 g, 4.5 mmol, 1.0 ) in dry A/.iV-dimethylformamidc (10 mL) under a nitrogen atmosphere at 0°C was added portion-wise sodium hydride (24 mg, 6.76 mmol, 60 % in mineral oil. 1.5 equiv.).
After stirring for 15 minutes in the cold the mixture was treated with a on of oxetan ylmethyl esulfonate (0.90 g, 5.41 mmol, 1.2 equiv.) in A/.iV-di methyl formamidc (5 mL).
The e was allowed to warm to room temperature and after 1 hour the reaction was ed by addition of water (30 mL) and was then extracted with ethyl acetate (150 mL). The organic layer was washed with water (7 x 30 mL) and brine (30 mL) and concentrated to dryness under vacuum to give a yellow oil. The crude product was purified by chromatography on silica gel (Interchim 80g column, eluting with 30 - 60% ethyl acetate/isohexane) to afford the title compound as a colourless solid (0.93g, 73%); ‘H NMR (400 MHz, CDCI3): 5 7.64 (s, 1H), 7.60 (s, 1H), 7.11 - 7.05 (m, 1H), 6.90 (d, /= 8.1 Hz, 1H), 6.34 (d, /= 8.1 Hz, 1H), 4.90 (dd, /= 6.3, J = 7.6 Hz, 2H), 4.55 (q, /= 6.1 Hz, 2H), 4.31 - 4.23 (m, 4H), 3.88 (s, 3H), 3.55 - 3.45 (m, 1H), 1.34 (t, 7 = 7.2 Hz, 3H). b) (E)(3-methoxy(oxetanylmethoxy)phenyl)acrylic acid o o .0. .0.
CTa £T0' A stirred mixture of ethyl (£’)(3-methoxy(oxetanylmethoxy)phenyl)acrylate (250 mg, 0.88 mmol, 1.0 equiv.) and lithium hydroxide drate (74 mg, 1.77 mmol, 2.0 ) in 30% aqueous dioxane (13 mL) was heated to 50°C for 2 hours. The mixture was concentrated in vacuo and then diluted with water (5 mL) and acidified with 2N hloric acid. The precipitate was filtered, washed with water and dried under vacuum to afford the title compound as a colourless solid (190 mg, 81%); ‘H NMR (400 MHz, DMSO): 8 7.56 (d, J = 16.2 Hz, 1H,), 7.37 (d,/= 1.8 Hz, 1H), 7.26 (dd, / = 8.3 Hz,/= 1.8 Hz, 1H), 7.08 (d,/= 8.3 Hz, 1H), 6.52 (d, /= 16.2 Hz, 1H), 4.76 (dd,/= 7.8 Hz,/= 6.1, Hz, 2H), 4.46 (dd,/= 6.1 Hz, / = 6.1 Hz, 2H), 4.29 (d, /= 6.8 Hz, 2H), 3.86 (3H, s), 3.49 - 3.43 (1H, m). c) (E)-N-(3-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide .0. .0.
'OH lXjl, CT0' H To a solution of (L)(3-mcthoxy(oxctanylmcthoxy)phcnyl(acrylic acid (60 mg, 0.227 mmol, 1 equiv.) in MiV-dimethylformamidc (2 mL) was added diisopropylethylamine (0.12 mL, 0.682 mmol 3 equiv.) ed by HATU (104 mg, 0.273 mmol, 1.2 equiv.) and 3- chloroaniline (29 mg, 0.227 mmol, 1 equiv.) and the mixture stirred overnight at room temperature. The product was purified by preparative HPLC and was obtained as an off-white solid (72 mg, 85%); lU NMR (400 MHz, CDCI3): 5 7.73 (m, 2H), 7.67 (s, 1H), 7.46 (dd, /= 8.1 Hz, /= 1.3 Hz, 1H), 7.37 (s, 1H), 7.14 - 7.09 (m, 2H), 7.05 (d, /= 1.8 Hz, 1H), 6.91 (d, /= 8.3 Hz, 1H), 6.43 (d, / = 16.2 Hz, 1H), 4.91 (dd, / = 7.7 Hz, / = 6.4 Hz, 2H), 4.56 (dd, / = 5.9 Hz, / = 5.9 Hz, 2H), 4.30 (d, / = 7.1 Hz, 2H), 3.88 (s, 3H), 3.54 - 3.47 (m, 1H); MS (ESI+) m/z 374/376 (M+H)+; 99.3 % purity, RT 3.32 min (Method 2).
/V-(3-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropane-lcarboxamide (148) .0. lXXc1 o/r"0' H a) ethyl 2-(3-methoxy(oxetanylmethoxy)phenyl)cyclopropane-l-carboxylate o o .0. .0.
£Ta oO^°' A stirred solution of trimethylsulfoxonium iodide (904 mg, 4.11 mmol, 3.0 equiv.) in dimethylsulfoxide (7 mL) was treated with sodium hydride (192 mg, 4.79 mmol, 60 % in mineral oil, 3.5 ). After 1 hour the resultant solution was added drop-wise to a solution of ethyl (£’)(3-methoxy(oxetanylmethoxy)phenyl)acrylate (292 mg, 1.36 mmol, 1 equiv.) m dimethylsulfoxide (7 mL). The mixture was then heated to 80 °C for 18 hours. The cooled mixture was poured into saturated ammonium chloride solution (50 mL) and ted with ethyl acetate (3 x 30 mL). The combined extracts were washed with brine, dried and concentrated to dryness under vacuum. The crude product was purified by chromatography on silica gel (Interchim 40g column, eluting with 30 - 60% ethyl acetate/isohexane) to afford the title compound as a colourless oil (203 mg, 48%). ‘H NMR (400 MHz, CDCI3) 8 6.83 (d, 7=8.1 Hz, 1H), 6.67 - 6.61 (m, 2H), 4.88 (dd, 7 = 7.6 Hz, 7= 6.3 Hz, 2H), 4.54 6.1 Hz, 7=6.1 Hz, 2H), 4.24 (d, 7 = 7.1 Hz, 2H), 4.21 - 4.14 (m, 2H), 3.84 (s, 3H), 3.50 - 3.41 (m, 1H), 2.48 (ddd, 7=9.1 Hz, 7 = 6.6 Hz, 7 = 4.0 Hz, 1H), 1.87 - 1.82 (m, 1H), 1.59 - 1.50 (m, 1H), 1.30- 1.25 (m, 4H). b) 2-(3-methoxy(oxetanylmethoxy)phenyl)cyclopropane-l-carboxylic acid o o .0. .0.
‘O' ‘OH CTa CTa The title compound was prepared in a similar manner to (£’)(3-methoxy(oxetan- 3-ylmethoxy)phenyl)acrylic acid from ethyl 2-(3-methoxy(oxetan ylmethoxy)phenyl)cyclopropane-l-carboxylate and lithium ide monohydrate and was isolated as a colourless solid (171 mg, 79%); ‘H NMR (400 MHz, CDCI3): 5 6.83 (d, 7= 8.1 Hz, 1H), 6.68 - 6.62 (m, 2H), 4.88 (dd, 7 = 7.6 Hz, 7= 6.3 Hz, 2H), 4.54 (dd, 7= 6.1 Hz, 7= 6.1 Hz, 2H), 4.24 (d, 7 = 7.1 Hz, 2H), 3.84 (s, 3H), 3.51 - 3.42 (m, 1H), 2.57 (ddd, 7= 9.2 Hz, 7= 6.6 Hz, 7 = 4.0 Hz, 1H), 1.88 - 1.82 (m, 1H), 1.66 - 1.59 (m, 1H), 1.36 (ddd, 7= 8.3 Hz 7= 6.7 Hz, 7 = 4.7 Hz, 1H). c) N-(3-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropane-l- carboxamide WO 44620 .o. o 'OH MX ocr"0' H The title compound was prepared using a similar method to (T)-A/-(3-chlorophcnyl) (3-methoxy(oxetanylmethoxy)phenyl)acrylamide (147) using 2-(3-methoxy(oxetan ylmethoxy)phenyl) cyclopropanecarboxylic acid and 3-chloroaniline and was obtained as an ite solid (70%); ‘H NMR (400 MHz, CDC13) 5 7.67 (s, 1H), 7.52 - 7.49 (m, 1H), 7.35 (d, 7= 7.8 Hz, 1H), 7.23 (dd, /= 8.1 Hz, /= 8.1 Hz, 1H), 7.08 (d, / = 7.8 Hz, 1H), 6.86 - 6.82 (m, 1H), 6.67 - 6.63 (m, 2H), 4.90 - 4.84 (m, 2H), 4.55 - 4.50 (m, 2H), 4.25 (d, / = 7.1 Hz, 2H), 3.80 (s, 3H), 3.49 - 3.40 (m, 1H), 2.55 (ddd, /= 9.1 Hz, /= 6.4 Hz, /= 4.0 Hz, 1H), 1.74 - 1.64 (m, 2H), 1.34 (ddd, / = 7.8 Hz, /= 6.6. Hz, / = 4.4 Hz, 1H). MS (ESI+) m/z 388/390 (M+H)+; 97.2% , RT 3.39 min (Method 2).
