# Patent

## Title
Imino sulfanone inhibitors of ENPP1

## Abstract

The present disclosure relates generally to inhibitors of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), compositions thereof, and methods of using said compounds and compositions thereof. More specifically, the present disclosure relates to sulfoximine-based inhibitors of ENPP1 and methods of their use for treating disease mediated by ENPP1.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to and the benefit of U.S. Provisional Application No. 63/019,853, filed on May 4, 2020, and U.S. Provisional Application No. 63/093,709, filed on Oct. 19, 2020, the entire disclosures of which are incorporated herein by reference in their entireties.


FIELD
The present disclosure relates generally to inhibitors of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), compositions thereof, and methods of using said compounds and compositions thereof. More specifically, the present disclosure relates to sulfoximine-based inhibitors of ENPP1 and methods of their use for treating disease mediated by ENPP1.
BACKGROUND
In certain human diseases, maintenance of the phosphorylated nucleotides can be dysregulated resulting in poor outcomes, severe complications, and even death. Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1), also known as ARHR2, COLED, M6S1, NPP1, NPPS, PC-1, PCA1 and PDNP1, is an enzyme that hydrolyzes phosphorylated nucleotides, including adenosine triphosphate (ATP) and 2′,3′-cyclic adenosine monophosphate-guanidine monophosphate (cGAMP). In some cases, ENPP1 consumes substrates preventing their role in resolving disease. The concomitant increase in hydrolysis products can also have detrimental effects. Therefore, inhibitors of ENNP1's enzyme activity will have a beneficial effect in certain human diseases.
Cells detecting aberrant DNA in the cytosol generate cGAMP, which is an activator of the immune response via the STING pathway. ATP activates immune cells via purinergic receptor signaling. ENPP1 can be expressed as a mechanism to degrade cGAMP and ATP and evade the immune response. Such expression of ENPP1 has been identified in cancers with especially poor prognosis. Therefore, ENPP1 inhibition can be an effective treatment in cancers, especially in cases where ENPP1 expression is high or cytosolic DNA levels are elevated. Adenosine monophosphate (AMP) is also a product of both ATP and cGAMP hydrolysis. Adenosine is generated from AMP by enzymes such as CD73, and further suppresses the immune response and supports tumor survival by adenosine receptor pathways.
ENPP1 has also been implicated in bacterial or viral infections, insulin resistance and type II diabetes, chondrocalcinosis and osteoarthritis, calcium pyrophosphate deposition disorder (CPPD), hypophosphatasia, and soft-tissue calcification disorders such as cardiac calcification after heart injury. Therefore, ENPP1 inhibition can be used to treat any of these disorders.
BRIEF SUMMARY
The present disclosure provides compounds of Formula (I), compositions thereof, and methods of using said compounds and compositions thereof for the treatment of diseases or conditions associated with ENPP1. In one aspect, provided is a compound of Formula (I)




or a pharmaceutically acceptable salt thereof, wherein W is




ring A is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is substituted or unsubstituted;
R1a and R2a are each independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, or optionally substituted C1-6 haloalkyl;
Y is —N— or —CH—;
X1 is —CR1b— or —N—;
X2 is —CR2b— or —N—;
X3 is —CR3b— or —N—;
X4 is —CR4b— or —N—;
X5 is —CR5b— or —N—;
X6 is —CR6b— or —N—;
R1b-R6b are each independently hydrogen, halogen, hydroxyl, C1-4 alkoxy optionally substituted with one or more halo substituents, cyano, C1-3 alkyl, C1-3 haloalkyl, nitro, —NR1cR2c, —NHC(O)R3c, or —C(O)NR4cR5c;
L is a bond, —O—, —C(O)—, —NR6c—, or —OCR7c—*, wherein * represents the point of attachment to




R1c-R7c are each independently hydrogen or C1-3 alkyl;
a1, a2, b1, and c4 are each independently 0, 1, 2, or 3; and
b2, c1-c3, d1-d4, e1, and e2 are each independently 1, 2, or 3.
In another aspect, provided is pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
In another aspect, provided is a method of inhibiting ENPP1 comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
In another aspect, provided is a method of treating cancer, a bacterial and/or viral infection, insulin resistance, type II diabetes, chondrocalcinosis, osteoarthritis, a soft-tissue calcification disorder, calcium pyrophosphate deposition disorder, or hypophosphatasia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.


DETAILED DESCRIPTION
The following description is presented to enable a person of ordinary skill in the art to make and use the various embodiments. Descriptions of specific devices, techniques, and applications are provided only as examples. Various modifications to the examples described herein will be readily apparent to those of ordinary skill in the art, and the general principles defined herein may be applied to other examples and applications without departing from the spirit and scope of the various embodiments. Thus, the various embodiments are not intended to be limited to the examples described herein and shown, but are to be accorded the scope consistent with the claims.
As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
Throughout this application, unless the context indicates otherwise, references to a compound of Formula (I) includes all subgroups of Formula (I) defined herein, such as Formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), including all substructures, subgenera, preferences, embodiments, examples and particular compounds defined and/or described herein. In some embodiments, references to a compound of Formula (I) and subgroups thereof, such as Formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), include ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co-crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopes and/or protected forms thereof. In some embodiments, references to a compound of Formula (I) and subgroups thereof, such as Formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), include polymorphs, solvates, co-crystals, isomers, tautomers and/or oxides thereof. In some embodiments, references to a compound of Formula (I) and subgroups thereof, such as Formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), include polymorphs, solvates, and/or co-crystals thereof. In some embodiments, references to a compound of Formula (I) and subgroups thereof, such as Formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), include isomers, tautomers and/or oxides thereof. In some embodiments, references to a compound of Formula (I) and subgroups thereof, such as Formula (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), include solvates thereof.
“Alkyl” encompasses straight and branched carbon chains having the indicated number of carbon atoms, for example, from 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms. For example, C1-6 alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms. When an alkyl residue having a specific number of carbons is named, all branched and straight chain versions having that number of carbons are intended to be encompassed; thus, for example, “propyl” includes n-propyl and isopropyl; and “butyl” includes n-butyl, sec-butyl, isobutyl and t-butyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
When a range of values is given (e.g., C1-6 alkyl), each value within the range as well as all intervening ranges are included. For example, “C1-6 alkyl” includes C1, C2, C3, C4, C5, C6, C1-6, C2-6, C3-6, C4-6, C5-6, C1-5, C2-5, C3-5, C4-5, C1-4, C2-4, C3-4, C1-3, C2-3, and C1-2 alkyl.
“Alkenyl” refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to 6 carbon atoms) and at least one carbon-carbon double bond. The group may be in either the cis or trans configuration (Z or E configuration) about the double bond(s). Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl), and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl).
“Alkynyl” refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond. Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl) and butynyl (e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl).
“Cycloalkyl” indicates a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, for example, 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms. Cycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as bridged and caged ring groups (e.g., norbornane, bicyclo[2.2.2]octane). In addition, one ring of a polycyclic cycloalkyl group may be aromatic, provided the polycyclic cycloalkyl group is bound to the parent structure via a non-aromatic carbon. For example, a 1,2,3,4-tetrahydronaphthalen-1-yl group (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group, while 1,2,3,4-tetrahydronaphthalen-5-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a cycloalkyl group. Examples of polycyclic cycloalkyl groups consisting of a cycloalkyl group fused to an aromatic ring are described below.
“Cycloalkenyl” indicates a non-aromatic carbocyclic ring, containing the indicated number of carbon atoms (e.g., 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms) and at least one carbon-carbon double bond. Cycloalkenyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl, as well as bridged and caged ring groups (e.g., bicyclo[2.2.2]octene). In addition, one ring of a polycyclic cycloalkenyl group may be aromatic, provided the polycyclic alkenyl group is bound to the parent structure via a non-aromatic carbon atom. For example, inden-1-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is considered a cycloalkenyl group, while inden-4-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a cycloalkenyl group. Examples of polycyclic cycloalkenyl groups consisting of a cycloalkenyl group fused to an aromatic ring are described below.
“Aryl” indicates an aromatic carbocyclic ring having the indicated number of carbon atoms, for example, 6 to 12 or 6 to 10 carbon atoms. Aryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some instances, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other instances, polycyclic aryl groups may include a non-aromatic ring fused to an aromatic ring, provided the polycyclic aryl group is bound to the parent structure via an atom in the aromatic ring. Thus, a 1,2,3,4-tetrahydronaphthalen-5-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydronaphthalen-1-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered an aryl group. Similarly, a 1,2,3,4-tetrahydroquinolin-8-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydroquinolin-1-yl group (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is not considered an aryl group. However, the term “aryl” does not encompass or overlap with “heteroaryl”, as defined herein, regardless of the point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups). In some instances, aryl is phenyl or naphthyl. In certain instances, aryl is phenyl. Additional examples of aryl groups comprising an aromatic carbon ring fused to a non-aromatic ring are described below.
“Heteroaryl” indicates an aromatic ring containing the indicated number of atoms (e.g., 5 to 12, or 5 to 10 membered heteroaryl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon. Heteroaryl groups do not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 1. Unless otherwise indicated, heteroaryl groups may be bound to the parent structure by a carbon or nitrogen atom, as valency permits. For example, “pyridyl” includes 2-pyridyl, 3-pyridyl and 4-pyridyl groups, and “pyrrolyl” includes 1-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl groups.
In some instances, a heteroaryl group is monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine) and tetrazine.
In some instances, both rings of a polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzoimidazole, benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzoisothiazole, benzothiadiazole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine, furo[2,3-b]pyridine, oxazolo[5,4-b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c]pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4-c]pyridine, furo[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine, [1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine, thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine, thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine, [1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine, thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine (e.g., 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole and imidazo[2,1-b]thiazole.
In other instances, polycyclic heteroaryl groups may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, provided the polycyclic heteroaryl group is bound to the parent structure via an atom in the aromatic ring. For example, a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl group. Examples of polycyclic heteroaryl groups consisting of a heteroaryl ring fused to a non-aromatic ring are described below.
“Heterocycloalkyl” indicates a non-aromatic, fully saturated ring having the indicated number of atoms (e.g., 3 to 10, or 3 to 7, membered heterocycloalkyl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon. Heterocycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. In addition, one ring of a polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl), provided the polycyclic heterocycloalkyl group is bound to the parent structure via a non-aromatic carbon or nitrogen atom. For example, a 1,2,3,4-tetrahydroquinolin-1-yl group (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkyl group, while 1,2,3,4-tetrahydroquinolin-8-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a heterocycloalkyl group. Examples of polycyclic heterocycloalkyl groups consisting of a heterocycloalkyl group fused to an aromatic ring are described below.
“Heterocycloalkenyl” indicates a non-aromatic ring having the indicated number of atoms (e.g., 3 to 10, or 3 to 7, membered heterocycloalkyl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon, and at least one double bond derived by the removal of one molecule of hydrogen from adjacent carbon atoms, adjacent nitrogen atoms, or adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl. Heterocycloalkenyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkenyl groups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl), dihydroimidazolyl (e.g., 2,3-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl), pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridinyl (e.g., 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl) and dihydropyridine (e.g., 1,2-dihydropyridine, 1,4-dihydropyridine). In addition, one ring of a polycyclic heterocycloalkenyl group may be aromatic (e.g., aryl or heteroaryl), provided the polycyclic heterocycloalkenyl group is bound to the parent structure via a non-aromatic carbon or nitrogen atom. For example, a 1,2-dihydroquinolin-1-yl group (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is considered a heterocycloalkenyl group, while 1,2-dihydroquinolin-8-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a heterocycloalkenyl group. Examples of polycyclic heterocycloalkenyl groups consisting of a heterocycloalkenyl group fused to an aromatic ring are described below.
Examples of polycyclic rings consisting of an aromatic ring (e.g., aryl or heteroaryl) fused to a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) include indenyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1,4]dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-1H-indazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 1,3-dihydrobenzo[c]isoxazolyl, 2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydrobenzo[d]oxazolyl, 2,3-dihydrobenzo[b]thiophenyl, 1,3-dihydrobenzo[c]thiophenyl, 1,3-dihydrobenzo[c]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl, 2,3-dihydrobenzo[d]thiazolyl, 5,6-dihydro-4H-cyclopenta[d]thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, 5,6-dihydro-4H-pyrrolo[3,4-d]thiazolyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, indolin-2-one, indolin-3-one, isoindolin-1-one, 1,2-dihydroindazol-3-one, 1H-benzo[d]imidazol-2(3H)-one, benzofuran-2(3H)-one, benzofuran-3(2H)-one, isobenzofuran-1(3H)-one, benzo[c]isoxazol-3(1H)-one, benzo[d]isoxazol-3(2H)-one, benzo[d]oxazol-2(3H)-one, benzo[b]thiophen-2(3H)-one, benzo[b]thiophen-3(2H)-one, benzo[c]thiophen-1(3H)-one, benzo[c]isothiazol-3(1H)-one, benzo[d]isothiazol-3(2H)-one, benzo[d]thiazol-2(3H)-one, 4,5-dihydropyrrolo[3,4-d]thiazol-6-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one, quinolin-4(3H)-one, quinazolin-4(3H)-one, quinazoline-2,4(1H,3H)-dione, quinoxalin-2(1H)-one, quinoxaline-2,3(1H,4H)-dione, cinnolin-4(3H)-one, pyridin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)-one, 1H-pyrrolo[3,2-b]pyridin-2(3H)-one, 1H-pyrrolo[3,2-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-b]pyridin-2(3H)-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one and 4,5-dihydropyrrolo[3,4-d]thiazol-6-one. As discussed herein, whether each ring is considered an aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group is determined by the atom through which the moiety is bound to the parent structure.
“Halogen” or “halo” refers to fluoro, chloro, bromo or iodo.
Unless otherwise indicated, compounds disclosed and/or described herein include all possible enantiomers, diastereomers, meso isomers and other stereoisomeric forms, including racemic mixtures, optically pure forms and intermediate mixtures thereof. Enantiomers, diastereomers, meso isomers and other stereoisomeric forms can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Unless specified otherwise, when the compounds disclosed and/or described herein contain olefinic double bonds or other centers of geometric asymmetry, it is intended that the compounds include both E and Z isomers. When the compounds described herein contain moieties capable of tautomerization, and unless specified otherwise, it is intended that the compounds include all possible tautomers.
“Protecting group” has the meaning conventionally associated with it in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site, and such that the group can readily be removed after the selective reaction is complete. A variety of protecting groups are disclosed, for example, in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999). For example, a “hydroxy protected form” contains at least one hydroxy group protected with a hydroxy protecting group. Likewise, amines and other reactive groups may similarly be protected.
The term “pharmaceutically acceptable salt” refers to a salt of any of the compounds herein which are known to be non-toxic and are commonly used in the pharmaceutical literature. In some embodiments, the pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compounds described herein and are not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.
If the compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the compound is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds (see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19). Those skilled in the art will recognize various synthetic methodologies that may be used to prepare pharmaceutically acceptable addition salts.
A “solvate” is formed by the interaction of a solvent and a compound. Suitable solvents include, for example, water and alcohols (e.g., ethanol). Solvates include hydrates having any ratio of compound to water, such as monohydrates, dihydrates and hemi-hydrates.
The term “substituted” means that the specified group or moiety bears one or more substituents including, but not limited to, substituents such as alkoxy, acyl, acyloxy, alkoxycarbonyl, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo and the like. The term “unsubstituted” means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. When a group or moiety bears more than one substituent, it is understood that the substituents may be the same or different from one another. In some embodiments, a substituted group or moiety bears from one to five substituents. In some embodiments, a substituted group or moiety bears one substituent. In some embodiments, a substituted group or moiety bears two substituents. In some embodiments, a substituted group or moiety bears three substituents. In some embodiments, a substituted group or moiety bears four substituents. In some embodiments, a substituted group or moiety bears five substituents.
By “optional” or “optionally” is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” encompasses both “alkyl” and “substituted alkyl” as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible, and/or inherently unstable. It will also be understood that where a group or moiety is optionally substituted, the disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.
The compounds disclosed and/or described herein can be enriched isotopic forms, e.g., enriched in the content of 2H, 3H, 11C, 13C and/or 14C. In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms can be made, for example, by the procedure described in U.S. Pat. Nos. 5,846,514 and 6,334,997. Such deuterated compounds may improve the efficacy and increase the duration of action of compounds disclosed and/or described herein. Deuterium substituted compounds can be synthesized using various methods, such as those described in: Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr. Pharm. Des., 2000; 6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.
The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
The terms “patient,” “individual,” and “subject” refer to an animal, such as a mammal, bird, or fish. In some embodiments, the patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows and humans. In some embodiments, the patient, individual, or subject is a human, for example a human that has been or will be the object of treatment, observation or experiment. The compounds, compositions and methods described herein can be useful in both human therapy and veterinary applications.
The term “therapeutically effective amount” or “effective amount” refers to that amount of a compound disclosed and/or described herein that is sufficient to affect treatment, as defined herein, when administered to a patient in need of such treatment. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease responsive to modulation (e.g., inhibition) of ENPP1. The therapeutically effective amount will vary depending upon, for example, the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound, the dosing regimen to be followed, timing of administration, the manner of administration, all of which can readily be determined by one of ordinary skill in the art. The therapeutically effective amount may be ascertained experimentally, for example by assaying blood concentration of the chemical entity, or theoretically, by calculating bioavailability.
“Treatment” (and related terms, such as “treat”, “treated”, “treating”) includes one or more of: inhibiting a disease or disorder; slowing or arresting the development of clinical symptoms of a disease or disorder; and/or relieving a disease or disorder (i.e., causing relief from or regression of clinical symptoms). The term covers both complete and partial reduction of the condition or disorder, and complete or partial reduction of clinical symptoms of a disease or disorder. Thus, compounds described and/or disclosed herein may prevent an existing disease or disorder from worsening, assist in the management of the disease or disorder, or reduce or eliminate the disease or disorder.
It is understood that embodiments described herein as “comprising” include “consisting of” and “consisting essentially of” embodiments.
Compounds
Compounds and salts thereof (such as pharmaceutically acceptable salts) are detailed herein, including in the Brief Summary and in the appended claims. Also provided are the use of all of the compounds described herein, including any and all stereoisomers, including geometric isomers (cis/trans), E/Z isomers, enantiomers, diastereomers, and mixtures thereof in any ratio including racemic mixtures, salts and solvates of the compounds described herein, as well as methods of making such compounds. Any compound described herein may also be referred to as a drug.
In one aspect, provided are compounds of Formula (I):




or a pharmaceutically acceptable salt thereof, wherein:

W is




ring A is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclo alkyl or heterocycloalkenyl, each of which is substituted or unsubstituted;
R1a and R2a are each independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, or optionally substituted C1-6 haloalkyl;
Y is —N— or —CH—;
X1 is —CR1b— or —N—;
X2 is —CR2b— or —N—;
X3 is —CR3b— or —N—;
X4 is —CR4b— or —N—;
X5 is —CR5b— or —N—;
X6 is —CR6b— or —N—;
R1b-R6b are each independently hydrogen, halogen, hydroxyl, C1-4 alkoxy optionally substituted with one or more halo substituents, cyano, C1-3 alkyl, C1-3 haloalkyl, nitro, —NR1cR2c, —NHC(O)R3c, or —C(O)NR4cR5c;
L is a bond, —O—, —C(O)—, —NR6c—, or —OCR7c—*, wherein * represents the point of attachment to




R1c-R7c are each independently hydrogen or C1-3 alkyl;
a1, a2, b1, and c4 are each independently 0, 1, 2, or 3; and
b2, c1-c3, d1-d4, e1, and e2 are each independently 1, 2, or 3.
In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, the compound is not (9-imino-9-oxido-1-oxa-9λ6-thia-4-azaspiro[5.5]undecan-4-yl)(2-methylquinolin-4-yl)methanone. In some embodiments, W is not




In some embodiments, W comprises a fused ring structure when W is





where two or more rings share a bond. In some embodiments, A is not heterocycloalkyl when W is





In some embodiments, W comprises a fused ring structure when W is





where two or more rings share a bond. In some embodiments, W comprises a fused ring structure when W is





In some embodiments, R1b-R6b are not morpholinyl or pyrazolyl. In some embodiments, R1b-R6b are not heterocycloalkyl or heteroaryl. In some embodiments, L is not —C(O)N(CH3)—*, wherein * represents the point of attachment to




In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, W is




wherein ring A, b1, and R1a are as defined for Formula I or any variation or embodiment thereof. In some embodiments, W is





In some such embodiments, b1 is 0. In some such embodiments, b1 is 1. In some such embodiments, b1 is 2. In some embodiments, b1 is 3. In some embodiments, W is








In some embodiments, W is








In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, W is




wherein ring A, b1, and R1a are as defined for Formula (I) or any variation or embodiment thereof. In some embodiments, W is





In some such embodiments, b1 is 0. In some such embodiments, b1 is 1. In some such embodiments, b1 is 2. In some embodiments, b1 is 3. In some embodiments, W is





In some embodiments, W is





In some embodiments, W is





In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, W is




wherein ring A, b1, and b2 are as defined for Formula (I) or any variation or embodiment thereof. In some embodiments, W is





In some such embodiments, b1 is 1 and b2 is 2. In some embodiments, W is





In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, W is




wherein ring A, b1, b2, and R1a are as defined for Formula (I) or an variation or embodiment thereof. In some embodiments, W is





In some such embodiments, b1 is 1 and b2 is 2. In some embodiments, W is





In some embodiments, W is





In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, ring A is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or hetereocycloalkenyl, each of which is substituted or unsubstituted. In some embodiments, ring A is C6-14 aryl, 4- to 14-membered heteroaryl, C3-10 cycloalkyl, C3-10 cycloalkenyl, 3- to 18-membered heterocycloalkyl, or 3- to 18-membered hetereocycloalkenyl, each of which is substituted or unsubstituted. In some embodiments, ring A is 4- to 14-membered heteroaryl, 3- to 18-membered heterocycloalkyl, or 3- to 18-membered hetereocycloalkenyl, each of which is substituted or unsubstituted, wherein the 4- to 14-membered heteroaryl, 3- to 18-membered heterocycloalkyl, or 3- to 18-membered hetereocycloalkenyl contains one, two, three, four, five, or six heteroatoms. In some embodiments, each heteroatom is independently selected from nitrogen, oxygen, and sulfur.
In some embodiments, ring A is aryl (e.g., phenyl). In some embodiments, ring A is phenyl substituted with halo (e.g., fluoro). In some embodiments, ring A is heteroaryl. In some embodiments, ring A is pyridyl (e.g., 2-pyridyl or 3-pyridyl). In some embodiments, ring A is cycloalkyl (e.g., cyclopentyl). In some embodiments, ring A is heterocyloalkyl (e.g., piperidinyl). In some embodiments, ring A is




In some embodiments, ring A





In some embodiments, ring A is





In some embodiments, ring A is substituted with one, two, three, four, five, or more substituents independently selected from halo, hydroxyl, C3-10 cycloalkyl, or C1-6 alkyl. In some embodiments, ring A is C6-14 aryl substituted with halo. In some embodiments, ring A is phenyl substituted with fluoro. In some embodiments, ring A is phenyl substituted with bromo. In some embodiments, ring A is 3- to 18-membered heterocycloalkyl substituted with hydroxyl. In some embodiments, ring A is piperidinyl substituted with hydroxyl. In some embodiments, ring A is 3- to 18-membered heterocycloalkyl substituted with C3-10 cycloalkyl. In some embodiments, ring A is piperidinyl substituted with C3-10 cycloalkyl.
It will be understood that when a moiety depicted herein is bonded to the remainder of a molecule at more than one position, the directionality of the moiety can be indicated by showing differentiated symbols, such as a squiggly line  and a dotted line ------, to represent the positions of such bonds with respect to the remainder of the molecule. For example, when W is




wherein ring A is





this denotes that bond shown with a squiggly line  in the azetidine ring corresponds to the bond shown with a squiggly line  in the





moiety, thereby providing the moiety





In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, R1a is C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by halo, hydroxyl, C1-3 alkoxy, or C3-6 cycloalkyl. In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, R1a is C1-6 alkyl. In some embodiments, R1a is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R1a is methyl. In some embodiments, R1a is C1-6 alkyl substituted by hydroxyl. In some embodiments, R1a is methyl substituted by hydroxyl, ethyl substituted by hydroxyl, n-propyl substituted by hydroxyl, isopropyl substituted by hydroxyl, n-butyl substituted by hydroxyl, isobutyl substituted by hydroxyl, sec-butyl substituted by hydroxyl, or tert-butyl substituted by hydroxyl. In some embodiments, R1a is C1-6 alkyl substituted by C1-3 alkoxy. In some embodiments, R1a is methyl substituted by C1-3 alkoxy, ethyl substituted by C1-3 alkoxy, n-propyl substituted by C1-3 alkoxy, isopropyl substituted by C1-3 alkoxy, n-butyl substituted by C1-3 alkoxy, isobutyl substituted by C1-3 alkoxy, sec-butyl substituted by C1-3 alkoxy, or tert-butyl substituted by C1-3 alkoxy. In some embodiments, R1a is methyl substituted by methoxy or ethyl substituted by methoxy. In some embodiments, R1a is C1-6 alkyl substituted by C3-6 cycloalkyl. In some embodiments, R1a is methyl substituted by C3-6 cycloalkyl, ethyl substituted by C3-6 cycloalkyl, n-propyl substituted by C3-6 cycloalkyl, isopropyl substituted by C3-6 cycloalkyl, n-butyl substituted by C3-6 cycloalkyl, isobutyl substituted by C3-6 cycloalkyl, sec-butyl substituted by C3-6 cycloalkyl, or tert-butyl substituted by C3-6 cycloalkyl. In some embodiments, R1a is methyl substituted by cyclopropyl.
In some embodiments, R1a and R2a are hydrogen, C1-6 alkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, or C1-6 haloalkyl. In some embodiments, R1a and R2a are optionally substituted with one, two, three, four, five, or more substituents each independently selected from halo, hydroxyl, C1-3 alkoxy, C3-6 cycloalkyl, and acyl. In some embodiments, acyl is —C(O)R1a1, wherein R1a1 is H or C1-6 alkyl. In some embodiments, R1a and R2a are optionally substituted with one, two, three, four, five, or more substituents each independently selected from fluoro, chloro, methoxy, ethoxy, cyclopropyl, and —C(O)CH3.
In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, b1 is 0, 1, or 2. In some embodiments, b1 is 0. In some embodiments, b1 is 1. In some embodiments, b1 is 2. In some embodiments, b1 is 3.
In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, W is




wherein c1-c4, Y, and R2a are as defined for Formula (I) or any variation or embodiment thereof. In some embodiments, Y is —N—. In some embodiments, Y is —CH—. In some embodiments, c1 is 2 and c2 is 2. In some embodiments, c3 is 1 and c4 is 1. In some embodiments, c3 is 2 and c4 is 1. In some embodiments, c1 is 2, c2 is 2, c3 is 1, and c4 is 1. In some embodiments, c1 is 2, c2 is 2, c3 is 2, and c4 is 1. In some embodiments, c4 is 0. In some embodiments, c1 is 2, c2 is 2, c3 is 1, and c4 is 0.

In some embodiments, W is




In some embodiments, R2a is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, or C1-6 haloalkyl. In some embodiments, R2a is methyl. In some embodiments, R2a is optionally substituted with one, two, three, four, five, or more groups selected from halo, hydroxyl, C1-3 alkoxy, C3-6 cycloalkyl, and —C(O)R1a1, wherein R1a1 is H or C1-6 alkyl. In some embodiments, R2a is C1-6 alkyl optionally substituted with hydroxyl.

In some embodiments, W is




In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, W is




wherein c1-c4, Y, b1, and R2a are as defined for Formula (I) or any variation or embodiment thereof. In some embodiments, Y is —N—. In some embodiments, Y is —CH—. In some embodiments, c1 is 2 and c2 is 2. In some embodiments, c3 is 1 and c4 is 1. In some embodiments, c3 is 2 and c4 is 1. In some embodiments, c1 is 2, c2 is 2, c3 is 1, and c4 is 1. In some embodiments, c1 is 2, c2 is 2, c3 is 2, and c4 is 1. In some embodiments, c1 is 1 and c2 is 1. In some embodiments, c1 is 1, c2 is 1, c3 is 1, and c4 is 1.

In some embodiments, W is




In some embodiments, R2a is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, or C1-6 haloalkyl. In some embodiments, R2a is methyl. In some embodiments, R2a is optionally substituted with one, two, three, four, five, or more groups selected from halo, hydroxyl, C1-3 alkoxy, C3-6 cycloalkyl, and —C(O)R1a1, wherein R1a1 is H or C1-6 alkyl. In some embodiments, R2a is C1-6 alkyl optionally substituted with hydroxyl. In some embodiments, W is





In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, W is




wherein d1-d4 are as defined for Formula (I) or any variation or embodiment thereof. In some embodiments, d1 is 2 and d2 is 2. In some embodiments, d1 is 1 and d2 is 1. In some embodiments, d3 is 2 and d4 is 1. In some embodiments, d3 is 1 and d4 is 1. In some embodiments, d1 is 2, d2 is 2, d3 is 2, and d4 is 1. In some embodiments, d1 is 1, d2 is 1, d3 is 1, and d4 is 1. In some embodiments, W is





In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, W is




wherein Y, e1, and e2 are as defined for Formula (I) or any variation or embodiment thereof. In some embodiments, Y is —N—. In some embodiments, Y is —CH—. In some embodiments, e1 is 2 and e2 is 2. In some embodiments, e1 is 1 and e2 is 2. In some embodiments, e1 is 3 and e2 is 2. In some embodiments, W is





In some embodiments, W is





In another aspect, the compound of Formula (I) is a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig):







or a pharmaceutically acceptable salt thereof, wherein ring A, R1a, R2a, Y, X1-X6, R1b-R6b, L, R1c-R6c, a1, a2, b1, b2, c1-c4, d1-d4, e1, and e2 are as defined for Formula (I) or any variation or embodiment thereof.

In some embodiments of Formula (I), (I-1), (I-2), (I-3), (I4), (I-5), (Ia), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a pharmaceutically acceptable salt thereof, X1 is —CR1b—. In some embodiments, X1 is —N—. In some embodiments, X2 is —CR2b—. In some embodiments, X2 is —N—. In some embodiments, X3 is —CR3b—. In some embodiments, X3 is —N—. In some embodiments, X4 is —CR4b—. In some embodiments, X4 is —N—. In some embodiments, X5 is —CR5b—. In some embodiments, X5 is —N—. In some embodiments, X6 is —CR6b—. In some embodiments, X6 is —N—. In some embodiments, X1 is —CR1b—, X2 is —CR2b—, X3 is —CR3b—, X4 is —CR4b—, X5 is —CR5b—, and X6 is —CR6b—. In some embodiments, X1 is —N—, X2 is —CR2b—, X3 is —CR3b—, X4 is —CR4b—, X5 is —CR5b—, and X6 is —CR6b—. In some embodiments, X1 is —CR1b—, X2 is —N—, X3 is —CR3b—, X4 is —CR4b—, X5 is —CR5b—, and X6 is —CR6b—. In some embodiments, X1 is —CR1b—, X2 is —CR3b—, X3 is —N—, X4 is —CR4b—, X5 is —CR5b—, and X6 is —CR6b—. In some embodiments, X1 is —CR1b—, X2 is —CR2b—, X3 is —CR3b—, X4 is —N—, X5 is —CR5b—, and X6 is —CRb—. In some embodiments, X1 is —CR1b—, X2 is —CR2b—, X3 is —CR3b—, X4 is —CR4b—, X5 is —N—, and X6 is —CR6b—. In some embodiments, X1 is —CR1b—, X2 is —CR2b—, X3 is —CR3b—, X4 is —CR4b—, X5 is —CR5b—, and X6 is —N—.
In some embodiments of Formula (I), (I-1), (I-2), (I-3), (I4), (I-5), (Ia), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a pharmaceutically acceptable salt thereof, the




portion is quinolin-4-yl, 1,5-naphthyridinyl-4-yl, 1,6-naphthyridinyl-4-yl, 1,7-naphthyridin-4-yl, 1,8-naphthyridin-4-yl, cinnolin-4-yl, or quinazolin-4-yl, each of which is substituted or unsubstituted. In some embodiments, the





portion is 6,7-dimethoxyquinolin-4-yl. In some embodiments, the





portion is 7-methoxyquinolin-4-yl.

In some embodiments of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a pharmaceutically acceptable salt thereof, the




portion is





some embodiments, the





portion of Formula (I) is





In some embodiments of Formula (I), (I-1), (I-2), (I-3), (I4), (I-5), (Ia), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a pharmaceutically acceptable salt thereof, X2 is R2b and X3 is R3b, wherein R2b and R3b are methoxy. In some embodiments, X1 is Rib, X2 is R2b, X3 is R3b, and X4 is R4b, wherein R2b and R3b are methoxy, and Rib and R4b are hydrogen. In some embodiments, X1 is R1b, X2 is R2b, X3 is R3b, and X4 is R4b, wherein R3b is methoxy, and Rib, R2b, and R4b are hydrogen.
In some embodiments of Formula (I), (I-1), (I-2), (I-3), (I4), (I-5), (Ia), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, the




portion is





In some embodiments, the





portion is





In some embodiments, the





portion is





In some embodiments, the





portion is





In some embodiments of Formula (I), (I-1), (I-2), (I-3), (I4), (I-5), (Ia), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a pharmaceutically acceptable salt thereof, the




portion is





In some embodiments of Formula (I), (I-1), (I-2), (I-3), (I4), (I-5), (Ia), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a pharmaceutically acceptable salt thereof, the




portion of Formula (I) is





In some embodiments of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a pharmaceutically acceptable salt thereof, the




portion is





In some embodiments of Formula (I), (I-1), (I-2), (I-3), (I4), (I-5), (Ia), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a acceptable salt thereof, the




portion of Formula (I) is





In some embodiments, the





portion of Formula (I) is





In some embodiments of Formula (I), (I-1), (I-2), (I-3), (I4), (I-5), (Ia), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a pharmaceutically acceptable salt thereof, the




portion of Formula (I) is





In some embodiments of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, L is a bond, —O—, —C(O)—, —NR6c—, or —OCR7c—*, wherein R6c is as defined for Formula (I) or any variation or embodiment thereof, and wherein * represents the point of attachment to




In some embodiments, L is a bond. In some embodiments, L is —O—. In some embodiments, L is —C(O)—. In some embodiments, L is —NR6c—. In some embodiments, L is —NH—. In some embodiments, L is —N(CH3)—. In some embodiments, L is —OCR7c—*, wherein * represents the point of attachment to





In some embodiments, L is —OC(CH3)—*.

In some embodiments of Formula (I), (I-1), (I-2), (I-3), (I4), (I-5), (Ia), (Ia-1), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, a1 and a2 are each independently 0, 1, or 2. In some embodiments, a1 is 0. In some embodiments, a1 is 1. In some embodiments, a1 is 2. In some embodiments, a2 is 0. In some embodiments, a2 is 1. In some embodiments, a2 is 2. In some embodiments, a1 is 0, and a2 is 0. In some embodiments, a1 is 0, and a2 is 1. In some embodiments, a1 is 0, and a2 is 2. In some embodiments, a1 is 1, and a2 is 0. In some embodiments, a1 is 2, and a2 is 0.
In some embodiments of Formula (I), (I-1), (I-2), (I-3), (I4), (I-5), (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig), or a pharmaceutically acceptable salt thereof, the




portion is a bond, —CH2—, —CH2CH2—, —O—, —OCH2—, —CH2O—, —CH2OCH2—, —C(O)—, —C(O)CH2—, —CH2C(O)—, —NH—, —NHCH2—, or —CH2NH—, wherein the left-hand side of each listed moiety is bonded to the remainder of the molecule on the side represented by the squiggly line , and the right-hand side of each listed moiety is bonded to the remainder of the molecule on the side represented by the dotted line ------.

In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, W is




and the





portion of Formula (I) is











In some embodiments, the





portion of Formula (I) is





In some embodiments, the





portion of Formula (I) is





In some embodiments, the





portion of Formula (I) is





In some embodiments, the




portion of Formula (I), or a pharmaceutically acceptable salt thereof, is











In some embodiments, the





portion of Formula (I) is





In some embodiments, the





portion of Formula (I) is





In some embodiments, the





portion of Formula (I) is





In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, W is




and the





portion of Formula (I) is





In some embodiments, the





portion of Formula (I) is





In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, W is




and the





portion of Formula (I) is





In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, W is




and the





portion of Formula (I) is. In some embodiments, the





portion of Formula (I) is





In some embodiments, the





portion of Formula (I) is





In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, W is




and the





portion of Formula (I) is





In some embodiments, the





portion of Formula (I) is





In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, W is




and the





portion of Formula (I) is





In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, W is




and the





portion of Formula (I) is





In one aspect, provided are compounds of Formula (Ia-1):




or a pharmaceutically acceptable salt thereof, wherein R2b, R3b, a1, a2, ring A, b1, and R1a are as defined for Formula (I) or any variation or embodiment thereof.

In one aspect, provided are compounds of Formula (Ia-2):




or a pharmaceutically acceptable salt thereof, wherein R1a and b1 are as defined for Formula (I) or any variation or embodiment thereof.

In one aspect, provided are compounds of Formula (Ia-3):




or a pharmaceutically acceptable salt thereof, wherein R1a and b1 are as defined for Formula (I) or any variation or embodiment thereof.

In one aspect, provided are compounds of Formula (Ia-4):




or a pharmaceutically acceptable salt thereof, wherein R1a, b1, X1, X2, X3, X4, X5, and X6 are as defined for Formula (I) or any variation or embodiment thereof.

In one aspect, provided are compounds of Formula (Ia-5):




or a pharmaceutically acceptable salt thereof, wherein R1a, b1, X1, X2, X3, X4, X5, and X6 are as defined for Formula (I) or any variation or embodiment thereof.

In one aspect, provided are compounds of Formula (Ia-6):




or a pharmaceutically acceptable salt thereof, wherein R1a, X1, X2, X3, X4, X5, and X6 are as defined for Formula (I) or any variation or embodiment thereof.

In one aspect, provided are compounds of Formula (Ie-1):




or a pharmaceutically acceptable salt thereof, wherein R2a, b1, X1, X2, X3, X4, X5, and X6 are as defined for Formula (I) or any variation or embodiment thereof.

In one aspect, provided are compounds of Formula (Ie-2):




or a pharmaceutically acceptable salt thereof, wherein R2a, b1, X1, X2, X3, X4, X5, and X6 are as defined for Formula (I) or any variation or embodiment thereof.