/V-(4-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol yl)methoxy)phenyl)cyclopropane-l-carboxamide (149) "Xo vO"1 a) 4-methoxy((l-methyl-lH-pyrazolyl)methoxy)benzaldehyde x \ \ Xo OH XT’ A stirred solution of (1-methyl-17/-pyrazolyl)methanol (0.74 g, 6.58 mmol, 1 equiv.) in tetrahydrofuran (30 mL) was treated with isovanillin (1.00 g, 6.58 mmol, 1 ) and triphenylphosphine (2.10 g, 7.89 mmol, 1.2 equiv.). The mixture was cooled to 0°C and diisopropyl azodicarboxylate (1.55 mL, 7.89 mmol, 1.2 equiv.) was added drop-wise. The mixture was then d to warm to room temperature and was stirred overnight. The mixture was concentrated to dryness under vacuum and the residue purified by chromatography on silica gel (Interchim 80 g column, eluting with 50 - 80% ethyl acetate/isohexane) to afford the title compound as a pale yellow oil (1.37 g, 85%) which was used without further purification; ^ NMR (400 MHz, CDCI3): 5 9.85 (s, 1H), 7.70 - 7.64 (m, 2H), 7.58 - 7.44 (m, 3H), 5.08 (s, 2H), 3.94 (s, 3H), 3.89 (s, 3H). b) ethyl (E)(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)acrylate \ \ To a stirred suspension of sodium hydride (205 mg, 5.12 mmol, 60 % in mineral oil, 1.5 equiv.) in tetrahydrofuran (10 mL) under a nitrogen atmosphere was added drop-wise a on of triethyl phosphonoacetate (840 mg, 3.76 mmol, 1.1 equiv.) in tetrahydrofuran (5 mL).
After 15 minutes a solution of 4-mcthoxy((l-methyl-1 /7-pyrazolyl)mcthoxy)bcnzaldchydc (840 mg, 3.41 mmol, 1.0 ) in tetrahydrofuran (15 mL) was slowly added and the mixture stirred for a further 4 hours. Water (30 mL) was added and the mixture extracted with ethyl acetate (150 mL). The organic phase was washed the brine, dried and concentrated to dryness under vacuum. The residue was ed by chromatography on silica gel (Interchim 80 g column, eluting with 50 - 80% ethyl acetate/isohexane) to afford the title compound as an offwhite solid (786 mg, 85%) which was used without r purification; ^ NMR (400 MHz, CDCI3) 5 7.61 (d, /= 16.3 Hz, 1H), 7.56 (s, 1H), 7.45 (s, 1H), 7.14 - 7.10 (m, 2H), 6.87 (d, / = 8.4 Hz, 1H), 6.28 (d, /= 16.3 Hz, 1H), 5.05 (s, 2H), 4.26 (q, /= 6.9 Hz, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 1.34 (t, 7 = 7.0 Hz, 3H). c) ethyl 2-(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)cyclopropane-l- carboxylate \ \ 0 "’Xo o ■O' •O' ] The title compound was prepared in a similar manner to ethyl 2-(3-methoxy (oxetanylmethoxy)phenyl)cyclopropane-l-carboxylate from ethyl (£’)(4-methoxy((lmethyl-lH-pyrazolyl )methoxy)phenyl)acrylate to afford the product as a cream solid (31%); Tl NMR (400 MHz, CDCI3): 5 7.53 (s, 1H), 7.44 (s, 1H), 6.79 (d, / = 8.3 Hz, 1H), 6.71 (d,/ = 2.0 Hz, 1H), 6.67 (dd, /= 8.2 Hz, /= 1.9 Hz, 1H), 4.99 (s, 2H), 4.17 (q, / = 7.2 Hz, 2H), 3.89 (s, 3H), 3.82 (s, 3H), 2.49 - 2.42 (m, 1H), 1.84 - 1.78 (m, 1H), 1.58 - 1.52 (m, 1H), 1.31 - 1.21 (m, d) 2-(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)cyclopropane-l-carboxylic \ \ o o "O' "O' The title compound was prepared in a similar manner to -(3-methoxy(oxetan- 3-ylmethoxy)phenyl)acrylic acid from ethyl 2-(4-mcthoxy((l-methyl-1 /7-pyrazol hoxy)phenyl)cyclopropane-l-carboxylate and lithium hydroxide monohydrate and was isolated as a pale yellow gum (94%); ‘H NMR (400 MHz, DMSO): 5 7.81 (s, 1H), 7.52 (s, 1H), 6.91 - 6.87 (m, 2H), 6.73 (dd, / = 8.3 Hz, / = 2.0 Hz, 1H), 4.96 (s, 2H), 3.87 (s, 3H), 3.74 (s, 3H), 2.41 - 2.34 (m, 1H), 1.83 - 1.77 (m, 1H), 1.45 - 1.29 (m, 2H). e) N-(4-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)- cyclopropane-1 -carboxamide \ \ (Method 2) (/?)(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)-N-(pyridin yl)acrylamide (150) a) (E)(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)acrylic acid \ \ 0 o ‘O' ‘O' The title compound was prepared in a similar manner to (£’)(3-methoxy(oxetan- 3-ylmethoxy)phenyl)acrylic acid from ethyl (£)(4-mcthoxy(( l-methyl-lH-pyrazol hoxy)phenyl)acrylate and lithium hydroxide monohydrate and was obtained as an offwhite solid (92%); ‘H NMR (400 MHz, DMSO) 5 12.25 (s, 1H), 7.84 (s, 1H), 7.61 - 7.47 (m, 3H), 7.26 (d, J=7.6 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.50 (d, J=15.6 Hz, 1H), 5.04 (s, 2H), 3.88 (s, 3H), 3.82 (s, 3H). b) (E)(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)-N-(pyridin yl)acrylamide \ \ Oo. o "OH »x° W "O' "O' The title nd was prepared using a similar method to (T)-A/-(3-chlorophcnyl) (3-methoxy(oxetanylmethoxy)phenyl)acrylamide (147) using -(4-methoxy((lmethyl-lH-pyrazolyl )methoxy)phenyl)acrylic acid and 3-aminopyridine and was obtained as an off-white solid (63%); NMR (400 MHz, CDC13) 5 8.64 (d, / = 2.5 Hz, 1H), 8.36 (d, / = 4.8 Hz, 1H), 8.31 (d, /= 8.3 Hz, 1H), 7.70 (d, /= 15.3 Hz, 1H), 7.64 (s, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 7.31 (dd, /= 8.3 Hz, / = 4.8 Hz, 1H), 7.17 - 7.12 (m, 2H), 6.89 (d, /= 8.3 Hz, 1H), 6.40 (d, /= 15.3 Hz, 1H), 5.04 (s, 2H), 3.90 (s, 3H), 3.89 (s, 3H); MS (ESI+) m/z 365 (M+H)+; 94.7% purity, RT 2.88 min (Method 3).