In another aspect, the compound of Formula (I) is a compound of Formula (I-1):




or a pharmaceutically acceptable salt thereof, wherein:

W is




ring A is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is substituted or unsubstituted;
R1a and R2a are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, or C1-6 haloalkyl;
Y is —N— or —CH—;
X1 is —CR1b— or —N—;
X2 is —CR2b— or —N—;
X3 is —CR3b— or —N—;
X4 is —CR4b— or —N—;
X5 is —CR5b— or —N—;
X6 is —CR6b— or —N—;
R1b-R6b are each independently hydrogen, halogen, hydroxyl, C1-4 alkoxy optionally substituted with one or more halo substituents, cyano, C1-3 alkyl, C1-3 haloalkyl, nitro, —NR1cR2c, —NHC(O)R3c, or —C(O)NR4cR5c;
L is a bond, —O—, —C(O)—, or —NR6—;
R1c-R6c are each independently hydrogen or C1-3 alkyl;
a1, a2, and b1 are each independently 0, 1, or 2; and
b2, c1-c4, d1-d4, e1, and e2 are each independently 1, 2, or 3.
In another aspect, the compound of Formula (I) is a compound of Formula (I-2):




or a pharmaceutically acceptable salt thereof, wherein:

W is




ring A is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is substituted or unsubstituted;
R1a and R2a are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, or C1-6 haloalkyl, wherein the C1-6 alkyl is optionally substituted by hydroxyl, C1-3 alkoxy, or C3-6 cycloalkyl;
Y is —N— or —CH—;
X1 is —CR1b— or —N—;
X2 is —CR2b— or —N—;
X3 is —CR3b— or —N—;
X4 is —CRb— or —N—;
X5 is —CR5b— or —N—;
X6 is —CR6b— or —N—;
R1b-R6b are each independently hydrogen, halogen, hydroxyl, C1-4 alkoxy optionally substituted with one or more halo substituents, cyano, C1-3 alkyl, C1-3 haloalkyl, nitro, —NR1cR2c, —NHC(O)R3c, or —C(O)NR4cR5c;
L is a bond, —O—, —C(O)—, or —NR6c—;
R1c-R6c are each independently hydrogen or C1-3 alkyl;
a1, a2, and b1 are each independently 0, 1, 2, or 3; and
b2, c1-c4, d1-d4, e1, and e2 are each independently 1, 2, or 3.
In one aspect, provided are compounds of Formula (I-3):




or a pharmaceutically acceptable salt thereof, wherein:

W is




ring A is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is substituted or unsubstituted;
R1a and R2a are each independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, or optionally substituted C1-6 haloalkyl;
Y is —N— or —CH—;
X1 is —CR1b— or —N—;
X2 is —CR2b— or —N—;
X3 is —CR3b— or —N—;
X4 is —CR4b— or —N—;
X5 is —CR5b— or —N—;
X6 is —CR6b— or —N—;
R1b-R6b are each independently hydrogen, halogen, hydroxyl, C1-4 alkoxy optionally substituted with one or more halo substituents, cyano, C1-3 alkyl, C1-3 haloalkyl, nitro, —NR1cR2c, —NHC(O)R3c, or —C(O)NR4cR5c;
L is —OCR7c—*, wherein * represents the point of attachment to




R1c-R5c and R7c are each independently hydrogen or C1-3 alkyl;
a1, a2, b1, and c4 are each independently 0, 1, 2, or 3; and
b2, c1-c3, d1-d4, e1, and e2 are each independently 1, 2, or 3.
In one aspect, provided are compounds of Formula (I4):




or a pharmaceutically acceptable salt thereof, wherein:

W is




R2a is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, or optionally substituted C1-6 haloalkyl;
Y is —N— or —CH—;
X1 is —CR1b— or —N—;
X2 is —CR2b— or —N—;
X3 is —CR3b— or —N—;
X4 is —CR4b— or —N—;
X5 is —CR5b— or —N—;
X6 is —CR6b— or —N—;
R1b-R6b are each independently hydrogen, halogen, hydroxyl, C1-4 alkoxy optionally substituted with one or more halo substituents, cyano, C1-3 alkyl, C1-3 haloalkyl, nitro, —NR1cR2c, —NHC(O)R3c, or —C(O)NR4cR5c;
L is a bond, —O—, —C(O)—, —NR6c—, or —OCR7c—*, wherein * represents the point of attachment to




R1c-R7c are each independently hydrogen or C1-3 alkyl;
a1, a2, b1, and c4 are each independently 0, 1, 2, or 3; and
c1-c3 are each independently 1, 2, or 3.
In one aspect, provided are compounds of Formula (I-5):




or a pharmaceutically acceptable salt thereof, wherein:

W is




ring A is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is substituted or unsubstituted;
R1a and R2a are each independently C1-6 alkyl substituted with halo or 3-6 membered heterocycloalkyl substituted with acyl;
Y is —N— or —CH—;
X1 is —CR1b— or —N—;
X2 is —CR2b— or —N—;
X3 is —CR3b— or —N—;
X4 is —CR4b— or —N—;
X5 is —CR5b— or —N—;
X6 is —CR6b— or —N—;
R1b-R6b are each independently hydrogen, halogen, hydroxyl, C1-4 alkoxy optionally substituted with one or more halo substituents, cyano, C1-3 alkyl, C1-3 haloalkyl, nitro, —NR1cR2c, —NHC(O)R3c, or —C(O)NR4cR5c;
L is a bond, —O—, —C(O)—, —NR6c—, or —OCR7c—*, wherein * represents the point of attachment to




R1c-R7c are each independently hydrogen or C1-3 alkyl;
a1, a2, b1, and c4 are each independently 0, 1, 2, or 3; and
b2, c1-c3, d1-d4, e1, and e2 are each independently 1, 2, or 3.
In some embodiments, provided herein are compounds and salts thereof described in Table 1.









TABLE 1





Compound




No.
Structure
Name

















1




(4-((6,7-dimethoxyquinolin-4- yl)oxy)phenyl)(imino)(methyl)-λ6-sulfanone


 


1R




(R)-(4-((6,7-dimethoxyquinolin-4- yl)oxy)phenyl)(imino)(methyl)-λ6-sulfanone


 


1S




(S)-(4-((6,7-dimethoxyquinolin-4- yl)oxy)phenyl)(imino)(methyl)-λ6-sulfanone


 


2




((6-(6,7-dimethoxyquinazolin-4-yl)pyridin-3- yl)methyl)(imino)(methyl)-λ6-sulfanone


 


3




(1-(2-(6,7-dimethoxyquinazolin-4- yl)acetyl)azetidin-3-yl)(imino)(methyl)-λ6- sulfanone


 


4




(1-(2-(6,7-dimethoxyquinazolin-4- yl)ethyl)azetidin-3-yl)(imino)(methyl)-λ6- sulfanone


 


5




(1-(2-(6,7-dimethoxyquinazolin-4- yl)ethyl)piperidin-4-yl)(imino)(methyl)-λ6- sulfanone


 


6




(1-imino-1-oxido-1λ6-thiomorpholino)(7- methoxyquinolin-4-yl)methanone


 


7




(2-(1-(6,7-dimethoxyquinazolin-4-yl)-1H- 1,2,3-triazol-4-yl)ethyl)(imino)(methyl)-λ6- sulfanone


 


8




(2-(1-(6,7-dimethoxyquinazolin-4-yl)piperidin- 4-yl)ethyl)(imino)(methyl)-λ6-sulfanone


 


9




(2-(1-(cinnolin-4-yl)piperidin-4- yl)ethyl)(imino)(methyl)-λ6-sulfanone


 


10




(2-fluoro-4-((7-methoxyquinolin-4- yl)oxy)phenyl)(imino)(methyl)-λ6-sulfanone


 


11




(3-((6,7-dimethoxyquinazolin-4- yl)methoxy)cyclopentyl)(imino)(methyl)-λ6- sulfanone


 


12




(3-fluoro-4-((7-methoxyquinolin-4- yl)oxy)phenyl)(imino)(methyl)-λ6-sulfanone


 


13




(4-(((6,7-dimethoxyquinazolin-4- yl)amino)methyl)phenyl)(imino)(methyl)-λ6- sulfanone


 


14




(4-(((6,7-dimethoxyquinazolin-4- yl)oxy)methyl)phenyl)(imino)(methyl)-λ6- sulfanone


 


15




(4-((6,7-dimethoxyquinazolin-4-yl)oxy)-2- fluorophenyl)(imino)(methyl)-λ6-sulfanone


 


16




(4-((6,7-dimethoxyquinazolin-4-yl)oxy)-3- fluorophenyl)(imino)(methyl)-λ6-sulfanone


 


17




(4-((6,7-dimethoxyquinazolin-4- yl)oxy)benzyl)(imino)(methyl)-λ6-sulfanone


 


18




(4-((6,7-dimethoxyquinazolin-4- yl)oxy)phenyl)(imino)(methyl)-λ6-sulfanone


 


19




(4-((6,7-dimethoxyquinazolin-4- yl)oxy)phenyl)(imino)(trifluoromethyl)-λ6- sulfanone


 


20




(4-(6,7-dimethoxyquinazolin-4- yl)benzyl)(imino)(methyl)-λ6-sulfanone


 


21




(4-(cinnolin-4-yl)benzyl)(imino)(methyl)-λ6- sulfanone


 


22




(4-(cinnolin-4-yloxy)phenyl)(imino)(methyl)- λ6-sulfanone


 


23




(6-((6,7-dimethoxyquinazolin-4- yl)oxy)pyridin-3-yl)(imino)(methyl)-λ6- sulfanone


 


24




(6,7-dimethoxyquinazolin-4-yl)(1-imino-1- oxido-1λ6-thiomorpholino)methanone


 


25




(7-(6,7-dimethoxyquinazolin-4-yl)-7- azaspiro[3.5]nonan-2-yl)(imino)(methyl)-λ6- sulfanone


 


26




1-(1-imino-1-oxido-1λ6-thiomorpholino)-2-(7- methoxyquinolin-4-yl)ethan-1-one


 


27




1-(6,7-dimethoxyquinazolin-4-yl)-2-(1-imino- 1-oxido-1λ6-thiomorpholino)ethan-1-one


 


28




1-imino-4-(2-(7-methoxyquinolin-4-yl)ethyl)- 1l6,4-thiazepane 1-oxide


 


29




1-imino-4-(2-(7-methoxyquinolin-4-yl)ethyl)- 1λ6-thiomorpholine 1-oxide


 


30




2-(1-imino-1-oxido-1λ6-thiomorpholino)-1-(7- methoxyquinolin-4-yl)ethan-1-one


 


31




2-(6,7-dimethoxyquinazolin-4-yl)-1-(1-imino- 1-oxido-1λ6-thiomorpholino)ethan-1-one


 


32




2-imino-6-((7-methoxyquinolin-4-yl)methyl)- 2λ6-thia-6-azaspiro[3.3]heptane 2-oxide


 


33




2-imino-7-(7-methoxyquinolin-4-yl)-2l4- isothiochromane 2-oxide


 


34




4-(2-(6,7-dimethoxyquinazolin-4-yl)ethyl)-1- imino-1l6,4-thiazepane 1-oxide


 


35




4-(2-(6,7-dimethoxyquinazolin-4-yl)ethyl)-1- imino-1λ6-thiomorpholine 1-oxide


 


36




6-((6,7-dimethoxyquinazolin-4-yl)methyl)-2- imino-2λ6-thia-6-azaspiro[3.3]heptane 2-oxide


 


37




6,7-dimethoxy-4-(2-(S-methylsulfonimidoyl)- 1,2,3,4-tetrahydroisoquinolin-7-yl)quinazoline


 


37S




(S)-6,7-dimethoxy-4-(2-(S- methylsulfonimidoyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)quinazoline


 


37R




(R)-6,7-dimethoxy-4-(2-(S- methylsulfonimidoyl)-1,2,3,4- tetrahydroisoquinolin-7-yl)quinazoline


 


38




6,7-dimethoxy-4-(2-(S-methylsulfonimidoyl)- 2,7-diazaspiro[3.5]nonan-7-yl)quinazoline


 


39




6-fluoro-4-(4-((S- methylsulfonimidoyl)methyl)phenyl)quinoline- 3-carbonitrile


 


40




6-fluoro-4-(4-(2-(S- methylsulfonimidoyl)ethyl)piperidin-1- yl)quinoline-3-carbonitrile


 


41




6-fluoro-4-(4-(S- methylsulfonimidoyl)phenoxy)quinoline-3- carbonitrile


 


42




6-fluoro-7-methoxy-4-(4-((S- methylsulfonimidoyl)methyl)phenyl)quinoline- 3-carbonitrile


 


43




6-fluoro-7-methoxy-4-(4-(2-(S- methylsulfonimidoyl)ethyl)piperidin-1- yl)quinoline-3-carbonitrile


 


44




6-fluoro-7-methoxy-4-(4-(S- methylsulfonimidoyl)phenoxy)quinoline-3- carbonitrile


 


44R




(R)-6-fluoro-7-methoxy-4-(4-(S- methylsulfonimidoyl)phenoxy)quinoline-3- carbonitrile


 


44S




(S)-6-fluoro-7-methoxy-4-(4-(S- methylsulfonimidoyl)phenoxy)quinoline-3- carbonitrile


 


45




6-methoxy-4-(4-((S- methylsulfonimidoyl)methyl)phenyl)quinoline- 3-carbonitrile


 


46




6-methoxy-4-(4-(2-(S- methylsulfonimidoyl)ethyl)piperidin-1- yl)quinoline-3-carbonitrile


 


47




6-methoxy-4-(4-(S- methylsulfonimidoyl)phenoxy)quinoline-3- carbonitrile


 


48




6-methyl-4-(4-((S- methylsulfonimidoyl)methyl)phenyl)quinoline- 3-carbonitrile


 


49




6-methyl-4-(4-(2-(S- methylsulfonimidoyl)ethyl)piperidin-1- yl)quinoline-3-carbonitrile


 


50




6-methyl-4-(4-(S- methylsulfonimidoyl)phenoxy)quinoline-3- carbonitrile


 


51




7-(6,7-dimethoxyquinazolin-4-yl)-2-imino-2l4- isothiochromane 2-oxide


 


52




7-methoxy-4-(2-(S-methylsulfonimidoyl)- 1,2,3,4-tetrahydroisoquinolin-7-yl)quinoline


 


52S




(S)-7-methoxy-4-(2-(S-methylsulfonimidoyl)- 1,2,3,4-tetrahydroisoquinolin-7-yl)quinoline


 


52R




(R)-7-methoxy-4-(2-(S-methylsulfonimidoyl)- 1,2,3,4-tetrahydroisoquinolin-7-yl)quinoline


 


53




7-methoxy-4-(2-(S-methylsulfonimidoyl)-2,7- diazaspiro[3.5]nonan-7-yl)quinoline


 


54




8-(6,7-dimethoxyquinazolin-4-yl)-2-(S- methylsulfonimidoyl)-2,8- diazaspiro[4.5]decane


 


54S




(S)-8-(6,7-dimethoxyquinazolin-4-yl)-2-(S- methylsulfonimidoyl)-2,8- diazaspiro[4.5]decane


 


54R




(R)-8-(6,7-dimethoxyquinazolin-4-yl)-2-(S- methylsulfonimidoyl)-2,8- diazaspiro[4.5]decane


 


55




8-(7-methoxyquinolin-4-yl)-2-(S- methylsulfonimidoyl)-2,8- diazaspiro[4.5]decane


 


55S




(S)-8-(7-methoxyquinolin-4-yl)-2-(S- methylsulfonimidoyl)-2,8- diazaspiro[4.5]decane


 


55R




(R)-8-(7-methoxyquinolin-4-yl)-2-(S- methylsulfonimidoyl)-2,8- diazaspiro[4.5]decane


 


56




8-methoxy-4-(4-((S- methylsulfonimidoyl)methyl)phenyl)quinoline- 3-carbonitrile


 


57




8-methoxy-4-(4-(2-(S- methylsulfonimidoyl)ethyl)piperidin-1- yl)quinoline-3-carbonitrile


 


58




8-methoxy-4-(4-(S- methylsulfonimidoyl)phenoxy)quinoline-3- carbonitrile


 


59




cyclopropyl(4-((6,7-dimethoxyquinazolin-4- yl)oxy)phenyl)(imino)-λ6-sulfanone


 


60




cyclopropyl(imino)(4-((7-methoxyquinolin-4- yl)oxy)phenyl)-λ6-sulfanone


 


60R




(R)-cyclopropyl(imino)(4-((7- methoxyquinolin-4-yl)oxy)phenyl)-λ6- sulfanone


 


60S




(S)-cyclopropyl(imino)(4-((7- methoxyquinolin-4-yl)oxy)phenyl)-λ6- sulfanone


 


61




imino((6-(7-methoxyquinolin-4-yl)pyridin-3- yl)methyl)(methyl)-λ6-sulfanone


 


62




imino(1-(2-(7-methoxyquinolin-4- yl)acetyl)azetidin-3-yl)(methyl)-λ6-sulfanone


 


63




imino(1-(2-(7-methoxyquinolin-4- yl)ethyl)azetidin-3-yl)(methyl)-λ6-sulfanone


 


64




imino(1-(2-(7-methoxyquinolin-4- yl)ethyl)piperidin-4-yl)(methyl)-λ6-sulfanone


 


65




imino(2-(1-(7-methoxy-1,5-naphthyridin-4- yl)piperidin-4-yl)ethyl)(methyl)-λ6-sulfanone


 


66




imino(2-(1-(7-methoxy-1,6-naphthyridin-4- yl)piperidin-4-yl)ethyl)(methyl)-λ6-sulfanone


 


67




imino(2-(1-(7-methoxy-1,8-naphthyridin-4- yl)piperidin-4-yl)ethyl)(methyl)-λ6-sulfanone


 


68




imino(2-(1-(7-methoxyquinolin-4-yl)-1H- 1,2,3-triazol-4-yl)ethyl)(methyl)-λ6-sulfanone


 


69




imino(2-(1-(7-methoxyquinolin-4-yl)piperidin- 4-yl)ethyl)(methyl)-λ6-sulfanone


 


70




imino(2-(1-(8-methoxy-1,5-naphthyridin-4- yl)piperidin-4-yl)ethyl)(methyl)-λ6-sulfanone


 


71




imino(2-(1-(8-methoxy-1,6-naphthyridin-4- yl)piperidin-4-yl)ethyl)(methyl)-λ6-sulfanone


 


72




imino(2-(1-(8-methoxyquinazolin-4- yl)piperidin-4-yl)ethyl)(methyl)-λ6-sulfanone


 


73




imino(3-((7-methoxyquinolin-4- yl)methoxy)cyclopentyl)(methyl)-λ6-sulfanone


 


74




imino(4-(((7-methoxyquinolin-4- yl)amino)methyl)phenyl)(methyl)-λ6-sulfanone


 


75




imino(4-(((7-methoxyquinolin-4- yl)oxy)methyl)phenyl)(methyl)-λ6-sulfanone


 


75R




(R)-imino(4-(((7-methoxyquinolin-4- yl)oxy)methyl)phenyl)(methyl)-l6-sulfanone


 


75S




(S)-imino(4-(((7-methoxyquinolin-4- yl)oxy)methyl)phenyl)(methyl)-l6-sulfanone


 


76




imino(4-((7-methoxy-1,5-naphthyridin-4- yl)oxy)phenyl)(methyl)-λ6-sulfanone


 


77




imino(4-((7-methoxy-1,6-naphthyridin-4- yl)oxy)phenyl)(methyl)-λ6-sulfanone


 


78




imino(4-((7-methoxy-1,8-naphthyridin-4- yl)oxy)phenyl)(methyl)-λ6-sulfanone


 


79




imino(4-((7-methoxyquinolin-4- yl)oxy)benzyl)(methyl)-λ6-sulfanone


 


80




imino(4-((7-methoxyquinolin-4- yl)oxy)phenyl)(methyl)-λ6-sulfanone


 


80R




(R)-imino(4-((7-methoxyquinolin-4- yl)oxy)phenyl)(methyl)-λ6-sulfanone


 


80S




(S)-imino(4-((7-methoxyquinolin-4- yl)oxy)phenyl)(methyl)-λ6-sulfanone


 


81 




imino(4-((7-methoxyquinolin-4- yl)oxy)phenyl)(trifluoromethyl)-λ6-sulfanone


 


82




imino(4-((8-methoxy-1,5-naphthyridin-4- yl)oxy)phenyl)(methyl)-λ6-sulfanone


 


83




imino(4-((8-methoxy-1,6-naphthyridin-4- yl)oxy)phenyl)(methyl)-λ6-sulfanone


 


84




imino(4-((8-methoxyquinazolin-4- yl)oxy)phenyl)(methyl)-λ6-sulfanone


 


85




imino(4-(7-methoxy-1,5-naphthyridin-4- yl)benzyl)(methyl)-λ6-sulfanone


 


86




imino(4-(7-methoxy-1,6-naphthyridin-4- yl)benzyl)(methyl)-λ6-sulfanone


 


87




imino(4-(7-methoxy-1,8-naphthyridin-4- yl)benzyl)(methyl)-λ6-sulfanone


 


88




imino(4-(7-methoxyquinolin-4- yl)benzyl)(methyl)-λ6-sulfanone


 


89




imino(4-(8-methoxy-1,5-naphthyridin-4- yl)benzyl)(methyl)-λ6-sulfanone


 


90




imino(4-(8-methoxy-1,6-naphthyridin-4- yl)benzyl)(methyl)-λ6-sulfanone


 


91




imino(4-(8-methoxyquinazolin-4- yl)benzyl)(methyl)-λ6-sulfanone


 


92




imino(6-((7-methoxyquinolin-4- yl)oxy)pyridin-3-yl)(methyl)-λ6-sulfanone


 


93




imino(7-(7-methoxyquinolin-4-yl)-7- azaspiro[3.5]nonan-2-yl)(methyl)-λ6-sulfanone


 


94




N-((1-(6,7-dimethoxyquinazolin-4- yl)piperidin-4- yl)methyl)methanesulfonimidamide


 


94S




(S)-N-((1-(6,7-dimethoxyquinazolin-4- yl)piperidin-4- yl)methyl)methanesulfonimidamide


 


94R




(R)-N-((1-(6,7-dimethoxyquinazolin-4- yl)piperidin-4- yl)methyl)methanesulfonimidamide


 


95




N-((1-(7-methoxyquinolin-4-yl)piperidin-4- yl)methyl)methanesulfonimidamide


 


96




4-(1-(6,7-dimethoxyquinolin-4-yl)-1H- pyrazol-4-yl)-1-imino-1λ6-thiomorpholine 1- oxide


 


97




4-(1-(6,7-dimethoxyquinolin-4-yl)-1H- pyrazol-4-yl)-1-iminohexahydro-1λ6-thiopyran 1-oxide


 


98




imino(4-(7-methoxyquinolin-4- yl)phenethyl)(methyl)-λ6-sulfanone


 


99




(4-(6,7-dimethoxyquinazolin-4- yl)phenethyl)(imino)(methyl)-λ6-sulfanone


 


100




imino(2-(6-(7-methoxyquinolin-4-yl)pyridin-3- yl)ethyl)(methyl)-λ6-sulfanone


 


101




imino(5-((7-methoxyquinolin-4- yl)oxy)pyridin-2-yl)(methyl)-λ6-sulfanone


 


102




2-imino-8-((7-methoxyquinolin-4-yl)methyl)- 2λ6-thia-8-azaspiro[4.5]decane 2-oxide


 


103




ethyl(imino)(4-((7-methoxyquinolin-4- yl)oxy)phenyl)-λ6-sulfanone


 


103R




(R)-ethyl(imino)(4-((7-methoxyquinolin-4- yl)oxy)phenyl)-λ6-sulfanone


 


103S




(S)-ethyl(imino)(4-((7-methoxyquinolin-4- yl)oxy)phenyl)-λ6-sulfanone


 


104




imino(4-(8-methoxyquinazolin-4- yl)phenethyl)(methyl)-λ6-sulfanone


 


105




2-imino-6-(7-methoxyquinolin-4-yl)-2λ6-thia- 6-azaspiro[3.3]heptane 2-oxide


 


106




1-imino-4-(((7-methoxyquinolin-4- yl)amino)methyl)hexahydro-λ6-thiopyran 1- oxide


 


107




1-imino-4-(((7-methoxyquinolin-4- yl)oxy)methyl)hexahydro-1λ6-thiopyran 1- oxide


 


107rr




(1r,4r)-4-(((6,7-dimethoxyquinolin-4- yl)oxy)methyl)-1-iminohexahydro-1λ6- thiopyran 1-oxide


 


107ss




(1s,4s)-4-(((6,7-dimethoxyquinolin-4- yl)oxy)methyl)-1-iminohexahydro-1λ6- thiopyran 1-oxide


 


108




imino((1-((7-methoxyquinolin-4- yl)methyl)azetidin-3-yl)methyl)(methyl)-λ6- sulfanone


 


109




imino(1-((7-methoxyquinolin-4- yl)methyl)azetidin-3-yl)(methyl)-λ6-sulfanone


 


110




imino(1-((7-methoxyquinolin-4- yl)methyl)piperidin-4-yl)(methyl)-λ6-sulfanone


 


111




1-imino-3-(((7-methoxyquinolin-4- yl)methyl)amino)tetrahydro-1H-1λ6-thiophene 1-oxide


 


112




1-imino-4-(((7-methoxyquinolin-4- yl)methyl)amino)hexahydro-1λ6-thiopyran 1- oxide


 


113




1-imino-4-(((7-methoxyquinolin-4- yl)methoxy)methyl)hexahydro-1λ6-thiopyran 1-oxide


 


114




{4-[(6-fluoro-7-methoxyquinolin-4- yl)oxy]phenyl}(imino)methyl-λ6-sulfanone


 


114R




(R)-{4-[(6-fluoro-7-methoxyquinolin-4- yl)oxy]phenyl}(imino)methyl-λ6-sulfanone


 


114S




(S)-{4-[(6-fluoro-7-methoxyquinolin-4- yl)oxy]phenyl}(imino)methyl-λ6-sulfanone


 


115




{4-[(6,7-dimethoxyquinolin-4-yl)oxy]-2- fluorophenyl}(imino)methyl-λ6-sulfanone


 


116




{4-[(6,7-dimethoxyquinolin-4-yl)oxy]-3- fluorophenyl}(imino)methyl-λ6-sulfanone


 


117




imino({3-[(7-methoxyquinolin-4- yl)oxy]phenyl})methyl-λ6-sulfanone


 


118




imino({4-[(8-methoxyquinolin-4- yl)oxy]phenyl})methyl-λ6-sulfanone


 


119




imino({4-[(7-methoxycinnolin-4- yl)oxy]phenyl})methyl-λ6-sulfanone


 


120




[cyclopropyl({4-[(6-fluoro-7- methoxyquinolin-4-yl)oxy]phenyl})imino-λ6- sulfanyl]one


 


120R




(R)-[cyclopropyl({4-[(6-fluoro-7- methoxyquinolin-4-yl)oxy]phenyl})imino-λ6- sulfanyl]one


 


120S




(S)-[cyclopropyl({4-[(6-fluoro-7- methoxyquinolin-4-yl)oxy]phenyl})imino-λ6- sulfanyl]one


 


121




4-{4-[imino(methyl)oxo-λ6- sulfanyl]phenoxy}-7-methoxyquinoline-3- carbonitrile


 


122




imino(2-methoxyethyl){4-[(7- methoxyquinolin-4-yl)oxy]phenyl}-λ6- sulfanone


 


123




(cyclopropylmethyl)(imino){4-[(7- methoxyquinolin-4-yl)oxy]phenyl}-λ6- sulfanone


 


124




imino({4-[(7-methoxy-2-methylquinolin-4- yl)oxy]phenyl})methyl-λ6-sulfanone


 


125




imino(methyl)[4-(quinolin-4-yloxy)phenyl]-λ6- sulfanone


 


126




{4-[(6-chloro-7-methoxyquinolin-4- yl)oxy]phenyl}(imino)methyl-λ6-sulfanone


 


127




{4-[(6,7-dimethoxycinnolin-4- yl)oxy]phenyl}(imino)methyl-λ6-sulfanone


 


128




{4-[(8-fluoro-7-methoxyquinolin-4- yl)oxy]phenyl}(imino)methyl-λ6-sulfanone


 


129




{5-[(6,7-dimethoxyquinolin-4-yl)oxy]pyridin- 2-yl}(imino)methyl-λ6-sulfanone


 


130




imino({4-[(6-methoxy-1,5-naphthyridin-4- yl)oxy]phenyl})methyl-λ6-sulfanone


 


131




7-fluoro-4-{4-[imino(methyl)oxo-λ6- sulfanyl]phenoxy}quinoline-3-carbonitrile


 


132




(2-hydroxy-2-methylpropyl)(imino){4-[(7- methoxyquinolin-4-yl)oxy]phenyl}-λ6- sulfanone


 


133




imino(3-{[(7-methoxyquinolin-4- yl)oxy]methyl}phenyl)methyl-λ6-sulfanone


 


133R




(R)-imino(3-{[(7-methoxyquinolin-4- yl)oxy]methyl}phenyl)methyl-λ6-sulfanone


 


133S




(S)-imino(3-{[(7-methoxyquinolin-4- yl)oxy]methyl}phenyl)methyl-λ6-sulfanone


 


134




imino(4-{[(8-methoxyquinolin-4- yl)oxy]methyl}phenyl)methyl-λ6-sulfanone


 


135




(3-fluoro-4-{[(7-methoxyquinolin-4- yl)oxy]methyl}phenyl)(imino)methyl-λ6- sulfanone


 


136




(4-{[6-fluoro-7-methoxyquinolin-4- yl)oxy]methyl}phenyl)(imino)methyl-λ6- sulfanone


 


137




(3-bromo-4-{[(7-methoxyquinolin-4- yl)oxy]methyl}phenyl)(imino)methyl-λ6- sulfanone


 


138




(4-{[(6,7-dimethoxyquinolin-4- yl)oxy]methyl}phenyl)(imino)methyl-λ6- sulfanone


 


139




imino({2-[1-(7-methoxyquinazolin-4- yl)piperidin-4-yl]ethyl})methyl-λ6-sulfanone


 


140




imino({2-[1-(8-methoxyquinolin-4- yl)piperidin-4-yl]ethyl})methyl-λ6-sulfanone


 


141




{2-[1-(6-chloro-7-methoxyquinolin-4- yl)piperidin-4-yl]ethyl}(imino)methyl-λ6- sulfanone


 


141R




(R)-{2-[1-(6-chloro-7-methoxyquinolin-4- yl)piperidin-4-yl]ethyl}(imino)methyl-λ6- sulfanone


 


141S




(S)-{2-[1-(6-chloro-7-methoxyquinolin-4- yl)piperidin-4-yl]ethyl}(imino)methyl-λ6- sulfanone


 


142




{2-[1-(6-chloro-7-methoxyquinazolin-4- yl)piperidin-4-yl]ethyl}(imino)methyl-λ6- sulfanone


 


142R




(R)-{2-[1-(6-chloro-7-methoxyquinazolin-4- yl)piperidin-4-yl]ethyl}(imino)methyl-λ6- sulfanone


 


142S




(S)-{2-[1-(6-chloro-7-methoxyquinazolin-4- yl)piperidin-4-yl]ethyl}(imino)methyl-λ6- sulfanone


 


143




4-(4-{2-[imino(methyl)oxo-λ6- sulfanyl]ethyl}piperidin-1-yl)-7- methoxyquinoline-3-carbonitrile


 


144




4-(4-{2-[imino(methyl)oxo-λ6- sulfanyl]ethyl}piperidin-1-yl)-6,7- dimethoxyquinoline-3-carbonitrile


 


145




{3-[1-(6,7-dimethoxyquinazolin-4- yl)piperidin-4-yl]propyl}(imino)methyl-λ6- sulfanone


 


146




imino({[1-(8-methoxyquinazolin-4- yl)piperidin-4-yl]methyl})methyl-λ6-sulfanone


 


146R




(R)-imino({[1-(8-methoxyquinazolin-4- yl)piperidin-4-yl]methyl})methyl-λ6-sulfanone


 


146S




(S)-imino({[1-(8-methoxyquinazolin-4- yl)piperidin-4-yl]methyl})methyl-λ6-sulfanone


 


147




{[1-(6,7-dimethoxyquinazolin-4-yl)piperidin- 4-yl]methyl}(imino)methyl-λ6-sulfanone


 


148




imino({[1-(7-methoxyquinolin-4-yl)piperidin- 4-yl]methyl})methyl-λ6-sulfanone


 


149




imino(methyl){2-[1-(quinolin-4-yl)piperidin-4- yl]ethyl}-λ6-sulfanone


 


150




{2-[1-(6-fluoro-7-methoxyquinolin-4- yl)piperidin-4-yl]ethyl}(imino)methyl-λ6- sulfanone


 


151




{2-[1-(6,7-dimethoxycinnolin-4-yl)piperidin- 4-yl]ethyl}(imino)methyl-λ6-sulfanone


 


152




6-chloro-4-(4-{2-[imino(methyl)oxo-λ6- sulfanyl]ethyl}piperidin-1-yl)-7- methoxyquinoline-3-carbonitrile


 


153




{2-[4-(6,7-dimethoxyquinazolin-4- yl)phenyl]ethyl}(imino)methyl-λ6-sulfanone


 


154




imino({2-[4-(8-methoxyquinazolin-4- yl)phenyl]ethyl})methyl-λ6-sulfanone


 


155




imino(methyl){[4-(quinolin-4- yl)phenyl]methyl}-λ6-sulfanone


 


156




[8-(6-chloro-7-methoxyquinolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](imino)methyl-λ6- sulfanone


 


156S




(S)-[8-(6-chloro-7-methoxyquinolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](imino)methyl-λ6- sulfanone


 


156R




(R)-[8-(6-chloro-7-methoxyquinolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](imino)methyl-λ6- sulfanone


 


157




N-{[1-(6-chloro-7-methoxyquinolin-4- yl)piperidin-4- yl]methyl}methanesulfonoimidamide


 


158




imino[8-(7-methoxy-1,8-naphthyridin-4-yl)- 2,8-diazaspiro[4.5]decan-2-yl]methyl-λ6- sulfanone


 


159




[8-(6,7-dimethoxyquinazolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](ethyl)imino-λ6- sulfanone


 


160




{cyclopropyl[8-(6,7-dimethoxyquinazolin-4- yl)-2,8-diazaspiro[4.5]decan-2-yl]imino-λ6- sulfanyl}one


 


160R




(R)-{cyclopropyl[8-(6,7-dimethoxyquinazolin- 4-yl)-2,8-diazaspiro[4.5]decan-2-yl]imino-λ6- sulfanyl}one


 


160S




(S)-{cyclopropyl[8-(6,7-dimethoxyquinazolin- 4-yl)-2,8-diazaspiro[4.5]decan-2-yl]imino-λ6- sulfanyl}one


 


161




[7-(6,7-dimethoxyquinolin-4-yl)-1,2,3,4- tetrahydroisoquinolin-2-yl](imino)methyl-λ6- sulfanone


 


161S




(S)-[7-(6,7-dimethoxyquinolin-4-yl)-1,2,3,4- tetrahydroisoquinolin-2-yl](imino)methyl-λ6- sulfanone


 


161R




(R)-[7-(6,7-dimethoxyquinolin-4-yl)-1,2,3,4- tetrahydroisoquinolin-2-yl](imino)methyl-λ6- sulfanone


 


162




N-{[4-(7-methoxyquinolin-4- yl)phenyl]methyl}methanesulfonoimidamide


 


163




imino[7-(7-methoxy-1,8-naphthyridin-4-yl)- 1,2,3,4-tetrahydroisoquinolin-2-yl]methyl-λ6- sulfanone


 


164




(4-{[(6,7-dimethoxyquinazolin-4- yl)oxy]methyl}piperidin-1-yl)(imino)methyl- λ6-sulfanone


 


165




(2-(1-(7,8-dimethoxyquinazolin-4-yl)piperidin- 4-yl)ethyl)(imino)(methyl)-l6-sulfanone


 


166




1-[3-({4-[(7-methoxyquinolin-4- yl)oxy]phenyl}imino-λ6-sulfanyl)azetidin-1- yl]ethan-1-one


 


167




imino({4-[(7-methoxyquinazolin-4- yl)oxy]phenyl})methyl-λ6-sulfanone


 


168




imino({4-[(7-methoxy-3-methylquinolin-4- yl)oxy]phenyl})methyl-λ6-sulfanone


 


169




(3-{[(6-fluoro-7-methoxyquinolin-4- yl)oxy]methyl}phenyl)(imino)methyl-λ6- sulfanone


 


169R




(R)-(3-{[(6-fluoro-7-methoxyquinolin-4- yl)oxy]methyl}phenyl)(imino)methyl-λ6- sulfanone


 


169S




(S)-(3-{[(6-fluoro-7-methoxyquinolin-4- yl)oxy]methyl}phenyl)(imino)methyl-λ6- sulfanone


 


170




imino(5-{[(7-methoxyquinolin-4- yl)oxy]methyl}furan-3-yl)methyl-λ6-sulfanone


 


171




4-{[(6,7-dimethoxyquinazolin-4- yl)oxy]methyl}-1-imino-1λ6-thian-1-one


 


172




imino(5-{[(7-methoxyquinolin-4- yl)oxy]methyl}pyridin-3-yl)methyl-λ6- sulfanone


 


173




(3-{[(6,7-dimethoxyquinazolin-4- yl)oxy]methyl}phenyl)(imino)methyl-λ6- sulfanone


 


174




imino(3-{[(7-methoxyquinazolin-4- yl)oxy]methyl}phenyl)methyl-λ6-sulfanone


 


175




(3-{[(6,7-dimethoxyquinolin-4- yl)oxy]methyl}phenyl)(imino)methyl-λ6- sulfanone


 


175R




(R)-(3-{[(6,7-dimethoxyquinolin-4- yl)oxy]methyl}phenyl)(imino)methyl-λ6- sulfanone


 


175S




(S)-(3-{[(6,7-dimethoxyquinolin-4- yl)oxy]methyl}phenyl)(imino)methyl-λ6- sulfanone


 


176




(3-{[(6-chloro-7-methoxyquinolin-4- yl)oxy]methyl}phenyl)(imino)methyl-λ6- sulfanone


 


177




(3-fluoro-5-{[(7-methoxyquinolin-4- yl)oxy]methyl}phenyl)(imino)methyl-λ6- sulfanone


 


177R




(R)-(3-fluoro-5-{[(7-methoxyquinolin-4- yl)oxy]methyl}phenyl)(imino)methyl-λ6- sulfanone


 


177S




(S)-(3-fluoro-5-{[(7-methoxyquinolin-4- yl)oxy]methyl}phenyl)(imino)methyl-λ6- sulfanone


 


178




imino({3-[(1R)-1-[(7-methoxyquinolin-4- yl)oxy]ethyl]phenyl})methyl-λ6-sulfanone


 


178R




(R)-imino({3-[(1R)-1-[(7-methoxyquinolin-4- yl)oxy]ethyl]phenyl})methyl-λ6-sulfanone


 


178S




(S)-imino({3-[(1R)-1-[(7-methoxyquinolin-4- yl)oxy]ethyl]phenyl})methyl-λ6-sulfanone


 


179




4-(4-{[imino(methyl)oxo-λ6- sulfanyl]methyl}piperidin-1-yl)-8- methoxyquinoline-3-carbonitrile