(E)-N-(3-chlorophenyl)(4-methoxymorpholinophenyl)acrylamide (151) a) ethyl (E)(4-methoxymorpholinophenyl)acrylate o o k^NH ‘O' ‘O' ‘O' o To a stirred mixture of ethyl (T)(3-bromomcthoxyphcnyl(acrylate (0.150 g, 0.53 mmol, 1.0 equiv.), morpholine (0.06 mL, 0.63 mmol, 1.2 equiv.), RuPhos (0.025 g, 0.05 mmol,. 0.1 equiv.) and sodium te/t-butoxide (0.111 g, 1.16 mmol, 2.2 equiv.) in dry, ed toluene was added palladium acetate (0.006g, 0.03 mmol, 0.05 equiv.) and the mixture stirred under a nitrogen atmosphere under reflux ght. The reaction was cooled to room temperature and filtered through a plug of celite which was washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was washed with water and brine and the solvent d in vacuo. The residue was purified by silica gel column chromatography (20-40% ethyl acetate in hexane as gradient) to afford the title nd as an amber oil (0.081 g, 52%); ^ NMR (400 MHz, CDCI3) d 7.63 (d, / = 16.7 Hz, 1H), 7.20 (dd, 7=8.3 Hz, / = 2.3 Hz, 1H), 7.10 - 7.09 (m, 1H), 6.86 (d, / = 8.6 Hz, 1H), 6.31 (d, / = 16.2 Hz, 1H), 4.26 (q, 7 = 7.1 Hz, 2H), 3.92- 3.88 (m, 7H), .07 (m, 4H), 1.34 (t, 7= 6.5 Hz, 3H). b) (E)-N-(3-chlorophenyl)(4-methoxymorpholinophenyl)acrylamide Ex Structure Data Method 152 /°- 0 ‘H NMR (400 MHz, CDC13): 5 8.54 Prepared according (d, 7= 7.8 Hz, 1H), 7.77 (s, 1H), to the method for Cl 7.71 (d, 7= 15.6 Hz, 1H), 7.40 (dd, 147 starting from 2- (£)-/V-(2-chloi'ophcnyl)(3- 7= 8.1 Hz, 7= 1.5 Hz, 1H), 7.34 - chloroaniline methoxy(oxetan 7.28 (m, 1H), 7.15 (dd, 7= 8.3 Hz, 7 ylmethoxy)phenyl)acrylamide = 2.0 Hz Hz, 1H), 7.11 -7.03 (m, 2H), 6.92 (d, 7= 8.3 Hz, 1H), 6.49 (d, 7= 16.2 Hz, 1H), 4.91 (dd, 7 = 7.8 Hz, 7= 6.3 Hz, 2H), 4.56 (dd, 7 = 6.1 Hz, 7= 6.1 Hz, 2H), 4.32 (d, 7 = 7.1 Hz, 2H), 3.92 (s, 3H), 3.55 - 3.47 (m, 1H); MS (ESI+) m/z 374/376 (M+H)+; 97.9 % purity RT 3.28 min d 2)_________ 153 Prepared according .0. W' ‘H NMR (400 MHz, CDC13) 5 7.69 (d, 7= 15.4 Hz, 1H), 7.57 (d, 7= 8.8 to the method for ocr* H Hz, 2H), 7.33 - 7.29 (m, 3H), 7.12 147 starting from 4- (dd, 7= 8.2 Hz, 7= 1.9 Hz, 1H), chloroaniline (£)-/V-(4-chl()i'ophcnyl)(3- 7.06 (d, J = 2.0 Hz, 1H), 6.91 (d, J = methoxy(oxetan 8.3 Hz, 1H), 6.40 (d, / = 15.4 Hz, ylmethoxy)phenyl)acrylamide 1H), 4.91 (dd,7=7.6 Hz,/= 6.3 Hz, 2H), 4.56 (dd, /= 6.1 Hz, 6.1 Hz, 2H), 4.30 (d, /= 7.1 Hz, 2H), 3.88 (s, 3H), 3.54 - 3.46 (m, 1H); MS (ESI+) m/z 374/376 (M+H)+ 99.5 % purity RT 3.31 min (Method 154 ‘H NMR (400 MHz, CDC13) 5 7.48 ed according (d, /= 8.1 Hz, 2H), 7.42 (s, 1H), to the method for ocr 7.28 (d, /= 8.8 Hz, 2H), 6.84 (d, / = 148 starting from 4- 8.1 Hz, 1H), 6.66 - 6.63 (m, 2H), chloroaniline /V-(4-chlorophenyl)(3 - 4.90 - 4.85 (m, 2H), 4.56 - 4.50 (m, methoxy(oxetan 2H), 4.24 (d, /= 7.1 Hz, 2H), 3.82 ylmethoxy)phenyl)cyclopropane- (s, 3H), 3.49 - 3.42 (m, 1H), 2.59 - 1-carboxamide 2.52 (m, 1H), 1.74 - 1.64 (m, 2H), 1.37 - 1.31 (m, 1H); MS (ESI+) m/z 388/390 (M+H)+97.8% purity, RT 3.37 min (Method 2)____________ 155 0 1^ ‘H NMR (400 MHz, CDC13) 5 8.42 ed according .0. (d, /= 7.3 Hz, 1H), 7.87 - 7.85 (m, to the method for cr°- Cl 1H), 7.37 (dd, 7=8.1 Hz,/= 1.3 148 starting from 2- N-(2-chlorophenyl) (3 - Hz, 1H), 7.30 - 7.27 (m, 1H), 7.06 - chloroaniline methoxy(oxetan 7.01 (m, 1H), 6.86 (d, /= 8.3 Hz, ylmethoxy)phenyl)cyclopropane- 1H), 6.72 (d, /= 2.0 Hz, 1H), 6.66 1-carboxamide (dd, 7=8.1 Hz,/= 2.0 Hz, 1H), 4.89 (dd, / = 7.6 Hz, /= 6.3 Hz, 2H), 4.54 (dd, /= 6.1 Hz, /= 6.1 Hz, 2H), 4.25 (d, /= 7.1 Hz, 2H), 3.86 (s, 3H), 3.51 -3.43 (m, 1H), 2.60 (ddd, /= 9.0 Hz, /= 6.5 Hz, / = 4.0 Hz, 1H), 1.79 - 1.68 (m, 2H), 1.42 - 1.36 (m, 1H); MS (ESI+) m/z 388/390 (M+H)+ 98.3% purity, RT 3.31 min (Method _______________ 156 »x= \ W, ‘H NMR (400 MHz, CDC13) 5 8.43 Prepared according - 8.39 (m, 1H), 7.85 (s, 1H), 7.53 (s, to the method for 1H), 7.45 (s, 1H), 7.37 (dd, /= 8.1 149 starting from 3- /V-(3 -chlorophenyl)(4- Hz, /= 1.3 Hz, 1H), 7.30 - 7.23 (m, chloroaniline methoxy((l-methyl-lH- 1H), 7.07 - 7.00 (m, 1H), 6.82 (d, / pyrazol = 8.3 Hz, 1H), 6.77 (d, /= 1.8 Hz, yl)methoxy)phenyl)cyclopropane- 1H), 6.70 (dd, /= 8.2 Hz, /= 1.6 1-carboxamide Hz, 1H), 5.01 (s, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 2.61 - 2.54 (m, 1H), 1.76 - 1.67 (m, 2H), 1.38 - 1.32 (m, 1H); MS (ESI+) m/z 412/414 (M+H)+; 99.6% purity, RT 3.43 min (Method 2).________________ 157 \ o 1HNMR(400MHz, : 5 ed according »Xo 8.43 - 8.39 (m, 1H), 7.85 (s, 1H), to the method for Cl 7.53 (s, 1H), 7.45 (s, 1H), 7.37 (dd, 149 starting from 2- /V-(2-chlorophenyl)(4- /= 8.1 Hz, /= 1.3 Hz, 1H), 7.29 chloroaniline methoxy((l-methyl-lH- (m, 1H), 7.07 - 7.00 (m, 1H), 6.82 pyrazol (d, /= 8.3 Hz, 1H), 6.77 (d, /= 1.8 yl)methoxy)phenyl)cyclopropane- Hz, 1H), 6.70 (dd, /= 8.2 Hz, J = 1-carboxamide 1.6 Hz, 1H), 5.01 (s, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 2.61 - 2.54 (m, 1H), 1.76 - 1.67 (m, 2H), 1.38 - 1.32 (m, 1H). MS (ESI+) m/z 412/414 (M+H)+; 98.5% purity. RT 3.29 min d 2)________________ 158 \ *H NMR (400 MHz, DMSO): 5 "XowX8.bJCL/ Prepared according .70 (s, 1H), 8.34 (s, 91 - to the method for d' 7.87 (m, 1H), 7.82 (s, 1H), 7.66 - 149 starting from 3- 2-(4-methoxy(( 1 -methyl-1H- 7.62 (m, 2H), 7.53 (s, 1H), 6.96 (d, (methylsulfonyl)ani pyrazolyl)methoxy)phenyl)-N - J= 2.0 Hz, 1H), 6.92 (d, J= 8.3 Hz, line (3 -(methylsulfonyl)phenyl) 1H), 6.76 (dd, /= 8.5 Hz, /= 1.9 cyclopropane-1 -carboxamide Hz, 1H), 4.97 (d, /= 3.3 Hz, 2H), 3.88 (s, 3H), 3.75 (s, 3H), 3.24 (s, 3H), 2.45 - 2.38 (m, 1H), 2.13 - 2.05 (m, 1H), 1.56 - 1.42 (m, 2H). MS (ESI+) m/z 456 (M+H)+; 98.3% purity. RT 3.03 min (Method 2). 159 \ o ‘H NMR (400 MHz, CDC13) 5 8.53 Prepared according Xo (d, /= 7.8 Hz, 1H), 7.76 (s, 1H), to the method for Cl 7.70 (d, J= 15.8 Hz, 1H), 7.57 (s, 150 starting from 2- (£)-/V-(2-chlorophcnyl)(4- 1H), 7.47 (s, 1H), 7.39 (dd, J= 8.1 chloroaniline methoxy((l-methyl-lH- Hz, /= 1.5 Hz, 1H), 7.34 - 7.28 (m, pyrazol 1H), 7.20 - 7.16 (m, 2H), 7.08 - 7.03 yl)methoxy)phenyl)acrylamide (m, 1H), 6.90 (d, /= 8.1 Hz, 1H), 6.43 (d, J= 15.8 Hz, 1H), 5.07 (s, 2H), 3.90 (s, 3H), 3.90 (s, 3H); MS (ESI+) m/z 398/400 ; 99.1% purity, RT 3.33 min (Method 160 \ va, ‘H NMR (400 MHz, CDC13) 5 7.74 Prepared according (dd, /= 2.1 Hz, /= 2.1 Hz, 1H), to the method for \o 7.68 (d, /= 14.9 Hz, 1H), 7.57 (s, 150 starting from 3- (£)-/V-(3-chlorophcnyl)(4- 1H), 7.49 - 7.44 (m, 3H), 7.29 - 7.23 chloroaniline methoxy((l-methyl-lH- (m, 1H), 7.16 - 7.08 (m, 3H), 6.88 pyrazol (d, /= 8.3 Hz, 1H), 6.35 (d, /= 15.4 yl)methoxy)phenyl)acrylamide Hz, 1H), 5.03 (s, 2H), 3.89 (s, 3H), 3.88 (s, 3H); MS (ESI+) m/z 398/400 (M+H)+; 99.5% purity, RT 3.35 min (Method 3)_________ Biological Activity r14Cl-Proline incorporation plus MTS viability assay The compounds of the disclosure were evaluated to determine the effect of inhibitors on collagen biosynthesis in a [14C]-proline incorporation assay and cell viability using a MTS tetrazolium reduction assay. In particular, the assay evaluated inhibition of TGF-P induced [14C]- proline incorporation in rat ial cells.
Table 1. ts and consumables t/Consumable er Cat No. 1097 / IRMC cells FibroTech (Shire) DMEM + ax Invitrogen 31966-021 Foetal Bovine Serum (FBS) Invitrogen 10082-147 Pen-Strep Invitrogen 15140-122 Ascorbic acid phosphate magnesium salt Sigma A8960-5G (APM)_______________________________ Chlorpromazine hydrochloride Sigma C8138-5G TGF-p 1 PreproTech 100-21 1M hydrochloric acid (HC1) Fluka 35328-1L Bovine serum albumin (BSA) Sigma A7906 [14C]-proline Perkin Elmer 250UC MTS Promega G5430 96 well CytoStar-T plates Perkin Elmer RPNQ0163 ve Topseal A-Plus Perkin Elmer 6050185 Day 1 - g cells: Seed IRMC cells at 10,000 cells/200pl (= 50,000 cells/ml) in DMEM supplemented with 5% FBS in 96 well CytoStar-T plates; Leave plates 1 hour at room temperature before transferring to 37°C/5% CO2 incubator and incubate overnight.
Day 2 - Serum starvation: Aspirate off media; Replace with 150pl of 150pM APM made up in DMEM supplemented with 0.1% FBS and 1% Pen-Strep (Starvation media); Return plates to the 37°C/5% CO2 incubator overnight.
Day 3: Compound addition: Add 20 pi of: 10X compound in starvation media, 10% DMSO in starvation media to controls and no TGF-P 1 blanks, 100 pM Chlorpromazine hloride to dead cell blanks, and Reference compound tranilast (ADS 143566) tested from IpM - 300pM; Return plates to 37°C/5% CO2 incubator and incubate for 4 hours; Add lOpl of: ng/ml TGF-P 1 (final tration = Ing/ml) to all wells except no TGF- pi blanks, and Starvation media to TGF-pi blanks; Add 20 |il of 1 |jCi/ml [14C]-proline (final concentration = 0.1 pCi/ml) and 1.5 mM APM (final concentration = 150 pM) made up in starvation media; Return plates to the 37°C/5% CO2 incubator and incubate for 44 hours.
Day 5: r14Cl-proline and MTS assay: Remove plates from tor and transfer to radioactive work area in ADI in appropriate container; Seal plates with adhesive seals; Place plates in counting cassettes and Count on Microbeta using n_14C protocol; Once plates have finished counting, remove seals and aspirate off media; Add 200 pi of 1:21 dilution of MTS t; Return plates to the 37°C/5% CO2 incubator and incubate for r 2 hours; Remove plates from incubator and transfer to radioactive work area in ADI in appropriate container; Seal plates with adhesive seals; Read absorbance at 490nm on Spectramax M5e.
Final Assay volumes / concentrations (Day 31: 150 pi cells in 150 pM APM made up in starvation media; 20 pi Compound / Controls / Blanks / Dead Cell Blanks in 1% DMSO; 10 pi 1 ng/ml or 0 ng/ml TGF-pi (Blanks); 20 pi 0.1 pCi/ml [14C]-proline / 150 pM APM.
IC50 generation - proline incorporation. TGF-pi-induced proline oration was determined by ction of basal (non-TGF-pi treated cells) CPM from the TGF-pi stimulated cell CPM. % tion of the 1% DMSO vehicle stimulated TGF-pi se at each concentration of compound was calculated by the formula: (100-(((test data - blank data)/(control data - blank data))* 100)). IC50 values were generated from the ated log dose-response curve fits using ActivityBase (IDBS).
CC50 generation - cell viability. The effects of compound on cell viability were quantified by comparison to the 1% DMSO vehicle-treated TGF-pi stimulated cells, which were used as the 100% viability reference. % cell viability at each concentration of compound was calculated by the formula: (((test data - blank data)/(control data - blank data))* 100). CC50 values were generated from the associated log dose-response curve fits using ActivityBase (IDBS).
Table 2 provides the assay results of the example compounds of the present disclosure.