 


179R




(R)-4-(4-{[imino(methyl)oxo-λ6- sulfanyl]methyl}piperidin-1-yl)-8- methoxyquinoline-3-carbonitrile


 


179S




(S)-4-(4-{[imino(methyl)oxo-λ6- sulfanyl]methyl}piperidin-1-yl)-8- methoxyquinoline-3-carbonitrile


 


180




imino({[1-(8-methoxyquinolin-4-yl)piperidin- 4-yl]methyl})methyl-λ6-sulfanone


 


181




[8-(6,7-dimethoxyquinazolin-4-yl)-8- azaspiro[4.5]decan-2-yl](imino)methyl-λ6- sulfanone


 


182




imino({[1-(8-methoxycinnolin-4-yl)piperidin- 4-yl]methyl})methyl-λ6-sulfanone


 


183




{[1-(6-fluoro-8-methoxyquinazolin-4- yl)piperidin-4-yl]methyl}(imino)methyl-λ6- sulfanone


 


183R




(R)-{[1-(6-fluoro-8-methoxyquinazolin-4- yl)piperidin-4-yl]methyl}(imino)methyl-λ6- sulfanone


 


183S




(S)-{[1-(6-fluoro-8-methoxyquinazolin-4- yl)piperidin-4-yl]methyl}(imino)methyl-λ6- sulfanone


 


184




{[2-(6-fluoro-7-methoxyquinolin-4-yl)-2- azaspiro[3.3]heptan-6- yl]methyl}(imino)methyl-λ6-sulfanone


 


184R




(R)-{[2-(6-fluoro-7-methoxyquinolin-4-yl)-2- azaspiro[3.3]heptan-6- yl]methyl}(imino)methyl-λ6-sulfanone


 


184S




(S)-{[2-(6-fluoro-7-methoxyquinolin-4-yl)-2- azaspiro[3.3]heptan-6- yl]methyl}(imino)methyl-λ6-sulfanone


 


185




{[4-hydroxy-1-(8-methoxyquinazolin-4- yl)piperidin-4-yl]methyl}(imino)methyl-λ6- sulfanone


 


185R




(R)-{[4-hydroxy-1-(8-methoxyquinazolin-4- yl)piperidin-4-yl]methyl}(imino)methyl-λ6- sulfanone


 


185S




(S)-{[4-hydroxy-1-(8-methoxyquinazolin-4- yl)piperidin-4-yl]methyl}(imino)methyl-λ6- sulfanone


 


186




{[2-(6,7-dimethoxyquinolin-4-yl)-2- azaspiro[3.3]heptan-6- yl]methyl}(imino)methyl-λ6-sulfanone


 


187




{[1-(8-ethoxyquinazolin-4-yl)piperidin-4- yl]methyl}(imino)methyl-λ6-sulfanone


 


188




{[2-(6,7-dimethoxycinnolin-4-yl)-2- azaspiro[3.3]heptan-6- yl]methyl}(imino)methyl-λ6-sulfanone


 


189




4-(4-{[cyclopropyl(imino)oxo-λ6- sulfanyl]methyl}piperidin-1-yl)-8- methoxyquinoline-3-carbonitrile


 


189R




(R)-4-(4-{[cyclopropyl(imino)oxo-λ6- sulfanyl]methyl}piperidin-1-yl)-8- methoxyquinoline-3-carbonitrile


 


189S




(S)-4-(4-{[cyclopropyl(imino)oxo-λ6- sulfanyl]methyl}piperidin-1-yl)-8- methoxyquinoline-3-carbonitrile


 


190




cyclopropyl(imino){[1-(8-methoxyquinazolin- 4-yl)piperidin-4-yl]methyl}-λ6-sulfanone


 


191




cyclobutyl({[4-hydroxy-1-(8- methoxyquinazolin-4-yl)piperidin-4- yl]methyl})imino-λ6-sulfanone


 


192




(3-{[(6-fluoro-7-methoxyquinolin-4- yl)amino]methyl}phenyl)(imino)methyl-λ6- sulfanone


 


193




cyclopropyl({[4-hydroxy-1-(8- methoxyquinazolin-4-yl)piperidin-4- yl]methyl})imino-λ6-sulfanone


 


193R




(R)-cyclopropyl({[4-hydroxy-1-(8- methoxyquinazolin-4-yl)piperidin-4- yl]methyl})imino-λ6-sulfanone


 


194S




(S)-cyclopropyl({[4-hydroxy-1-(8- methoxyquinazolin-4-yl)piperidin-4- yl]methyl})imino-λ6-sulfanone


 


194




{[8-hydroxy-5-(8-methoxyquinazolin-4-yl)-5- azaspiro[2.5]octan-8- yl]methyl}(imino)methyl-λ6-sulfanone


 


195




ethyl({[4-hydroxy-1-(8-methoxyquinazolin-4- yl)piperidin-4-yl]methyl})imino-λ6-sulfanone


 


195R




(R)-ethyl({[4-hydroxy-1-(8- methoxyquinazolin-4-yl)piperidin-4- yl]methyl})imino-λ6-sulfanone


 


195S




(S)-ethyl({[4-hydroxy-1-(8- methoxyquinazolin-4-yl)piperidin-4- yl]methyl})imino-λ6-sulfanone


 


196




{[1-(8-ethoxyquinazolin-4-yl)-4- hydroxypiperidin-4-yl]methyl}(imino)methyl- λ6-sulfanone


 


197




8-ethoxy-4-(4-{[imino(methyl)oxo-λ6- sulfanyl]methyl}piperidin-1-yl)quinoline-3- carbonitrile


 


198




4-(4-hydroxy-4-{[imino(methyl)oxo-λ6- sulfanyl]methyl}piperidin-1-yl)-8- methoxyquinoline-3-carbonitrile


 


198R




(R)-4-(4-hydroxy-4-{[imino(methyl)oxo-λ6- sulfanyl]methyl}piperidin-1-yl)-8- methoxyquinoline-3-carbonitrile


 


198S




(S)-4-(4-hydroxy-4-{[imino(methyl)oxo-λ6- sulfanyl]methyl}piperidin-1-yl)-8- methoxyquinoline-3-carbonitrile


 


199




{[4-hydroxy-1-(8-methoxy-2- methylquinazolin-4-yl)piperidin-4- yl]methyl}(imino)methyl-λ6-sulfanone


 


200




8-(fluoromethoxy)-4-(4-{[imino(methyl)oxo- λ6-sulfanyl]methyl}piperidin-1-yl)quinoline-3- carbonitrile


 


201




4-(4-{[imino(methyl)oxo-λ6- sulfanyl]methyl}piperidin-1-yl)-8-methoxy-2- methylquinoline-3-carbonitrile


 


202




{[1-(3-fluoro-8-methoxyquinolin-4- yl)piperidin-4-yl]methyl}(imino)methyl-λ6- sulfanone


 


203




5-fluoro-4-(4-{[imino(methyl)oxo-λ6- sulfanyl]methyl}piperidin-1-yl)-8- methoxyquinoline-3-carbonitrile


 


204




{2-[3-(6,7-dimethoxyquinolin-4- yl)phenyl]ethyl}(imino)methyl-λ6-sulfanone


 


205




[8-(6-fluoro-7-methoxyquinolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](imino)methyl-λ6- sulfanone


 


205R




(R)-[8-(6-fluoro-7-methoxyquinolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](imino)methyl-λ6- sulfanone


 


205S




(S)-[8-(6-fluoro-7-methoxyquinolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](imino)methyl-λ6- sulfanone


 


206




[2-(6,7-dimethoxyquinazolin-4-yl)-2,7- diazaspiro[3.5]nonan-7-yl](imino)methyl-λ6- sulfanone


 


207




[2-(6,7-dimethoxyquinazolin-4-yl)-2,8- diazaspiro[4.5]decan-8-yl](imino)methyl-λ6- sulfanone


 


208




[8-(6,7-dimethoxyquinolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](imino)methyl-λ6- sulfanone


 


208R




(R)-[8-(6,7-dimethoxyquinolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](imino)methyl-λ6- sulfanone


 


208S




(S)-[8-(6,7-dimethoxyquinolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](imino)methyl-λ6- sulfanone


 


209




[9-(6,7-dimethoxyquinazolin-4-yl)-3,9- diazaspiro[5.5]undecan-3-yl](imino)methyl-λ6- sulfanone


 


210




6-fluoro-4-{2-[imino(methyl)oxo-λ6-sulfanyl]- 2,8-diazaspiro[4.5]decan-8-yl}-7- methoxyquinoline-3-carbonitrile


 


211




[8-(6,7-dimethoxycinnolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](imino)methyl-λ6- sulfanone


 


211R




(R)-[8-(6,7-dimethoxycinnolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](imino)methyl-λ6- sulfanone


 


211S




(S)-[8-(6,7-dimethoxycinnolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](imino)methyl-λ6- sulfanone


 


212




[8-(6-chloro-7-methoxyquinazolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](imino)methyl-λ6- sulfanone


 


213




[8-(6,7-dimethoxy-2-methylquinazolin-4-yl)- 2,8-diazaspiro[4.5]decan-2-yl](imino)methyl- λ6-sulfanone


 


214




imino[7-(8-methoxyquinazolin-4-yl)-1,7- diazaspiro[3.5]nonan-1-yl]methyl-λ6-sulfanone


 


215




imino[8-(8-methoxyquinazolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl]methyl-λ6-sulfanone


 


216




[7-(6,7-dimethoxyquinazolin-4-yl)-2,7- diazaspiro[4.4]nonan-2-yl](imino)methyl-λ6- sulfanone


 


217




imino[2-(8-methoxyquinazolin-4-yl)-2,6- diazaspiro[3.4]octan-6-yl]methyl-λ6-sulfanone


 


218




{cyclopropyl[8-(6-fluoro-7-methoxyquinolin- 4-yl)-2,8-diazaspiro[4.5]decan-2-yl]imino-λ6- sulfanyl}one


 


218R




(R)-{cyclopropyl[8-(6-fluoro-7- methoxyquinolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl]imino-λ6- sulfanyl}one


 


218S




(S)-{cyclopropyl [8-(6-fluoro-7- methoxyquinolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl]imino-λ6- sulfanyl}one


 


219




[8-(6-chloro-7-methoxycinnolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](imino)methyl-λ6- sulfanone


 


219R




(R)-[8-(6-chloro-7-methoxycinnolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](imino)methyl-λ6- sulfanone


 


219S




(S)-[8-(6-chloro-7-methoxycinnolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](imino)methyl-λ6- sulfanone


 


220




[8-(6-chloro-7-methoxy-3-methylcinnolin-4- yl)-2,8-diazaspiro[4.5]decan-2- yl](imino)methyl-λ6-sulfanone


 


221




ethyl[8-(6-fluoro-7-methoxyquinazolin-4-yl)- 2,8-diazaspiro[4.5]decan-2-yl]imino-λ6- sulfanone


 


222




4-{6-[imino(methyl)oxo-λ6-sulfanyl]-2,6- diazaspiro[3.4]octan-2-yl}-8- methoxyquinoline-3-carbonitrile


 


222R




(R)-4-{6-[imino(methyl)oxo-λ6-sulfanyl]-2,6- diazaspiro[3.4]octan-2-yl}-8- methoxyquinoline-3-carbonitrile


 


222S




(S)-4-{6-[imino(methyl)oxo-λ6-sulfanyl]-2,6- diazaspiro[3.4]octan-2-yl}-8- methoxyquinoline-3-carbonitrile


 


223




imino[6-(8-methoxyquinazolin-4-yl)-2,6- diazaspiro[3.4]octan-2-yl]methyl-λ6-sulfanone


 


223R




(R)-imino[6-(8-methoxyquinazolin-4-yl)-2,6- diazaspiro[3.4]octan-2-yl]methyl-λ6-sulfanone


 


223S




(S)-imino[6-(8-methoxyquinazolin-4-yl)-2,6- diazaspiro[3.4]octan-2-yl]methyl-λ6-sulfanone


 


224




[8-(6-fluoro-7-methoxyquinazolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](imino)methyl-λ6- sulfanone


 


225




{[8-(6-chloro-7-methoxycinnolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](cyclopropyl)imino- λ6-sulfanyl}one


 


226




4-{2-[imino(methyl)oxo-λ6-sulfanyl]-2,8- diazaspiro[4.5]decan-8-yl}-7- methoxyquinoline-6-carbonitrile


 


227




[8-(3-fluoro-6,7-dimethoxyquinolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](imino)methyl-λ6- sulfanone


 


228




[8-(6,7-dimethoxy-3-methylcinnolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](imino)methyl-λ6- sulfanone


 


229




[(3R)-3-{[(6-fluoro-7-methoxyquinolin-4- yl)oxy]methyl}pyrrolidin-1-yl](imino)methyl- λ6-sulfanone


 


229R




(R)-[(3R)-3-{[(6-fluoro-7-methoxyquinolin-4- yl)oxy]methyl}pyrrolidin-1-yl](imino)methyl- λ6-sulfanone


 


229S




(S)-[(3R)-3-{[(6-fluoro-7-methoxyquinolin-4- yl)oxy]methyl}pyrrolidin-1-yl](imino)methyl- λ6-sulfanone


 


230




[(3S)-3-{[(6-fluoro-7-methoxyquinolin-4- yl)oxy]methyl}pyrrolidin-1-yl](imino)methyl- λ6-sulfanone


 


230R




(R)-[(3S)-3-{[(6-fluoro-7-methoxyquinolin-4- yl)oxy]methyl}pyrrolidin-1-yl](imino)methyl- λ6-sulfanone


 


230S




(S)-[(3S)-3-{[(6-fluoro-7-methoxyquinolin-4- yl)oxy]methyl}pyrrolidin-1-yl](imino)methyl- λ6-sulfanone


 


231




imino({4-[(7-methoxyquinolin-4- yl)methoxy]phenyl})methyl-λ6-sulfanone


 


232




imino({3-[(7-methoxyquinolin-4- yl)methoxy]phenyl})methyl-λ6-sulfanone


 


233




imino[2-(7-methoxyquinolin-4-yl)- 2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-5- yl]methyl-λ6-sulfanone


 


234




imino({2-[1-(7-methoxyquinolin-4-yl)-1H- pyrazol-4-yl]ethyl})methyl-λ6-sulfanone


 


235




imino({4-[(7-methoxyquinolin-4- yl)oxy]piperidin-1-yl})methyl-λ6-sulfanone


 


236




imino[7-(8-methoxyquinazolin-4-yl)-2,7- diazaspiro[3.5]nonan-2-yl]methyl-λ6-sulfanone


 


237




{[2-(6,7-dimethoxyquinazolin-4-yl)-2- azaspiro[3.3]heptan-6- yl]methyl}(imino)methyl-λ6-sulfanone


 


237R




(R)-{[2-(6,7-dimethoxyquinazolin-4-yl)-2- azaspiro[3.3]heptan-6- yl]methyl}(imino)methyl-λ6-sulfanone


 


237S




(S)-{[2-(6,7-dimethoxyquinazolin-4-yl)-2- azaspiro[3.3]heptan-6- yl]methyl}(imino)methyl-λ6-sulfanone


 


238




imino({[(3S)-1-(8-methoxyquinazolin-4- yl)pyrrolidin-3-yl]methyl})methyl-λ6- sulfanone


 


238R




(R)-imino({[(3S)-1-(8-methoxyquinazolin-4- yl)pyrrolidin-3-yl]methyl})methyl-λ6-sulfanone


 


238S




(S)-imino({[(3S)-1-(8-methoxyquinazolin-4- yl)pyrrolidin-3-yl]methyl})methyl-λ6- sulfanone


 


239




imino({[(3R)-1-(8-methoxyquinazolin-4- yl)pyrrolidin-3-yl]methyl})methyl-λ6- sulfanone


 


239R




(R)-imino({[(3R)-1-(8-methoxyquinazolin-4- yl)pyrrolidin-3-yl]methyl})methyl-λ6- sulfanone


 


239S




(S)-imino({[(3R)-1-(8-methoxyquinazolin-4- yl)pyrrolidin-3-yl]methyl})methyl-λ6- sulfanone


 


240




[8-(6,7-dimethoxyquinazolin-4-yl)-2,8- diazaspiro[4.5]decan-2-yl](2-hydroxy-2- methylpropyl)imino-λ6-sulfanone


 


241




{8-[6-(fluoromethoxy)-7-methoxyquinazolin- 4-yl]-2,8-diazaspiro[4.5]decan-2- yl}(imino)methyl-λ6-sulfanone


 


242




imino(methyl)[(1s,4s)-4-[(7-methoxyquinolin- 4-yl)oxy]cyclohexyl]-λ6-sulfanone


 


243




imino(methyl)[(1r,4r)-4-[(7-methoxyquinolin- 4-yl)oxy]cyclohexyl]-λ6-sulfanone


 


244




[cyclopropyl(3-{[(6-fluoro-7- methoxyquinolin-4- yl)oxy]methyl}phenyl)imino-λ6-sulfanyl]one


 


245




imino({3-[(1S)-1-[(7-methoxyquinolin-4- yl)oxy]ethyl]phenyl})methyl-λ6-sulfanone


 


246




imino({[1-(8-methoxyquinazolin-4-yl)-1,2,3,6- tetrahydropyridin-4-yl]methyl})methyl-λ6- sulfanone









In some variations, any of the compounds described herein, such as a compound of Formula (I), (I-1), (1-2), (1-3), (IA), (1-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or any variation thereof, or a compound of Table 1 may be deuterated (e.g., a hydrogen atom is replaced by a deuterium atom). In some of these variations, the compound is deuterated at a single site. In other variations, the compound is deuterated at multiple sites. Deuterated compounds can be prepared from deuterated starting materials in a manner similar to the preparation of the corresponding non-deuterated compounds. Hydrogen atoms may also be replaced with deuterium atoms using other method known in the art.
Any formula given herein, such as Formula (I), (I-1), (I-2), (I-3), (I4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof in any ratio, are considered within the scope of the formula. Thus, any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. Additionally, any formula given herein is intended to refer also to any one of hydrates, solvates, and amorphous and polymorphic forms of such compounds, and mixtures thereof, even if such forms are not listed explicitly. In some embodiments, the solvent is water and the solvates are hydrates.
Representative examples of compounds detailed herein, including intermediates and final compounds, are depicted in the tables and elsewhere herein. It is understood that in one aspect, any of the compounds may be used in the methods detailed herein, including, where applicable, intermediate compounds that may be isolated and administered to an individual.
The compounds depicted herein may be present as salts even if salts are not depicted, and it is understood that the compositions and methods provided herein embrace all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.
In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, provided are pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
Any variation or embodiment of W, Ring A, a1, a2, b1, b2, c1, c2, c3, c4, d1, d2, d3, d4, e1, e2, Y, X1, X2, X3, X4, X5, X6, R1a, R2a, R1a1, R1b, R2b, R3b, R4b, R5b, R6b, R1c, R2c, R3c, R4c, R5c, R6c, R7c, or L provided herein can be combined with every other variation or embodiment of W, Ring A, a1, a2, b1, b2, c1, c2, c3, c4, d, d2, d3, d4, e1, e2, Y, X1, X2, X3, X4, X5, X6, R1a, R2a, R1a1, R1b, R2b, R3b, R4b, R5b, R6b, R1c, R2c, R3c, R4c, R5c, R6c, R7c, or L as if each combination had been individually and specifically described.
As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence.
Formula (I) includes all subformulae thereof. For example, Formula (I) includes compounds of Formula (I-1), (I-2), (I-3), (I4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig).
The compound names provided herein, including in Table 1, are provided by ChemDraw Professional 19.1. One of skilled in the art would understand that the compounds may be named or identified using various commonly recognized nomenclature systems and symbols. By way of example, the compounds may be named or identified with common names, systematic or non-systematic names. The nomenclature systems and symbols that are commonly recognized in the art of chemistry include, for example, Chemical Abstract Service (CAS), ChemBioDraw Ultra, and International Union of Pure and Applied Chemistry (IUPAC).
Compositions
Also provided are compositions, such as pharmaceutical compositions, that include a compound disclosed and/or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, carriers, excipients, and the like. Suitable medicinal and pharmaceutical agents include those described herein. In some embodiments, the pharmaceutical composition includes a pharmaceutically acceptable excipient or adjuvant and at least one chemical entity as described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, provided are compositions, such as pharmaceutical compositions that contain one or more compounds described herein, or a pharmaceutically acceptable salt thereof.
In some embodiments, provided is a pharmaceutically acceptable composition comprising a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some aspects, a composition may contain a synthetic intermediate that may be used in the preparation of a compound described herein. The compositions described herein may contain any other suitable active or inactive agents.
Any of the compositions described herein may be sterile or contain components that are sterile. Sterilization can be achieved by methods known in the art. Any of the compositions described herein may contain one or more compounds that are substantially pure.
Also provided are packaged pharmaceutical compositions, comprising a pharmaceutical composition as described herein and instructions for using the composition to treat a patient suffering from a disease or condition described herein.
Methods of Use
As described herein, the compounds of the present disclosure are inhibitors of ENPP1 enzymatic activity. In one aspect, the compounds and pharmaceutical compositions herein may be used to inhibit ENPP1. In another aspect, the compounds and pharmaceutical compositions herein may be used to treat or prevent a disease or condition in an individual.
The inhibitory activity of the compounds described herein against ENPP1 may be determined and measured by methods known in the art including, but not limited to, inhibition of ENPP1 hydrolysis of 2′,3′-cGAMP (Cyclic guanosine monophosphate-adenosine monophosphate) (Mardjuki, R. et al. (2020), Journal of Biological Chemistry, 295(15), 4881-4892), inhibition of ENPP1 hydrolysis of pNP-TMP (p-nitrophenyl thymidine 5′-monophosphate), or inhibition of ENPP1 hydrolysis of pNP-AMP (p-nitrophenyl adenosine 5′-monophosphate) (Lee, S. et al. (2017), Frontiers in Pharmacology 8, 54).
In one aspect, provided herein is a method of inhibiting ENPP1 comprising contacting a cell with an effective amount of a compound or a pharmaceutical composition as described herein. In some embodiments, provided herein are methods of inhibiting ENPP1 comprising contacting a cell with an effective amount of a compound Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of inhibiting ENPP1 comprising contacting a cell with an effective amount of a pharmaceutical composition comprising a compound a compound Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In one variations of the aforementioned embodiments, the cell is contacted in vitro. In other variations of the aforementioned embodiments, the cell is contacted in vivo.
In another aspect, the compounds and pharmaceutical compositions herein may be used to treat or prevent a disease or condition in an individual, comprising administering an effective amount of a compound or a pharmaceutical composition as described herein. When used in a prophylactic manner, the compounds disclosed and/or described herein may prevent a disease or disorder from developing in an individual at risk of developing the disease or disorder, or lessen the extent of a disease or disorder that may develop.
In some embodiments, provided herein are methods of treating or preventing a disease or condition in an individual, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition as described herein. In some embodiments, provided herein are methods of treating or preventing a disease or condition in an individual, comprising administering to the subject a therapeutically effective amount of a compound Formula (I), (I-1), (I-2), (I-3), (I4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods of treating or preventing a disease or condition in an individual, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound a compound Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or a compound of Table 1, or a pharmaceutically acceptable salt thereof.
In some embodiments, the disease or condition is mediated by ENPP1. In some embodiments, the disease or condition is cancer. In some embodiments, the disease or condition is a bacterial or viral infection. In certain embodiments, the disease or condition is a bacterial infection. In certain other embodiments, the disease or condition is a viral infection. In some embodiments, the disease or condition is insulin resistance. In some embodiments, the disease or condition is type II diabetes. In some embodiments, the disease or condition is chondrocalcinosis. In some embodiments, the disease or condition is osteoarthritis. In some embodiments, the disease or condition is a soft-tissue calcification disorder. In certain embodiments, the disease or condition is cardiac calcification after heart injury. In some embodiments, the disease or condition is calcium pyrophosphate deposition disorder (CPPD). In some embodiments, the disease or condition is hypophosphatasia (HPP).
In some embodiments, provided are methods of treating or preventing cancer in an individual, comprising administering to the individual in need thereof a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided are methods of treating or preventing cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one chemical entity as described herein. Also provided herein is the use of a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a compound of Table 1, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of a disease in a subject.
In some embodiments, provided herein are methods of treating cancer, comprising administering to an individual in need thereof a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. Also provided herein is the use of a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a compound of Table 1, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of a cancer.
In some embodiments, the provided are methods of treating a bacterial and/or viral infection in an individual, comprising administering to the individual in need thereof a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. Also provided herein is the use of a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a compound of Table 1, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of a bacterial and/or viral infection.
In some embodiments, provided are methods of treating insulin resistance in an individual, comprising administering to the individual in need thereof a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. Also provided herein is the use of a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a compound of Table 1, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of a insulin resistance.
In some embodiments, the provided are methods of treating type II diabetes, comprising administering to the individual in need thereof a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. Also provided herein is the use of a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a compound of Table 1, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of type II diabetes.
In some embodiments, provided are methods of treating chondrocalcinosis in an individual, comprising administering to the individual in need thereof a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. Also provided herein is the use of a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a compound of Table 1, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of chondrocalcinosis.
In some embodiments, provided are methods of treating osteoarthritis in an individual, comprising administering to the individual in need thereof a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. Also provided herein is the use of a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a compound of Table 1, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of osteoarthritis.
In some embodiments, provided are methods of treating a soft-tissue calcification disorder in an individual, comprising administering to the individual in need thereof a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the soft-tissue calcification disorder is cardiac calcification after heart injury. Also provided herein is the use of a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a compound of Table 1, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of a soft-tissue calcification disorder. In certain embodiments, the soft-tissue calcification disorder is cardiac calcification after heart injury.
In some embodiments, provided are methods of treating calcium pyrophosphate deposition disorder (CPPD) in an individual, comprising administering to the individual in need thereof a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. Also provided herein is the use of a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a compound of Table 1, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of calcium pyrophosphate deposition disorder (CPPD).
In some embodiments, provided are methods of treating hypophosphatasia (HPP) in an individual, comprising administering to the individual in need thereof a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. Also provided herein is the use of a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig), or a compound of Table 1, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of hypophosphatasia (HPP).
Dosages
The compounds and compositions disclosed and/or described herein are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease state. While human dosage levels have yet to be optimized for the chemical entities described herein, generally, a daily dose ranges from about 0.01 to 100 mg/kg of body weight; in some embodiments, from about 0.05 to 10.0 mg/kg of body weight, and in some embodiments, from about 0.10 to 1.4 mg/kg of body weight. Thus, for administration to a 70 kg person, in some embodiments, the dosage range would be about from 0.7 to 7000 mg per day; in some embodiments, about from 3.5 to 700.0 mg per day, and in some embodiments, about from 7 to 100.0 mg per day. The amount of the chemical entity administered will be dependent, for example, on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician. For example, an exemplary dosage range for oral administration is from about 5 mg to about 500 mg per day, and an exemplary intravenous administration dosage is from about 5 mg to about 500 mg per day, each depending upon the compound pharmacokinetics.
Administration of the compounds and compositions disclosed and/or described herein can be via any accepted mode of administration for therapeutic agents including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the compound or composition is administered orally or intravenously. In some embodiments, the compound or composition disclosed and/or described herein is administered orally.
Pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms, such as tablet, capsule, powder, liquid, suspension, suppository, and aerosol forms. The compounds disclosed and/or described herein can also be administered in sustained or controlled release dosage forms (e.g., controlled/sustained release pill, depot injection, osmotic pump, or transdermal (including electrotransport) patch forms) for prolonged timed, and/or pulsed administration at a predetermined rate. In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of a precise dose.
The compounds disclosed and/or described herein can be administered either alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium croscarmellose, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). Generally, depending on the intended mode of administration, the pharmaceutical composition will contain about 0.005% to 95%, or about 0.5% to 50%, by weight of a compound disclosed and/or described herein. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa.
In some embodiments, the compositions will take the form of a pill or tablet and thus the composition may contain, along with a compounds disclosed and/or described herein, one or more of a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and/or a binder (e.g., starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives). Other solid dosage forms include a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides) encapsulated in a gelatin capsule.
Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing or suspending etc. a compound disclosed and/or described herein and optional pharmaceutical additives in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of the compound contained in such parenteral compositions depends, for example, on the physical nature of the compound, the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.01% to 10% in solution are employable, and may be higher if the composition is a solid which will be subsequently diluted to another concentration. In some embodiments, the composition will comprise from about 0.2 to 2% of a compound disclosed and/or described herein in solution.
Pharmaceutical compositions of the compounds disclosed and/or described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the pharmaceutical composition may have diameters of less than 50 microns, or in some embodiments, less than 10 microns.
In addition, pharmaceutical compositions can include a compound disclosed and/or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, and the like. Suitable medicinal and pharmaceutical agents include those described herein.
Kits
Also provided are articles of manufacture and kits containing any of the compounds or pharmaceutical compositions provided herein. The article of manufacture may comprise a container with a label. Suitable containers include, for example, bottles, vials, and test tubes. The containers may be formed from a variety of materials such as glass or plastic. The container may hold a pharmaceutical composition provided herein. The label on the container may indicate that the pharmaceutical composition is used for preventing, treating or suppressing a condition described herein, and may also indicate directions for either in vivo or in vitro use.
In one aspect, provided herein are kits containing a compound or composition described herein and instructions for use. The kits may contain instructions for use in the treatment of any disease or condition described herein in an individual in need thereof. A kit may additionally contain any materials or equipment that may be used in the administration of the compound or composition, such as vials, syringes, or IV bags. A kit may also contain sterile packaging.
Combinations
The compounds and compositions described and/or disclosed herein may be administered alone or in combination with other therapies and/or therapeutic agents useful in the treatment of the aforementioned disorders.
The compounds and compositions described and/or disclosed herein may be combined with one or more other therapies to treat the diseases or conditions described herein, including but not limited to cancer, bacterial and/or viral infections, insulin resistance, type II diabetes, chondrocalcinosis, osteoarthritis, calcium pyrophosphate deposition disorder (CPPD), hypophosphatasia, and soft-tissue calcification disorders (such as cardiac calcification after heart injury).
General Synthetic Methods
Compounds of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) will now be described by reference to illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. In addition, one of skill in the art will recognize that protecting groups may be used to protect certain functional groups (amino, carboxy, or side chain groups) from reaction conditions, and that such groups are removed under standard conditions when appropriate. Unless otherwise specified, the variables are as defined above in reference to Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig).
Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g. a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
General methods of preparing compounds described herein are depicted in exemplified methods below. Variable groups in the schemes provided herein are defined as for Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ia-4), (Ia-5), (Ia-6), (Ib), (Ic), (Id), (Ie), (Ie-1), (Ie-2), (If), or (Ig) or any variation thereof. Other compounds described herein may be prepared by similar methods.
In some embodiments, compounds provided herein may be synthesized according to Scheme 1, Scheme 2, Scheme 3, and/or Scheme 4.




Scheme 1 outlines an exemplary route to the synthesis of compounds of general formula IV wherein the group W1 has structure a, b, c or d. Compounds of general formula III are prepared from heteroaryl chlorides of general formula I and alcohols or phenols of general formula II via an Ullman-type coupling or SNAr reaction with heat, as either a neat mixture or in a suitable solvent such as isopropanol (reaction step a). Compounds of general formula III are then oxidized with, for example, PhI(OAc)2, in the presence of an ammonia source, such as ammonium acetate, to provide compounds of general formula IV (reaction step b).




Scheme 2 summarizes an exemplary route toward compounds of general formula VIII where A is an aryl or heteroaryl ring or bicycle. Brominated heteroaryls of general formula V are cross-coupled with boronic acids or boronic esters of general formula VI, wherein the group W2 is a, b or c, by heating in the presence of a palladium catalyst, such as Pd(PPh3)4 or Pd(dppf)Cl2, and a base, such as Na2PO4, Na2CO3 or CsCO3, under with heating, for example between 80 and 120° C. (reaction step c), to yield compounds of general formula VII Sulfoximines of general formula VIII may be prepared from compounds of general formula VII via conditions described in Scheme 1 for the preparation of general formula III (reaction step b).




Compounds of the general formula XI may be prepared as outlined in Scheme 3. Heteroaryl chlorides of general formula I are reacted with amines of general formula IX under SNAr conditions that include heating, for example between 80 C and 100° C. with an appropriate base, such as K2CO3, Et3N or iPr2NEt, in a polar solvent such as DMF (reaction step d) to give compounds of general formula X. Sulfoximines of general formula XI may be prepared from the compounds of general formula X via conditions described in Scheme 1 for the preparation of III (reaction step b). A variety of amines may be employed in this route. For example, amines of general formula IX wherein W3 is e-n will provide their respective sulfoximines XIV.




Amides of general formula XIV may be prepared from carboxylic acids of general formula XII with amines of general formula IX (wherein W3 is e-o) via intermediate general formula XIII. Various standard condensation reactions may be used (reaction step e). For example, carbodiimide reagents such as DCC or EDC may be employed with an acyl transfer reagent such as HOBt, HOAt, or DMAP. Uronium salts such as HATU or TBTU may also be used with addition of a base, such as iPr2NEt. Sulfoximines general formula XIV may be prepared from the intermediate compounds of general formula XIII via conditions described in Scheme 1 for the preparation of III (reaction step b).
Abbreviations
dppf: 1,1′-bis(diphenylphosphino)ferrocene
de: diastereomeric excess (% major diastereomer−% minor diastereomer)
DAST: diethylaminosulfur trifluoride
DCC: dicyclohexyl carbodiimide
DMF-DMA: dimethylformamide dimethylacetal
EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
ee: enantiomeric excess (% major enantiomer−% minor enantiomer)
HOBt: Hydroybenzotriazole
HOAt: 1-hydroxy-7-azabenzotriazole
DIAD: diisopropyl azodicarboxylate
DMAP: 4-(dimethylamino)pyridine
HATU: (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
TBDMS: tert-butyl-dimethylsilyl
T-buxphos-Pd-G3: [(2-Di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate
TBTU: 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate
TFA: trifluoroacetic acid
Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
ENUMERATED EMBODIMENTS


    1. A compound of Formula (I)






or a pharmaceutically acceptable salt thereof, wherein:

W is




ring A is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, each of which is substituted or unsubstituted;
R1a and R2a are each independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, or C1-6 haloalkyl, wherein the C1-6 alkyl is optionally substituted by hydroxyl, C1-3 alkoxy, or C3-6 cycloalkyl;
Y is —N— or —CH—;
X1 is —CR1b— or —N—;
X2 is —CR2b— or —N—;
X3 is —CR3b— or —N—;
X4 is —CR4b— or —N—;
X5 is —CR5b— or —N—;
X6 is —CR6b— or —N—;
R1b-R6b are each independently hydrogen, halogen, hydroxyl, C1-4 alkoxy optionally substituted with one or more halo substituents, cyano, C1-3 alkyl, C1-3 haloalkyl, nitro, —NR1cR2c, —NHC(O)R3c, or —C(O)NR4cR5c;
L is a bond, —O—, —C(O)—, or —NR6c—;
R1c-R6c are each independently hydrogen or C1-3 alkyl;
a1, a2, and b1 are each independently 0, 1, 2, or 3; and
b2, c1-c4, d1-d4, e1, and e2 are each independently 1, 2, or 3.

    2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein W is






    3. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein W is






    4. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein W is






    5. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein W is






    6. The compound of any one of embodiments 2-5, or a pharmaceutically acceptable salt thereof, wherein A is aryl.
    7. The compound of any one of embodiments 2-5, or a pharmaceutically acceptable salt thereof, wherein A is heteroaryl.
    8. The compound of any one of embodiments 2-5, or a pharmaceutically acceptable salt thereof, wherein A is heterocycloalkyl.
    9. The compound of any one of embodiments 2-5, or a pharmaceutically acceptable salt thereof, wherein A is






    10. The compound of embodiment 3, or a pharmaceutically acceptable salt thereof, wherein A is






    11. The compound of embodiment 5, or a pharmaceutically acceptable salt thereof, wherein A is






    12. The compound of any one of embodiments 2-11, or a pharmaceutically acceptable salt thereof, wherein R1a is C1-6 alkyl.
    13. The compound of embodiment 12, or a pharmaceutically acceptable salt thereof, wherein R1a is methyl.
    14. The compound of any one of embodiments 2-13, or a pharmaceutically acceptable salt thereof, wherein b1 is 0.
    15. The compound of any one of embodiments 2-13, or a pharmaceutically acceptable salt thereof, wherein b1 is 2.
    16. The compound of embodiment 3, or a pharmaceutically acceptable salt thereof, wherein W is






    17. The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein W is






    18. The compound of embodiment 5, or a pharmaceutically acceptable salt thereof, wherein W is






    19. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein W is






    20. The compound of embodiment 19, or a pharmaceutically acceptable salt thereof, wherein W is






    21. The compound of embodiment 19 or 20, or a pharmaceutically acceptable salt thereof, wherein R2a is C1-6 alkyl.
    22. The compound of embodiment 15, or a pharmaceutically acceptable salt thereof, wherein R2a is methyl.
    23. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein W is






    24. The compound of embodiment 23, or a pharmaceutically acceptable salt thereof, wherein W is






    25. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein W is






    26. The compound of embodiment 25, or a pharmaceutically acceptable salt thereof, wherein W is






    27. The compound of any one of embodiments 1-26, or a pharmaceutically acceptable salt thereof, wherein the






portion of Formula (I) is





    28. The compound of any one of embodiments 1-24, or a pharmaceutically acceptable salt thereof, wherein the






portion of Formula (I) is





    29. The compound of embodiment 27 or 28, or a pharmaceutically acceptable salt thereof, wherein R2b and R3b are methoxy, and R1b and R4b are hydrogen.
    30. The compound of embodiment 27 or 28, or a pharmaceutically acceptable salt thereof, wherein R3b is methoxy, and R1b, R2b, and R4b are hydrogen.
    31. The compound of any one of embodiments 1-30, or a pharmaceutically acceptable salt thereof, wherein L is a bond.
    32. The compound of any one of embodiments 1-30, or a pharmaceutically acceptable salt thereof, wherein L is —O—.
    33. The compound of any one of embodiments 1-30, or a pharmaceutically acceptable salt thereof, wherein L is —C(O)—.
    34. The compound of any one of embodiments 1-30, or a pharmaceutically acceptable salt thereof, wherein L is —NR6c—.
    35. The compound of any one of embodiments 1-30, or a pharmaceutically acceptable salt thereof, wherein L is —NH—.
    36. The compound of any one of embodiments 1-35, or a pharmaceutically acceptable salt thereof, wherein a1 is 0.
    37. The compound of any one of embodiments 1-35, or a pharmaceutically acceptable salt thereof, wherein a1 is 1.
    38. The compound of any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, wherein a2 is 0.
    39. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of compounds of Table 1.
    40. A pharmaceutical composition comprising a compound of any one of embodiments 1-39, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
    41. A method of inhibiting ENPP1 comprising contacting a cell with an effective amount of a compound of any one of embodiments 1-39, or a pharmaceutically acceptable salt thereof.
    42. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-39, or a pharmaceutically acceptable salt thereof.
    43. A method of treating a bacterial and/or viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-39, or a pharmaceutically acceptable salt thereof.
    44. A method of treating insulin resistance in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-39, or a pharmaceutically acceptable salt thereof.
    45. A method of treating type II diabetes in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-39, or a pharmaceutically acceptable salt thereof.
    46. A method of treating chondrocalcinosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-39, or a pharmaceutically acceptable salt thereof.
    47. A method of treating osteoarthritis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-39, or a pharmaceutically acceptable salt thereof.
    48. A method of treating a soft-tissue calcification disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-39, or a pharmaceutically acceptable salt thereof.
    49. The method of embodiment 48, wherein the soft-tissue calcification disorder is cardiac calcification after heart injury.
    50. A method of treating calcium pyrophosphate deposition disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-39, or a pharmaceutically acceptable salt thereof.
    51. A method of treating hypophosphatasia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1-39, or a pharmaceutically acceptable salt thereof.


Particular non-limiting examples are provided in the Example section below.
EXAMPLES
The following examples are offered to illustrate but not to limit the compositions, uses, and methods provided herein. The compounds are prepared using the general methods described above.
Synthesis of Intermediates
Synthesis of Intermediate 4-chloro-6-fluoro-7-methoxy-quinoline




Step 1: A mixture of 4-fluoro-3-methoxyaniline (10 g, 71 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (13 g, 92 mmol), trimethoxymethane (11 g, 99 mmol), and MeCN (150 mL) was degassed and purged with N2, and then stirred at 80° C. for 16 h under an N2 atmosphere. The mixture was concentrated, and the residue was triturated with petroleum ether at 25° C. for 30 min. The mixture was filtered and dried to provide 5-[(4-fluoro-3-methoxy-anilino)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (16 g).
Step 2: A mixture of 5-[(4-fluoro-3-methoxy-anilino)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (16 g, 53 mmol) and Dowtherm® A (80 mL) was degassed and purged with N2, and then the mixture was stirred at 220° C. for 3 h under N2 atmosphere. The mixture was triturated with petroleum ether at 25° C. for 30 min and the solid mixture was filtrated and dried to provide 6-fluoro-7-methoxy-quinolin-4-ol (10 g).
Step 3: To a mixture of 6-fluoro-7-methoxy-quinolin-4-ol (9.2 g, 48 mmol) and iPr2NEt (20 mL, 115 mmol) in MeCN (100 mL) was added POCl3 (60 mL, 644 mmol). Then the mixture was degassed and purged with N2 and stirred at 80° C. for 12 hours under an N2 atmosphere. The reaction mixture was cooled and concentrated. The residue was dissolved into ethyl acetate (200 ml) and was washed with saturated aqueous NaHCO3 (200 ml). The organic phase was washed with brine (150 mL), dried with Na2SO4, filtered, concentrated to provide 4-chloro-6-fluoro-7-methoxy-quinoline (9.8 g).
Synthesis of 4-chloro-7-methoxy-quinoline-6-carbonitrile




4-Chloro-7-methoxy-quinoline-6-carbonitrile was prepared in three steps from 4-amino-2-methoxy-benzonitrile in the manner described for the synthesis of intermediate 4-chloro-6-fluoro-7-methoxy-quinoline.
Synthesis of Intermediate 4-chloro-6-fluoro-7-methoxyquinazoline hydrochloride




Step 1: To a −15° C. mixture of 4-fluoro-3-methoxy-aniline (15 g, 110 mmol), CH2Cl2 (240 mL), and K2CO3 (15 g, 110 mmol), Br2 (5.5 mL, 110 mmol) was added slowly. After stirring for 1 h, the mixture was diluted with H2O (150 mL) and extracted with CH2Cl2 (100 mL×2). The organic phases were combined, extracted with brine (50 mL), dried over Na2SO4, filtered, concentrated, and triturated with CH2Cl2 (40 mL) and hexane (50 mL) at 20° C. for 30 min to provide 2-bromo-4-fluoro-5-methoxy-aniline (19 g).
A mixture of 2-bromo-4-fluoro-5-methoxy-aniline (24 g, 110 mmol), THF (250 mL) was added (Boc)2O (57 g, 260 mmol), and DMAP (2.7 g, 22 mmol) was stirred at 20° C. for 12 h. The mixture was concentrated, diluted with H2O (100 mL), and extracted with EtOAc (80 mL×2). The extracts were combined, washed with brine (50 mL), dried over Na2SO4, filtered, concentrated, and purified by chromatography (10-50% EtOAc in petroleum ether) to provide tert-butyl N-(2-bromo-4-fluoro-5-methoxy-phenyl)-N-tert-butoxycarbonyl-carbamate (41 g).
Step 2: To a −78° C. mixture of tert-butyl N-(2-bromo-4-fluoro-5-methoxy-phenyl)-N-tert-butoxycarbonyl-carbamate (20 g, 48 mmol) and THF (150 mL) was added n-BuLi (2.5 M in hexanes, 29 mL) and the mixture was stirred at −78° C. for 1 h. Saturated aqueous NH4Cl (5.0 mL) was added at 0° C., followed by H2O (100 mL). The mixture was extracted with EtOAc (70 mL×2), and the extracts were combined, washed with brine (40 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (10-50% EtOAc in petroleum ether to provide tert-butyl 2-((tert-butoxycarbonyl)amino)-5-fluoro-4-methoxybenzoate (16 g).
Step 3: To a mixture of tert-butyl 2-(tert-butoxycarbonylamino)-5-fluoro-4-methoxybenzoate (9.0 g, 26 mmol), and CH2Cl2 (50 mL) was added TFA (21 mL, 280 mmol). The mixture was stirred at 20° C. for 2 h, concentrated, diluted with H2O (40 mL), and extracted with EtOAc (30 mL×2). The combined extracts were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (10-100% EtOAc in petroleum ether) to provide 2-amino-5-fluoro-4-methoxybenzoic acid (3.1 g).
Step 4: A mixture of 2-amino-5-fluoro-4-methoxy-benzoic acid (1.0 g, 5.4 mmol) and formamide (9.1 mL, 230 mmol) was stirred at 160° C. for 5 h. The mixture was combined with H2O (20 mL). The resulting precipitate was filtered and triturated with MeOH (8.0 mL) at 20° C. for 30 min to provide 6-fluoro-7-methoxyquinazolin-4-ol (0.42 g).
Step 5: A mixture of 6-fluoro-7-methoxy-quinazolin-4-ol (0.40 g, 2.1 mmol) in SOCl2 (8.0 mL) and DMF (15 mg) was stirred at 80° C. for 12 h. The mixture was concentrated to provide 4-chloro-6-fluoro-7-methoxyquinazoline hydrochloride (0.55 g).
Synthesis of Intermediate 4-chloro-3-fluoro-6,7-dimethoxyquinoline




Step 1: Fuming nitric acid (98%, 7.5 mL, 210 mmol) was added slowly to a stirring mixture of 6,7-dimethoxyquinolin-4-ol (20 g, 97 mmol) and propionic acid (450 mL) at 20° C. The mixture was stirred at 100° C. for 6 h, then cooled to 0° C., and the resulting precipitate filtered and washed with hexane. The solids were triturated with a mixture of 1:5 MeOH/MTBE (300 mL) at 20° C. for 30 min to afford 6,7-dimethoxy-3-nitroquinolin-4-ol (22 g).
Step 2: A mixture of 6,7-dimethoxy-3-nitroquinolin-4-ol (11 g, 44 mmol), SOCl2 (100 mL), and DMF (0.32 g, 4.4 mmol) was stirred at 90° C. for 12 h, then was concentrated to provide 4-chloro-6,7-dimethoxy-3-nitroquinoline hydrochloride (13 g).
Step 3: SnCl2·2H2O (67 g, 300 mmol) was added to a mixture of 4-chloro-6,7-dimethoxy-3-nitroquinoline hydrochloride (13 g, 43 mmol), AcOH (29 mL), and EtOH (230 mL). The mixture was stirred at 80° C. for 12 h, then was concentrated, and combined with CH2Cl2 (400 mL) and NaOH (4M, 80 mL). The mixture was filtered through diatomaceous earth, and concentrated to provide 4-chloro-6,7-dimethoxy-quinolin-3-amine (10 g).
Step 4: To a 0° C. mixture of 4-chloro-6,7-dimethoxy-quinolin-3-amine (5.0 g, 21 mmol) and THF (50 mL) was added dropwise HBF4 (40%, 9.8 mL, 63 mmol). The mixture was stirred for 30 min, and NaNO2 (1.6 g, 23 mmol) in H2O (6.3 mL) was added dropwise at 0° C. The resulting mixture was stirred at 0° C. for 30 min, then it was filtered and the filtrate was stirred at 170° C. for 1 h. The reaction was concentrated and purified by silica chromatography (0-50% MeOH in CH2Cl2) to afford 4-chloro-3-fluoro-6,7-dimethoxyquinoline (0.24 g).
Synthesis of Intermediate 4-chloro-8-ethoxyquinazoline




Step 1: A degassed mixture of methyl 3-hydroxy-2-nitro-benzoate (15 g, 76 mmol), iodoethane (24 g, 152 mmol), K2CO3 (21 g, 152 mmol) and DMF (75 mL) was stirred at 20° C. for 12 h under an N2 atmosphere. The mixture was poured into water (150 mL) and extracted with EtOAc (2×80 mL). The extracts were washed with brine (50 mL), dried over Na2SO4, and concentrated to provide methyl 3-ethoxy-2-nitrobenzoate (17 g).
Step 2: A degassed mixture of methyl 3-ethoxy-2-nitrobenzoate (6.0 g, 27 mmol), NaOH (3.2 g, 80 mmol), H2O (30 mL), and THF (30 mL) was stirred at 70° C. for 1 h, then was concentrated to remove THF. The mixture was extracted with EtOAc (30 mL), then the aqueous phase was acidified with HCl (4 N) to pH 2 and extracted with EtOAc (2×50 mL). The extracts were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated to provide 3-ethoxy-2-nitro-benzoic acid (5.0 g).
Step 3: A degassed mixture of 3-ethoxy-2-nitrobenzoic acid (5.0 g, 24 mmol), MeOH (50 mL), and 10% Pd/C (2.0 g, 4.7 mmol) was stirred under H2 (15 psi) at 20° C. for 12 h. The mixture was filtered and the filtrate was concentrated to provide compound 2-amino-3-ethoxy-benzoic acid (2.8 g).
Step 4: A mixture of 2-amino-3-ethoxy-benzoic acid (2.8 g, 15 mmol) and formamide (2.8 g, 62 mmol) was stirred at 165° C. for 4 h. The reaction was poured into water (30 mL) and the resulting precipitate was filtered, washed with water (10 mL×2), and dried to provide 8-ethoxyquinazolin-4-ol (1.5 g).
Step 5: A mixture of 8-ethoxyquinazolin-4-ol (0.29 g, 1.5 mmol), SOCl2 (5 mL, 69 mmol) and DMF (11 mg, 150 μmol) was stirred at 80° C. for 12 hours. The mixture was concentrated to provide compound 4-chloro-8-ethoxyquinazoline (0.29 g).
Synthesis of Intermediate 4-chloro-8-ethoxyquinoline-3-carbonitrile




Step 1: To a mixture of methyl 3-ethoxy-2-nitrobenzoate (7.5 g, 33 mmol) in EtOH (50 mL) were added Fe (19 g, 0.33 mol) and NH4Cl (14 g, 0.27 mol). The mixture was stirred at 70° C. for 12 h, then was filtered and the filtrate was concentrated. The residue was combined with water (50 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with brine (30 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (9%-17% EtOAc in petroleum ether) to provide methyl 2-amino-3-ethoxy-benzoate (6.0 g).
Step 2: A degassed mixture of methyl 2-amino-3-ethoxy-benzoate (5.0 g, 26 mmol) and DMF-DMA (3.4 mL, 26 mmol) was stirred at 110° C. for 12 h under an N2 atmosphere. The mixture was concentrated to provide methyl 2-[(E)-dimethylaminomethyleneamino]-3-ethoxy-benzoate (4.5 g).
Step 3: To a mixture of CH3CN (1.7 mL, 32 mmol) and THF (25 mL) was added BuLi (2.5 M, 13) at −70° C. After stirring for 0.5 h, methyl 2-[(E)-dimethylaminomethyleneamino]-3-ethoxy-benzoate (4.0 g, 16 mmol) in THF (30 mL) was added and the mixture and stirred at −70 for 1.5 h. HOAc (3.7 mL, 64 mmol) was added, and the mixture was poured into water (30 mL) and the resulting mixture was extracted with EtOAc (2×30 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to provide 8-ethoxy-4-hydroxy-quinoline-3-carbonitrile (2.1 g).
Step 4: A degassed mixture of 8-ethoxy-4-hydroxy-quinoline-3-carbonitrile (0.25 g, 1.2 mmol), SOCl2 (5 mL, 69 mmol) and DMF (20 μL, 0.26 mmol) was stirred at 90° C. for 2 h under an N2 atmosphere. The mixture was concentrated to provide 4-chloro-8-ethoxyquinoline-3-carbonitrile (0.40 g).
Synthesis of Intermediate 4-chloro-8-(fluoromethoxy)quinoline-3-carbonitrile




Step 1: To a mixture of methyl 3-hydroxy-2-nitro-benzoate (3.0 g, 15 mmol) and DMF (30 mL) was added 65% NaH (1.4 g, 38 mmol), which was stirred at 0° C. for 0.5 h. Fluoro(iodo)methane (2.9 g, 18 mmol) was added at 25° C. and the mixture stirred for 12 h. Saturated aqueous NH4Cl (20 ml) was added slowly, and the mixture was filtered, concentrated, and combined with EtOAc (50 mL) and washed with H2O (30 ml×3). The extracts were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to provide methyl 3-(fluoromethoxy)-2-nitro-benzoate (3.3 g).
Step 2: Pd/C (1.0 g, 10%) was added to methyl 3-(fluoromethoxy)-2-nitro-benzoate (4.9 g, 21 mmol) and EtOH (50 mL) under an N2 atmosphere. The suspension was degassed then stirred under an H2 (15 psi) at 20° C. for 8 h. The mixture was filtered and the filtrate was concentrated to provide methyl 2-amino-3-(fluoromethoxy)benzoate (3.50 g).
Steps 3-5 were run from 2-amino-3-(fluoromethoxy)benzoate in the manner described in Steps 2-4 of the synthesis of Intermediate 4-chloro-8-ethoxyquinoline-3-carbonitrile to provide 4-chloro-8-(fluoromethoxy)quinoline-3-carbonitrile.
Synthesis of Intermediate 4-chloro-5-fluoro-8-methoxyquinoline-3-carbonitrile




Step 1: A mixture of 5-fluoro-2-methoxy-aniline (4.0 g, 28 mmol) and ethyl (Z)-2-cyano-3-ethoxy-prop-2-enoate (4.8 g, 28 mmol) was stirred at 150° C. for 2 h. The resulting solid was cooled and triturated with petroleum ether (15 mL) at 20° C. for 30 min to give (E)-ethyl 2-cyano-3-((5-fluoro-2-methoxyphenyl)amino)acrylate (7.0 g).
Step 2: A mixture of (E)-ethyl 2-cyano-3-((5-fluoro-2-methoxyphenyl)amino)acrylate (1.0 g, 3.8 mmol) and Ph2O (10 mL) was stirred at 250° C. for 6 h, then at 280° C. for 6 h. The mixture was cooled and the resulting precipitate was stirred with petroleum ether (30 mL) at 80° C. for 15 min and cooled to 40° C. The suspension was filtered, and the filter cake was washed with petroleum ether (5 mL×3) to give 5-fluoro-4-hydroxy-8-methoxyquinoline-3-carbonitrile (0.58 mg).
Step 3: A mixture of 5-fluoro-4-hydroxy-8-methoxyquinoline-3-carbonitrile (0.50 g, 2.3 mmol) and POCl3 (3.0 mL, 32 mmol) was stirred at 120° C. for 12 h. The mixture was concentrated and saturated NaHCO3 (5 mL) was added to adjust its pH to 8. The solids were isolated by filtration and the filter cake was washed with water (0.5 mL×3) and petroleum ether (3 mL). This solid was triturated with MTBE (8 mL) at 70° C. for 15 min and cooled to 20° C., filtered, washed with MTBE (0.5 mL×3) and petroleum ether (3 mL) to provide 4-chloro-5-fluoro-8-methoxyquinoline-3-carbonitrile (0.47 g).
Synthesis of Intermediate 4-chloro-8-methoxy-2-methylquinoline-3-carbonitrile




Step 1: A degassed mixture of ethyl (E)-2-cyano-3-ethoxy-but-2-enoate (6.3 g, 34 mmol), 2-methoxyaniline (3.9 mL, 34 mmol), and EtOH (50 mL) was stirred at 90° C. for 4 h under an N2 atmosphere. The mixture was concentrated and purified by silica chromatography (0-25% EtOAc in petroleum ether) to provide ethyl (Z)-2-cyano-3-(2-methoxyanilino)but-2-enoate (2.7 g).
Step 2: Ethyl (Z)-2-cyano-3-(2-methoxyanilino)but-2-enoate (2.5 g, 9.0 mmol) and DOWTHERM® A (50 mL) were stirred at 280° C. for 10 h. The mixture was triturated with petroleum ether at 20° C. for 30 min to provide 4-hydroxy-8-methoxy-2-methyl-quinoline-3-carbonitrile (1.3 g).
Step 3: A degassed mixture of 4-hydroxy-8-methoxy-2-methyl-quinoline-3-carbonitrile (0.85 g, 3 mmol), DMF (4.3 μL, 55 μmol), and SOCl2 (10 mL) was stirred at 20° C. for 12 h under an N2 atmosphere. The mixture was concentrated and purified by silica chromatography (0-100% EtOAc in petroleum ether) to provide 4-chloro-8-methoxy-2-methylquinoline-3-carbonitrile (0.40 g).
Synthesis of Intermediate 4-chloro-6, 7-dimethoxy-3-methylcinnoline




Step 1: To a mixture of 2-amino-4, 5-dimethoxybenzonitrile (7.0 g, 39 mmol) and THF (70 mL) was added EtMgCl (2 M, 79 mL) slowly at 0° C. The mixture was stirred at 50° C. for 2 h, aqueous HCl was added (2 N, 80 mL), and the pH adjusted to 9 by the addition of saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc (2×100 mL), extracts were combined, washed with brine (50 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (5-100% EtOAc in petroleum ether) to provide 1-(2-amino-4,5-dimethoxy-phenyl)propan-1-one (4.3 g).
Step 2: To a mixture of 1-(2-amino-4, 5-dimethoxy-phenyl) propan-1-one (3.3 g, 16 mmol), conc. HCl (53 mL), and H2O (6.6 mL) was added NaNO2 (1.1 g, 16 mmol) in H2O (6.6 mL) slowly over 10 min at −5° C. The mixture was stirred at −5° C. for 1 h, then at 60° C. for 4 h. The solids were isolated by filtration and washed with H2O (20.0 mL×3) and dried to provide crude 6,7-dimethoxy-3-methyl-cinnolin-4-ol (4.4 g).
Step 3: A mixture of crude 6,7-dimethoxy-3-methyl-cinnolin-4-ol (4.3 g, 520 mmol), SOCl2 (30 mL), and DMF (0.15 mL, 2.0 mmol) was stirred at 80° C. for 2 h under an N2 atmosphere. The mixture was concentrated and purified by preparative HPLC (15-45% MeCN in water, 10 mM NH4CO3) to provide 4-chloro-6,7-dimethoxy-3-methylcinnoline (1.5 g).
Synthesis of Intermediate 4-chloro-3-fluoro-8-methoxyquinoline




Step 1: To POCl3 (60 mL) was added 2-fluoropropanedioic acid (1 g, 8.2 mmol) and the mixture was heated to reflux for 30 min then cooled to 60° C. and 2-methoxyaniline (1.0 g, 8.2 mmol) was added slowly. The mixture was heated to 140° C. for 15 h, concentrated, and ice water (5 g) was added. After stirring for 0.5 h, ammonia was added until the pH reached 10. The resulting precipitate was collected by filtration and purified by silica chromatography (0-50% EtOAc in petroleum ether) to provide 2,4-dichloro-3-fluoro-8-methoxy-quinoline (0.38 g).
Step 2: A mixture of 2,4-dichloro-3-fluoro-8-methoxy-quinoline (0.38 g, 1.54 mmol), H2O (2.5 mL), dioxane (5 mL), 10% Pd/C (0.2 g), Et3N (3.9 mL, 28 mmol), and formic acid (0.23 μL, 6.2 mmol) was stirred at 90° C. for 16 h. The mixture was filtered, and the filtrate was concentrated and purified by silica chromatography (0-50% EtOAc in petroleum ether) to provide 4-chloro-3-fluoro-8-methoxyquinoline (0.12 g).
Synthesis of Intermediate 4,6-dichloro-7-methoxycinnoline hydrochloride




Step 1: To a mixture of 1-(2-amino-4-methoxy-phenyl)ethanone (3.5 g, 21 mmol) and THF (60 mL) was added NCS (3.1 g, 23 mmol). The mixture was stirred at 60° C. for 2 h, poured into H2O (60 mL) and extracted with EtOAc (2×40 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, concentrated, and triturated with CH2Cl2/petroleum ether (5 mL) at 20° C. for 10 min to provide compound 1-(2-amino-5-chloro-4-methoxy-phenyl)ethanone (2.8 g).
Step 2: A solution of NaNO2 (0.97 g, 14 mmol) in H2O (7.5 mL) was added slowly to 1-(2-amino-5-chloro-4-methoxy-phenyl)ethanone (2.8 g, 14 mmol) in 12 N HCl (60 mL) at −5° C. The mixture was stirred for 1 h, then stirred at 60° C. for 4 hours. The resulting precipitate was filtered and washed with water (20 mL×2) to provide 6-chloro-7-methoxy-cinnolin-4-ol hydrochloride (1.8 g).
Step 3: A degassed mixture of 6-chloro-7-methoxy-cinnolin-4-ol hydrochloride (1.8 g, 8.5 mmol), DMF (62 mg, 0.85 mmol), and SOCl2 (49 g, 410 mmol) was stirred at 90° C. for 2 h. The mixture was concentrated provide compound 4,6-dichloro-7-methoxycinnoline hydrochloride (2.2 g).
Synthesis of Intermediate 4,6-dichloro-7-methoxy-3-methylcinnoline hydrochloride




Step 1: A degassed mixture of 2-amino-4-methoxy-benzonitrile (10 g, 67 mmol), NCS (9.9 g, 74 mmol), and THF (150 mL) was stirred at 60° C. for 12 h under an N2 atmosphere. The mixture was poured into saturated aqueous NaHCO3 (100 mL) extracted with EtOAc (2×100 mL). The extracts were washed with brine (50 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (5-25% EtOAc in petroleum ether) to provide 2-amino-5-chloro-4-methoxy-benzonitrile (7.2 g).
Step 2: To a mixture of 2-amino-5-chloro-4-methoxy-benzonitrile (4.7 g, 26 mmol) and THF (20 mL) was added EtMgCl (2 M in THF, 52 mL). The mixture was stirred at 50° C. for 12 h, and 50 mL of 2M HCl was added slowly. Saturated aqueous NaHCO3 was added to adjust the pH to 9, and the resulting mixture was extracted with EtOAc (2×80 mL). The extracts were washed with brine (10 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (5-17% EtOAc in petroleum ether) to provide 1-(2-amino-5-chloro-4-methoxy-phenyl)propan-1-one (3.2 g).
Step 3: A solution of NaNO2 (1.0 g, 15 mmol) in 10 mL of H2O was added slowly to a mixture of 1-(2-amino-5-chloro-4-methoxy-phenyl)propan-1-one (3.2 g, 15 mmol), H2O (6 mL), and conc. HCl (45 mL) at −5° C. After addition, the mixture was stirred for 1 h and then at 50° C. for 3 h. The resulting precipitate was filtered and washed with water (50 mL×2) to provide 6-chloro-7-methoxy-3-methyl-cinnolin-4-ol (2.5 g).
Step 4: A mixture of 6-chloro-7-methoxy-3-methyl-cinnolin-4-ol (2.5 g, 11 mmol), SOCl2 (25 mL, 0.35 mol), DMF (40 mg, 0.55 mol) was stirred at 80° C. for 2 h, then was concentrated to provide 4,6-dichloro-7-methoxy-3-methylcinnoline hydrochloride (3.2 g).
Synthesis of Intermediate 1-(3-((4-hydroxyphenyl)thio)azetidin-1-yl)ethan-1-one




Step 1: To a 0° C. mixture of 1-(3-hydroxyazetidin-1-yl) ethanone (2.0 g, 17 mmol), CH2Cl2 (20 mL) was added Et3N (7.3 mL, 52 mmol) and toluene sulfonyl chloride (5.0 g, 26 mmol). The mixture was stirred at 20° C. for 2 h, then was poured into water (30.0 mL) and extracted with EtOAc (2×30 mL). The combined extracts were washed with brine (10.0 mL), dried over Na2SO4, concentrated and purified by silica chromatography (0-100% EtOAc/petroleum ether) to provide (1-acetylazetidin-3-yl) 4-methylbenzenesulfonate (4.35 g).
Step 2: A degassed mixture of (1-acetylazetidin-3-yl) 4-methylbenzenesulfonate (2.0 g, 7.4 mmol), DMSO (20 mL), Cs2CO3 (4.8 g, 15 mmol) and 4-methoxybenzenethiol (1.8 mL, 15 mmol) was stirred at 60° C. for 12 h under an N2 atmosphere. The mixture was poured into water (30.0 mL) and extracted with EtOAc (30.0 mL×2). The combined extracts were washed with brine (20.0 mL×2), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-100% EtOAc/petroleum ether) to provide 1-[3-(4-methoxyphenyl)sulfanylazetidin-1-yl]ethanone (1.5 g).
Step 3: To a degassed −78° C. mixture of 1-[3-(4-methoxyphenyl)sulfanylazetidin-1-yl]ethanone (1.4 g, 6.0 mmol) and CH2Cl2 (20 mL) was added BBr3 (2.9 mL, 30 mmol). The mixture was stirred at 25° C. for 12 h under an N2 atmosphere, MeOH (5.0 mL) added slowly, and the resulting mixture was concentrated, combined with water (10 mL), and extracted with EtOAc (10.0 mL×2). The combined extracts were washed with aqueous of NaHCO3 (10 mL×2), dried over Na2SO4, filtered, and concentrated to provide 1-(3-((4-hydroxyphenyl)thio)azetidin-1-yl)ethan-1-one (1.4 g, 78% purity).
Synthesis of Intermediate 6-(methylthio)pyridin-3-ol




A solution of t-BuLi (1.9 M, 3.2 mL, 6.0 mmol) was added dropwise to 2-bromo-5-hydroxypyridine (0.35 g, 2.0 mmoL) and 10 mL of THF at −78° C. The mixture was stirred for 10 min at −78 C and dimethyldisulfide (0.36 mL, 4.0 mmol) was added slowly. The resulting mixture was stirred for 15 min, then warmed to room temperature and stirred for 2 h. Saturated aqueous NH4Cl and 2M HCl were added until a pH of 3 was achieved. The phases were separated, and the aqueous phase was extracted with EtOAc (3×). The initial organic phase was combined with the EtOAc extracts, dried over Na2SO4, filtered, and concentrated to provide 6-(methylthio)pyridin-3-ol (0.22 g, 1.5 mmol).
Synthesis of Intermediate 4-(cyclopropylthio)phenol




Step 1: A mixture of 4-methoxybenzenethiol (0.37 g, 2.6 mmol), K2CO3 (0.54 g, 3.9 mmol), DMF (5 mL), and cyclopropyl bromide (0.27 mL, 3.4 mmol) was heated to 120° C. under and Ar atmosphere overnight. After cooling, cold water and EtOAc were added. The organic phase was separated and washed with cold water (4×) and brine. The organic layer was dried over Na2SO4, filtered, concentrated, then purified by chromatography on silica get (1-25% EtOAc in heptane) to obtain 0.38 g of cyclopropyl(4-methoxyphenyl)sulfane.
Step 2: To a mixture of cyclopropyl(4-methoxyphenyl)sulfane (0.36 g, 2.0 mmol) and CH2Cl2 (50 mL) at 5° C. was added BBr3 (1M in CH2Cl2, 11 mL, 11 mmol). After stirring for 2 days at room temperature, additional BBr3 (1M in CH2Cl2, 11 mL, 11 mmol) was added and the mixture stirred overnight. Saturated aqueous NaHCO3 was added (15 mL) followed by water, and the mixture was extracted with CH2Cl2 (3×). The combined extracts were dried over Na2SO4, filtered and concentrated to provide 0.33 g of 4-(cyclopropylthio)phenol.
Synthesis of Intermediate (3-fluoro-5-(methylthio)phenyl)methanol




Step 1: A mixture of 1-bromo-3,5-difluoro-benzene (3.0 mL, 26 mmol), DMF (30 mL), and 93% NaSMe (1.8 mL, 26 mmol) was stirred at 20° C. for 12 h. The mixture was poured into saturated aqueous of NH4Cl (50 mL) and extracted with EtOAc (50 mL×2). The combined extracts were washed with brine (20 mL×2), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0  ̃20% EtOAc/petroleum ether) to provide 1-bromo-3-fluoro-5-methylsulfanylbenzene (2.8 g).
Step 2: BuLi (1.6 M, 5.4 mL) was added to 1-bromo-3-fluoro-5-methylsulfanylbenzene (1.9 g, 8.6 mmol) in THF (10 mL) at −78° C., and the mixture was stirred at −78° C. for 15 min. DMF (0.79 mL, 10 mmol) was added and the mixture was stirred at −78° C. for 0.5 h. Saturated aqueous NH4Cl (10 mL) was added at −78° C. and then the mixture was stirred at 25° C. for 30 min and was extracted with EtOAc (20 mL×3). The combined extracts were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by silica chromatography (0-35% EtOAc/petroleum ether) to provide 3-fluoro-5-methylsulfanyl-benzaldehyde (0.79 g).
Step 3: LiAlH4 (0.25 g, 6.5 mmol) was added to 3-fluoro-5-methylsulfanyl-benzaldehyde (0.74 g, 4.4 mmol) in THF (20 mL) at 0° C. The mixture was stirred at 20° C. for 2 h, and 0.25 mL of H2O, aqueous NaOH (15%, 0.25 mL), and an additional 0.25 mL of H2O were added slowly in sequence. The mixture was stirred at 20° C. for 10 min then extracted with EtOAc (10 mL×2). The combined extracts were dried over Na2SO4, filtered, concentrated and purified by silica chromatography (0-70% EtOAc/petroleum ether) to provide (3-fluoro-5-(methylthio)phenyl)methanol (0.47 g).
Synthesis of Intermediate (4-(methylthio)furan-2-yl)methanol




Step 1: A mixture of 4-bromofuran-2-carbaldehyde (5.0 g, 29 mmol), EtOH (9 mL), ethyl orthoformate (6.6 g, 45 mmol), and NH4Cl (1.5 g, 29 mmol) was stirred at 90° C. for 12 h. The mixture was concentrated, combined with 20 mL of H2O, and extracted with EtOAc (2×20 mL). The combined extracts were washed with saturated NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (5-10% EtOAc in petroleum ether) to provide 4-bromo-2-(diethoxymethyl)furan (6.4 g, 26 mmol).
Step 2: A solution of n-BuLi (2.5 M, 3.8 mL, 9.5 mmol) was slowly added to a stirring mixture of 4-bromo-2-(diethoxymethyl)furan (2.0 g, 8.0 mmol) and THF (20 mL) at −70° C. The mixture was stirred at −70° C. for 0.5 h, and (methyldisulfanyl)methane (0.91 g, 9.6 mmol) in THF (2 mL) was added. The mixture was poured to sat NH4Cl (30 mL) and extracted with EtOAc (2×30 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to provide 2-(diethoxymethyl)-4-methylsulfanyl-furan (1.7 g) that was used without further purification.
Step 3: A mixture of 2-(diethoxymethyl)-4-methylsulfanyl-furan (1.7 g, 7.9 mmol), THF (20 mL), and 2M HCl (20 mL, 40 mmol) was stirred at 20° C. for 0.5 h, then was poured into water (30 mL) and extracted with EtOAc (2×30 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, and concentrated to provide 4-methylsulfanylfuran-2-carbaldehyde (1.1 g) that was used without purification.
Step 4: To a mixture of 4-methylsulfanylfuran-2-carbaldehyde (1.1 g, 7.7 mmol) and MeOH (10 mL) was added NaBH4 (590 mg, 15 mmol). The mixture was stirred at 25° C. for 1 h, then was concentrated, combined with H2O (30 mL), and extracted with EtOAc (2×30 mL). The extracts were combined, washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (10-100% EtOAc in petroleum ether) to provide (4-(methylthio)furan-2-yl)methanol (0.7 g).
Synthesis of Intermediate (3-cyclopropylsulfanylphenyl) methanol




Step 1: A mixture of 3-sulfanylbenzoic acid (2.0 g, 13 mmol), DMSO (20 mL), t-BuOK (3.6 g, 32 mmol) and bromocyclopropane (1.6 mL, 20 mmol) was stirred at 80° C. for 24 h. Aqueous HCl (1 M) was added to bring the pH to 2-3, and the mixture was extracted with EtOAc (20 mL×2). The combined extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to provide 3-cyclopropylsulfanylbenzoic acid (2.4 g).
Step 2: To LiAlH4 (0.86 g, 23 mmol) and THF (10 mL) was added slowly 3-cyclopropylsulfanylbenzoic acid (2.2 g, 11 mmol) in THF (20 mL) at 0° C. The mixture was stirred at 20° C. for 12 h and H2O (1 mL) was added slowly, followed by 15% NaOH (1 mL) and H2O (3 mL). The mixture was filtered, and the filtrate was concentrated, diluted with EtOAc (20 mL), washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (33-50% EtOAc in petroleum ether) to provide (3-cyclopropylsulfanylphenyl) methanol (2.0 g).
Synthesis of Intermediate 1 methylthio)phenyl)ethan-1-ol




Step 1: A degassed mixture of (1R)-1-(3-bromophenyl)ethanol (5.0 g, 25 mmol), TBDMSCl (4.5 g, 30 mmol), imidazole (2.4 g, 35 mmol), and DMF (50 mL) was stirred at 20° C. for 16 h under an N2 atmosphere. The reaction was poured into water (60 mL) and extracted with EtOAc (2×60 mL). The organic phase was washed with brine (60 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (10-20% EtOAc in Petroleum ether) to provide [(1R)-1-(3-bromophenyl)ethoxy]-tert-butyl-dimethylsilane (7 g).
Step 2: A solution of BuLi (2.5 M, 13 mL) was added slowly to [(1R)-1-(3-bromophenyl)ethoxy]-tert-butyl-dimethyl-silane (7.0 g, 22 mmol) in THF (50 mL) at −78° C. After addition, the mixture was stirred for 30 min and 1,2-dimethyldisulfane (2.2 mL, 24 mmol) was added slowly at −78° C. The resulting mixture was stirred at 20° C. for 2 h, poured into saturated aqueous NH4Cl (50 mL), and extracted with EtOAc (50 mL×2). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to provide tert-butyl-dimethyl-[(1R)-1-(3-methylsulfanylphenyl)ethoxy]silane (6.5 g).
Step 3: A mixture of tert-butyl-dimethyl-[(1R)-1-(3-methylsulfanylphenyl)ethoxy]silane (6.5 g, 23 mmol), EtOH (50 mL), and HCl (2 M, 50 mL) was stirred at 20° C. for 2 h. The mixture was concentrated and extracted with EtOAc (2×30 mL). The combined extracts were washed with brine (20 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (10-25% EtOAc in petroleum ether) to provide (R)-1-(3-(methylthio)phenyl)ethan-1-ol (2.7 g).
Synthesis of Intermediate (1r,4r)-4-(methylthio)cyclohexan-1-ol




Step 1: A degassed mixture of 7-oxabicyclo[2.2.1]heptane (1.0 g, 10 mmol), thiourea (1.2 g, 15 mmol), p-TsOH (2.9 g, 17 mmol), EtOH (10 mL) was stirred at 90° C. for 12 h. NaOH (1.3 g, 33 mmol) and H2O (3 mL) were added and the mixture was stirred at 90° C. for 2 h, then was concentrated, combined with H2O (20 mL) and extracted with EtOAc (2×20 mL). The extracts were washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (20-50% EtOAc in petroleum ether) to provide 4-[(4-hydroxycyclohexyl)disulfanyl]cyclohexanol (0.5 g).
Step 2: To a mixture of 4-[(4-hydroxycyclohexyl)disulfanyl]cyclohexanol (0.4 g, 1.5 mmol), THF (8 mL), and H2O (0.2 mL) was added Bu3P (0.34 g, 1.7 mmol). To the solution was added MeI (0.86 g, 6.1 mmol) and K2CO3 (1.3 g, 9.1 mmol). The mixture was stirred at 25° C. for 12 h, poured into H2O (30 mL) and the resulting mixture was extracted with EtOAc (2×30 mL), washed with brine (10 mL), dried over anhydrous Na2SO4, concentrated, and purified by silica chromatography (20-50% EtOAc in petroleum ether) to afford (1r,4r)-4-(methylthio)cyclohexan-1-ol (0.22 g).
Synthesis of Intermediate (1r,4s)-4-(methylthio)cyclohexan-1-ol




Step 1: To a mixture of (1r,4r)-4-(methylthio)cyclohexan-1-ol (0.70 g, 4.8 mmol), 4-nitrobenzoic acid (1.2 g, 7.2 mmol), PPh3 (2.5 g, 9.6 mmol), and THF (30 mL) was added DIAD (1.9 g, 9.6 mmol). The mixture was stirred at 20° C. for 12 h, poured into H2O (30 mL), and extracted with EtOAc (2×30 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (5-17%, EtOAc in petroleum ether) to provide (1s,4s)-4-(methylthio)cyclohexyl 4-nitrobenzoate (1.1 g).
Step 2: A mixture of (1s,4s)-4-(methylthio)cyclohexyl 4-nitrobenzoate (0.90 g, 3.0 mmol) in THF (9.0 mL), H2O (3.0 mL), and LiOH H2O (0.64 g, 15 mmol) was stirred at 20° C. for 2 h. The mixture was poured into water (30 mL) and extracted with EtOAc (2×30 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (10-50% EtOAc in petroleum ether) to provide (1r,4s)-4-(methylthio)cyclohexanol (0.50 g).
Synthesis of Intermediate 6-((methylthio)methyl)-2-azaspiro[3.3]heptane trifluoroacetate




Step 1: To a mixture of tert-butyl 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (6.0 g, 26 mmol) and CH2Cl2 (30 mL) was added slowly Et3N (5.3 g, 53 mmol) and MsCl (3.6 g, 32 mmol) at 0° C. The mixture was stirred at 20° C. for 2 h, poured into saturated aqueous NaHCO3 (100 mL), and extracted with EtOAc (2×100 mL). The combined extracts were washed with brine (50 mL), dried over Na2SO4, and concentrated to provide tert-butyl 6-(methylsulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (12 g).
Step 2: To a mixture of tert-butyl 6-(methylsulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (5.0 g, 16 mmol) in EtOH (50 mL) was added 20% aqueous NaSMe (10 mL, 33 mmol). The mixture was stirred at 25° C. for 2 h, then was concentrated, and extracted with EtOAc (2×30 mL). The combined extracts were washed with brine (30 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (17%-50% EtOAc in petroleum ether) to provide tert-butyl 6-(methylsulfanylmethyl)-2-azaspiro[3.3]heptane-2-carboxylate (3.6 g).
Step 3: TFA (14 mL, 190 mmol) was added to a mixture of tert-butyl 6-(methylsulfanylmethyl)-2-azaspiro[3.3]heptane-2-carboxylate (3.6 g, 14 mmol) and CH2Cl2 (20 mL). The mixture was stirred at 20° C. for 12 h and was concentrated to provide 6-((methylthio)methyl)-2-azaspiro[3.3]heptane trifluoroacetate (6.8 g).
Synthesis of Intermediate 2-(methylthio)-8-azaspiro[4.5]decane hydrochloride




Step 1: To a 0° C. mixture of tert-butyl 3-hydroxy-8-azaspiro[4.5]decane-8-carboxylate (4.0 g, 16 mmol), CBr4 (7.8 g, 24 mmol), and CH2Cl2 (50 mL) was added PPh3 (6.2 g, 24 mmol). The mixture was stirred at 25° C. for 12 h, concentrated, and purified by silica chromatography (10-20% EtOAc in petroleum ether) to afford tert-butyl 3-bromo-8-azaspiro[4.5]decane-8-carboxylate (3.0 g).
Step 2: To a mixture of tert-butyl 3-bromo-8-azaspiro[4.5]decane-8-carboxylate (3.0 g, 9.4 mmol) and EtOH (20 mL) was added 20% sodium methanethiolate in H2O (4.9 g, 14 mmol). The mixture was stirred at 25° C. for 2 h, concentrated to a small volume, poured into H2O (30 mL) and extracted with EtOAc (2×30 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to provide tert-butyl 3-methylsulfanyl-8-azaspiro[4.5]decane-8-carboxylate (2.6 g).
Step 3: To a mixture of tert-butyl 3-methylsulfanyl-8-azaspiro[4.5]decane-8-carboxylate (0.26 mg, 0.91 mmol) and EtOAc (5.0 mL) was added HCl/EtOAc (4 M, 5.0 mL). The mixture was stirred at 25° C. for 2 h and concentrated to provide 2-(methylthio)-8-azaspiro[4.5]decane hydrochloride (200 mg).
Synthesis of Intermediate 4-(cyclopropylsulfanylmethyl)piperidine trifluoroacetate




Step 1: A mixture of tert-butyl 4-(sulfanylmethyl)piperidine-1-carboxylate (1.0 g, 4.3 mmol) DMSO (15 mL), t-BuOK (1 M, 4.8 mL), and bromocyclopropane (0.58 g, 4.8 mmol) was stirred at 15° C. for 12 h. EtOAc (10 mL) was added, and the mixture was washed with H2O (5 mL×3) and brine (5 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-50% EtOAc in petroleum ether) to provide tert-butyl 4-(cyclopropylsulfanylmethyl)piperidine-1-carboxylate (0.55 g).
Step 2: To a mixture of tert-butyl 4-(cyclopropylsulfanylmethyl)piperidine-1-carboxylate (0.45 g, 1.7 mmol) and CH2Cl2 (4.5 mL) was added TFA (2.3 g, 20 mmol). The mixture was stirred at 15° C. for 2 h, then was concentrated, combined with toluene (10 mL) and then concentrated again to provide 4-(cyclopropylsulfanylmethyl)piperidine trifluoroacetate (0.45 g).
Synthesis of Intermediate 4-((methylthio)methyl)piperidin-4-ol




Step 1: To a mixture of 60% NaH (0.40 g, 10 mmol) and DMSO (10 mL) was added trimethyl sulfoxonium iodide (2.2 g, 10 mmol) at 20° C. After addition, the mixture was stirred for 2 h, and tert-butyl 4-oxopiperidine-1-carboxylate (2.0 g, 10 mmol) in DMSO (10 mL) was added slowly. The resulting mixture was stirred at 55° C. for 2 h, diluted with H2O and extracted with MTBE (30 mL×2). The combined extracts were washed with brine (20 mL×2), dried over Na2SO4, filtered, and concentrated to provide tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (2.2 g).
Step 2: To a mixture of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (1.5 g, 7.0 mmol) and EtOH (10 mL) was added 20% NaSMe in water (3.4 mL, 11 mmol). The mixture was stirred at 20° C. for 2 h, concentrated, diluted with H2O (30 mL) and extracted with EtOAc (20 mL×2). The combined extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to provide tert-butyl 4-hydroxy-4-(methylsulfanylmethyl)piperidine-1-carboxylate (1.8 g).
Step 3: To a mixture of tert-butyl 4-hydroxy-4-(methylsulfanylmethyl)piperidine-1-carboxylate (1.8 g, 6.9 mmol) in EtOAc (8.0 mL) was added 4M HCl in EtOAc (4 M, 13 mL). The mixture was stirred at 20° C. for 2 h and concentrated to provide 4-(methylsulfanylmethyl)piperidin-4-ol hydrochloride (1.3 g).
Intermediates in Table 2 were prepared via route described in the synthesis of Intermediate 4-((methylthio)methyl)piperidin-4-ol by using the reagents indicated.