Table 2.
IC50 (pM) CC50 (pM) 106 1.579 25.096 9 1.94 25.478 7 1.97 62.54 159 2.427 > 10 143 2.814 7.2 120 3.218 10.799 82 3.419 13.516 87 3.688 12.102 145 3.705 11.741 121 3.792 8.473 126 3.812 > 27.546 102 3.871 11.411 3 3.936 71.142 150 4.075 >31.623 136 4.134 16.263 4 4.317 323.001 88 4.449 12.372 89 4.662 19.784 77 4.689 26.47 141 4.851 13.502 93 5.227 17.24 8 5.335 109.497 139 5.363 9.028 6.038 66.438 40 6.764 >300 115 7.028 45.398 11 7.073 2 81 7.146 24.877 113 7.747 32.642 149 8.353 > 54.772 91 8.376 18.074 105 8.439 79.717 140 8.469 36.121 148 8.475 77.555 85 8.92 108.723 154 8.972 >300 100 9.293 36.959 57 9.366 >76.621 79 9.52 23.378 12 10.203 334.782 14 10.367 48.916 2 10.43 >300 10.55 368.548 1 10.945 >300 138 10.976 50.896 52 11.341 140.287 6 11.381 >300 128 11.494 24.402 28 11.555 146.496 11.804 37.171 132 11.965 16.564 59 12.121 147.593 71 12.195 3 129 12.329 28.878 157 12.644 45.334 45 12.949 307.408 24 12.974 41.361 112 12.984 >300 44 13.224 11.074 26 13.454 189.712 98 13.549 288.628 31 13.855 >300 110 13.871 >300 64 14.211 141.569 114 14.277 82.035 118 14.309 25.477 74 14.679 318.544 84 14.749 >300 107 14.877 > 100 76 14.886 18.084 53 14.962 225.798 72 14.967 >300 137 15.354 30.79 51 15.489 >300 130 15.589 51.799 36 15.84 15.168 22 16.353 240.422 101 16.956 119.375 42 16.965 51.963 66 16.98 >300 122 17.15 234.488 18 17.196 150.629 134 17.475 >300 125 17.633 >300 95 17.637 110.748 156 17.822 > 100 37 18.027 29.157 63 18.184 79.385 65 18.279 151.764 155 18.722 196.232 123 19.333 >300 146 19.577 >300 19 19.665 122.039 60 20.321 100.172 144 20.928 81.022 117 21.354 >300 27 21.443 119.603 131 21.553 17.713 94 21.653 35.043 90 21.9 >300 16 22.338 107.391 133 23.44 >300 67 23.469 6 48 23.861 309.178 54 24.004 >300 109 24.26 >300 80 24.46 > 100 119 24.717 74.751 41 24.845 341.082 86 24.928 >300 21 24.975 >300 25.24 303.574 49 25.264 30.57 29 25.632 >300 158 25.888 68.838 23 26.313 103.647 32 27.356 32.019 75 27.608 >300 103 27.994 264.891 34 28.437 37.258 47 29.103 >300 33 29.249 199.079 111 29.977 >300 160 30.356 >300 78 30.45 404.427 151 31.551 >300 17 31.645 >300 142 31.687 >300 56 32.238 150.03 83 32.469 >300 73 33.076 >300 96 33.626 >300 99 34.747 >300 124 34.752 >300 153 35.395 >300 127 35.415 82.939 13 36.042 96.448 37.416 301.223 152 38.173 >300 38 38.23 236.349 147 39.084 >300 58 39.221 265.689 39.506 >300 108 40.398 >300 104 41.364 280.87 55 44.339 86.083 43 44.556 >300 68 44.861 >300 135 45.273 >300 45.547 >300 97 46.208 >300 46 46.579 186.19 50 47.422 107.475 39 48.256 85.832 69 48.351 691.029 61 48.932 276.157 62 49.012 320.758 92 49.215 108.846 70 49.759 >300 116 60.453 294.25 116 192.65 >300 FT011 16 119 Pharmacokinetic studies Discrete oral pharmacokinetic studies were performed for e compounds 116, 107, and 102. 116: 2 mg/kg and 20 mg/kg of 116 were administered as single doses to male Sprague Dawley (SD) rats. 75 mg/kg and 350 mg/kg of 116 were administered daily (5 days) to male Sprague Dawley (SD) rats. Figure 1 shows the time versus concentration profile after administration of the initial dose of all dosing groups. No adverse compound related effects were observed at any dose level, and little to no se in plasma trations were observed between the 75 and 350 mg/kg/day dosing groups. However, trough concentrations for the 350 mg/kg/day dosing group were lower than expected hout the 5-day study {Figure 2).
The pharmacokinetic results were compared to the known compound (E)(3-(3- methoxy(propyn-l-yloxy)phenyl)acrylamido)benzoic acid (FT011), which has an IC50 of 17 pM and a CCsoof 119 pM in the assays described above. Figure 3 shows that coverage of IC50 ve to a 200 day regime of (E)(3-(3-methoxy(propyn-l- yloxy)phenyl)acrylamido)benzoic acid (shown as a straight line at 0.10 of the y-axis in Figure 3) was superior for 116 at 75 mg/kg and 350 mg/kg even though it possesses a less potent IC50. 107: 2 mg/kg and 20 mg/kg of 107 were administered as single doses to male e Dawley (SD) rats. 75 mg/kg and 350 mg/kg of 107 were administered daily (5 days) to male Sprague Dawley (SD) rats. Figure 4 shows the time versus concentration profile after administration of the initial dose of all dosing groups. No adverse compound related effects were observed at any dose level, and an increase in plasma concentrations were observed between the 75 and 350 mg/kg/day dosing . In addition, trough trations for the 75 and 350 mg/kg/day dosing group were consistent with dosing amounts throughout the 5-day study {Figure 5).
The pharmacokinetic results were also compared to the known compound (E)(3-(3- methoxy(propyn-l-yloxy)phenyl)acrylamido)benzoic acid (FT011). Figure 6 shows that coverage of IC50 ve to a 200 mg/kg/day regime of (E)(3-(3-methoxy(propyn-lyloxy )phenyl)acrylamido)benzoic acid (shown as a straight line at 0.10 of the y-axis in Figure 6) was superior for 107 at 350 mg/kg. 102: 2 mg/kg and 20 mg/kg of 102 were administered as single doses to male Sprague Dawley (SD) rats. 75 mg/kg and 350 mg/kg of 102 were administered daily (5 days) to male Sprague Dawley (SD) rats. Figure 7 shows the time versus concentration profile after administration of the initial dose of all dosing groups. An increase in plasma concentrations were observed between the 75 and 350 mg/kg/day dosing groups. In addition, trough concentrations for the 75 and 350 mg/kg/day dosing group were consistent with dosing amounts throughout the -day study (Figure 8).
The cokinetic results were also compared to the known compound (E)(3-(3- methoxy(propyn-l-yloxy)phenyl)acrylamido)benzoic acid (FT011). Figure 9 shows that coverage of IC50 relative to a 200 mg/kg/day regime of (E)(3-(3-methoxy(propyn-lyloxy )phenyl)acrylamido)benzoic acid (shown as a straight line at 0.10 of the y-axis in Figure 9) was superior for 102 at 20 mg/kg, 75 mg/kg and 350 mg/kg.
Equivalents and Scope In the claims es such as "a," "an," and "the" may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include "or" n one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.
The invention includes embodiments in which y one member of the group is present in, ed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are t in, employed in, or otherwise relevant to a given product or s.
Furthermore, the invention encompasses all variations, combinations, and ations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to e one or more limitations found in any other claim that is dependent on the same base claim. Where elements are ted as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any t(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been ically set forth in haec verba herein. It is also noted that the terms "comprising" and "containing" are intended to be open and permits the inclusion of additional elements or steps.
Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise t from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.
The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single ment or in combination with any other ments or portions thereof. The tion of an embodiment herein includes that embodiment as any single ment or in combination with any other embodiments or portions thereof.