TABLE 2







Thiol and Base 
Acid 


Intermediate Name
Structure
(Step 2)
(Step 3)







4-((ethylthio) methyl)piperidin- 4-ol




Ethanethiol,  Cs2CO3
HCl/ EtOAc


 


4-((cyclopropylthio) methyl)piperidin- 4-ol




Cyclopropylthiol, NaH
TFA









Synthesis of Intermediate 4-((cyclobutylthio)methy)piperidin-4-ol hydrochloride




Step 1: A mixture of sodium sulfide nonahydrate (5.6 g, 23 mmol), MeOH (125 mL), TsOH hydrate (7.1 g, 38 mmol) was stirred under N2 at 0° C. for 15 min. Tert-butyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (2.0 g, 9.4 mmol) in MeOH (10 mL) was then added and the mixture was stirred under N2 at 0° C. for 1 h, then at 20° C. for 1 h. Saturated aqueous NaHCO3 (40 mL) was added slowly at 0° C. followed by brine (40 mL), The mixture was extracted with EtOAc (50 mL×3), and the extracts were combined, washed with brine (40 mL×2), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-40% EtOAc in petroleum ether) to provide tert-butyl 4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate (1.53 g).
Step 2: A mixture of tert-butyl 4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate (1.2 g, 4.9 mmol), bromocyclobutane (0.60 g, 4.4 mmol), DMF (20 mL) and NaOMe (0.32 g, 5.9 mmol) was stirred at 50° C. for 5 h under an N2 atmosphere. Saturated aqueous NH4Cl (40 mL) was added dropwise at 0° C., followed by brine (40 mL). The mixture was extracted with EtOAc (50 mL×3) and the combined extracts were washed with water (40 mL×3) and brine (40 mL×2), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-30% EtOAc in petroleum ether) to provide tert-butyl 4-((cyclobutylthio)methyl)-4-hydroxypiperidine-1-carboxylate (0.80 g).
Step 3: To a mixture of tert-butyl 4-((cyclobutylthio)methyl)-4-hydroxypiperidine-1-carboxylate (0.40 g, 1.3 mmol) and MeOH (6 mL) was added HCl/MeOH (4M, 6.9 mL). The mixture was stirred at 20° C. for 5 h, concentrated to give 4-((cyclobutylthio)methyl)piperidin-4-ol hydrochloride (0.28 g).
Synthesis of Intermediate 8-((Methylthio)methyl)-5-azaspiro[2.5]octan-8-ol hydrochloride




Step 1: A mixture of trimethylsulfonium iodide (2.5 g, 12 mmol), DMSO (25 mL), and 60% NaH (0.60 g, 15 mmol) was stirred at 30° C. for 30 min and tert-butyl 8-oxo-5-azaspiro[2.5]octane-5-carboxylate (0.90 g, 4.0 mmol) in DMSO (5 mL) was added dropwise and the mixture was stirred at 20° C. for 12 h. Saturated aqueous NH4Cl (5 mL) and water (50 mL) were added. The mixture was extracted with EtOAc (2×50 mL) and the extracts were combined, washed with water (40 mL×3), brine (40 mL×2), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-40% EtOAc in petroleum ether) to provide tert-butyl 5-oxa-9-azadispiro[2.0.24.43]decane-9-carboxylate (0.50 g).
Step 2: A mixture of tert-butyl 5-oxa-9-azadispiro[2.0.24.43]decane-9-carboxylate (0.50 g, 2.1 mmol), EtOH (20 mL), NaSMe (0.33 g, 4.5 mmol) was stirred at 20° C. for 5 h. Water (10 mL) was added, and the mixture was extracted with EtOAc (2×20 mL), the extracts were combined, washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-40% EtOAc in petroleum ether) to provide tert-butyl 8-hydroxy-8-((methylthio)methyl)-5-azaspiro[2.5]octane-5-carboxylate (0.50 g).
Step 3: A 0° C. mixture of tert-butyl 8-hydroxy-8-((methylthio)methyl)-5-azaspiro[2.5]octane-5-carboxylate (0.50 g, 1.7 mmol), MeOH (5 mL), and HCl (4 M in MeOH, 5 mL) was stirred as it warmed to 20° C. over 3 h. The mixture was concentrated to provide 8-((methylthio)methyl)-5-azaspiro[2.5]octan-8-ol hydrochloride (0.39 g).
Synthesis of Intermediate imino(methyl)(2-(piperidin-4-yl)ethyl)-λ6-sulfanone hydrochloride




Step 1: PPh3 (8.6 g, 32.8 mmol) and CBr4 (10.9 g, 32.9 mmol) were added in portions into a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (5.0 g, 21.8 mmol) in CH2Cl2 (50 mL). After stirring at 20° C. for 20 h, the mixture was washed with brine (20 mL×3), dried over Na2SO4, filtered, concentrated purified by silica gel chromatography (0-80% EtOAc/petroleum ether) to afford the tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate (6.0 g).
Step 2: To a solution of tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate (1.0 g, 3.4 mmol) in EtOH (15 mL) at 20° C. was added NaSMe (1.65 g, 4.7 mmol, 20% in water) dropwise and the mixture was stirred at 20° C. for 12 h, concentrated, and dissolved in 30 mL of EtOAc. The solution was washed with brine (10 mL×3) and concentrated and purified by silica gel chromatography (0-30% EtOAc/Petroleum ether) to afford tert-butyl 4-(2-(methylthio)ethyl)piperidine-1-carboxylate (730 mg).
Step 3: To a solution of tert-butyl 4-(2-(methylthio)ethyl)piperidine-1-carboxylate (300 mg, 1.2 mmol) in EtOH (12 mL) at 20° C. was added PhI(OAc)2 (1.5 g, 4.7 mmol) and NH4OAc (270 mg, 3.5 mmol). The mixture was stirred at 20° C. for 12 h, then concentrated, and purified by silica gel chromatography (0-100% of 33% of EtOH in EtOAc in petroleum ether) to afford the tert-butyl 4-(2-(methylsulfonimidoyl)ethyl)piperidine-1-carboxylate (310 mg).
Step 4: To a solution of tert-butyl 4-(2-(S-methylsulfonimidoyl)ethyl)piperidine-1-carboxylate (310 mg, 1.1 mmol) in EtOAc (1.5 mL) at 20° C. was added HCl/EtOAc (4 M, 1.24 mL). The mixture was stirred at 20° C. for 2 hours, then was concentrated to give 4-(2-(methylsulfonimidoyl)ethyl)piperidine as a hydrochloride salt (260 mg) that was used without purification.
Intermediates in Table 3 were prepared via the route described for the synthesis of Intermediate imino(methyl)(2-(piperidin-4-yl)ethyl)-λ6-sulfanone hydrochloride by using the thiol indicated.









TABLE 3





Compound Name
Structure
Thiol







imino(methyl)(3-(piperidin-4- yl)propyl)-λ6-sulfanone










 


(4-(aminomethyl)phenyl) (imino)(methyl)-λ6-sulfanone










 


((4-hydroxypiperidin-4- yl)methyl)(imino)(methyl)-λ6- sulfanone

















Synthetic Example S-1
Synthesis of (4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)(imino)(methyl)-λ6-sulfanone (Compound 1)
Step 1: Synthesis of 6,7-dimethoxy-4(4-(methylthio)phenoxy)quinoline




A mixture of 4-chloro-6,7-dimethoxyquinoline (500 mg, 2.24 mmol) and 4-(methylsulfanyl)phenol (942 mg, 3 eq., 6.72 mmol) was heated at 170° C. for 1 hour. The residue was diluted with saturated Na2CO3 (50 mL)/MeOH (15 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-50% EtOAc/Petroleum Ether) delivered 6,7-dimethoxy-4-(4-(methylthio)phenoxy)quinoline (400 mg, 1.15 mmol).
Step 2: Synthesis of (4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)(imino)(methyl)-λ6-sulfanone




To a solution of 6,7-dimethoxy-4-(4-(methylthio)phenoxy)quinoline (106 mg, 0.31 mmol) in EtOH (2 mL) were added NH4OAc (94.0 mg, 1.2 mmol) and PhI(OAc)2 (295 mg, 3 eq., 916 μmol). The mixture was stirred at 20° C. for 12 h. The mixture was poured into H2O (50 mL) and extracted with EtOAc (20 mL×3). The organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. Purification by prep-HPLC (15-35% [10 mM NH4HCO3] in MeCN in water) afforded of (4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)(imino)(methyl)-λ6-sulfanone (Compound 1) (60 mg). ESI m/z: 359.1 (M+H). 1H NMR (400 MHz, DMSO-d6) δ: 8.56 (d, J=5.1 Hz, 1H), 8.02 (d, J=8.6 Hz, 2H), 7.45-7.40 (m, 4H), 6.69 (d, J=5.1 Hz, 1H), 4.28 (s, 1H), 3.95 (s, 3H), 3.90 (s, 3H), 3.10 (s, 3H).
Synthetic Example S-2
Synthesis of {4-[(6-fluoro-7-methoxyquinolin-4-yl)oxy]phenyl}(imino)methyl-λ6-sulfanone (Compound 114)
Step 1: Synthesis of 6-fluoro-7-methoxy-4-(4-(methylthio)phenoxy)quinoline




A mixture of 4-chloro-6-fluoro-7-methoxy-quinoline (2.0 g, 9.5 mmol) and 4-methylsulfanylphenol (2.7 g, 19 mmol) was degassed and purged with N2, and then the mixture was stirred at 170° C. for 2 hours under an N2 atmosphere. The mixture was combined with EtOAc (80 mL) and washed with NaOH (1N, 30 mL×4). The organic phase was washed with brine (20 mL×2), dried over Na2SO4, filtered and concentrated to provide 6-fluoro-7-methoxy-4-(4-methylsulfanylphenoxy)quinoline (2.0 g).
Step 2: Synthesis of {4-[(6-fluoro-7-methoxyquinolin-4-yl)oxy]phenyl}(imino)methyl-λ6-sulfanone




A mixture of 6-fluoro-7-methoxy-4-(4-methylsulfanylphenoxy)quinoline (1.2 g, 3.8 mmol), PhI(OAc)2 (3.7 g, 11 mmol), NH4OAc (1.2 g, 15 mmol), and EtOH (20 mL) was degassed and purged with N2, and the mixture was stirred at 25° C. for 2 hours under an N2 atmosphere. The mixture was concentrated and purified first by silica chromatography and then by preparative HPLC (column: Welch Xtimate C18 250*70 mm #10 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B %: 18%-48%, 25 min) to afford {4-[(6-fluoro-7-methoxyquinolin-4-yl)oxy]phenyl}(imino)methyl-λ6-sulfanone (Compound 114) (0.42 g).
Compounds 10, 12, 18, 44, 75-80, 84, 103, 115-128 and 166-167 were prepared in a similar manner as Compound 1 in Example S-1 and Compound 114 in Example S-2 from the aryl chlorides and phenol derivatives indicated in Table 4.











TABLE 4









MS 


Cmpd
Structure
Aryl Chloride
Alcohol
(m/z)







 10












347.0 (M + H)


 


 12












347.1 (M + H)


 


 18












360.0 (M + H)


 


 44












372.1 (M + H)


 


 78












330.0 (M + H)


 


 79












343.0 (M + H)


 


 80












329.0 (M + H)


 


 84












330.0 (M + H)


 


103












343.0 (M + H)


 


115












377.0 (M + H)


 


116












377.1 (M + H)


 


117












329.1 (M + H)


 


118












329.0 (M + H)


 


119












330.0 (M + H)


 


120












373.0 (M + H)


 


121












354.1 (M + H)


 


122












373.1 (M + H)


 


123












369.0 (M + H)


 


124












343.0 (M + H)


 


125












299.0 (M + H)


 


126












362.9 (M + H)


 


127












360.0 (M + H)


 


128












347.0 (M + H)


 


166












412.1 (M + H)


 


167












330.0 (M + H)









Synthetic Example S-3
Synthesis of imino({5-[(7-methoxyquinolin-4-yl)oxy]pyridin-2-yl})methyl-λ6-sulfanone (Compound 101)
Step 1: Synthesis of 7-methoxy-4-((6-(methylthio)pyridin-3-yl)oxy)quinoline




A mixture of 4-chloro-7-methyoxyquinoline (50 mg, 0.26 mmol), 6-(methylthio)pyridin-3-ol (44 mg, 0.31 mmol), Cs2CO3 (0.13 g, 0.39 mmol), and 2 mL of DMSO was stirred for 3 h at 100′° C. The mixture was directly purified by reverse phase HPLC (5-100%/MeCN in water (10 mM NH4HCO3)) to provide 7-methoxy-4-((6-(methylthio)pyridin-3-yl)oxy)quinoline (60 mg, 0.20 mmol).
Step 2: Synthesis of imino({5-[(7-methoxyquinolin-4-yl)oxy]pyridin-2-yl})methyl-λ6-sulfanone




Ammonium carbamate (24 mg, 0.30 mmol) and PhI(OAc)2 (140 mg, 0.42 mmol) were added to a mixture of 7-methoxy-4-((6-(methylthio)pyridin-3-yl)oxy)quinoline (60 mg, 0.20 mmol) and 2 mL of methanol. The mixture was stirred for 1 h and the mixture was directly purified by reverse phase HPLC (5-98% MeCN in water (10 mM NH4HCO3)) to provide imino({5-[(7-methoxyquinolin-4-yl)oxy]pyridin-2-yl})methyl-λ6-sulfanone (Compound 101) (38 mg, 0.12 mmol). ESI MS m/z: 330.1 (M+H).
Compounds 22, 47, 50, 58, 60, 76, 77, 129-132, and 168 were prepared from the aryl chlorides, phenol derivatives, and bases indicated in Table 5 in the manner of steps 1 and 2 of Synthetic Example S-3.












TABLE 5










MS 


Cmpd
Structure
Chloro Compound
Alcohol
Base
(m/z)







 22












CsCO3
300.1 (M + H)


 


 47












K2CO3
354.1 (M + H)


 


 50












K2CO3
338.1 (M + H)


 


 58












K2CO3
354.1 (M + H)


 


 60












CsCO3
355.0 (M + H)


 


 76












CsCO3
330.1 (M + H)


 


 77












CsCO3
330.1 (M + H)


 


129












CsCO3
360.1 (M + H)


 


130












CsCO3
330.1 (M + H)


 


131












CsCO3
342.1 (M + H)


 


132












CsCO3
387.0 (M + H)


 


168












CsCO3
343.1 (M + H)









Synthetic Example S-4
Synthesis of imino(3-{[(7-methoxyquinolin-4-yl)oxy]methyl}phenyl)methyl-λ6-sulfanone (Compound 133)
Step 1: Synthesis of 7-methoxy-4-((3-(methylthio)benzyl)oxy)quinoline




To a mixture of (3-methylsulfanylphenyl)methanol (0.80 g, 5.2 mmol) and DMF (10 mL) was added NaH (0.26 g, 6.5 mmol, 60% in mineral oil). The mixture was stirred at 0° C. for 30 min, and 4-chloro-7-methoxy-quinoline (0.50 g, 2.6 mmol) in DMF (5 mL) was added dropwise. The mixture was stirred at 20° C. for 12 h, water (5 mL) added and the mixture extracted with EtOAc (20 mL×2). The combined extracts were washed with brine (10 mL×2), dried over Na2SO4, filtered and concentrated, and purified by chromatography on silica gel (0-100% Ethyl acetate/Petroleum ether gradient) to provide 7-methoxy-4-[(3-methylsulfanylphenyl)methoxy]quinoline (0.44 g).
Step 2: Synthesis of imino(3-{[(7-methoxyquinolin-4-yl)oxy]methyl}phenyl)methyl-λ6-sulfanone




To a mixture of 7-methoxy-4-[(3-methylsulfanylphenyl)methoxy]quinoline (0.39 g, 1.3 mmol) in EtOH (1 mL) was added PhI(OAc)2 (1.2 g, 3.8 mmol) and NH4OAc (0.40 mg, 5.0 mmol). The reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated and purified by prep-HPLC (Kromasil C18 (250×50 mm×10 um); mobile phase: [water (10 mM NH4HCO3)-MeCN]; B %: 15%-45%) to provide imino(3-{[(7-methoxyquinolin-4-yl)oxy]methyl}phenyl)methyl-λ6-sulfanone (Compound 133) (101 mg). ESI m/z: 343.0 (M+H).
Compounds 14, 75, 134-138, and 169-178 were prepared from the aryl chlorides, alcohol, and bases indicated in Table 6 in the manner described in Synthetic Example S-4.












TABLE 6










MS 


Cmpd
Structure
Chloro Compound
Alcohol
Solvent
(m/z)







 14












NaH/DMF
374.1 (M + H)


 


 75












EtOH
343.1 (M + H)


 


107












NaH/CH2Cl2
321.2 (M + H)


 


134












EtOH
343.0 (M + H)


 


135












NaH/DMF
361.0 (M + H)


 


136












NaH/DMF
361.0 (M + H)


 


137












NaH/DMF
422.9 (M + H)


 


138












NaH/DMF
373.0 (M + H)


 


169












NaH/DMF
361.1 (M + H)


 


170












NaH/DMF
333.0 (M + H)


 


171












NaH/DMF
352.2 (M + H)


 


172












NaH/DMF
344.1 (M + H)


 


173












NaH/DMF
374.0 (M + H)


 


174












NaH/DMF
344.1 (M + H)


 


175












NaH/DMF
373.1 (M + H)


 


176












NaH/DMF
377.0 (M + H)


 


177












NaH/DMF
361.1 (M + H)


 


178












NaH/DMF
357.2 (M + H)









Separation of diastereomers of 4-[(1-imino-1-oxido-3, 4, 5, 6-tetrahydro-2H-thiopyran-4-yl)methoxy]-7-methoxy-quinoline (Compound 107)
The diastereomers of 4-[(1-imino-1-oxido-3, 4, 5, 6-tetrahydro-2H-thiopyran-4-yl)methoxy]-7-methoxy-quinoline (Compound 107) were separated by reverse-phase HPLC (Phenomenex Gemini-NX 150×30 mm, 5 um; 15-45% MeCN in H2O (0.1% TFA)) to provide Compound 107a (first eluting) and Compound 107b (second eluting) as TFA salts.
Synthetic Example S-5
Synthesis of imino({2-[1-(8-methoxyquinazolin-4-yl)piperidin-4-yl]ethyl})methyl-λ6-sulfanone (Compound 72)




To a mixture of imino-methyl-oxo-[2-(4-piperidyl)ethyl]-X6-sulfane HCl (130 mg, 573 umol) and 4-chloro-8-methoxy-quinazoline (113 mg, 0.58 mmol) in iPrOH (9 mL) was added iPrNEt2 (363.6 mg, 2.81 mmol). The mixture was stirred at 90° C. for 12 h, then concentrated and purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B %: 8%-38%, 8 min) to afford imino({2-[1-(8-methoxyquinazolin-4-yl)piperidin-4-yl]ethyl})methyl-λ6-sulfanone (Compound 72) (26.3 mg). ESI MS m/z: 349.1 (M+H).
Compounds 8, 43, 57, 69, 74, 139-152, 165, and 196-203 were prepared from the aryl chlorides and amines under conditions indicated in Table 7 in the manner of Synthetic Example S-5.












TABLE 7










MS 


Cmpd
Structure
Chloro Compound
Amine
Conditions
(m/z)







 8












iPrOH
379.1 (M + H)


 


 43












iPr2NEt, nBuOH 120° C. μW
391.1 (M + H)


 


 57












iPrOH
373.1 (M + H)


 


 69












nBuOH
348.1 (M + H)


 


 74












iPr2NEt, nBuOH 140° C.
342.0 (M + H)


 


139












iPrOH
349.2 (M + H)


 


140












nBuOH
348.1 (M + H)


 


141












nBuOH
382.1 (M + H)


 


142












iPrOH
383.0 (M + H)


 


143












CsCO3, DMF
373.1 (M + H)


 


144












iPrOH
403.1 (M + H)


 


145












iPrOH
393.0 (M + H)


 


146












iPrOH
335.0 (M + H)


 


147












iPrOH
365.10 (M + H)


 


148












nBuOH
334.10 (M + H)


 


149












iPr2NEt, nBuOH 120° C. μW
318.1 (M + H)


 


150












iPr2NEt, nBuOH 120° C. μW
366.1 (M + H)


 


151












iPr2NEt, nBuOH 120° C.
379.1 (M + H)


 


152












iPr2NEt, iPrOH 90° C. μW
407.0 (M + H)


 


165












iPrOH
379.1 (M + H)


 


196












iPr2NEt, iPrOH 80° C.
365.0 (M + H)


 


197












iPr2NEt, iPrOH 90° C.
373.2 (M + H)


 


198












iPr2NEt, iPrOH 90° C.
375.2 (M + H)


 


199












iPr2NEt, iPrOH 20° C.
365.1 (M + H)


 


200












iPr2NEt, iPrOH 90° C.
377.1 (M + H)


 


201












iPr2NEt, iPrOH 90° C.
373.1 (M + H)


 


202












iPr2NEt, nBuOH 140° C.
352.1 (M + H)


 


203












iPr2NEt, nBuOH 140° C.
377.1 (M + H)









Synthetic Example S-6
Synthesis of {2-[4-(6,7-dimethoxyquinazolin-4-yl)phenyl]ethyl}(imino)methyl-λ6-sulfanone (Compound 153)
Step 1: Synthesis of 4-bromophenethyl 4-methylbenzenesulfonate




To a mixture of 2-(4-bromophenyl)ethanol (1.4 mL, 10 mmol) and 20 mL of CH2Cl2 was added pyridine (2.4 mL, 30 mmol) and toluenesulfonyl chloride (2.3 g, 12 mmol) at 0° C. The mixture was stirred at 20° C. for 12 h, poured into 30 mL of water and extracted with CH2Cl2 (30.0 mL×2). The extracts were washed with saturated aqueous of NaHCO3 (20.0 mL×2) and brine (20.0 mL×2), dried over Na2SO4, filtered and concentrated and purified by silica gel chromatography (0-52% EtOAc/pet. ether) to afford the compound 2-(4-bromophenyl)ethyl 4-methylbenzenesulfonate (2.4 g).
Step 2: Synthesis of 4-bromophenethyl)(methyl)sulfane




To a mixture of 2-(4-bromophenyl) ethyl 4-methylbenzenesulfonate (0.5 g, 1.4 mmol), NMP (1.5 mL), and THF (2.5 mL) was added NaSMe (20%, 0.67 mL, 2.11 mmol). The mixture was stirred at 20° C. for 12 h, concentrated, diluted with aqueous Na2CO3 (20 mL) and extracted with EtOAc (10.0 mL×2). The extracts were washed with brine (10.0 mL×2), dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-100% EtOAc/pet. ether) provided (4-bromophenethyl)(methyl)sulfane (0.3 g).
Step 3: Synthesis of 4,4,5,5-tetramethyl-2-(4-(2-(methylthio)ethyl)phenyl)-1,3,2-dioxaborolane




To a mixture of 1-bromo-4-(2-methylsulfanylethyl)benzene (0.25 g, 1.1 mmol) and dioxane (10.0 mL) was added Pd(dppf)Cl2CH2Cl2 (88 mg, 0.11 mmol), KOAc (0.21 g, 2.2 mmol) and bis(pinacolato)diboron (0.33 mg, 1.3 mmol). The mixture was degassed and purged with N2 for 3 times, then stirred at 80° C. for 3 hours under an N2 atmosphere. The mixture was poured into water (10.0 mL) and extracted with EtOAc (10.0 mL×2). The extracts were washed with brine (10.0 mL×2), dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (0-35% EtOAc/pet. ether) to afford 4,4,5,5-tetramethyl-2-(4-(2-(methylthio)ethyl)phenyl)-1,3,2-dioxaborolane (0.22 g, 70% purity).
Step 4: Synthesis of 6,7-dimethoxy-4-(4-(2-(methylthio)ethyl)phenyl)quinazoline




To a mixture of 4-chloro-6,7-dimethoxy-quinazoline (0.15 g, 0.668 mmol), dioxane (8.0 mL), and H2O (1.6 mL) was added Pd(dppf)Cl2CH2Cl2 (55 mg, 67 μmol), K2CO3 (190 mg, 1.3 mmol) and 4,4,5,5-tetramethyl-2-(4-(2-(methylthio)ethyl)phenyl)-1,3,2-dioxaborolane (180 mg, 0.65 mmol). The mixture was degassed and purged with N2 three times and stirred at 80° C. for 12 h under an N2 atmosphere. The mixture was poured into water (10.0 mL) and extracted with EtOAc (10.0 mL×2). The combined extracts were washed with brine (10.0 mL×2), dried over Na2SO4, filtered, and concentrated to give the crude product 6,7-dimethoxy-4-(4-(2-(methylthio)ethyl)phenyl)quinazoline (0.3 g, 50% purity).
Step 5: Synthesis of {2-[4-(6,7-dimethoxyquinazolin-4-yl)phenyl]ethyl}(imino)methyl-λ6-sulfanone




{2-[4-(6,7-dimethoxyquinazolin-4-yl)phenyl]ethyl}(imino)methyl-λ6-sulfanone (Compound 153) was prepared from 6,7-dimethoxy-4-(4-(2-(methylthio)ethyl)phenyl)quinazoline in the manner described for S-1. ESI MS m/z: 372.1 (M+H).
Compounds 88, 98, 154-155, and 204 were prepared from the aryl halide and boronic ester indicated in Table 8 in the manner of steps 4 and 5 in Synthetic Example S-6.











TABLE 8









MS 


Cmpd
Structure
Aryl halide
Boronate
(m/z)







 88












327.2  (M + H)


 


 98












341.1  (M + H)


 


154












342.1 (M + H)


 


155












297.1  (M + H)


 


204












371.2  (M + H)









Synthetic Example S-7
Synthesis of [8-(6,7-dimethoxyquinazolin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl](imino)methyl-λ6-sulfanone (Compound 54)
Step 1: Synthesis of tert-butyl 8-(6,7-dimethoxyquinazolin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate




To a mixture of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (1.0 g, 4.2 mmol) and iPr2NEt (3.0 mL, 17 mmol), and iPrOH (20 mL) was added 4-chloro-6,7-dimethoxy-quinazoline (0.90 g, 4.0 mmol) and the mixture was stirred at 90° C. for 4 h. The reaction mixture was concentrated and triturated with MTBE/iPrOH/H2O (3/1/1, 25 mL) at 25° C. for 15 min. The suspension was filtered to afford the compound tert-butyl 8-(6,7-dimethoxyquinazolin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (2.0 g).
Step 2: Synthesis of 6,7-dimethoxy-4-(2,8-diazaspiro[4.5]decan-8-yl)quinazoline




To a mixture of tert-butyl 8-(6,7-dimethoxyquinazolin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (2.0 g, 4.7 mmol) and THF (10 mL) was added HCl/EtOAc (4 M, 6 mL, 24 mmol) dropwise and the mixture was stirred at 25° C. for 8 h. HCl/MeOH (4 M, 6 mL, 24 mmol) was added and the mixture was stirred at 25° C. for another 12 h. The reaction mixture was concentrated, and the residue dissolved in water (25 mL). Solid NaHCO3 (about 200 mg) was added to adjust its pH to 8 and NaCl was (about 150 mg) until it reached the saturation point. The mixture was extracted with CH2Cl2/iPrOH (3/1, 30 mL×7). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was lyophilized to give the compound 6,7-dimethoxy-4-(2,8-diazaspiro[4.5]decan-8-yl)quinazoline (1.2 g).
Step 3: Synthesis of [8-(6,7-dimethoxyquinazolin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl](imino)methyl-λ6-sulfanone




To a mixture of PPh3Cl2 (0.36 M, 21 mL) and CHCl3 (21 mL) was added Et3N (1.3 mL, 9.0 mmol) under N2 at 0° C. and the mixture was stirred at 0° C. for 15 min. N-[tert-butyl(dimethyl)silyl]methanesulfonamide (0.67 g, 3.2 mmol) was added and the mixture was stirred at 0° C. for 15 min before being added to a mixture of 6,7-dimethoxy-4-(2,8-diazaspiro[4.5]decan-8-yl)quinazoline (0.70 g, 2.1 mmol), Et3N (1.4 mL, 10 mmol), and CHCl3 (21 mL) at 0° C. under N2. The mixture was stirred at 25° C. for 5 h, then was concentrated, and purified by prep-HPLC (column: Phenomenex Luna C18 200*40 mm*10 um; mobile phase: [water (0.2% FA)-ACN]; B %: 1%-30%, 8 min) to provide [8-(6,7-dimethoxyquinazolin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl](imino)methyl-λ6-sulfanone (Compound 54) (0.50 g) as a formic acid salt. ESI MS m/z: 406.1 (M+H).
Synthetic Example S-8
Synthesis of [8-(6-fluoro-7-methoxyquinolin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl](imino)methyl-λ6-sulfanone (Compound 205)




Step 1: A degassed mixture of 4-chloro-6-fluoro-7-methoxy-quinoline (75 g, 0.35 mol), tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (85 g, 0.35 mol), iPr2NEt (0.19 L, 1.1 mol), n-BuOH (0.75 L) was stirred at 140° C. for 12 h under an N2 atmosphere. The mixture was concentrated and poured into H2O (3 L) and extracted with EtOAc (2×1.5 L). The combined extracts were washed with brine (500 mL), dried over Na2SO4, and concentrated to provide tert-butyl 8-(6-fluoro-7-methoxy-4-quinolyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (295 g).
Step 2: A solution of 4M HCl in EtOAc (0.75 L) was added slowly to stirring tert-butyl 8-(6-fluoro-7-methoxy-4-quinolyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (150 g, 0.36 mol) and EtOAc (0.4 L) and the mixture was stirred at 20° C. for 12 h. The mixture was concentrated, then mixed with 1 L of MeOH and AmberLyst-21 added until the pH was 9. The mixture was filtered, concentrated, and triturated with petroleum ether/EtOAc (1:1, 1 L) at 20° C. for 0.5 h to afford compound 8-(6-fluoro-7-methoxy-4-quinolyl)-2,8-diazaspiro[4.5]decane (120 g).
Step 3: A mixture of Ph3PCl2 (0.36 M, 0.53 L) and Et3N (29 g, 0.29 mol) was stirred at 0° C. for 0.25 h. N-[tert-butyl(dimethyl)silyl]methanesulfonamide (40 g, 190 mmol) was added at 0° C. and stirred for 0.25 h. The solution was added dropwise to a mixture of 8-(6-fluoro-7-methoxy-4-quinolyl)-2,8-diazaspiro[4.5]decane (30 g, 95 mmol), Et3N (19 g, 190 mmol) and CHCl3 (0.3 L) at 0° C. and stirred at 20° C. for 12 h. The mixture was concentrated and EtOAc was added (2.5 L) followed by aqueous HCl (1 N, 1 L). The aqueous phase was adjusted to pH 8 with saturated NaHCO3. The precipitate was filtered and the filter cake was washed with water (0.5 L×2). The collected solid was dried to provide [8-(6-fluoro-7-methoxyquinolin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl](imino)methyl-λ6-sulfanone (Compound 205) (120 g). ESI MS m/z: 393.2 (M+H).
Compounds 53, 55, 94, 156-160, and 206-226 were prepared from the aryl halides and amines under the conditions indicated in Table 9 in the manner of Synthetic Examples S-7 and S-8.












TABLE 9










MS 


Cmpd
Structure
Aryl Halide
Amine
Cond
(m/z)







 53
















361.0  (M + H)


 


 54
















375.1  (M + H)


 


 94
















380.1  (M + H)


 


156
















409.0  (M + H)


 


157
















383.0  (M + H)


 


158
















376.1  (M + H)


 


159
















420.1  (M + H)


 


160
















432.1  (M + H)


 


206
















392.2  (M + H)


 


207
















406.2  (M + H)


 


208
















405.1  (M + H)


 


209
















420.1  (M + H)


 


210
















418.1  (M + H)


 


211
















406.1  (M + H)


 


212
















410.2  (M + H)


 


213
















420.1  (M + H)


 


214
















362.2  (M + H)


 


215
















376.1  (M + H)


 


216
















392.2  (M + H)


 


217
















348.2  (M + H)


 


218
















419.2  (M + H)


 


219
















410.0  (M + H)


 


220
















424.0  (M + H)


 


221
















408.3  (M + H)


 


222
















372.1  (M + H)


 


223
















348.2  (M + H)


 


224
















394.1  (M + H)


 


225
















436.1  (M + H)


 


226
















400.1  (M + H)









Synthetic Example S-9
Synthesis of [7-(6,7-dimethoxyquinolin-4-yl)-1,2,3,4-tetrahydroisoquinolin-2-yl](imino)methyl-λ6-sulfanone (Compound 161)
Step 1: Synthesis of tert-butyl 7-(6,7-dimethoxyquinazolin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate




A mixture of 4-chloro-6,7-dimethoxy-quinoline (1.1 g, 4.6 mmol), tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (2.0 g, 5.6 mmol), KOAc (0.91 g, 9.3 mmol), Pd(PPh3)4 (0.27 g, 0.23 mmol), dioxane (10 mL), and H2O (2 mL) was degassed and purged with N2 and then stirred at 110° C. for 12 hours under a N2 atmosphere. The residue was diluted with water (50 mL) and extracted with EtOAc (50 mL×2). The combined extracts were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated, and purified by silica chromatography (Petroleum ether/EtOAc, 9-100%) to provide tert-butyl 7-(6,7-dimethoxy-4-quinolyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.1 g).
Step 2: Synthesis of [7-(6,7-dimethoxyquinolin-4-yl)-1,2,3,4-tetrahydroisoquinolin-2-yl](imino)methyl-λ6-sulfanone




To a mixture of tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.1 g, 3.1 mmol) and EtOAc (5 mL) was added 4 M HCl in EtOAc (12.7 mL). The mixture was stirred at 20° C. for 2 h, then was concentrated and 30 mL of saturated aqueous NaHCO3 was added. The mixture was extracted with EtOAc (20 mL×2) and extracts were combined and washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to provide 6,7-dimethoxy-4-(1,2,3,4-tetrahydroisoquinolin-7-yl)quinoline (0.54 g).
To a mixture of Ph3PCl2 (0.36 M, 6.5 mL) and CHCl3 (3 mL) was added dropwise Et3N (0.33 mL, 2.3 mmol) at 0° C. The mixture was stirred at this temperature for 15 mins, and N-[tert-butyl(dimethyl)silyl]methanesulfonamide (0.49 g, 2.3 mmol) was added and the mixture stirred at 0° C. for 15 mins. 6,7-dimethoxy-4-(1,2,3,4-tetrahydroisoquinolin-7-yl)quinoline (0.5 g, 1.6 mmol) and Et3N (1.1 mL, 7.8 mmol) was added at 0° C. The resulting mixture was stirred at 20° C. for 1.5 h before being concentrated and purified by prep-HPLC (column: Phenomenex Luna C18 200*40 mm*10 um; mobile phase: [water (0.2% FA)-ACN]; B %: 1%-40%, 8 min) to provide [7-(6,7-dimethoxyquinolin-4-yl)-1,2,3,4-tetrahydroisoquinolin-2-yl](imino)methyl-λ6-sulfanone (Compound 161) (71 mg). ESI MS m/z=398.1 (M+H).
Compounds 37, 52, and 162-163 were prepared from the aryl halide and boronic ester indicated in Table 10 in the manner described in Synthetic Example S-9.