This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by nce. If there is a conflict between any of the incorporated references and the instant ication, the specification shall control. In addition, any particular embodiment of the present ion that falls within the prior art may be itly excluded from any one or more of the claims. e such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.
Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the ed claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the ing claims.

Claims (18)

1. A compound of Formula I: or a pharmaceutically acceptable salt f; wherein T is ; X is O; Y is O; Z is a bond; R1 is C2-4 alkynyl; R2 is C1-4 alkyl; R3 is hydrogen, alkyl, alkynyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, n R3 is optionally substituted with –NRaRb or alkyl; R4 and R5 are hydrogen; each occurrence of R6 is, independently, F, Cl or Br; G is hydrogen; m is 1 or 2; and each occurrence of Ra and Rb is, independently, hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, heterocyclyl, C(O)OC1-6 alkyl, C(O)C1-6 alkyl, or Ra and Rb together with the atoms to which they are attached form a heterocyclyl ring.
2. A compound of Formula I: or a ceutically acceptable salt f; wherein T is ; X is O; Y is O; Z is a bond; R1 is C2-4 alkynyl; R2 is C1-4 alkyl; R3 is en, alkyl, alkynyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R3 is optionally substituted with -NRaRb or alkyl; R4 and R5 are hydrogen; G is C(O)R7; R7 is NHR9; m is 0; R9 is tetrazolyl, pyridinyl, pyrazolyl, imidazolyl, or triazolyl, each of which is optionally substituted with up to two alkyl groups; and each occurrence of Ra and Rb is, independently, hydrogen, acyl, alkyl, alkenyl, l, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, heterocyclyl, C(O)OC1-6 alkyl, C(O)C1-6 alkyl, or Ra and Rb together with the atoms to which they are attached form a heterocyclyl ring.
3. A compound of Formula I-i: or a pharmaceutically acceptable salt thereof; wherein X is O and Y is NR10; X is NR10 and Y is O; or X is NR10 and Y is NR10; each occurrence of Rg and Rh is, ndently, hydrogen or alkyl, or Rg and Rh together with the carbon atom to which they are attached form a carbonyl; t is 1 or 2; each occurrence of R10 is, independently, hydrogen or C1-4 alkyl optionally substituted with 1-3 independent substituents R8; each occurrence of R8 is, independently, alkyl, alkynyl, hydroxyl, , carboxyl, oxo, aryl, heteroaryl, heterocyclyl, -NRaRb, -S(O)2Rc, or -CO2Rd; and each occurrence of Ra, Rb, Rc, and Rd is, independently, hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, heterocyclyl, C(O)OC1-6 alkyl, C(O)C1-6 alkyl, or Ra and Rb together with the atoms to which they are attached form a cyclyl ring.
4. The compound according to claim 3, or a ceutically acceptable salt thereof, wherein R10 is methyl .
5. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein R10 is hydrogen .
6. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein: X is O; Y is NR10; and R10 is C1-4 alkyl .
7. The compound ing to claim 3, or a pharmaceutically acceptable salt thereof, wherein: X is NR10; Y is O; and R10 is C1-4 alkyl .
8. The compound ing to any one of claims 3 to 7, or a pharmaceutically acceptable salt thereof, wherein t is 2.
9. The compound according to any one of claims 3 to 8, or a pharmaceutically acceptable salt thereof, wherein each occurrence of Rg and Rh is hydrogen.
10. The compound according to any one of claims 3 to 8, or a ceutically acceptable salt thereof, n t is 2; and wherein one occurrence of Rg and Rh is hydrogen, and the other occurrence of Rg and Rh is that Rg and Rh er with the carbon atom to which they are attached form a carbonyl.
11. A compound selected from the group consisting of: (E)-N-(2-fluorophenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (1); (E)(3-methoxy(propynyloxy)phenyl)-N-(2-(5-methyl-1H-1,2,4-triazol yl)phenyl)acrylamide (2); (E)-N-(2-chlorophenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (3); (E)-N-(2-bromophenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (4); (E)(3-methoxy(propynyloxy)phenyl)-N-(o-tolyl)acrylamide (5); (E)-N-(2-cyanophenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (6); (E)-N-(3,4-dichlorophenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (7); (E)-N-(2-(2H-tetrazolyl)phenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (16); (E)-N-(2-(1,2,4-oxadiazolyl)phenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (17); (E)(3-methoxy(propynyloxy)phenyl)-N-(2-(5-methyl-1,2,4-oxadiazolyl)phenyl)- acrylamide (18); (E)(3-methoxy(propynyloxy)phenyl)-N-(2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol yl)phenyl)acrylamide (19); (E)-N-(2-(1,2,4-oxadiazolyl)phenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (20); (E)-N-(2-(1,3,4-oxadiazolyl)phenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (21); (3-methoxy(propynyloxy)phenyl)-N-(2-(1-methyl-1H-pyrazolyl)phenyl)- acrylamide (22); (E)(3-methoxy(propynyloxy)phenyl)-N-(2-(3-methyl-1H-1,2,4-triazol yl)phenyl)acryl-amide (23); (E)-N-(2-(1H-pyrazolyl)phenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (24); (E)-N-(2-(1H-imidazolyl)phenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (25); (E)(3-methoxy(propynyloxy)phenyl)-N-(2-(1-methyl-1H-imidazol yl)phenyl)acrylamide (26); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(methylsulfonyl)benzamide (27); (E)(3-methoxy(propynyloxy)phenyl)-N-(2-(3-methyl-1,2,4-oxadiazol yl)phenyl)acryl-amide (28); (3-methoxy(propynyloxy)phenyl)-N-(2-(5-methyl-1,3,4-oxadiazolyl)phenyl)- acrylamide (29); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(2H-tetrazolyl)benzamide (31); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(1-methylpiperidin yl)benzamide (36); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(oxetanyl)benzamide (38); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(pyridinyl)benzamide (44); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(1-methyl-1H-pyrazol yl)benzamide (47); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(1-methyl-1H-pyrazol yl)benzamide (48); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(piperidinyl)benzamide (49); (E)(3-(3-methoxy((1-methylpyrrolidinyl)oxy)phenyl)acrylamido)benzoic acid (51); (E)-N-(3-cyanophenyl)[2-[2-(dimethylamino)ethoxy]methoxypropynoxyphenyl ]propenamide (76); ((E)-N-(2-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxy(propyn yloxy)phenyl)acrylamide (77); (E)(3-(2-(2-(dimethylamino)ethoxy)methoxy(propynyloxy)phenyl)acrylamido)- benzoic acid (78); (E)-N-(2-cyanophenyl)[3-methoxy(1-methylazetidinyl)oxypropynoxyphenyl ]propenamide (79); 2-[[(E)(3-methoxypropynoxypyrrolidinyloxyphenyl)propenoyl]amino]benzoic acid (80); (E)-N-(2-cyanophenyl)[3-methoxy(1-methylpyrrolidinyl)oxypropynoxyphenyl ]propenamide (81); (E)-N-(2-cyanophenyl)(3-methoxypropynoxypyrrolidinyloxy-phenyl)prop enamide (82); 2-[[(E)[3-methoxy(4-piperidyloxy)propynoxy-phenyl]propenoyl]amino]benzoic acid (83); 2-[[(E)[3-methoxy(2-morpholinoethoxy)propynoxy-phenyl]prop enoyl]amino]benzoic acid (84); (E)-N-(2-cyanophenyl)[3-methoxy(2-morpholinoethoxy)propynoxy-phenyl]prop enamide (85); 2-[[(E)[2-[3-(dimethylamino)propoxy]methoxypropynoxy-phenyl]prop enoyl]amino]benzoic acid (86); (2-cyanophenyl)[2-[3-(dimethylamino)propoxy]methoxypropynoxyphenyl 2-enamide (87); (E)-N-(2-cyanophenyl)[3-methoxy(4-piperidyloxy)propynoxy-phenyl]prop enamide (88); (E)-N-(2-cyanophenyl)[3-methoxy[(1-methylpiperidyl)oxy]propynoxyphenyl ]propenamide (89); 2-[[(E)[4-(cyclopropylmethoxy)[2-(dimethylamino)ethoxy]methoxy-phenyl]prop enoyl]amino]benzoic acid (90); (E)-N-(3-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide (91); (E)-N-(2-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide (92); (E)-N-(3-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide (93); (E)-N-(2-cyanophenyl)[2-[2-(dimethylamino)ethoxy]methoxy-phenyl]propenamide (94); (E)(3-(3,4-dimethoxy(propynyloxy)phenyl)acrylamido)benzoic acid (95); (E)(3-(3,4-dimethoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (96); (E)(3-(3-methoxy(4-methylpiperazinyl)phenyl)acrylamido)benzoic acid (97); (E)(3-(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl)acrylamido)benzoic acid (98); (E)(3-(3-methoxy(1-methyl-1,2,3,6-tetrahydropyridinyl)phenyl)acrylamido)benzoic acid (99); (E)(3-(4-methoxymorpholinophenyl)acrylamido)benzoic acid (101); (E)(3-(3-methoxymorpholinophenyl)acrylamido)benzoic acid (103); (E)(3-(4-methoxy(1-methyl-1,2,3,6-tetrahydropyridinyl)phenyl)acrylamido)benzoic acid (104); 2-[[(E)(4-methyl-2,3-dihydro-1,4-benzoxazinyl)propenoyl]amino]benzoic acid (107); (E)-N-(2-(1,2,4-oxadiazolyl)phenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (108); (E)(3-(4-methyloxo-3,4-dihydro-2H-benzo[b][1,4]oxazinyl)acrylamido)benzoic acid (109); (E)(3-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazinyl)acrylamido)benzoic acid (110); (3-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazinyl)acrylamido)benzoic acid (111); (3-(4-methyloxo-3,4-dihydro-2H-benzo[b][1,4]oxazinyl)acrylamido)benzoic acid (112); (E)(3-ethyl(propynyloxy)phenyl)-N-(2-(3-methyl-1H-1,2,4-triazolyl)phenyl)- acrylamide (114); (E)(3-(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)acrylamido)benzoic acid (116); (E)chloro(3-(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)acrylamido)benzoic acid (117); (E)-N-(4-fluorophenyl)(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl)acrylamide (120); N-(4-cyanophenyl)(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl)cyclopropane carboxamide (121); 2-(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)-N-(4-fluorophenyl)cyclopropane carboxamide (122); (E)(3-ethyl(propynyloxy)phenyl)-N-(2-fluorophenyl)acrylamide (123); (E)-N-(4-cyanophenyl)(3-ethyl(propynyloxy)phenyl)acrylamide (124); (E)(3-ethyl(propynyloxy)phenyl)-N-(4-fluorophenyl)acrylamide (125); (E)(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)-N-(2-fluorophenyl)acrylamide (127); (E)(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)-N-(4-fluorophenyl)acrylamide (128); (E)-N-(4-cyanophenyl)(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)acrylamide (129); (E)(3-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazinyl)acrylamido)benzoic acid (130); (E)-N-(4-cyanophenyl)(3-methoxy((1-methylpyrrolidinyl)oxy)phenyl)acrylamide (131); (E)-N-(4-fluorophenyl)(3-methoxy((1-methylpyrrolidinyl)oxy)phenyl)acrylamide (132); N-(4-fluorophenyl)(3-methoxy(propynyloxy)phenyl)cyclopropanecarboxamide (133); N-(4-cyanophenyl)(3-methoxy(propynyloxy)phenyl)cyclopropanecarboxamide (135); N-(4-fluorophenyl)(3-methoxy((1-methylpyrrolidinyl)oxy)phenyl)cyclopropane carboxamide (136); N-(4-cyanophenyl)(3-methoxy((1-methylpyrrolidinyl)oxy)phenyl)cyclopropane amide (137); N-(2-fluorophenyl)(3-methoxy((1-methylpyrrolidinyl)oxy)phenyl)cyclopropane carboxamide (138); (4-cyanophenyl)(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl)acrylamide (139); (E)(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl)-N-(2-(3-methyl-1H-1,2,4-triazol yl)phenyl)acrylamide (140); (E)-N-(2-fluorophenyl)(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl)acrylamide (141); N-(4-fluorophenyl)(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl)cyclopropane carboxamide (143); 2-(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl)-N-(2-(3-methyl-1H-1,2,4-triazol yl)phenyl)cyclopropanecarboxamide (144); N-(2-fluorophenyl)(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl)cyclopropane amide (145); (E)-N-(3-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide (147); N-(3-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropanecarboxamide (148); N-(4-chlorophenyl)(4-methoxy((1-methyl-1H-pyrazolyl)methoxy)phenyl)cyclopropane- 1-carboxamide (149); (E)-N-(3-chlorophenyl)(4-methoxymorpholinophenyl)acrylamide (151); (E)-N-(2-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide (152); (E)-N-(4-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide (153); N-(4-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropanecarboxamide (154); N-(2-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropanecarboxamide (155); N-(3-chlorophenyl)(4-methoxy((1-methyl-1H-pyrazolyl)methoxy)phenyl)cyclopropane- 1-carboxamide (156); hlorophenyl)(4-methoxy((1-methyl-1H-pyrazolyl)methoxy)phenyl)cyclopropane- 1-carboxamide (157); 2-(4-methoxy((1-methyl-1H-pyrazolyl)methoxy)phenyl)-N-(3-(methylsulfonyl)phenyl) cyclopropanecarboxamide (158); (E)-N-(2-chlorophenyl)(4-methoxy((1-methyl-1H-pyrazol yl)methoxy)phenyl)acrylamide (159); (E)-N-(3-chlorophenyl)(4-methoxy((1-methyl-1H-pyrazol yl)methoxy)phenyl)acrylamide (160); (E)(3-methoxy(propynyloxy)phenyl)-N-phenylacrylamide (8); methyl (E)(3-(3-methoxy(propynyloxy)phenyl)acryloyl)-1,2,3,4-tetrahydroquinoline- 4-carboxylate (9) (E)(3,4-dihydroquinolin-1(2H)-yl)(3-methoxy(propynyloxy)phenyl)propen one (10); (E)(3,4-dihydroquinoxalin-1(2H)-yl)(3-methoxy(propynyloxy)phenyl)propen- 1-one (11); (E)(2,3-dihydro-4H-benzo[b][1,4]oxazinyl)(3-methoxy(propyn yloxy)phenyl)propenone (12); (E)-N-((trans)aminocyclohexyl)(3-methoxy(propynyloxy)phenyl)acrylamide (13); (E)(4-hydroxy-3,4-dihydroquinolin-1(2H)-yl)(3-methoxy(propyn yloxy)phenyl)propenone (14); (3-hydroxy-1H-indazolyl)(3-methoxy(propynyloxy)phenyl)propenone (15); (E)-N-(2-(dimethylamino)ethyl)(3-(3-methoxy(propyn 1yloxy) phenyl) acrylamido) benzamide (30); (E)-N-(3-(dimethylamino)propyl)(3-(3-methoxy(propynyloxy)phenyl)acrylamido) benzamide (32); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(2-methoxyethyl)benzamide (33); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(2-(4-methylpiperazin yl)benzamide (34); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(2-morpholino ethyl)benzamide (35); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-((1-methylpiperidin yl)methyl)benzamide (37); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-((tetrahydrofuran yl)methyl)benzamide (39); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-((1-methyl-1H-imidazol yl)methyl)benzamide (40); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(pyridin