TABLE 10









MS 


Cmpd
Structure
Aryl Halide
Boronate
(m/z)







37












399.0  (M + H)


 


52












368.1  (M + H)


 


162












342.0  (M + H)


 


163












369.1  (M + H)









Synthetic Example S-10
Synthesis of 1-imino-4-[2-(7-methoxyquinolin-4-yl)acetyl]-1λ6-thiomorpholin-1-one (Compound 26)
Step 1. Synthesis of methyl 2-(7-methoxyquinolin-4-yl)acetate




To a stirring mixture of 7-methoxy-4-methylquinoline (0.52 g, 3.0 mmol), dimethyl carbonate (0.33 mL, 3.9 mmol), and THF (6.0 mL) at 0° C. was added 1M LiHMDS in THF (12 mL, 12 mmol). The mixture warmed to ambient temperature and was stirred for 1 h. Saturated aqueous NH4Cl (10 mL) was added and the mixture stirred overnight. Water was added and the mixture extracted with CH2Cl2. The extracts were dried over Na2SO4, filtered, concentrated and purified by silica chromatography (10%-70% EtOAc in heptane) to provide 0.66 g of methyl 2-(7-methoxyquinolin-4-yl)acetate.
Step 2. Synthesis of 2-(7-methoxyquinolin-4-yl)-1-thiomorpholinoethan-1-one




Trimethylaluminum (2M in toluene; 0.12 mL, 0.24 mmol) was added to a stirring mixture of thiomorpholine (0.023 mL, 0.24 mmol) and toluene (3.0 mL). After stirring 30 min, methyl 2-(7-methoxyquinoline-4-yl)acetate (0.046 g, 0.20 mmol) was added. The mixture was heated at 80° C. for 18 h, cooled to ambient temperature, and 10 drops of 1N aqueous HCl was added. Water was then added, the pH adjusted to  ̃4 with aqueous saturated NaHCO3, and the mixture was extracted with CH2Cl2. The extracts were dried over Na2SO4, filtered, concentrated, and purified by reverse phase preparative HPLC (5-50% MeCN in water, 0.1% NH4HCO3) to provide 54 mg of 2-(7-methoxyquinolin-4-yl)-1-thiomorpholinoethan-1-one.
Step 3. Synthesis of 1-imino-4-[2-(7-methoxyquinolin-4-yl)acetyl]-1λ6-thiomorpholin-1-one




A mixture of 2-(7-methoxyquinolin-4-yl)-1-thiomorpholinoethan-1-one (54 mg, 0.18 mmol), methanol (3.5 mL), ammonium carbamate (20 mg, 0.26 mmol) and PhI(OAc)2 (0.11 g, 0.35 mmol) was stirred 3 hours. Additional ammonium carbamate (10 mg, 0.13 mmol) and PhI(OAc)2 (56 mg, 0.18 mmol) were added and the mixture stirred for 1 h. After concentration, the mixture was purified by silica chromatography (0-3% MeOH in CH2Cl2) to provide 18 mg of 1-imino-4-[2-(7-methoxyquinolin-4-yl)acetyl]-1λ6-thiomorpholin-1-one (Compound 26). ESI MS m/z: 334.1 (M+H).
Synthetic Example S-11
Synthesis of 1-imino-4-(7-methoxyquinoline-4-carbonyl)-1λ6-thiomorpholin-1-one (Compound 6)
Step 1: Synthesis of (7-methoxyquinolin-4-yl)(thiomorpholino)methanone




To a stirring mixture of 7-methoxyquinoline-4-carboxylic acid (41 mg, 0.20 mmol), EDC (42 mg, 0.22 mmol), ethyl cyano(hydroxyamino)acetate (2.8 mg, 0.020 mmol) and DMF (3.0 mL) was added thiomorpholine (25 mg, 0.24 mmol). After stirring for 3 h, the mixture was directly purified by reverse phase preparative HPLC (ReproSil column (5-40); 5-40% MeCN in water, 0.1% NH4HCO3) provided 52 mg of (7-methoxyquinolin-4-yl)(thiomorpholino)methanone.
Step 2: Synthesis of 1-imino-4-(7-methoxyquinoline-4-carbonyl)-1λ6-thiomorpholin-1-one




1-imino-4-(7-methoxyquinoline-4-carbonyl)-1λ6-thiomorpholin-1-one (Compound 6) was prepared from (7-methoxyquinolin-4-yl)(thiomorpholino)methanone in the manner described for Step 3 in the synthesis of Compound 26 (Synthetic Example S-10). ESI MS m/z: 320.1 (M+H).
Synthetic Example S-12
Synthesis of (4-{[(6,7-dimethoxyquinazolin-4-yl)oxy]methyl}piperidin-1-yl)(imino)methyl-λ6-sulfanone (Compound 164)




(4-{[(6,7-dimethoxyquinazolin-4-yl)oxy]methyl}piperidin-1-yl)(imino)methyl-λ6-sulfanone was prepared in three steps. In step 1, tert-butyl 4-(((6,7-dimethoxyquinazolin-4-yl)oxy)methyl)piperidine-1-carboxylate was prepared from 4-chloro-6,7-dimethoxyquinazoline in the manner described to Step 1 in the synthesis of Compound 133 (Synthetic Example S-4), except DMF was used as solvent instead of EtOH. (4-{[(6,7-dimethoxyquinazolin-4-yl)oxy]methyl}piperidin-1-yl)(imino)methyl-λ6-sulfanone (Compound 164) was prepared in two steps from tert-butyl 4-(((6,7-dimethoxyquinazolin-4-yl)oxy)methyl)piperidine-1-carboxylate in the same manner as Steps 2 and 3 of the synthesis of Compound 54 (Synthetic Example S-7). ESI MS m/z: 381.1 (M+H).
Compounds 229-230 were prepared from the aryl halide and alcohol indicated in Table 11 in the manner described in Synthetic Example S-12.











TABLE 11









MS 


Cmpd
Structure
Aryl Halide
Alcohol
(m/z)







229












354.1 (M + H)


 


230












354.1  (M + H)









Synthetic Example S-13
Synthesis of 4-(4-{[imino(methyl)oxo-λ6-sulfanyl]methyl}piperidin-1-yl)-8-methoxyquinoline-3-carbonitrile (Compound 179)




Step 1: To a mixture of 4-chloro-8-methoxy-quinoline-3-carbonitrile hydrochloride (4.1 g, 16 mmol) and iPrOH (80 mL) was added iPr2NEt (14 mL, 80 mmol) and 4-(methylsulfanylmethyl)piperidine hydrochloride (2.9 g, 16 mmol). The mixture was stirred at 90° C. for 4 h, cooled, concentrated, and triturated with H2O (20 mL) for 30 min and MTBE (20 mL) for 30 minutes to provide 8-methoxy-4-[4-(methylsulfanylmethyl)-1-piperidyl]quinoline-3-carbonitrile (5.4 g).
Step 2: A mixture of 8-methoxy-4-[4-(methylsulfanylmethyl)-1-piperidyl]quinoline-3-carbonitrile (5.9 g, 18 mmol), EtOH (50 mL), PhI(OAc)2 (17 g, 54 mmol) and NH4OAc (5.6 g, 72 mmol). The mixture was stirred at 20° C. for 2 h, concentrated and triturated with 1120 (30 mL) for 30 min, and purified by preparative HPLC (2-25% MeCN/water (0.23% formic acid)) to afford 8-methoxy-4-[4-[(methylsulfonimidoyl)methyl]-1-piperidyl]quinoline-3-carbonitrile (2.7 g). ESI MS m/z: 359.1 (M+H).
Compounds 180-195 were prepared from aryl chlorides and amines under conditions indicated in Table 12 in the manner described in Synthetic Example S-13.












TABLE 12










MS 


Cmpd
Structure
Chloro Compound
Amine
Conditions
(m/z)







180












iPr2NEt, nBuOH 140° C.
334.1  (M + H)


 


181












iPr2NEt, nBuOH 90° C.
405.1  (M + H)


 


182












Cs2CO3, DMSO, 80° C.
335.1  (M + H)


 


183












iPr2NEt, nBuOH 20° C.
353.2  (M + H)


 


184












iPr2NEt, nBuOH 140° C.
364.2  (M + H)


 


185












iPr2NEt, iPrOH 20° C.
351.2  (M + H)


 


186












iPr2NEt, nBuOH 140° C.
376.1  (M + H)


 


187












iPr2NEt, iPrOH 15° C.
349.1  (M + H)


 


188












iPr2NEt, iPrOH 120° C.
377.2  (M + H)


 


189












iPr2NEt, iPrOH 120° C.
385.1  (M + H)


 


190












iPr2NEt, iPrOH 90° C.
361.2  (M + H)


 


191












iPr2NEt, iPrOH 40° C.
391.1  (M + H)


 


192












iPr2NEt, nBuOH 160° C.
360.1  (M + H)


 


193












iPr2NEt, iPrOH 40° C.
377.2  (M + H)


 


194












iPr2NEt, iPrOH, 20° C.
377.1  (M + H)


 


195












iPr2NEt, iPrOH, 20° C.
365.1  (M + H)









Synthetic Example S-14
Synthesis of [8-(3-fluoro-6,7-dimethoxyquinolin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl](imino)methyl-λ6-sulfanone (Compound 227)




Step 1: A mixture of 4-chloro-3-fluoro-6,7-dimethoxy-quinoline (0.21 g, 0.85 mmol), dioxane (1.0 mL), Cs2CO3 (0.57 g, 1.7 mmol), Pd(OAc)2 (19 mg), [1-(2-diphenylphosphanyl-1-naphthyl)-2-naphthyl]-diphenyl-phosphane (54 mg, 87 μmol), and tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate hydrochloride (0.24 g, 0.85 mmol) was stirred at 140° C. for 12 h under an N2 atmosphere. The mixture was concentrated, combined with H2O (10 mL) and extracted with EtOAc (10 mL×2). The extracts were combined, washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated, and purified by silica chromatography (10%-100% EtOAc in petroleum ether) to provide tert-butyl8-(3-fluoro-6,7-dimethoxyquinolin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate hydrochloride (0.36 g).
Step 2: A mixture of tert-butyl 8-(3-fluoro-6,7-dimethoxy-4-quinolyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (0.36 g, 0.81 mmol), EtOAc (7.0 mL), and HCl/EtOAc (4 M, 3.6 mL) was stirred at 20° C. for 2 h, then was concentrated to provide 3-fluoro-6,7-dimethoxy-4-(2,8-diazaspiro[4.5]decan-8-yl)quinoline (0.30 g).
Step 3: A mixture of Ph3PCl2 (0.36 M in CHCl3, 3.6 mL), CHCl3 (8.0 mL), and Et3N (0.27 mg, 2.6 mmol) was stirred at 0° C. for 0.5 h. 8-(3-fluoro-6,7-dimethoxy-4-quinolyl)-2,8-diazaspiro[4.5]decane hydrochloride (0.25 mg, 0.66 mmol) was added at 0° C. and it was stirred for 0.5 h. N-[tert-butyl(dimethyl)silyl]methanesulfonamide (0.27 g, 1.3 mmol) and Et3N (0.27 g, 2.6 mmol) were added at 20° C. After stirring for 1 h, the mixture was concentrated, and 1M HCl (5.0 mL) was added to adjust the pH to 3, and H2O (5.0 mL) was added. The mixture was extracted with EtOAc (15 mL), and the pH of the aqueous phase was adjusted to pH 7 with saturated NaHCO3 (5.0 mL). The solution was purified directly by preparative HPLC (1-30% MeCN in H2O (0.2% formic acid)) to provide 3-fluoro-6,7-dimethoxy-4-(2-(S-methylsulfonimidoyl)-2,8-diazaspiro[4.5]decan-8-yl)quinoline (Compound 227) (69 mg). ESI MS m/z: 423.2 (M+H).
Synthetic Example S-15
Synthesis of [8-(6,7-dimethoxy-3-methylcinnolin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl](imino)methyl-λ6-sulfanone (Compound 228)




Compound 228 was prepared in the same manner as Compound 227 in Synthetic Example S-14 with 4-chloro-6, 7-dimethoxy-3-methyl-cinnoline in place of 4-chloro-3-fluoro-6,7-dimethoxy-quinoline in step 1. ESI MS m/z: 420.3 (M+H).
Synthetic Example S-16
Synthesis of imino({4-[(7-methoxyquinolin-4-yl)methoxy]phenyl})methyl-λ6-sulfanone (Compound 231)




Step 1: To a 0° C. mixture of (7-methoxy-4-quinolyl)methanol (50 mg, 0.26 mmol) and 4-methylsulfanylphenol (44 mg, 0.31 mmol), and THF (2.0 mL) was added PPh3 (140 mg, 0.53 mmol) followed by dropwise addition of DIAD (110 mg, 0.52 mmol) in THF (0.5 mL). The resulting mixture was stirred at 25° C. for 12 h, H2O (5 mL) was added and the mixture was extracted with 15 mL of EtOAc and the extract was washed with 10 mL of brine, dried over Na2SO4, filtered, concentrated, and purified by chromatography over silica (10-100%/EtOAc in hexanes) to provide 7-methoxy-4-[(4-methylsulfanylphenoxy)methyl]quinoline (40 mg).
Step 2: A mixture of 7-methoxy-4-[(4-methylsulfanylphenoxy)methyl]quinoline (40 mg, 0.13 mmol), EtOH (1.00 mL), PhIOAc2 (124 mg, 0.41 mmol), and NH4OAc (39 mg, 0.51 mmol) was stirred at 25° C. for 2 h. The reaction mixture was concentrated and purified by preparative HPLC (20-40% MeCN in water, 0.1%) to provide imino({4-[(7-methoxyquinolin-4-yl)methoxy]phenyl})methyl-λ6-sulfanone (Compound 231) (2.3 mg). ESI MS m/z: 343.0 (M+H).
Synthetic Example S-17
Synthesis of imino({3-[(7-methoxyquinolin-4-yl)methoxy]phenyl})methyl-λ6-sulfanone (Compound 232)




Imino({3-[(7-methoxyquinolin-4-yl)methoxy]phenyl})methyl-λ6-sulfanone (Compound 232) was prepared in two steps from (7-methoxy-4-quinolyl)methanol and 4-methylsulfanylphenol in manner described in Synthetic Example S-16. ESI MS m/z: 343.0 (M+H).
Synthetic Example S-18
Synthesis of imino[2-(7-methoxyquinolin-4-yl)-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl]methyl-λ6-sulfanone (Compound 233)




Step 1: A mixture of 4-chloro-7-methoxyquinoline (0.5 g, 2.6 mmol), tert-butyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (0.63 g, 2.8 mmol), Xantphos (0.3 g, 0.52 mmol), K3PO4 (1.1 g, 5.2 mmol), Pd2(dba)3 (0.24 g, 0.26 mmol), and dioxane (10 ml) was heated at 140° C. for 2 h in a microwave reactor. The mixture was poured into H2O (20 mL), extracted with EtOAc (20.0 mL×2). The combined extracts were washed with brine (20 mL×2), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-100% EtOAc in petroleum ether) to provide tert-butyl 2-(7-methoxy-4-quinolyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.3 g with 85% purity).
Step 2: To a mixture of tert-butyl 2-(7-methoxy-4-quinolyl)-6, 7-dihydro-4H-pyrazolo[4, 3-c]pyridine-5-carboxylate (1.5 g, 3.9 mmol) and EtOAc (2.0 mL) was added HCl/EtOAc (4 M, 7.4 mL) and the mixture was stirred at 25° C. for 2 h. The mixture was concentrated, combined MeOH (20 mL) and amberlyst-21 (2.0 g) was added. The mixture was filtered and concentrated to provide 7-methoxy-4-(4, 5, 6, 7-tetrahydropyrazolo[4, 3-c]pyridin-2-yl)quinoline (1.0 g).
Step 3: To Ph3PCl2 (0.36 M, 5.0 mL) in CHCl3 (2.0 mL) was added Et3N (0.37 mL, 2.7 mmol) and the mixture was stirred at 0° C. for 10 min. N-[tert-butyl(dimethyl)silyl]methanesulfonamide (0.37 g, 1.8 mmol) was added and the mixture was stirred at 0° C. for 20 min, then 7-methoxy-4-(4,5,6,7-tetrahydropyrazolo[4, 3-c]pyridin-2-yl)quinoline (0.5 g, 1.8 mmol) and Et3N (0.75 mL, 5.4 mmol) in CHCl3 (3 mL) was added at 0 TC. The mixture was stirred at 25° C. for 90 min and was concentrated. The residue was combined with MeOH (1.0 mL) and 1M aqueous HCl (40.0 mL, 40 mmol) was added. The mixture was stirred at 20° C. for 10 min, the mixture was concentrated and purified by reverse-phase HPLC (1-40%/MeCN/water (0.2% formic acid)] to provide imino[2-(7-methoxyquinolin-4-yl)-2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl]methyl-λ6-sulfanone (Compound 233) (89 mg). ESI MS m/z: 358.1 (M+H).
Synthetic Example S-19
Synthesis of imino({2-[1-(7-methoxyquinolin-4-yl)-1H-pyrazol-4-yl]ethyl})methyl-λ6-sulfanone (Compound 234)




Step 1: A mixture of 2-(1H-pyrazol-4-yl) ethanol (0.64 g, 5.7 mmol), 4-chloro-7-methoxy-quinoline (1.0 g, 5.2 mmol), tBuONa (1.5 g, 16 mmol), T-buxphosPh-G3 (0.41 g, 0.52 mmol), and THF (10 mL) was degassed with bubbling N2, then was stirred at 110° C. for 12 h under an N2 atmosphere. The mixture was poured into H2O (10 mL) and extracted with EtOAc (10.0 mL×2). The combined extracts were washed with brine (10 mL×2), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (0-100% EtOAc/petroleum ether to provide 2-[1-(7-methoxy-4-quinolyl)pyrazol-4-yl]ethanol (0.27 g).
Step 2: To a 0° C. mixture of 2-[1-(7-methoxy-4-quinolyl) pyrazol-4-yl]ethanol (0.22 g, 0.82 mmol) and CH2Cl2 (5.0 mL) were added PPh3 (0.32 g, 1.2 mmol) and CBr4 (0.41 g, 1.2 mmol). The mixture was stirred at 20° C. for 12 h, then was concentrated, poured into water (10 mL), and extracted with EtOAc (10.0 mL×2). The combined extracts were washed with brine (10.0 mL×2), dried over Na2SO4, filtered, and concentrated to provide 4-[4-(2-bromoethyl) pyrazol-1-yl]-7-methoxy-quinoline (0.27 g) that was used without purification.
Step 3: A mixture of 4-[4-(2-bromoethyl)pyrazol-1-yl]-7-methoxy-quinoline (0.25 g, 0.75 mmol), EtOH (5 mL), aqueous NaSMe (20%, 0.48 mL, 1.5 mmol) was stirred at 20° C. for 12 h under N2. The mixture was poured into H2O (10 mL) and extracted with EtOAc (10 mL×2). The combined extracts were washed with brine (10 mL×2), dried over Na2SO4, filtered, concentrated, and purified by preparative TLC (SiO2, 10:1:1 CH2Cl2/MeOH/EtOAc, then 4:1:1 petroleum ether/EtOAc/THF) to provide 7-methoxy-4-[4-(2-methylsulfanylethyl)pyrazol-1-yl]quinoline (0.12 g).
Step 4: A mixture of 7-methoxy-4-[4-(2-methylsulfanylethyl)pyrazol-1-yl]quinoline (0.10 g, 0.33 mmol), EtOH (2 mL), PhI(OAc)2 (0.32 g, 1.0 mmol), and NH4OAc (0.10 g, 1.3 mmol) was stirred at 20° C. for 1 h. The mixture was concentrated and purified by preparative TLC (SiO2, 10:1 CH2Cl2/MeOH) to provide 7-methoxy-4-(4-(2-(S-methylsulfonimidoyl)ethyl)-1H-pyrazol-1-yl)quinoline (Compound 234) (15 mg). ESI MS m/z: 331.2 (M+H)
Synthetic Example S-20
Synthesis of imino({4-[(7-methoxyquinolin-4-yl)oxy]piperidin-1-yl})methyl-λ6-sulfanone (Compound 235)




Step 1: To a mixture of 7-methoxyquinolin-4-ol (1.0 g, 5.7 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (1.2 g, 5.7 mmol) in THF (25 mL) was added PPh3 (3.0 g, 11 mmol) followed by the dropwise addition of DIAD (2.2 mL, 11 mmol) in THF (5 mL) at 0° C. The resulting mixture was stirred at 25° C. for 12 h, then was concentrated, combined with H2O (20 mL) and extracted with EtOAc (20.00 mL×2). The combined extracts were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by silica chromatography (10-100% petroleum ether/EtOAc) to afford tert-butyl 4-[(7-methoxy-4-quinolyl)oxy]piperidine-1-carboxylate (2.2 g).
Step 2: A mixture of tert-butyl 4-[(7-methoxy-4-quinolyl)oxy]piperidine-1-carboxylate (2.0 g, 5.6 mmol), EtOAc (3 mL), and 4 M HCl in EtOAc (30 mL, 120 mmol) was stirred at 25° C. for 2 h. The mixture was concentrated to provide 7-methoxy-4-(4-piperidyloxy)quinoline hydrochloride (1.9 g).
Step 3: To a mixture of Ph3PCl2 (0.36 M, 27 mL, 9.7 mmol) in CHCl3 (10 mL) was added Et3N (1.4 mL, 9.6 mmol) at 0° C. The mixture was stirred for 15 min, then N-[tert-butyl(dimethyl)silyl]methanesulfonamide (2.0 g, 9.7 mmol) was added and stirred at 0° C. for 15 min. 7-methoxy-4-(4-piperidyloxy)quinoline (1.0 g, 3.9 mmol) and Et3N (1.35 mL, 9.7 mmol) was added at 0° C. and the resulting mixture was stirred at 20° C. for 1.5 h. The mixture was concentrated to afford tert-butyl-[[[4-[(7-methoxy-4-quinolyl)oxy]-1-piperidyl]-methyl-oxo-λ6-sulfanylidene]amino]-dimethyl-silane (1.8 g, crude), a portion of which (1.60 g, 3.5 mmol) was combined with MeOH (10.00 mL) and aqueous HCl (1 M, 8.0 mL, 8 mmol). The mixture was stirred at 25° C. for 30 min, and saturated aqueous NaHCO3 (15 mL) was added. The mixture was extracted with EtOAc (20 mL) and the extract was washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by reverse-phase HPLC (10-30% MeCN in H2O (0.2% formic acid)) to afford imino({4-[(7-methoxyquinolin-4-yl)oxy]piperidin-1-yl})methyl-λ6-sulfanone (Compound 235) (310 mg). ESI MS m/z: 336.0 (M+H).
Synthetic Example S-21
Synthesis of imino[7-(8-methoxyquinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl]methyl-λ6-sulfanone (Compound 236)




Step 1: To a 0° C. mixture of PPh3OCl2 (0.36 M, 26 mL) and CHCl3 (26 mL) under nitrogen was added Et3N (1.7 mL, 12 mmol) and the mixture was stirred at 0° C. for 15 min. N-[tert-butyl(dimethyl)silyl]methanesulfonamide (0.9 g, 4.3 mmol) was added and the mixture was stirred at 0° C. for 15 min. This mixture was added into a solution of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (0.75 g, 2.9 mmol) and Et3N (1.7 mL, 12 mmol) in CHCl3 (25 mL) at 0° C. and the mixture was stirred at 0° C. for 0.5 hour and then at 25° C. for 1.5 hours. The reaction mixture was concentrated and purified by silica gel chromatography (0-90% THF in (1:1 EtOAc/petroleum ether)) to provide tert-butyl 2-(S-methylsulfonimidoyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (0.54 g).
Step 2: To a mixture of tert-butyl 2-(S-methylsulfonimidoyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (0.49 g, 1.6 mmol) in CH2Cl2 (20 mL) at 0° C. was added TFA (1 mL, 14 mmol). The mixture was stirred at 25° C. for 4 h, then was concentrated under to give 2-(S-methylsulfonimidoyl)-2,7-diazaspiro[3.5]nonane trifluoroacetate (0.58 mg).
Step 3: To a mixture of 2-(S-methylsulfonimidoyl)-2,7-diazaspiro[3.5]nonane trifluoroacetate (0.33 g, 1.0 mmol) and 4-chloro-8-methoxy-quinazoline hydrochloride (0.2 g, 0.86 mmol) in isopropanol (10 mL) was added iPr2NEt (1.3 mL, 7.6 mmol) and the mixture was stirred at 20° C. for 12 h. The mixture was concentrated and purified by reverse-phase HPLC (15-35% MeCN in H2O (10 mM NH4HCO3)) to afford imino[7-(8-methoxyquinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl]methyl-λ6-sulfanone (Compound 236) (145 mg). ESI MS m/z: 362.2 (M+H).
Synthetic Example S-22
Synthesis of [8-(6,7-dimethoxyquinazolin-4-yl)-8-azaspiro[4.5]decan-2-yl](imino)methyl-λ6-sulfanone (Compound 237)




Steps 1 & 2: A mixture of tert-butyl 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (0.90 g, 3.9 mmol), CH2Cl2 (15 mL) and TFA (4.5 mL, 61 mmol) was stirred at 25° C. for 2 h, then was concentrated. The resulting residue, iPrOH (25 mL), iPr2NEt (6.1 mL, 35 mmol), and 4-chloro-6,7-dimethoxy-quinazoline (1.6 g, 7.0 mmol) were stirred together at 80° C. for 2 h. The mixture was concentrated and purified by reversed-phase HPLC (basic condition) to provide [2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl]methanol (110 mg, 92% purity) in two batches (110 mg, 92% purity; 500 mg, 42% purity).
Step 2: A mixture of [2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl]methanol (0.41 g, 1.3 mmol), CH2Cl2 (10 mL), Et3N (0.40 g, 3.9 mmol), and MsCl (0.30 g, 2.6 mmol) was stirred at 25° C. for 12 h, then was concentration and combined with H2O (15 mL) and extracted with EtOAc (15 mL×2). The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to give [2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl]methylmethanesulfonate (130 mg).
Step 4: A mixture of [2-(6,7-dimethoxyquinazolin-4-yl)-2-azaspiro[3.3]heptan-6-yl]methyl methanesulfonate (0.11 g, 1.0 eq), EtOH (5 mL), and 20% aqueous NaSMe (0.15 mL) was stirred at 25° C. for 2 h, then was concentrated, diluted with H2O (10 mL), and extracted with EtOAc (10 mL×2). The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to provide 6,7-dimethoxy-4-[6-(methylsulfanylmethyl)-2-azaspiro[3.3]heptan-2-yl]quinazoline (100 mg).
Step 5: A mixture of 6,7-dimethoxy-4-[6-(methylsulfanylmethyl)-2-azaspiro[3.3]heptan-2-yl]quinazoline (90 mg, 0.26 mmol) in EtOH (5 mL) was added DIB (251 mg, 0.78 mmol) and NH4OAc (80 mg, 1.0 mmol) was stirred at 20° C. for 2 h, then was concentrated and purified by preparative HPLC (1-30% MeCN in H2O (10 mM NH4HCO3)) to provide 8-(6,7-dimethoxyquinazolin-4-yl)-8-azaspiro[4.5]decan-2-yl](imino)methyl-X-sulfanone (Compound 237) (24 mg). ESI MS m/z: 377.2 (M+H).
Compounds 238-239 were prepared from aryl halide and alcohol under conditions indicated in Table 13 in the manner described in Synthetic Example S-22.











TABLE 13









MS 


Cmpd
Structure
Aryl Halide
Alcohol
(m/z)







238












321.0 (M + H)


 


239












321.1 (M + H)









Synthetic Example S-23
Synthesis of [8-(6,7-dimethoxyquinazolin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl](2-hydroxy-2-methylpropyl)imino-λ6-sulfanone (Compound 240)




A solution of BuLi (2.5 M, 2.0 mL) was added slowly to a −78° C. stirring mixture of 6,7-dimethoxy-4-(2-(S-methylsulfonimidoyl)-2,8-diazaspiro[4.5]decan-8-yl)quinazoline (0.04 g, 0.99 mmol) and THF (5 mL). After stirring for 30 min, acetone (0.29 mL, 4.0 mmol) was added slowly at −78° C. The reaction mixture was warmed up to 25° C., stirred for 1 h, concentrated, and purified by preparative HPLC (20-40%/MeCN/H2O (10 mM NH4HCO3)) to provide 1-[[8-(6,7-dimethoxyquinazolin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl]sulfonimidoyl]-2-methyl-propan-2-ol (Compound 240) (8.5 mg). ESI MS m/z: 464.3 (M+H).
Synthetic Example S-24
Synthesis of {8-[6-(fluoromethoxy)-7-methoxyquinazolin-4-yl]-2,8-diazaspiro[4.5]decan-2-yl}(imino)methyl-λ6-sulfanone (Compound 241)




Step 1: A degassed mixture of (4-hydroxy-7-methoxy-quinazolin-6-yl) acetate (5.0 g, 21 mmol), SOCl2 (50 mL, 690 mmol), and DMF (0.5 mL) was stirred at 85° C. for 12 h under an N2 atmosphere. The reaction was concentrated to provide (4-chloro-7-methoxy-quinazolin-6-yl) acetate (5.1 g).
Step 2: A degassed mixture of (4-chloro-7-methoxy-quinazolin-6-yl) acetate (2.4 g, 9.5 mmol), tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (1.9 g, 7.9 mmol), Et3N (6.6 mL, 47 mmol), and CHCl3 (30 mL) was stirred at 20° C. for 12 h under an N2 atmosphere. The crude product stirred with a mixture of petroleum ether and ethyl acetate (7:1) at 20° C. for 30 min. Solids were filtered away, and the filtrate was concentrated, and purified by silica chromatography (1:0:0:0 to 0:20:4:1 petroleum ether/EtOAc:CH2Cl2:MeOH) to provide tert-butyl 8-(6-acetoxy-7-methoxy-quinazolin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (2.6 g).
Step 3: A degassed mixture of tert-butyl 8-(6-acetoxy-7-methoxy-quinazolin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (2.3 g, 5.1 mmol), LiOH H2O (0.65 g, 15 mmol), MeOH (94 mL), and H2O (47 mL) was stirred at 20° C. for 12 h under an N2 atmosphere. The mixture was concentrated and extracted with EtOAc (25 mL×10), dried over Na2SO4, filtered and concentrated tert-butyl 8-(6-hydroxy-7-methoxy-quinazolin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (1.7 g).
Step 4: A 0° C. mixture of tert-butyl 8-(6-hydroxy-7-methoxy-quinazolin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (1.6 g, 3.9 mmol), DMF (20 mL), and 60% NaH (0.44 g, 11 mmol) was stirred for 0.5 h. Fluoroiodomethane (0.69 g, 4.3 mmol) was added and the mixture was stirred at 20° C. 12 h. Saturated aqueous NH4Cl (20 ml) was added, then the mixture was filtered, and the filtrate concentrated and purified by silica chromatography (0-100% EtOAc in petroleum ether) to provide tert-butyl 8-[6-(fluoromethoxy)-7-methoxy-quinazolin-4-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate (1.37 g).
Step 5: A mixture of tert-butyl 8-[6-(fluoromethoxy)-7-methoxy-quinazolin-4-yl]-2,8-diazaspiro [4.5]decane-2-carboxylate (1.3 g, 2.8 mmol), EtOAc (6 mL), and HCl (6 M in EtOAc, 15 mL) was stirred at 20° C. for 12 h. The mixture was concentrated to provide 4-(2,8-diazaspiro[4.5]decan-8-yl)-6-(fluoromethoxy)-7-methoxy-quinazoline hydrochloride (1.0 g).
Step 6: N-[tert-butyl(dimethyl)silyl]methanesulfonamide (1.1 g, 5.2 mmol) was added into Ph3PCl2 (0.36 M in CHCl3, 14 mL) at 0° C. After stirring for 0.5 h, a mixture of 4-(2,8-diazaspiro[4.5]decan-8-yl)-6-(fluoromethoxy)-7-methoxy-quinazoline (0.60 g, 1.7 mmol), CH3Cl (5 mL), Et3N (1.5 mL, 10 mmol) was added and the mixture was stirred at 20° C. for 12 h. The mixture was concentrated and purified by preparative HPLC (1-20% MeCN in H2O (0.2% formic acid)) to provide {8-[6-(fluoromethoxy)-7-methoxyquinazolin-4-yl]-2,8-diazaspiro[4.5]decan-2-yl}(imino)methyl-λ6-sulfanone (Compound 241) (75 mg). ESI MS m/z: 424.1 (M+H).
Synthetic Example S-25
Synthesis of imino(methyl)[(1s,4s)-4-[(7-methoxyquinolin-4-yl)oxy]cyclohexyl]-λ6-sulfanone (Compound 242)




Step 1: To a mixture of (1r,4r)-4-(methylthio)cyclohexan-1-ol (0.17 g, 1.2 mmol), 7-methoxyquinolin-4-ol (0.24 g, 1.4 mmol), PPh3 (0.61 g, 2.3 mmol), THF (7 mL) was added DIAD (470 mg, 2.32 mmol, 2.0 eq). The mixture was stirred at 20° C. for 12 h, concentrated, and purified by silica chromatography (50-100% EtOAc in petroleum ether) to provide 7-methoxy-4-(4-methylsulfanylcyclohexoxy)quinoline (0.15 g).
Step 2: A mixture of 7-methoxy-4-(4-methylsulfanylcyclohexoxy)quinoline (0.15 mg, 0.49 mmol), EtOH (3 mL), PhI(OAc)2 (0.48 mg, 1.5 mmol), and NH4OAc (0.15 mg, 2.0 mmol). The mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated in and purified by preparative HPLC (1-30% MeCN/water (0.2% formic acid) to provide imino(methyl)[(1s,4s)-4-[(7-methoxyquinolin-4-yl)oxy]cyclohexyl]-λ6-sulfanone (Compound 242) (36 mg). ESI MS m/z: 335.1.
Compounds 243-245 in Table 14 were prepared from the aryl hydroxide and alcohol indicated by the procedure described in Synthetic Example S-25.











TABLE 14









MS 


Cmpd
Structure
Aryl Hydroxide
Alcohol
(m/z)







243












335.0 (M + H)


 


244












387.2 (M + H)


 


245












357.1 (M + H)









Synthetic Example S-26
Synthesis of imino({[1-(8-methoxyquinazolin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl]methyl})methyl-λ6-sulfanone (Compound 246)




Step 1: A mixture of DAST (1.2 g, 7.6 mmol) and CH2Cl2 (10 mL) was added slowly to a stirring mixture of tert-butyl 4-hydroxy-4-(methylsulfanylmethyl)piperidine-1-carboxylate (2.0 g, 7.6 mmol) and CH2Cl2 (5.0 mL) at −70° C. After stirring at −70° C. for 0.5 h, the resulting mixture was stirred at 20° C. for 12 h, then was poured into water (20 mL) and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (20 mL), dried over Na2SO4, concentrated, and purified by silica chromatography (0-50% EtOAc in petroleum ether) to provide tert-butyl 4-fluoro-4-(methylsulfanylmethyl)piperidine-1-carboxylate (1.0 g).
Step 2: A mixture of tert-butyl 4-fluoro-4-(methylsulfanylmethyl)piperidine-1-carboxylate (0.25 g, 0.95 mmol) and HCl/EtOAc (6 M, 5.0 mL) was stirred at 20° C. for 2 h under an N2 atmosphere. The mixture was concentrated to provide 4-fluoro-4-(methylsulfanylmethyl)piperidine hydrochloride (0.20 g).
Step 3: To a mixture of 4-fluoro-4-(methylsulfanylmethyl)piperidine hydrochloride (0.25 g, 1.2 mmol) and iPrOH (5.0 mL) was added iPr2NEt (0.81 g, 6.2 mmol) and 4-chloro-8-methoxy-quinazoline (0.29 g, 1.2 mmol) and the resulting mixture was stirred at 20° C. for 2 h, then was concentrated, combined with water (30 mL), and extracted with EtOAc (2×30 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, concentrated, to provide 4-[4-fluoro-4-(methylsulfanylmethyl)-1-piperidyl]-8-methoxy-quinazoline (0.47 g).
Step 4: A mixture of 4-[4-fluoro-4-(methylsulfanylmethyl)-1-piperidyl]-8-methoxy-quinazoline (0.47 g, 1.4 mmol), in EtOH (5.0 mL), PhI(OAc)2 (1.4 g, 4.3 mmol), and NH4OAc (0.45 g, 5.7 mmol) was stirred for 2 h. The mixture was concentrated and purified by preparative HPLC (1-25% MeCN in H2O, 0.2% formic acid) to provide imino({[1-(8-methoxyquinazolin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl]methyl})methyl-λ6-sulfanone (Compound 246) (20 mg). ESI MS m/z: 333.1 (M+H).
Table 15 describes chiral separation conditions for specific examples where supercritical CO2 is the non-polar co-solvent.







TABLE 15







SFC Separation Conditions













Conditions (column & polar






Compound
co-solvent system)
First
ee %
Second
ee %















1
Phenomenex-Cellulose-2
 1S
>99
 1R
>99



(250 mm*30 mm,10 μm)



55% [0.1% NH3/H2O in MeOH]


44
Chiralpak (250 × 30 mm, 5 μm)
 44a
>99
 44b
>99



40% [0.1% NH3/H2O in EtOH]


54
Chiralpak AS (250 × 30 mm, 10 μm)
 54a
>99
 54b
99



40% [0.1% NH3/H2O in EtOH]


55
Chiralpak IC (250 × 30 mm, 10 μm)
 55a
99
 55b
98



57% [0.1% NH3/H2O in MeOH]


60
Chiralpak IC (250 × 20 mm, 5 μm)
 60a
>99
 60b
99



50% [20 mM NH3 in MeOH]


75
Chiralpak AS-3 (50 × 4.6 mm, 3 μm)
 75a
>99
 75b
99



35% [0.1% NH3/H2O in EtOH]


80
Phenomenex-Cellulose-2
 80a
>99
 80b
99



(250 mm*50 mm,10 μm)



55% [0.1% NH3/H2O in MeOH]


103
Chiralpak OD (250 × 30 mm, 10 μm)
103a
>99
103b
>99



50% (0.1% NH3/H2O in iPrOH)


114
Chiralcel OD (250 × 30 mm, 10 μm);
114a
>99
114b
>99



43% [0.1% NH3/H2O iPrOH]


133
Chiralpak AS (250 × 30 mm, 10 μm)
133a
>99
133b
95



45% [0.1% NH3/H2O in iPrOH]


141
Chiralpak IC (250 × 30 mm, 10 μm)
141a
98
141b
99



60% [0.1% NH3/H2O in iPrOH]


146
Chiralpak AD (250 × 30 mm, 10 μm);
146a
>99
146b
>99



60% [0.1% NH3/H2O in MeOH]


160
Regis (S,S) Whelk-O1 (250 × 30 mm, 5 μm)
160a
>99
160b
98.5



62.5% [0.1% NH3/H2O in EtOH]


161
Regis (S,S) Whelk-O1 (250 × 30 mm, 5 μm)
161a
83
161b
90



45% [0.1% NH3/H2O in MeOH]


169
Chiralpak AS (250 × 30 mm, 10 μm)
169a
>99
169b
>99



45% [0.1% NH3/H2O in iPrOH]


175
Chiralpak AS (250 × 30 mm, 10 μm)
175a
>99
175b
>99



52% [0.1% in iPrOH]


177
Chiralpak AD (250 × 30 mm, 10 μm);
177a
>99
177b
99.0



55% [0.1% NH3/H2O in EtOH]


178
Chiralpak AD (250 × 30 mm, 10 μm);
178a
>99
178b
98



50% [0.1% NH3/H2O in MeOH]


179
Phenomenex-Cellulose-2
179a
>99
179b
>99



(250 mm*50 mm, 10 μm)



60% [0.1% NH3/H2O in MeOH]


183
Chiralpak AD (250 × 30 mm, 10 μm);
183a
>99
183b
>99



65% [0.1% NH3/H2O in EtOH]


184
Phenomenex-Cellulose-2
184a
>99
184b
97



(250 mm*50 mm, 10 μm)



60% [0.1% NH3/H2O in MeOH]


185
Chiralpak AD (250 × 30 mm, 10 μm);
185a
>99
185b
>99



60% [0.1% NH3/H2O in EtOH]


189
Chiralpak AD (250 × 30 mm, 10 μm);
189a
>99
189b
98.9



35% EtOH


193
Phenomenex-Cellulose-2
193a
>99
193b
98.6



(250 mm*50 mm,10 μm) 60% EtOH


195
Chiralpak AD (250 × 30 mm, 10 μm);
195a
>99
195b
98.7



63% [0.1% NH3/H2O in EtOH]


198
Chiralpak AD (250 × 30 mm, 10 μm);
198a
99
198b
98



46% [0.1% NH3/H2O in MeOH]


205
Chiralpak AS (250 × 30 mm, 10 μm)
205a
>99
205b
>99



25% [0.1% in iPrOH]


208
Chiralpak AD (250 × 30 mm, 10 μm);
208a
>99
208b
97.9



46% [0.1% NH3/H2O in EtOH]


211
Chiralpak AS (250 × 30 mm, 10 μm)
211a
>99
211b
>99



40% [0.1% in MeOH]


218
Regis (S,S) Whelk-O1 (250 × 30 mm, 5 μm)
218a
>99
218b
>99



50% [0.1% NH3/H2O in EtOH]


219
Phenomenex-Cellulose-2
219a
>99
219b
95.4



(250 mm*50 mm, 10 μm)



50% [0.1% NH3/H2O in EtOH]


222
Chiralpak AS (250 × 30 mm, 10 μm)
222a
>99
222b
96.9



35% [0.1% NH3/H2O in EtOH]


223
Chiralpak IG (250 × 30 mm, 10 μm);
223a
>99
223b
>99



60% [0.1% NH3/H2O in EtOH]


229
Chiralpak AD (250 × 30 mm, 10 μm);
229a
>99 (de)
229b
>99 (de)



42% [0.1% NH3/H2O in iPrOH]


230
Chiralpak IG (250 × 30 mm, 10 μm);
230a
>99
230b
>99



50% [0.1% NH3/H2O in MeOH]


237
Chiralpak AD (250 × 30 mm, 10 μm);
237a
>99
237a
>99



55% [0.1% NH3/H2O in EtOH]


238
Chiralpak AD (250 × 30 mm, 10 μm);
238a
>99
238b
>99



60% [0.1% NH3/H2O in MeOH]


239
Chiralpak IG (250 × 30 mm, 10 μm);
239a
>99
239b
97.3



60% [0.1% NH3/H2O in MeOH]
















TABLE 16







1H NMR data for examples at 400 MHz









Compound
Solvent
δ ppm





 1
DMSO-d6
8.56 (d, J = 5.1 Hz, 1H), 8.02 (d, J = 8.6 Hz, 2H), 7.45-7.40 (m,




4H), 6.69 (d, J = 5.1 Hz, 1H), 4.28 (s, 1H), 3.95 (s, 3H), 3.90 (s,




3H), 3.10 (s, 3H)


 6
DMSO-d6
8.88 (d, J = 4.4 Hz, 1H), 7.80 (dd, J = 33.4, 9.1 Hz, 1H), 7.47 (d, J =




28.7 Hz, 1H), 7.47 (d, J = 2.6 Hz, 1H), 7.31 (dd, J = 9.1, 2.6 Hz,




1H), 4.55-4.14 (m, 1H), 3.94 (s, 3H), 4.07-3.70 (m, 2H), 3.45 (s,




2H), 3.28 (d, J = 19.1 Hz, 2H), 3.18-2.92 (m, 1H), 2.91-2.73 (m,




1H).


 8
CDCl3
8.67 (s, 1H), 7.24 (s, 1H), 7.09 (s, 1H), 4.20 (br d, 13.2 Hz, 2H),




4.03 (s, 3H), 4.00 (s, 3H), 3.22-3.13 (m, 2H), 3.12-3.03 (m, 2H),




3.02 (s, 3H), 2.62 (br s, 1H), 2.00-1.86 (m, 4H), 1.77 (br s, 1H),




1.59-1.48 (m, 2H)


 10
CDCl3
8.76 (d, J = 5.2 Hz, 1H), 8.07-7.98 (m, 2H), 7.48 (d, J = 2.8 Hz,




1H), 7.26-7.22 (m, 1H), 7.08-7.03 (m, 1H), 7.27-7.21 (m, 1H), 6.73




(d, J = 5.2 Hz, 1H), 3.99 (s, 3H), 3.30 (s, 3H), 3.02 (br s, 1H)


 12
DMSO-d6
8.68 (d, J = 5.13 Hz, 1H), 8.19 (d, J = 9.13 Hz, 1H), 8.01 (br d, J =




10.13 Hz, 1H), 7.87 (br d, J = 8.38 Hz, 1H), 7.65 (t, J = 8.07 Hz,




1H), 7.46 (d, J = 2.00 Hz, 1H), 7.33 (dd, J = 9.13, 2.13Hz, 1H),




6.63 (d, J = 5.13 Hz, 1H), 4.45 (br s, 1H), 3.95 (s, 3H), 3.17 (s, 3H)


 18
DMSO-d6
8.56 (s, 1 H), 7.99-8.06 (m, 2 H), 7.51-7.57 (m, 3 H), 7.39 (s, 1




H), 4.28 (s, 1 H), 3.97 (d, J = 6.62 Hz, 6 H), 3.12 (s, 3 H)


 22
DMSO-d6
8.91 (s, 1H), 8.54 (d, J = 8.6 Hz, 1H), 8.28 (d, J = 8.2 Hz, 1H), 8.10-




8.02 (m, 3H), 7.96 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.58-7.51 (m,




2H), 4.32 (s, 1H), 3.13 (s, 3H)


 26
DMSO-d6
δ 8.72 (d, J = 4.5 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.39 (d, J = 2.6




Hz, 1H), 7.24 (dd, J = 9.3, 2.6 Hz, 1H), 7.21 (d, J = 4.6 Hz, 1H),




4.36-4.23 (m, 2H), 4.13-4.03 (m, 2H), 3.92 (s, 3H), 3.87 (s, 1H),




3.85-3.75 (m, 1H), 3.67-3.56 (m, 1H), 3.28-3.07 (m, 2H), 3.06-




2.91 (m, 2H).


 43
CDCl3
8.67 (s, 1H), 7.58 (d, J = 12.4 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H),




4.05 (s, 3H), 3.79 (br d, J = 12.4 Hz, 2H), 3.55-3.40 (m, 2H), 3.24-




3.13 (m, 2H), 3.05 (s, 3H), 2.05-1.93 (m, 4H), 1.85-1.75 (m, 2H),




1.67-1.52 (m, 2H)


 44
DMSO-d6
9.15 (s, 1H), 7.98-7.93 (m, 2H), 7.85-7.79 (m, 2H), 7.33-7.26 (m,




2H), 4.25 (s, 1H), 4.09 (s, 3H), 3.07 (s, 3H)


 47
DMSO-d6
9.06 (s, 1H), 8.15 (d, J = 9.3 Hz, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.68




(dd, J = 9.3, 2.9 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 2.9




Hz, 1H), 4.28 (s, 1H), 3.82 (s, 3H), 3.08 (s, 3H).


 50
DMSO-d6
9.16 (s, 1H), 8.14 (d, J = 8.7 Hz, IH), 7.99-7.92 (sym. m, 2H),




7.89 (dd, J = 8.6, 2.0 Hz, 1H), 7.84 (s, 1H), 7.35-7.26 (sym. m,




2H), 4.27 (s, 1H), 3.08 (s, 3H), 2.51 (s, 3H)


 53
DMSO-d6
8.60 (d, J = 5.2 Hz, 1 H), 8.16 (s, 1 H), 7.89 (d, J = 9.2 Hz, 1 H),




7.31 (d, J = 2.4 Hz, 1 H), 7.17-7.19 (dd, J = 9.2, 2.4 Hz, 1 H), 6.84




(d, J = 5.2 Hz, 1 H), 3.90 (s, 3 H), 3.54-3.63 (m, 4 H), 3.09 (m, 3




H), 2.89 (s, 4 H), 1.95-1.98 (m, 4 H)


 54
DMSO-d6
8.51 (s, 1H), 8.15 (s, 1H), 7.20 (s, 1H), 7.11 (s, 1H), 3.91 (m, 6H),




3.67-3.52 (m, 5H), 3.33-3.22 (m, 3H), 3.17-3.07 (m, 2H), 2.79 (s,




3H), 1.92-1.83 (m, 2H), 1.80-1.63 (m, 4H).


 55
DMSO-d6
8.59 (d, J = 5.13 Hz, 1H), 8.15 (s, 1H), 7.88 (d, J = 9.26 Hz, 1H),




7.31 (d, J = 2.63 Hz, 1H), 7.17 (dd, J = 9.26, 2.63 Hz, 1H), 6.86 (d,




J = 5.13 Hz, 1H), 3.89 (s, 3H), 3.35-3.24 (m, 2H), 3.19-3.06(m,




6H), 2.80 (s, 3H), 1.87-1.72 (m, 6H)


 57
DMSO-d6
8.56 (s, 1H), 7.60-7.62 (m, 1H), 7.51-7.55 (m, 1H), 7.26-7.28 (m,




1H), 4.02 (s, 3H), 3.90-3.93 (m, 2H), 3.45-3.51 (m, 2H), 3.27-3.29




(m, 2H), 3.04 (s, 3H), 1.92-1.97 (m, 4 H), 1.80-1.90 (m, 1H), 1.59-




1.61 (m, 1H))


 58
DMSO-d6
9.17 (s, 1H), 7.94 (d, J = 8.8 Hz, 2H), 7.68 (t, J = 8.1 Hz, 1H), 7.49




(t, J = 8.7 Hz, 2H), 7.29 (d, J = 8.9 Hz, 2H), 4.26 (s, 1H), 4.03 (s,




3H), 3.07 (s, 3H)


 60
DMSO-d6
8.71 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 9.1 Hz, 1H), 8.02-7.95 (m,




2H), 7.45 (d, J = 2.5 Hz, 1H), 7.45-7.38 (m, 2H), 7.30 (dd, J =




9.2, 2.6 Hz, 1H), 6.72 (d, J = 5.1 Hz, 1H), 4.28 (s, 1H), 3.94 (s,




3H), 2.75-2.65 (m, 1H), 1.17-1.09 (m, 1H), 1.03-0.87 (m, 3H)


 69
CDCl3
7.38 (d, J = 2.4 Hz, 1H), 7.15-7.08 (m, 1H), 6.73 (d, J = 5.2 Hz, 1H),




3.95 (s, 3H), 3.61 (br d, J = 12.4 Hz, 2H), 3.24-3.13 (m, 2H), 3.03




(s, 3H), 2.88-2.75 (m, 2H), 2.63 (br s, 1H), 2.04-1.82 (m, 4H),




1.65-1.58 (br s, 3H)


 72
CDCl3
8.78 (s, 1H), 7.47-7.33 (m, 2H), 7.11 (d, J = 7.2 Hz, 1H), 4.35 (br d,




J = 13.2 Hz, 2H), 4.06 (s, 3H), 3.21-3.05 (m, 4H), 3.02 (s, 3H), 2.62




(br s, 1H), 1.98-1.85 (m, 4H), 1.85-1.72 (m, 1H), 1.57-1.46 (m, 2H)


 74
DMSO-d6
9.97-10.00 (brs, 1H), 8.62 (d, J = 5.6 Hz 1H), 8.39 (d, J = 7.6 Hz,




1H), 7.90 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.33-7.37




(m, 2H), 6.64 (d, J = 7.2 Hz, 1H), 4.83-4.86 (m, 2H), 4.21 (brs,




1H), 3.92 (s, 3H), 3.02 (s, 3H)


 75
DMSO-d6
8.69 (d, J = 5.25 Hz, 1 H) 8.14 (d, J = 9.13 Hz, 1 H) 8.01 (s, 1 H) 7.99




(s, 1 H) 7.79 (s, 1 H) 7.77 (s, 1 H) 7.36 (d, J = 2.50 Hz, 1 H) 7.24




(dd, J = 9.07, 2.56 Hz, 1 H) 7.02 (d, J = 5.38 Hz, 1 H) 5.52 (s, 2 H)




3.93 (s, 3 H) 3.10 (s, 3 H).


 76
DMSO-d6
8.84 (d, J = 5.0 Hz, 1H), 8.71 (d, J = 2.8 Hz, 1H), 8.01-7.94 (m,




2H), 7.84 (d, J = 2.8 Hz, 1H), 7.36-7.29 (m, 2H), 7.07 (d, J = 5.1




Hz, 1H), 4.24 (s, 1H), 4.00 (s, 3H), 3.09 (s, 3H).


 77
DMSO-d6
9.42 (s, 1H), 8.82 (d, J = 5.2 Hz, 1H), 8.11-8.04 (m, 2H), 7.60-




7.52 (m, 2H), 7.26 (s, 1H), 6.61 (d, J = 5.2 Hz, 1H), 4.33 (br, 1H),




4.02 (s, 3H), 3.13 (s, 3H)


 79
DMSO-d6
2.81 (s, 3 H) 3.67 (s, 1 H) 3.93 (s, 3 H) 4.43 (d, J = 3.31 Hz, 2 H)




6.53 (d, J = 5.29 Hz, 1 H) 7.26-7.32 (m, 3 H) 7.41 (d, J = 2.43 Hz, 1




H) 7.57 (d, J = 8.60 Hz, 2 H) 8.18 (d, J = 9.04 Hz, 1 H) 8.62 (d,




J = 5.07 Hz, 1 H)


 80
DMSO-d6
8.69 (d, J = 5.07 Hz, 1 H), 8.10 (d, J = 9.04 Hz, 1 H), 7.98-8.04




(m, 2 H), 7.37-7.49 (m, 3 H), 7.29 (dd, J = 9.15, 2.54 Hz, 1 H),




6.69 (d, J =5.29 Hz, 1 H), 4.25 (s, 1 H), 3.93 (s, 3 H), 3.09 (s, 3 H)


 84
DMSO-d6
8.71 (s, 1 H) 8.03-8.09 (m, 2 H) 7.91 (dd, J = 8.25, 1.00 Hz, 1 H)




7.73 (t, J = 8.13 Hz, 1 H) 7.57-7.64 (m, 1 H) 7.57-7.65 (m, 1 H)




7.53 (dd, J = 7.88, 0.75 Hz, 1 H) 4.30 (s, 1 H) 4.01 (s, 3 H) 3.14-




3.15 (m, 1 H) 3.15 (d, J = 0.75 Hz, 2 H)


 88
DMSO-d6
8.86 (d, J = 4.5 Hz, 1H), 7.78 (d, J = 9.2 Hz, 1H), 7.66-7.59 (m,




2H), 7.59-7.52 (m, 2H), 7.48 (d, J = 2.6 Hz, 1H), 7.32 (d, J = 4.5




Hz, 1H), 7.26 (dd, J = 9.2, 2.6 Hz, 1H), 4.57-4.42 (m, 2H), 3.94




(s, 3H), 3.73 (s, 1H), 2.86 (s, 3H)


 98
DMSO-d6
8.84 (d, J = 4.52 Hz, 1H), 7.76 (d, J = 9.29 Hz, 1H), 7.52-7.43(m,




5H), 7.30-7.21(m, 2H), 3.94 (s, 3H), 3.76 (s, 1H), 3.46-3.39(m,




2H), 3.17-3.09 (m, 2H), 2.95 (s, 3H)


101
DMSO-d6
8.75 (d, J = 2.7 Hz, 1H), 8.72 (d, J = 5.1 Hz, 1H), 8.17 (dd, J = 8.9,




4.1 Hz, 2H), 7.96 (dd, J = 8.6, 2.7 Hz, 1H), 7.47 (d, J = 2.5 Hz,




1H), 7.33 (dd, J = 9.2, 2.5 Hz, 1H), 6.77 (d, J = 5.2 Hz, 1H), 4.50




(s, 1H), 3.95 (s, 3H), 3.20 (s, 3H)


103
DMSO-d6
8.71 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.97 (d, J = 8.8 Hz,




2H), 7.50-7.39 (m, 3H), 7.32-7.24 (m, 1H), 6.71 (d, J = 5.2 Hz, 1H),




4.23 (s, 1H), 3.94 (s, 3H), 3.22-3.10 (m, 2H), 1.18-1.03 (m, 3H)


107a
DMSO-d6
9.05 (br d, J = 6.36 Hz, 1 H) 8.22-8.32 (m, 1 H) 7.30-7.63 (m, 3




H) 4.42 (br d, J = 6.14 Hz, 2 H) 3.99 (s, 3 H) 3.75 (br s, 3 H) 3.16




(brs, 1 H) 2.36 (br d, J = 14.69 Hz, 2 H) 2.24-2.48 (m, 1 H) 1.90




(brd, J = 12.93 Hz, 2H)


107b
acetone-d6
8.94-9.08 (m, 1 H) 8.32-8.43 (m, 1 H) 8.00 (d, J = 2.19 Hz, 1 H)




7.40-7.52 (m, 2 H) 4.64-4.70 (m, 2 H) 4.04 (br d, J = 3.29 Hz, 3




H) 3.56-3.81 (m, 4 H) 3.24-3.35 (m, 1 H) 2.50-2.71 (m, 3 H)




2.13-2.28 (m, 2 H)


114
DMSO-d6
8.70 (d, J = 5.26 Hz, 1 H) 8.02-8.04 (m, 2 H) 7.94 (d, J = 11.84 Hz,




1 H) 7.66 (d, J = 8.11 Hz, 1 H) 7.43-7.46 (m, 2 H) 6.75 (d, J = 5.26




Hz, 1 H) 4.29 (br s, 1 H) 4.03 (s, 3 H) 3.11 (s, 3 H)


115
CDCl3
8.64 (d, J = 5.2 Hz, 1H), 8.06-7.99 (m, 1H), 7.48 (s, 1H), 7.34 (s,




1H), 7.07 (br d, J = 8.8 Hz, 1H), 7.03-7.00 (m, 1H), 6.74 (d, J = 5.2




Hz, 1H), 4.07 (s, 3H), 4.01 (s, 3H), 3.31 (s, 3H), 3.02 (br s, 1H)


116
DMSO-d6
8.54 (d, J = 5.3 Hz, 1H), 8.01 (dd, J = 2.1, 10.1 Hz, 1H), 7.86 (dd, J =




1.2, 8.4 Hz, 1H), 7.63 (t, J = 8.2 Hz, 1H), 7.49 (s, 1H), 7.44 (s,




1H), 6.62 (d, J = 5.1 Hz, 1H), 4.46 (s, 1H), 3.94 (d, J = 9.7 Hz, 6H),




3.16 (s, 3H)


125
DMSO-d6
3.12 (s, 3 H) 4.28 (s, 1 H) 6.86 (d, J = 5.04 Hz, 1 H) 7.47 (d, J = 8.55




Hz, 2 H) 7.68 (s, 1 H) 7.86 (br d, J = 1.32 Hz, 1 H) 8.04 (d, J = 8.77




Hz, 2 H) 8.08 (d, J = 8.55 Hz, 1 H) 8.24 (d, J = 8.11 Hz, 1 H) 8.79 (d,




J = 5.04 Hz, 1 H)


126
DMSO-d6
8.73 (d, J = 5.13 Hz, 1 H) 8.26 (s, 1 H) 8.01-8.07 (m, 2 H) 7.62 (s,




1 H) 7.44-7.50 (m, 2 H) 6.72 (d, J = 5.25 Hz, 1 H) 4.29 (s, 1 H)




4.25-4.32 (m, 1 H) 4.05 (s, 2 H) 4.01-4.08 (m, 1 H) 3.12 (s, 2 H)




3.08 -3.15 (m, 1 H) 2.50 (dt, J = 3.63, 1.81 Hz, 74 H)


127
DMSO-d6
8.71 (s, 1 H) 8.05 (d, J = 8.76 Hz, 2 H) 7.81 (s, 1 H) 7.48 (d, J = 8.76




Hz, 2 H) 7.39 (s, 1 H) 4.28 (s, 1 H) 4.06 (s, 3 H) 3.98 (s, 3 H) 3.12




(s, 3 H)


128
DMSO-d6
3.12 (d, J = 0.75 Hz, 3 H) 4.04 (s, 3 H) 4.29 (s, 1 H) 6.75 (d, J = 5.00




Hz, 1 H) 7.48 (d, J = 8.76 Hz, 2 H) 7.70 (br d, J = 1.38 Hz, 1 H) 8.02-




8.08 (m, 3 H) 8.76 (d, J = 5.00 Hz, 1 H)


129
DMSO-d6
8.74 (d, J = 2.7 Hz, 1H), 8.58 (d, J = 5.1 Hz, 1H), 8.17 (d, J = 8.6




Hz, 1H), 7.94 (dd, J = 8.6, 2.7 Hz, 1H), 7.46 (d, J = 5.0 Hz, 2H),




6.78 (d, J = 5.2 Hz, 1H), 4.49 (s, 1H), 3.96 (s, 3H), 3.92 (s, 3H),




3.19 (s, 3H)


130
DMSO-d6
8.76 (d, J = 5.0 Hz, 1H), 8.32 (d, J = 9.1 Hz, 1H), 7.98-7.88 (m,




2H), 7.35 (d, J = 5.0 Hz, 1H), 7.29 (dd, J = 9.0, 1.3 Hz, 3H), 4.22




(s, 1H), 3.68 (s, 3H), 3.07 (s, 3H).


131
DMSO-d6
9.32 (s, 1H), 8.10 (dd, J = 8.6, 1.2 Hz, 1H), 8.03 (td, J = 8.1, 5.4




Hz, 1H), 7.96-7.88 (sym. m, 2H), 7.57 (ddd, J = 11.8, 7.9, 1.2 Hz,




1H), 7.29-7.21 (sym. m, 2H), 4.25 (s, 1H), 3.08 (s, 3H).


133
DMSO-d6
3.10 (s, 3 H) 3.90 (s, 3 H) 4.30 (s, 1 H) 5.48 (s, 2 H) 7.01 (d, J = 5.48




Hz, 1 H) 7.21 (dd, J = 9.21, 2.41 Hz, 1 H) 7.34 (d, J = 2.19 Hz, 1 H)




7.64-7.71 (m, 1 H) 7.84 (d, J = 7.45 Hz, 1 H) 7.94 (br d, J = 7.89 Hz,




1 H) 8.06-8.14 (m, 2 H) 8.67 (d, J = 5.26 Hz, 1 H)


134
DMSO-d6
8.68 (d, J = 5.02 Hz, 1 H), 7.99 (d, J = 8.28 Hz, 2 H), 7.67-7.84 (m,




3 H), 7.49 (t, J = 8.09 Hz, 1 H), 7.20 (d, J = 7.53 Hz, 1 H), 7.15 (d,




J = 5.27 Hz, 1 H), 5.50 (s, 2 H), 4.24 (s, 1 H), 3.94 (s, 3 H), 3.08 (s,




3 H)


139
CDCl3
8.67 (s, 1H),7.75 (d, J = 9.2 Hz, 1H), 7.21 (d, J = 2.8 Hz, 1H), 7.08-




7.03 (s, 1H), 4.32 (br d, J = 13.2 Hz, 2H), 3.95 (s, 3H), 3.21-3.06 (m,




4H), 3.02 (s, 3H), 2.61 (br s, 1H), 1.98-1.85 (m, 4H), 1.85-1.71 (m,




1H), 1.26 (s, 2H)


140
CDCl3
8.74 (d, J = 4.8 Hz, 1H), 7.58-7.49 (m, 1H), 7.42-7.38 (m, 1H), 7.01




(d, J = 7.6 Hz, 1H), 6.88 (d, J = 4.8 Hz, 1H), 4.08 (s, 3H), 3.62 (br d,




J = 12.4 Hz, 2H), 3.23-3.13 (m, 2H), 3.03 (s, 3H), 2.86-2.74 (m, 2H),




2.63 (br s, 1H), 2.02-1.85 (m, 4H), 1.66-1.56 (m, 3H)


146
DMSO-d6
8.59 (s, 1H), 7.45 (d, J = 4.4 Hz, H), 7.27-7.29 (m, 1H), 4.19-4.22




(m, 2H), 3.93 (s, 3H), 3.73 (s, 1H), 3.10-3.18 (m, 4H), 2.96 (s, 3H),




2.29-2.30 (m, 1 H), 2.02-2.09 (m, 2H), 1.51-1.57 (m, 2H)


149
CDCl3
8.66 (d, J = 5.2 Hz, 1H), 7.98 (d, J = 7.2 Hz, 1H), 7.93 (d, J = 8.4




Hz, 1H), 7.72-7.65 (m, 1H), 7.55-7.49 (m, 1H), 6.96 (d, J = 5.2 Hz,




1H), 3.62 (br s, 1H), 3.52-3.44 (m, 2H), 3.18-3.08 (m, 2H), 2.91 (s,




3H), 2.80-2.70 (m, 2H), 2.01-1.91 (m, 2H), 1.81-1.72 (m, 2H),




1.67-1.46 (m, 3H)


151
DMSO-d6
8.78 (s, 1 H) 7.61 (s, 1 H) 7.05 (s, 1 H) 3.99 (s, 3 H) 3.98 (s, 3 H)




3.57-3.69 (m, 3 H) 3.08-3.18 (m, 2 H) 2.86-2.96 (m, 5 H) 1.89




(brd, J = 11.13 Hz, 2H) 1.72-1.83 (m, 2 H) 1.64 (ddd, J = 10.63,




7.07, 3.69 Hz, 1 H) 1.44-1.58 (m, 2 H)


153
DMSO-d6
9.12 (s, 1H), 7.80 (d, J = 8.07 Hz, 2H), 7.53 (d, J = 8.19 Hz, 2H),




7.44 (s, 1H), 7.33 (s, 1H), 6.12-5.99 (m, 1H), 4.01 (s, 3H), 3.84 (s,




3H), 3.45-3.41 (m, 2H), 3.15 (br dd, J = 9.23, 3.48 Hz, 2H), 2.94 (s,




3H).


154
DMSO-d6
9.29 (s, 1H), 7.73 (d, J = 8.16 Hz, 2H), 7.63 (quin, J = 7.81 Hz,




2H), 7.54 (d, J = 8.03 Hz, 2H), 7.48 (d, J = 6.53 Hz, 1H), 4.02 (s,




3H), 3.76 (s, 1H), 3.48-3.40(m, 2H), 3.20-3.11 (m, 2H), 2.95 (s,




3H)


155
CDCl3
7.76 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 3.67 (s, 2H), 1.97




(s, 3H), 1.34 (s, 12H).


160
DMSO-d6
8.52 (d, J = 1.75 Hz, 1 H) 7.10-7.24 (m, 2 H) 3.92 (dd, J = 7.13, 1.64




Hz, 6 H) 3.50-3.71 (m, 5 H) 3.15-3.25 (m, 2 H) 2.57 (br s, 1 H)




1.68-1.89 (m, 6 H) 0.84-1.01 (m, 4 H)


161
DMSO-d6
8.71 (d, J = 4.4 Hz, 1 H), 7.46 (s, 1 H), 7.36-7.44 (m, 3 H), 7.25




(d, J = 4.4 Hz, 1 H), 7.19 (s, 1 H), 4.40-4.52 (m, 2 H), 3.96 (s, 3




H), 3.77 (s, 4 H), 3.43-3.58 (m, 2 H), 3.01 (br t, J = 5.6 Hz, 2 H),




2.84 (s, 3 H)


162
DMSO-d6
2.88 (s, 3 H) 3.93 (s, 3 H) 4.24 (s, 2 H) 7.24 (dd, J = 9.26, 2.75 Hz, 1




H) 7.28 (d, J = 4.50 Hz, 1 H) 7.45-7.51 (m, 3 H) 7.53-7.59 (m, 2




H) 7.76 (d, J = 9.26 Hz, 1 H) 8.84 (d, J = 4.50 Hz, 1 H)


165
DMSO-d6
1.41 (q, J = 11.21 Hz, 2 H) 1.74-2.02 (m, 5 H) 3.56 (br d, J = 12.67




Hz, 4 H) 3.69 (s, 3 H) 3.91 (s, 3 H) 3.97 (br t, J = 7.84 Hz, 2 H) 4.05




(s, 3 H) 4.73 (br s, 2 H) 7.53 (d, J = 9.54 Hz, 1 H) 7.94 (d, J = 9.54




Hz, 1 H) 8.63 (s, 1 H)


166
DMSO-d6
8.72 (d, J = 5.26 Hz, 1H), 8.10 (d, J = 9.21 Hz, 1H), 8.05-7.98(m,




2H), 7.48-7.42(m, 3H), 7.33-7.26(m, 1H), 6.74 (d, J = 5.04 Hz,




1H), 4.77 (d, J = 3.51 Hz, 1H), 4.34-4.23(m, 3H), 4.01-3.92 (m,




5H), 1.74 (s, 3H)


167
DMSO-d6
8.69 (s, 1 H) 8.30 (d, J = 8.94 Hz, 1 H) 8.02-8.08 (m, 2 H) 7.56-




7.62 (m, 2 H) 7.43 (s, 1 H) 7.42 (d, J = 8.58 Hz, 2 H) 4.32 (s, 1 H)




4.00 (s, 3 H) 3.15 (s, 3 H)


168
DMSO-d6
8.86 (s, 1H), 7.83-7.93 (m, 2H), 7.67 (d, J = 8.8 Hz, 1H), 7.48 (d,




J = 2.4 Hz, 1H), 7.17-7.28 (m, 1H), 6.97-7.06 (m, 2H), 4.15 (s, 1H),




3.92 (s, 3H), 3.04 (s, 3H), 2.21 (s, 3H)


169
DMSO-d6
8.67 (d, J = 5.25 Hz, 1 H) 8.11 (s, 1 H) 7.93 (d, J = 7.88 Hz, 1 H) 7.79-




7.87 (m, 2 H) 7.64-7.70 (m, 1 H) 7.54 (d, J = 8.25 Hz, 1 H) 7.07




(d, J = 5.25 Hz, 1 H) 5.49 (s, 2 H) 4.29 (s, 1 H) 3.99 (s, 3 H) 3.09 (s,




3 H)


170
DMSO-d6
8.70 (d, J = 5.38 Hz, 1 H) 8.32 (s, 1 H) 8.00 (d, J = 9.13 Hz, 1 H) 7.35




(d, J = 2.50 Hz, 1 H) 7.19 (dd, J = 9.13, 2.50 Hz, 1 H)7.11 (d, J = 5.38




Hz, 1 H) 7.08 (s, 1 H) 7.07-7.09 (m, 1 H) 5.41 (s, 2 H) 4.45 (s, 1




H) 3.91 (s, 3 H) 3.13-3.20 (m, 3 H)


171
DMSO-d6
25° C.: 8.60 (s, 1 H) 7.30 (br d, J = 9.21 Hz, 2 H) 4.29-4.49 (m, 2




H) 3.92 (br d, J = 12.28 Hz, 6 H) 3.66 (s, 1 H) 3.42 (br s, 1 H) 2.94-




3.17 (m, 4 H) 2.05-2.25 (m, 3 H) 1.68-1.89 (m, 2 H)




80° C.: 8.60 (s, 1 H) 7.22-7.41 (m, 2 H) 4.47 (br dd, J = 10.58, 6.39




Hz, 2 H) 3.94 (d, J = 13.01 Hz, 6 H) 3.45 (br s, 1 H) 3.25 (br s, 1 H)




2.96-3.09 (m, 4 H) 2.04-2.28 (m, 3 H) 1.88 (q, J = 12.57 Hz, 2 H)


172
DMSO-d6
9.08 (d, J = 2.0 Hz, 1H), 9.03 (s, 1H), 8.70 (d, J = 5.2 Hz, 1H), 8.48




(s, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.21 (dd,




J = 9.2, 2.4 Hz, 1H), 7.05 (d, J = 5.2 Hz, 1H), 5.54 (s, 2H), 4.60 (s,




1H), 3.91 (s, 3H), 3.20 (s, 3H).