ylmethyl)benzamide (41); (3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(2-(pyridin yl)ethyl)benzamide (42); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(pyridin ylmethyl)benzamide (43); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(pyridin ylmethyl)benzamide (45); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(2-(pyridin yl)ethyl)benzamide (46); (E)(3-(3-methoxy(piperidinylmethoxy)phenyl)acrylamido)benzoic acid (50); (E)(3-(4-((3,5-dimethylisoxazolyl)methoxy)methoxyphenyl)acrylamido)benzoic acid (52); (E)(3-(3-methoxy((1-methyl-1H-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (53); (3-(3-methoxy(oxetanylmethoxy)phenyl)acrylamido)benzoic acid (54); (3-(3-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (56); (E)(3-(3-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (57); (E)(3-(3-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (59); (E)(3-(3-methoxy((1-methyl-1H-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (60); (E)(3-(4-methoxy(2-methoxyethoxy)phenyl)acrylamido)benzoic acid (61); (E)(3-(4-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (62); (E)(3-(4-methoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (63); (E)(3-(4-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (64); (E)(3-(4-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (65); (E)(3-(4-methoxy((1-methyl-1H-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (66); (E)(3-(4-methoxy((1-methyl-1H-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (67); (E)(3-(3-methoxy((4-methylpiperazinyl)methyl)phenyl)acrylamido)benzoic acid (68); (E)(3-(3-methoxy(morpholinomethyl)phenyl)acrylamido)benzoic acid (69); (E)(3-(4-methoxy(((1-methylpiperidinyl)oxy)methyl)phenyl)acrylamido)benzoic acid (E)(3-(4-methoxy((propynyloxy)methyl)phenyl)acrylamido)benzoic acid (71); (E)(3-(3-methoxy((propynyloxy)methyl)phenyl)acrylamido)benzoic acid (72); (E)(3-(4-methoxy(methoxymethyl)phenyl)acrylamido)benzoic acid (73); (E)(3-(4-methoxy((propynylamino)methyl)phenyl)acrylamido)benzoic acid (74); (E)(3-(3-methoxy((propynylamino)methyl)phenyl)acrylamido)benzoic acid (75); (E)(3-(4-ethylmethoxyphenyl)acrylamido)benzoic acid (100); 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid (102); (E)(3-(3-ethylmethoxyphenyl)acrylamido)benzoic acid (105); (E)(3-(3-(cyclopropylmethyl)methoxyphenyl)acrylamido)benzoic acid (106); (2H-benzo[b][1,4]oxazin-4(3H)-yl)(3-ethyl(propynyloxy)phenyl)propen one (113); (E)(2H-benzo[b][1,4]oxazin-4(3H)-yl)(2-(2-(dimethylamino)ethoxy)-3,4- dimethoxyphenyl)-propenone (115); (E)(2H-benzo[b][1,4]oxazin-4(3H)-yl)(3-methoxy((1-methylpyrrolidin yl)oxy)phenyl)propenone (118); (2H-benzo[b][1,4]oxazin-4(3H)-yl)(2-(3-methoxy(propynyloxy) phenyl) cyclopropyl) methanone (119); (E)(3-ethyl(propynyloxy)phenyl)(3-hydroxy-1H-indazolyl)propenone (126); (3-hydroxy-1H-indazolyl)(2-(3-methoxy(propynyloxy)phenyl)cyclopropyl) methanone (134); (E)(3-hydroxy-1H-indazolyl)(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl)prop- 2-enone (142); (3-hydroxy-1H-indazolyl)(2-(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl) ropyl)methanone (146); (E)(4-methoxy((1-methyl-1H-pyrazolyl)methoxy)phenyl)-N-(pyridinyl)acrylamide (150); and pharmaceutically acceptable salts thereof .
12. The compound according to claim 11, wherein the compound is selected from the group ting of: (E)(3-(4-methoxy((1-methyl-1H-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (66); (E)(3-(3-methoxy((4-methylpiperazinyl)methyl)phenyl)acrylamido)benzoic acid (68); (E)(3-(3-methoxy(morpholinomethyl)phenyl)acrylamido)benzoic acid (69); 2-[[(E)(4-methyl-2,3-dihydro-1,4-benzoxazinyl)propenoyl]amino]benzoic acid (107); (E)(3-(4-methyloxo-3,4-dihydro-2H-benzo[b][1,4]oxazinyl)acrylamido)benzoic acid (109); (E)(3-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazinyl)acrylamido)benzoic acid (110); (E)(3-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazinyl)acrylamido)benzoic acid (111); (E)(3-(4-methyloxo-3,4-dihydro-2H-benzo[b][1,4]oxazinyl)acrylamido)benzoic acid (112); and pharmaceutically acceptable salts f.
13. A ceutical composition sing a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14. Use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13, in the manufacture of a medicament for treating a disease or condition associated with fibrosis in a subject in need thereof.
15. The use according to claim 14, wherein the disease or condition is selected from the group ting of fibrotic skin disorders, lung disease, heart disease, kidney disease, and cirrhosis of the liver.
16. The use according to claim 15, wherein the disease or condition is kidney e.
17. The use according to claim 16, wherein the kidney disease is ssive kidney disease, glomerulonephritis, diabetic kidney disease, diabetic nephropathy, systemic lupus, primary glomerulonephritis, membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, diffuse proliferative ulonephritis, membranous focal segmental glomerulosclerosis, secondary glomerulonephritis, or ischemic nephropathy.
18. The method of claim 16, wherein the kidney e is focal segmental glomerulosclerosis. Single and multi-day oral dosing of 11S to male SD rats at 5 and 350 mg/kg/day 1000000 100000 LfTT-rr J? 10000 i 1000 o 100 E —0—2 mg/kg/day 10 —□—20 mg/kg/day 75 mg/kg/day ■m—350 mg/kg/day T T T T 0 K 'J 10 15 20 25 Time post dose (hours) SUBSTITUTE SHEET (RULE 26) Plasma concentrations of 116 following daily 75 or 350 mg/kg/day oral dosing to SD rats 100000 l 10000 1 1000 o 100 ~-~o-~~75 mg/kg/day —□—350 mg/kg/day 0 20 40 60 80 100 120 140 Time post first dose (hours) FIG, 2 SUBSTITUTE SHEET (RULE 26) 100.00 —o--—2 mg/kg/day -o- 20 mg/kg/day —&—75 day —350 mg/kg/day FT011 200 mg/kg/day 10.00 G* 1.00 0.01 T T T T 1 0 5 10 15 20 25 SUBSTITUTE SHEET (RULE 26) Single and multi-day oral dosing of 107 to male SD rats at 2,20,75 and 350 mg/kg/day i 1000 o 100 2 mg/kg/day m -~h>~-2Q mg/kg/day O-, 10 -*—75 mg/kg/day —h—350 day T T 1 or 10 15 20 25 Time post dose (hours) SUBSTITUTE SHEET (RULE 26) Plasma trations of 107 following daily 75 or 350 mg/kg/day oral dosing to SD rats I 1000 Ou 10 mg/kg/day —□—350 mg/kg/day 20 40 60 80 100 120 140 Time post dose (hours) SUBSTITUTE SHEET (RULE 26) WO 44620 Percentage IC5Q coverage following daily oral dosing with 107 at 2,20,75 and 350 mg/kg/day 100.00 2 mg/kg/day —□— 20 mg/kg/day —&—75 mg/kg/day 10.00 3> 1.00 0,10 iOK X Mv. X 0,01 T T T r 5 10 15 20 25 Time post dose (hours) SUBSTITUTE SHEET (RULE 26) 100000 E 10000 i 1000 100 ■■.......o E mg/kg/day 10"—I —□—20 mg/kg/day —&r—7h mg/kg/day 350 day T T T 1 0 or 10 15 20 25 SUBSTITUTE SHEET (RULE 26) Plasma concentrations of 102 following daily 75 or 350 mg/kg/day oral dosing to SD rats 'vSSS « 1000I m -0—75 mg/kg/day —o—350 day 100 T T T T T T 1 0 20 40 60 80 100 120 140 Time post dose (hours) SUBSTITUTE SHEET (RULE 26) 100,00 -V--— g, 3=Q-— —©—2mg/kg/day 20 mg/kg/day —^— 75 mg/kg/day -~h*--~350 mg/kg/day ----- FT011 200 mg/kg/day 0 5 10 15 20 25 SUBSTITUTE SHEET (RULE 26)
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