173
DMSO-d6
8.66 (s, 1 H) 8.13 (s, 1 H) 7.91 (d, J = 7.88 Hz, 1 H) 7.82 (d, J = 7.75




Hz, 1 H) 7.65 (t, J = 7.69 Hz, 1 H) 7.40 (s, 1 H) 7.34 (s, 1 H) 5.74 (s,




2 H) 4.27 (s, 1 H) 3.96 (s, 3 H) 3.92 (s, 3 H) 3.08 (s, 3 H)


174
DMSO-d6
8.79 (s, 1 H) 8.11 (s, 1 H) 7.93 (br d, J = 7.75 Hz, 1 H) 7.83 (br d,




J = 7.63 Hz, 1 H) 7.59-7.74 (m, 3 H) 7.44 (d, J = 7.75 Hz, 1 H) 5.74




(s, 2 H) 4.27 (s, 1 H) 3.97 (s, 3 H) 3.08 (s, 3 H)


175
DMSO-d6
8.54 (d, J = 5.25 Hz, 1 H) 8.18 (s, 1 H) 7.92 (br d, J = 7.50 Hz, 1 H)




7.82 (br d, J = 7.75 Hz, 1 H) 7.64-7.70 (m, 1 H) 7.43 (s, 1 H) 7.33




(s, 1 H) 7.32-7.35 (m, 1 H) 6.99 (d, J = 5.38 Hz, 1 H) 5.50 (s, 2 H)




4.29 (s, 1 H) 3.91 (d, J = 7.13 Hz, 6 H) 3.09 (s, 3 H)


176
DMSO-d6
8.71 (d, J = 5.2 Hz, 1H), 8.09-8.18 (m, 2H), 7.95 (d, J = 8.0 Hz,




1H), 7.86 (d, J = 7.6 Hz, 1H), 7.64-7.73 (m, 1H), 7.52 (s, 1H), 7.08




(d, J = 5.6 Hz, 1H), 5.50 (s, 2H), 4.30 (s, 1H), 4.01 (s, 3H), 3.10 (s,




3H)


177
MeOD
8.61 (d, J = 5.50 Hz, 1H), 8.21 (d, J = 9.26 Hz, 1H), 8.05 (s, 1H),




7.79-7.74 (m, 1H), 7.67 (br d, J = 9.01 Hz, 1H), 7.32 (d, J = 2.50




Hz, 1H), 7.23 (dd, J = 9.19, 2.56 Hz, 1H), 6.98(d, J = 5.50 Hz, 1H),




5.51 (s, 2H), 3.96 (s, 3 H), 3.20 (s, 3H)


178
DMSO-d6
8.54 (dd, J = 5.38, 2.13 Hz, 1 H) 8.20 (dd, J = 9.13, 1.63 Hz, 1 H)




8.07 (d, J = 7.75 Hz, 1 H) 7.86 (d, J = 8.00 Hz, 1 H) 7.78 (t, J = 6.57




Hz, 1 H) 7.60 (td, J = 7.75, 2.75 Hz, 1 H) 7.20-7.33 (m, 2 H) 6.81




(t, J = 5.69 Hz, 1 H) 5.98 (quin, J = 5.78 Hz, 1 H) 4.23 (s, 1 H) 3.90




(s, 3 H) 3.00-3.08 (m, 3 H) 1.68-1.76 (m, 3 H)


179
DMSO-d6
8.69 (s, 1 H) 7.54-7.62 (m, 2 H) 7.27-7.37 (m, 1 H) 3.96 (s, 3 H)




3.71-3.86 (m, 3H) 3.40-3.54 (m, 2 H) 3.17 (d, J = 6.25 Hz, 2 H)




2.98 (s, 3 H) 2.26-2.40 (m, 1 H) 2.00-2.20 (m, 2 H) 1.56-1.73




(m, 2H)


180
DMSO-d6
8.49 (d, J = 7.00 Hz, 1 H) 7.61-7.65 (m, 2 H) 7.53 (dd, J = 5.00, 4.00




Hz, 1 H) 7.24 (d, J = 7.00 Hz, 1 H) 4.17 (br d, J = 13.13 Hz, 2 H) 4.09




(s, 3 H) 4.04 (br d, J = 6.25 Hz, 2 H) 3.81 (s, 3 H) 3.48 (br t, J = 11.82




Hz, 2 H) 2.60-2.70 (m, 1 H) 2.10 (br t, J = 14.63 Hz, 2 H) 1.64-




1.77 (m, 2H)


181
DMSO-d6
8.51 (s, 1 H) 7.20 (s, 1 H) 7.07-7.16 (m, 1 H) 3.86-3.99 (m, 6 H)




3.46-3.75 (m, 6 H) 2.79-2.91 (m, 3 H) 1.94-2.10 (m, 3 H) 1.56-




1.86 (m, 7H)


182
DMSO-d6
8.96 (s, 1H), 7.69-7.62 (m, 1H), 7.45 (d, J = 8.33 Hz, 1H), 7.23 (d,




J = 7.67 Hz, 1H), 4.02 (s, 3H), 3.74 (s, 1H), 3.66 (br d, J = 12.28




Hz, 2H), 3.14 (d, J = 6.36 Hz, 2H), 3.04-2.97(m, 2H), 2.96 (s, 3H),




2.29-2.18(m, 1H), 2.15-2.00(m, 2H), 1.68-1.55 (m, 2H)


183
DMSO-d6
8.58 (s, 1 H) 7.26 (dd, J = 11.07, 2.52 Hz, 1 H) 7.11 (dd, J = 9.76,




2.52 Hz, 1 H) 4.13 (br d, J = 13.37 Hz, 2 H) 3.95 (s, 3 H) 3.72 (s, 1




H) 3.05-3.20 (m, 4 H) 2.95 (s, 3 H) 2.21-2.36 (m, 1 H) 1.93-




2.10 (m, 2H) 1.42-1.59 (m, 2 H)


184
DMSO-d6
8.39 (d, J = 5.25 Hz, 1 H) 7.71 (d, J = 13.26 Hz, 1 H) 7.44 (d, J = 8.76




Hz, 1 H) 6.25 (d, J = 5.38 Hz, 1 H) 4.44 (s, 2 H) 4.29 (s, 2 H) 4.02




(s, 3 H) 3.43-3.68 (m, 1 H) 3.25 (dd, J = 7.00, 2.00 Hz, 2 H) 2.91




(s, 3 H) 2.74 (br t, J = 7.88 Hz, 1 H) 2.46-2.54 (m, 2 H) 2.08-2.31




(m, 2 H)


185
DMSO-d6
8.58 (s, 1 H), 7.42-7.48 (m, 2 H), 7.26-7.27 (m, 1 H), 5.69 (br s, 1




H), 4.00 (m, 3H), 3.96 (s, 3 H), 3.55 (m, 3H), 3.26-3.30 (m, 1 H),




3.02 (s, 3 H), 1.95-0.97 (m, 2 H), 1.88-1.89 (m, 2 H)


186
DMSO-d6
8.22 (d, J = 5.2 Hz, 1 H), 7.16 (d, J = 9.2 Hz, 2 H), 6.14 (d, J = 5.2




Hz, 1 H), 4.36 (s, 2 H), 4.18 (s, 2 H), 3.86 (s, 3 H), 3.85 (s, 3 H),




3.54 (s, 1 H), 3.17 (br d, J = 4.2 Hz, 2 H), 2.82 (s, 3 H), 2.61-2.72




(m, 2H), 2.07-2.18 (m, 2 H)


187
DMSO-d6
8.59 (s, 1H), 7.46-7.39(m, 2H), 7.25 (dd, J = 5.94, 3.06 Hz, 1H),




4.23-4.13(m, 4H), 3.71 (s, 1H), 3.19-3.07 (m, 4H), 2.95 (s, 3H),




2.29 (br s, 1H), 2.10-1.95(m, 2H), 1.52 (br d, J = 12.13 Hz, 2H),




1.43 (t, J = 7.00 Hz, 3H)


188
DMSO-d6
8.16 (s, 1H), 7.44 (s, 1H), 7.12 (s, 1H), 4.53 (s, 2H), 4.34 (s, 2H),




3.94 (d, J = 4.65 Hz, 7H), 3.55 (s, 1H), 3.19 (dd, J = 7.03, 2.63 Hz,




2H), 2.84 (s, 3H), 2.68 (q, J = 8.07 Hz, 2H), 2.21-2.10 (m, 2H)


189
DMSO-d6
8.67 (s, 1H), 7.53-7.56 (m, 2H), 7.29-7.32 (m, 1H), 3.94 (s, 3H),




3.77-3.80 (m, 2H), 3.56 (s, 1H), 3.41-3.44 (m, 2H), 3.12 (d, J = 7.0




Hz, 2H), 2.66-2.67 (m, 1H), 2.32-2.37 (m, 1 H), 2.06-2.15 (m, 2H),




1.63-1.66 (m, 2H), 1.05-1.14 (m, 1H), 0.89-0.94 (m, 2H), 0.82-0.87




(m, 1H)


190
DMSO-d6
8.58 (s, 1 H) 7.45 (d, J = 4.50 Hz, 2 H) 7.24-7.30 (m, 1 H) 4.20 (br




d, J = 12.88 Hz, 2 H) 3.92 (s, 3 H) 3.50 (s, 1 H) 3.15 (br t, J = 12.51




Hz, 2 H) 3.00-3.09 (m, 2 H) 2.58-2.69 (m, 1 H) 2.34 (br d,




J = 10.63 Hz, 1 H) 1.97-2.12 (m, 2 H) 1.54 (q, J = 11.67 Hz, 2 H)




1.01-1.09 (m, 1 H) 0.81-0.94 (m, 3 H)


191
DMSO-d6
8.57 (s, 1H), 8.14 (s, 1H), 7.39-7.50 (m, 2H), 7.25-7.28 (m, 1H),




3.97-4.20 (m, 3H), 3.81 (s, 3H), 3.44-3.53 (m, 1H), 3.02-3.17 (m,




2H), 2.33-2.47 (m, 3H), 2.12-2.30 (m, 3H), 1.97-2.07(m, 2H), 1.76-




1.90(m, 2H), 1.59-1.68(m, 2H)


192
DMSO-d6
8.24 (d, J = 5.25 Hz, 1 H) 8.13 (d, J = 13.38 Hz, 1 H) 7.88 (d, J = 8.38




Hz, 2 H) 7.79 (br t, J = 6.00 Hz, 1 H) 7.58 (d, J = 8.38 Hz, 2 H) 7.36




(d, J = 8.76 Hz, 1 H) 6.24 (d, J = 5.38 Hz, 1 H) 4.62 (d, J = 5.88 Hz, 2




H) 4.14 (s, 1 H) 3.95 (s, 3 H) 3.03 (s, 3 H)


193
DMSO-d6
8.58 (s, 1H), 7.50-7.40(m, 2H), 7.27 (dd, J = 7.32, 1.44 Hz, 1H),




5.93 (br s, 1H), 4.06-3.95 (m, 3H), 3.92 (s, 3 H), 3.55-3.43 (m, 2H),




3.34 (s, 1H), 3.30 (br s, 1H), 2.77-2.68 (m, 1H), 2.06-1.99(m, 2H),




1.95-1.79(m, 2H), 1.11-1.03(m, 1H), 0.98-0.82(m, 3 H)


194
DMSO-d6
8.67 (s, 1H), 7.56-7.72 (m, 3H), 6.07 (br s, 1H), 4.70 (br s, 1H),




4.42-4.55 (m, 1H), 3.89-4.23 (m, 7H), 3.59 (br s, 3H), 2.54-2.60




(m, 1H), 2.05-2.18 (m, 1H), 0.91 (br s, 1H), 0.82 (br s, 1H), 0.53




(br s, 1H), 0.35 (br s, 1H)


195
DMSO-d6
8.50-8.64 (m, 1 H) 7.41-7.55 (m, 2 H) 7.22-7.35 (m, 1 H) 5.76-




5.90 (m, 1 H) 3.97-4.02 (m, 2 H) 3.96 (br d, J = 3.50 Hz, 1 H) 3.92




(s, 3 H) 3.42-3.55 (m, 2 H) 3.19-3.31 (m, 2 H) 3.15-3.18 (m, 1




H) 3.11 (qd, J = 7.34, 2.00 Hz, 2 H) 1.79-2.09 (m, 4 H) 1.19-1.30




(m, 3 H)


196
DMSO-d6
8.59 (s, 1 H) 7.40-7.49 (m, 2 H) 7.26 (dd, J = 7.44, 1.06 Hz, 1 H)




5.66 (br s, 1 H) 4.18 (q, J = 7.00 Hz, 2 H) 4.00 (br s, 2 H) 3.96 (br s,




1 H) 3.46-3.58 (m, 2 H) 3.40-3.45 (m, 1 H) 3.27 (s, 1 H) 3.03 (s,




3 H) 1.93-2.01 (m, 2 H) 1.84-1.93 (m, 2 H) 1.43 (t, J = 6.94 Hz, 3




H)


197
DMSO-d6
8.69 (s, 1 H) 7.48-7.64 (m, 2 H) 7.29 (dd, J = 5.69, 3.31 Hz, 1 H)




4.20 (q, J = 6.92 Hz, 2 H) 3.79 (br s, 1 H) 3.75 (br d, J = 6.88 Hz, 2




H) 3.44 (brt, J = 12.51 Hz, 2 H) 3.32 (s, 43 H)3.29 (s, 1 H)3.15 (d,




J = 6.25 Hz, 2 H) 2.97 (s, 3 H) 2.02-2.17 (m, 2 H) 1.57-1.72 (m, 2




H) 1.44 (t, J = 6.94 Hz, 3H)


198
DMSO-d6
1.99 (br s, 2 H), 2.03-2.12 (m, 2 H), 3.05 (s, 3 H), 3.36 (s, 1 H),




3.42-3.50 (m, 1 H), 3.54-3.63 (m, 2 H), 3.65-3.77 (m, 2 H),




3.94 (s, 3 H), 4.02 (s, 1 H), 5.72 (s, 1 H), 7.30 (t, J = 4.4 Hz, 1 H),




7.52-7.59 (m, 2 H), 8.68 (s, 1 H)


199
DMSO-d6
8.15 (s, 1 H) 7.40-7.47 (m, 1 H) 7.32-7.39 (m, 1 H) 7.21 (d,




J = 7.25 Hz, 1 H) 3.95 (br s, 2 H) 3.90 (s, 3 H) 3.41-3.50 (m, 2 H)




3.39 (s, 1 H) 3.26 (s, 2 H) 3.02 (s, 3 H) 2.52 (br s, 3 H) 1.82-2.00




(m, 4 H)


200
DMSO-d6
8.74 (s, 1 H) 7.78 (br d, J = 8.25 Hz, 1 H) 7.52-7.66 (m, 2 H) 6.10




(s, 1 H) 5.96 (s, 1 H) 3.82 (br d, J = 12.76 Hz, 2 H) 3.77 (s, 1 H) 3.48




(br t, J = 12.38 Hz, 2 H) 3.15 (br d, J = 6.13 Hz, 2 H) 2.97 (s, 3 H)




2.01-2.19 (m, 2H) 1.64 (q, J = 10.84 Hz, 2 H)


201
DMSO-d6
7.46-7.55 (m, 2 H) 7.24-7.29 (m, 1 H) 3.93 (s, 3 H) 3.68-3.79




(m, 3 H) 3.45 (br t, J = 12.38 Hz, 2 H) 3.15 (d, J = 6.38 Hz, 2 H) 2.97




(s, 3 H) 2.68 (s, 3 H) 2.29 (br d, J = 3.50 Hz, 1 H) 2.00-2.16 (m, 2




H) 1.63 (q, J = 11.34 Hz, 2 H)


202
DMSO-d6
7.70 (d, J = 14 Hz, 1H), 7.25-7.26 (m, 2H), 7.02-7.04 (m, 1H),




4.22-4.25 (m, 2H), 3.99 (s, 3H), 3.17-3.24 (dm, 2H), 3.02-3.07 (m,




5H), 2.32 (m, 1 H), 2.02-2.13 (m, 2H), 1.54-1.62 (m, 2H)


203
DMSO-d6
8.63 (s, 1H), 7.19-7.35 (m, 2H), 3.91 (s, 3H), 3.65-3.81 (m, 3H),




3.38-3.44 (m, 2H), 3.10 (d, J = 6.4 Hz, 2H), 2.95 (s, 3H), 2.19-2.34




(m, 1H), 1.94-2.12 (m, 2H), 1.50-1.59 (m, 2H)


204
DMSO-d6
8.70 (d, J = 4.8 Hz, 1 H), 7.48-7.55 (m, 2 H), 7.41-7.47 (m, 3 H),




7.26 (d, J = 4.8 Hz, 1 H), 7.14 (s, 1 H), 3.94 (s, 3 H), 3.74 (s, 3 H),




3.69 (s, 1 H), 3.42 (dd, J = 9.6, 6.8 Hz, 2 H), 3.31 (s, 3 H), 3.08-




3.16 (m, 2 H), 2.89 (s, 3 H ), 2.49 (dt, J = 3.6, 1.6 Hz, 2 H)


205
DMSO-d6
8.55-8.61 (m, 1 H) 7.55-7.61 (m, 1 H) 7.45-7.51 (m, 1 H) 6.87-




6.95 (m, 1 H) 3.94-3.98 (m, 3 H) 3.59-3.67 (m, 1 H) 3.21-3.30




(m, 2 H) 2.99-3.17 (m, 6 H) 2.75-2.81 (m, 3 H) 1.70-1.86 (m, 6 H)


206
DMSO-d6
8.33 (s, 1H), 8.15 (s, 1H), 7.21 (s, 1H), 7.13 (s, 1H), 4.23 (br s,




4H), 3.89 (d, J = 2.38 Hz, 6H), 3.55 (br s, 1H), 3.21-3.08 (m, 4H),




2.74 (s, 3H), 1.87 (br t, J = 5.21 Hz, 4 H)


207
DMSO-d6
8.32 (s, 1H) 8.16 (s, 1 H) 7.54 (s, 1H) 7.12 (s, 1 H) 4.02 (br t,




J = 6.88 Hz, 2 H) 3.90 (d, J = 1.50 Hz, 6 H) 3.70 (s, 2 H) 3.08-3.20




(m, 4 H) 2.75 (s, 3 H) 1.90 (br t, J = 6.88 Hz, 2 H) 1.59-1.73 (m, 4 H)


208
acetone-d6
8.50 (d, J = 5.04 Hz, 1 H) 8.15 (s, 1 H) 7.28-7.43 (m, 2 H) 6.90 (d,




J = 5.04 Hz, 1 H) 3.96 (d, J = 1.75 Hz, 6 H) 3.33-3.46 (m, 2 H) 3.10-




3.32 (m, 6 H) 2.82 (s, 3 H) 1.86-2.00 (m, 6 H)


209
DMSO-d6
8.50 (s, 1H), 7.18 (s, 1H), 7.11 (s, 1H), 3.89-3.91 (s, 6H), 3.61 (m,




4H), 3.09-3.16 (m, 4H), 2.73 (s, 3H), 1.60-1.65 (m, 8H)


210
DMSO-d6
8.70 (s, 1 H) 7.76 (d, J = 12.63 Hz, 1 H) 7.57 (d, J = 8.50 Hz, 1 H)




4.03 (s, 3 H) 3.66 (d, J = 1.25 Hz, 1 H) 3.53-3.63 (m, 4 H) 3.27-




3.33 (m, 2 H) 3.15-3.22 (m, 2 H) 2.82 (d, J = 1.38 Hz, 3 H) 1.76-




1.92 (m, 6 H)


211
DMSO-d6
8.68-8.87 (m, 1 H) 7.54-7.64 (m, 1 H) 7.02-7.09 (m, 1 H) 3.90-




4.05 (m, 6 H) 3.31-3.34 (m, 2 H) 3.28 (br s, 2 H) 3.09-3.21 (m, 4




H) 2.75-2.85 (m, 3 H) 1.69-1.91 (m, 6 H)


212
MeOD
8.50 (s, 1H), 7.98 (s, 1H), 7.24 (s, 1H), 4.03 (s, 3H), 3.81-3.84 (m,




4H), 3.41-3.44 (m, 2H), 3.26-3.80 (m, 2H), 2.93 (s, 3H), 1.95-1.99




(m, 2H), 1.80-1.87 (m, 4H)


213
DMSO-d6
8.15 (s, 1 H), 8.12-8.18 (m, 1 H), 7.15 (s, 1 H), 7.09 (s, 1 H), 3.91




(s, 3 H), 3.89 (s, 3 H), 3.57 (br d, J = 4.0 Hz, 4 H), 3.23-3.29 (m, 2




H), 3.09-3.16 (m, 2 H), 2.80 (s, 3 H), 2.49 (s, 3 H), 1.85 (t, J = 6.8




Hz, 2H), 1.68-1.80 (m, 4 H)


214
DMSO-d6
8.60 (s, 1 H) 7.42-7.53 (m, 2 H) 7.28 (dd, J = 6.25, 2.74 Hz, 1 H)




4.15-4.28 (m, 2 H) 3.92 (s, 3 H) 3.76 (t, J = 7.34 Hz, 2 H) 3.50-




3.54 (m, 1 H) 2.99-3.12 (m, 2 H) 2.86 (s, 3 H) 1.98-2.28 (m, 6 H)


215
DMSO-d6
8.58 (s, 1 H) 8.15 (s, 1 H) 7.42-7.49 (m, 2 H) 7.27 (dd, J = 7.02,




1.97 Hz, 1 H) 3.92 (s, 3 H) 3.63-3.71 (m, 4 H) 3.28 (br d, J = 7.02




Hz, 2 H) 3.08-3.18 (m, 2 H) 2.80 (s, 3 H) 1.65-1.87 (m, 6 H)


216
DMSO-d6
8.32 (s, 1 H), 8.14 (s, 1 H), 7.50 (s, 1 H), 7.11 (s, 1 H), 3.94-4.09




(m, 2 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.78-3.87 (m, 2 H), 3.76 (s, 1




H), 3.28-3.38 (m, 2 H), 3.17-3.27 (m, 2 H), 2.81 (s, 3 H), 1.86-




2.08 (m, 4 H)


217
DMSO-d6
8.46-8.53 (m, 1 H), 8.14 (s, 1 H), 7.50-7.56 (m, 1 H), 7.47 (t, J =




8.0 Hz, 1 H), 7.36 (d, J = 7.6 Hz, 1 H), 4.50 (br s, 4 H), 3.90-3.98




(m, 4 H), 3.42-3.53 (m, 2 H), 3.28 (br d, J = 5.6 Hz, 2 H), 2.83 (s,




3 H), 2.20 (t, J = 6.8 Hz, 2 H)


218
DMSO-d6
8.62 (d, J = 6.8 Hz, 1 H), 7.87 (d, J = 12.4 Hz, 1 H), 7.79 (d, J = 8.0




Hz, 1 H), 7.15 (d, J = 7.2 Hz, 1 H), 4.04 (s, 3 H), 3.77 (br s, 3 H),




3.61-3.71 (m, 3 H), 3.45-3.51 (m, 2 H), 3.38-3.45 (m, 1 H),




2.52-2.54 (m, 1 H), 2.03 (t, J = 7.2 Hz, 2 H), 1.78-1.92 (m, 4 H),




1.38-1.47 (m, 1 H), 1.32-1.37 (m, 2 H), 1.23-1.32 (m, 1 H)


219
DMSO-d6
8.91 (s, 1 H) 7.97 (s, 1 H) 7.80 (s, 1 H) 4.08 (s, 3 H) 3.60-3.65 (m,




1 H) 3.35-3.43 (m, 4 H) 3.25-3.31 (m, 2 H) 3.15 (d, J = 4.13 Hz, 2




H) 2.81 (d, J = 1.50 Hz, 3 H) 1.74-1.92 (m, 6 H)


220
DMSO-d6
8.13-8.20 (m, 1 H) 7.75-7.86 (m, 1 H) 4.06 (s, 3 H) 3.62-3.67




(m, 1 H) 3.30 (br d, J = 7.25 Hz, 6 H) 3.16-3.24 (m, 2 H) 2.78-




2.86 (m, 6H) 1.89 (t, J = 7.00 Hz, 2 H) 1.70-1.83 (m, 4 H)


221
DMSO-d6
1.37 (t, J = 7.2 Hz, 3 H), 1.73-1.89 (m, 4 H), 1.96-2.06 (m, 2 H),




3.40-3.49 (m, 2 H), 3.60 (br t, J = 6.8 Hz, 2 H), 3.79-3.88 (m, 2




H), 4.04 (s, 3 H), 4.06-4.19 (m, 4 H), 7.66 (d, J = 7.8 Hz, 1 H),




7.97 (d, J = 12.2 Hz, 1 H), 8.82 (s, 1 H)


222
DMSO-d6
2.21 (br t, J = 6.8 Hz, 2 H), 2.81 (s, 3 H), 3.23-3.29 (m, 2 H), 3.47




(br d, J = 9.2 Hz, 2 H), 3.90 (s, 3 H), 4.68-4.83 (m, 4 H), 7.25 (d, J =




7.8 Hz, 1 H), 7.39 (t, J = 8.0 Hz, 1 H), 7.62 (d, J = 8.0 Hz, 1 H),




8.25 (s, 1 H), 8.41 (s, 1 H)


223
DMSO-d6
8.43 (s, 1 H) 7.78 (d, J = 8.50 Hz, 1 H) 7.39 (t, J = 8.19 Hz, 1 H) 7.26




(d, J = 7.88 Hz, 1 H) 4.02 (s, 2 H) 3.71 (d, J = 8.13 Hz, 2 H) 3.57 (br




s, 1 H) 2.89 (s, 3 H) 2.18 (br t, J = 6.69 Hz, 2 H)


224
DMSO-d6
1.62-1.77 (m, 4 H), 1.82 (t, J = 6.8 Hz, 2 H), 2.80 (s, 3 H), 3.06-




3.15 (m, 2 H), 3.21-3.34 (m, 2 H), 3.56-3.70 (m, 4 H), 3.99 (s, 3




H), 7.38 (d, J = 8.4 Hz, 1 H), 7.66 (d, J = 12.4 Hz, 1 H), 8.16 (s, 1




H), 8.56 (s, 1 H)


225
DMSO-d6
8.74 (s, 1H), 8.28 (s, 1H), 7.34 (m, 1H), 4.09-4.20 (m, 7H), 3.73-




3.83 (m, 2H), 3.58-3.65 (m, 2H), 3.32-3.38 (m, 1H), 2.20 (t, J = 7.2




Hz, 2H), 1.95-2.11 (m, 4H), 1.34-1.62 (m, 4H)


226
DMSO-d6
8.71 (d, J = 5.13 Hz, 1 H) 8.33 (s, 1 H) 7.50 (s, 1 H) 6.96 (d, J = 5.25




Hz, 1 H) 4.03 (s, 3 H) 3.63 (s, 1 H) 3.19-3.30 (m, 4 H) 3.14 (br d,




J = 4.50 Hz, 2 H) 2.81 (d, J = 1.38 Hz, 3 H) 1.75-1.89 (m, 6 H)


227
DMSO-d6
1.71-1.82 (m, 4H), 1.83-1.89 (m, 2 H), 2.81 (s, 3 H), 3.11-3.19




(m, 2 H), 3.27-3.46 (m, 6 H), 3.65 (br s, 1 H), 3.91 (s, 3 H), 3.93




(s, 3 H), 7.26 (s, 1 H), 7.33 (s, 1 H), 8.23 (s, 1 H), 8.54 (d, J = 4.4




Hz, 1 H)


228
DMSO-d6
7.58 (s, 1H), 7.23 (s, 1H), 3.97 (d, J = 1.50 Hz, 6H), 3.62 (s, 1H),




3.31-3.16(m, 8H), 2.80 (d, J = 9.63 Hz, 6H), 1.89 (br t, J = 7.00 Hz,




2H), 1.83-1.68(m, 4H)


229
DMSO-d6
9.12 (d, J = 6.6 Hz, 1 H) 8.22 (t, J = 10.6 Hz, 1 H) 7.95 (d, J = 7.5 Hz,




1 H) 7.51 (br d, J = 6.6 Hz, 1 H) 4.49-4.66 (m, 2 H) 4.07 (s, 3 H)




3.82-3.91 (m, 1 H) 3.68 (s, 3 H) 3.49-3.65 (m, 2 H) 3.36-3.48




(m, 1H) 2.99 (dt, J = 14.1, 7.1 Hz, 1 H) 2.21-2.35 (m, 1 H) 1.90-




2.05 (m, 1H)


229a
DMSO-d6
8.64 (d, J = 5.2 Hz, 1H), 7.80 (d, J = 12.0 Hz, 1H), 7.52 (d, J = 8.4




Hz, 1H), 6.96 (d, J = 5.2 Hz, 1H), 4.14-4.28 (m, 2H), 3.99 (s, 3H),




3.66 (br s, 1H), 3.46-3.56 (m, 1H), 3.20-3.31 (m, 2H), 3.02-3.14




(m, 1H), 2.74-2.88 (m, 4H), 2.07-2.19 (m, 1H), 1.78-1.86 (m, 1H).


229b
DMSO-d6
8.65 (d, J = 5.2 Hz, 1H), 7.80 (d, J = 12.0 Hz, 1H), 7.52 (d, J = 8.4




Hz, 1H), 6.97 (d, J = 5.6 Hz, 1H), 4.14-4.30 (m, 2H), 3.99 (s, 3H),




3.65 (s, 1H), 3.48-3.57 (m, 1H), 3.34-3.39 (m, 1H), 3.15-3.25 (m,




1H), 3.05-3.12 (m, 1H), 2.74-2.86 (m, 4H), 2.06-2.19 (m, 1H),




1.72-1.86 (m, 1H)


230
DMSO-d6
8.66 (d, J = 5.2 Hz, 1H), 7.81 (dd, J = 12.0, 4.4 Hz, 1H), 7.52 (d, J =




8.4 Hz, 1H), 6.97 (d, J = 5.2 Hz, 1H), 4.17-4.30 (m, 2H), 4.10 br




s, 1H), 3.99 (s, 3H), 3.48-3.59 (m, 1H), 3.28-3.41 (m, 2H), 3.21-




3.28 (m, 1H), 3.14-3.20 (m, 3H), 3.05-3.13 (m, 1H), 2.77-2.85 (m,




4H), 2.09-2.19 (m, 1H), 1.79-1.82 (m, 1H)


231
DMSO-d6
8.82 (d, J = 4.4 Hz, 1 H), 8.08 (d, J = 9.2 Hz, 1 H), 7.84-7.89 (m,




2 H), 7.49 (d, J = 4.4 Hz, 1 H), 7.45 (d, J = 2.8 Hz, 1 H), 7.27-7.35




(m, 3 H), 5.72 (s, 2 H), 4.08 (s, 1 H), 3.93 (s, 3 H), 3.02 (s, 3 H)


232
DMSO-d6
8.84 (d, J = 4.4 Hz, 1 H), 8.10 (d, J = 9.2 Hz, 1 H), 7.65 (s, 1 H),




7.51-7.58 (m, 3 H), 7.46 (d, J = 2.4 Hz, 1 H), 7.37-7.42 (m, 1 H),




7.31-7.36 (m, 1 H), 5.72 (s, 2 H), 4.22 (s, 1 H), 3.94 (s, 3 H), 3.25-




3.30 (m, 1 H), 3.06-3.10 (m, 3 H), 2.99-3.05 (m, 1 H), 2.52-




2.56 (m, 1 H), 1.23 (s, 1 H)


233
DMSO-d6
8.88 (d, J = 4.88 Hz, 1H), 8.38 (d, J = 9.38 Hz, 1H), 8.25 (s, 1H),




7.49 (d, J = 2.50 Hz, 1H), 7.45 (d, J = 4.75 Hz, 1H), 7.33 (dd, J =




9.38, 2.63 Hz, 1H), 4.38(s, 2H), 3.95 (s, 3H), 3.78 (br s, 1H), 3.66-




3.49(m, 2H), 2.95-2.88 (m, 2H), 2.85 (s, 3H)


234
DMSO-d6
8.85 (d, J = 5.04 Hz, 1H), 8.29-8.22 (m, 1H), 8.21-8.15 (m, 1H),




7.93-7.88 (m, 1H), 7.50-7.43(m, 2H), 7.36-7.29 (m, 1H), 4.03-




3.97(m, 3H), 3.61-3.52 (m, 2H), 3.22-3.14(m, 2H), 3.07 (s, 3H),




1.95-1.86(m, 1H)


235
DMSO-d6
8.64 (d, J = 5.2 Hz, 1 H), 8.17 (s, 1 H), 8.09 (d, J = 9.2 Hz, 1 H),




7.32 (d, J = 2.4 Hz, 1 H), 7.19 (dd, J = 9.2, 2.4 Hz, 1 H), 6.97 (d,




J = 5.2 Hz, 1 H), 4.89 (dt, J = 6.8, 3.2 Hz, 1 H), 3.90 (s, 3 H) 3.33-




3.46 (m, 2 H) 3.18-3.31 (m, 2 H) 2.80 (s, 3 H) 2.03-2.14 (m, 2 H)




1.90 (brd, J = 7.00 Hz, 2 H)


236
DMSO-d6
8.59 (s, 1H), 7.40-7.49 (m, 2H), 7.24-7.29 (m, 1H), 3.92 (s, 3H),




3.51-3.65 (m, 9H), 2.88 (s, 3H), 1.68-2.02 (m, 4H)


237
DMSO-d6
8.33 (s, 1 H), 7.18 (s, 1 H), 7.12 (s, 1 H), 4.57 (br s, 2 H), 4.39 (br




s, 2 H), 3.90 (s, 6 H), 3.55 (s, 1 H), 3.19 (dd, J = 7.2, 2.4 Hz, 2 H),




2.85 (s, 3 H), 2.65-2.74 (m, 1 H), 2.43-2.49 (m, 2 H), 2.15 (q, J =




10.8 Hz, 2 H)


238
DMSO-d6
8.43 (s, 1H), 8.15 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.35-7.40 (m,




1H), 7.25 (d, J = 7.2 Hz, 1H), 4.06-4.18 (m, 1H), 3.80-3.97 (m,




5H), 3.65-3.77 (m, 1H), 3.24-3.41 (m, 2H), 2.96 (s, 3H), 2.72-2.86




(m, 1H), 2.21-2.32 (m, 1H), 1.71-1.88 (m, 1H)


238a
DMSO-d6
8.43 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.35-7.39 (m, 1H), 7.25 (d,




J = 7.6 Hz, 1H), 4.08-4.17 (m, 1H), 3.85-3.95 (m, 5H), 3.78 (s, 1H),




3.67-3.76 (m, 1H), 3.32-3.39 (m, 1H), 3.14-3.29 (m, 1H), 2.96 (s,




3H), 2.73-2.85 (m, 1H), 2.19-2.32 (m, 1H), 1.72-1.88 (m, 1H)


238b
DMSO-d6
8.43 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.35-7.39 (m, 1H), 7.25 (d,




J = 8.0 Hz, 1H), 4.08-4.12 (m, 1H), 3.83-3.95 (s, 4H), 3.61-3.82 (m,




2H), 3.24-3.33 (m, 2H), 2.96 (s, 3H), 2.73-2.84 (m, 1H), 2.18-2.32




(m, 1H), 1.74-1.89 (m, 1H)


239
DMSO-d6
8.43 (s, 1 H) 8.16 (s, 1 H) 7.76 (d, J = 8.63 Hz, 1 H) 7.37 (t, J = 8.25




Hz, 1 H) 7.25 (d, J = 7.75 Hz, 1 H) 4.07-4.14 (m, 1 H) 3.89 (s, 6 H)




3.65-3.75 (m, 2 H) 3.22-3.38 (m, 2 H) 2.96 (s, 3 H) 2.73-2.84




(m, 1 H) 2.19-2.31 (m, 1 H) 1.72-1.89 (m, 1 H)


240
DMSO-d6
8.52 (s, 1 H) 7.20 (s, 1 H) 7.13 (s, 1 H) 5.74 (br s, 1H) 4.18 (br s, 1




H) 3.92 (d, J = 7.00 Hz, 6 H) 3.67-3.69 (m, 1 H) 3.61 (br s, 2 H)




3.37-3.46 (m, 4 H) 3.36-3.39 (m, 3 H) 2.98-3.22 (m, 2 H) 1.85




(br t, J = 7.07 Hz, 2 H) 1.74 (br s, 4 H) 1.36 (s, 3 H) 1.23 (s, 3 H)


241
DMSO-d6
8.52 (s, 1 H) 7.60 (s, 1 H) 7.24 (s, 1 H) 5.93 (s, 1 H) 5.79 (s, 1 H)




4.02 (s, 3 H) 3.71-3.87 (m, 4 H) 3.41 -3.51 (m, 2 H) 3.25-3.31




(m, 2 H) 2.95 (s, 3 H) 1.99 (t, J = 7.13 Hz, 2 H) 1.80-1.93 (m, 4 H)


242
DMSO-d6
8.61 (d, J = 5.29 Hz, 1 H) 8.12-8.14 (m, 1 H) 8.06-8.11 (m, 1 H)




7.25-7.30 (m, 1 H) 7.14-7.21 (m, 1 H) 6.89-6.95 (m, 1 H) 4.94-




5.01 (m, 1 H) 3.87-3.90 (m, 3 H) 3.03-3.08 (m, 1 H) 2.81-2.85




(m, 3 H) 2.15-2.24 (m, 2 H) 1.97 (br d, J = 9.04 Hz, 2 H) 1.61-




1.94 (m, 5H)


243
DMSO-d6
8.58-8.69 (m, 1 H) 8.13-8.19 (m, 1 H) 7.98-8.07 (m, 1 H) 7.27-




7.35 (m, 1 H) 7.14-7.23 (m, 1 H) 6.98-7.06 (m, 1 H) 4.61-4.76




(m, 1 H) 3.87-3.95 (m, 3 H) 3.05 (tt, J = 11.80, 3.33 Hz, 1 H) 2.84-




2.91 (m, 3 H) 2.18-2.37 (m, 4 H) 1.52-1.81 (m, 4 H)


244
DMSO-d6
8.64 (d, J = 5.26 Hz, 1 H) 8.03 (s, 1 H) 7.75-7.91 (m, 3 H) 7.63 (t,




J = 7.78 Hz, 1 H) 7.51 (d, J = 8.33 Hz, 1 H) 7.04 (d, J = 5.26 Hz, 1 H)




5.47 (s, 2 H) 4.26 (s, 1 H) 3.96 (s, 3 H) 2.59-2.69 (m, 1 H) 1.04-




1.12 (m, 1 H) 0.79-0.99 (m, 3 H)


245
DMSO-d6
8.54 (dd, J = 5.32, 2.06 Hz, 1 H) 8.20 (dd, J = 9.13, 1.38 Hz, 1 H)




8.07 (br d, J = 7.50 Hz, 1 H) 7.86 (br d, J = 7.88 Hz, 1 H) 7.78 (br t,




J = 6.44 Hz, 1 H) 7.60 (td, J = 7.72, 2.69 Hz, 1 H) 7.19-7.33 (m, 2




H) 7.19-7.33 (m, 1 H) 6.81 (t, J = 5.57 Hz, 1 H) 5.93-6.04 (m, 1




H) 4.22 (br s, 1 H) 3.90 (s, 3 H) 3.04 (d, J = 3.88 Hz, 3 H) 1.72 (d,




J = 6.25 Hz, 3 H)


246
DMSO-d6
8.57 (s, 1 H) 7.39-7.55 (m, 2 H) 7.28 (d, J = 7.02 Hz, 1 H) 5.92 (br




s, 1 H) 4.27 (br s, 2 H) 3.92 (s, 3 H) 3.85 (br d, J = 8.99 Hz, 1 H)




3.83-3.90 (m, 1 H) 3.77-3.82 (m, 1 H) 3.77-3.82 (m, 1 H) 3.74




(br s, 1 H) 2.88 (s, 3 H) 2.57 (br s, 2 H)









Biological Example B-1
Inhibition of ENPP1 Hydrolysis of 2′,3′-cGAMP
Assay 1: Test compounds were plated in a 3× dilution scheme in a 384 well plate. To 50 nL of test compound in DMSO was added 2.5 μL ENPP-1 ECD in Assay Buffer (Tris-HCl pH 8.0 (50 mM), NaCl (150 mM), and 0.01% Triton X-100 in water (2.5 nM final concentration). Enzyme was omitted in control wells reserved to define maximum inhibition (max). Control wells were reserved to define no inhibition (min), and DMSO was used in place of compound solution. The plate was centrifuged for 30 s, and the mixture was incubated for 30 min. 2.5 μL of 2,3-cGAMP in Assay Buffer (final conc: 24 μM; KM=24 μM) was added and the plate was centrifuged and incubated for 30 min. AMP-GloTM Reagent I (Promega Corp.; 5 μL) was added, the plate was centrifuged for 1 min and incubated for 60 min. AMP Detection solution (100 μL) was added to each well, the plate centrifuged and incubated for 60 min. Luminescence was measured with an Envision plate reader, and % Inhibition was calculated for each well as: (([max−min]−[test−min])/[max−min]. IC50 values were calculated from concentration vs. % Inhibition data via a four-parameter variable slope model and converted to KI values via the Cheng/Prusoff Equation (KI=IC50/(1+[substrate]/KM). Known ENPP1 inhibitors have the following IC50 values in Assay 1:

    8-(3-cyano-6-fluoro-7-methoxyquinolin-4-yl)-2,8-diazaspiro[4.5]decane-2-sulfonamide, 2.9 nM;
    4-[(6,7-dimethoxyquinolin-4-yl)oxy]benzene-1-sulfonamide, 190 nM;
    N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}aminosulfonamide, 490 nM;
    7-(6,7-dimethoxyquinazolin-4-yl)-1,2,3,4-tetrahydroisoquinoline-2-sulfonamide, 11 nM;
    N-{[4-(7-methoxyquinolin-4-yl)phenyl]methyl}aminosulfonamide, 29 nM;
    N-{2-[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]ethyl}aminosulfonamide, 31 nM.


Compound 1 had a KI of 5.1 nM. Compound 1 has an IC50 of 17 nM. Compound 8 has an IC50 of 6.9 nM. Compound 80 has an IC50 of 1.4 nM. Compound 161 has an IC50 of 1.3 nM. Additional results are summarized in Table 17 and Table 18.
Assay 2: Compared to the conditions in Assay 1, this assay has a larger dynamic range and ensures the system is under steady-state conditions by reducing the enzyme concentration in the assay. This allows discrimination among very potent compounds and allows for conversion of IC50 data to KIs.
Test compounds were plated in a 3× dilution scheme in a 384 well plate. To 50 nL of test compound in DMSO was added 2.5 μL ENPP-1 ECD in Assay Buffer (Tris-HCl pH 8.0 (50 mM), NaCl (150 mM), and 0.01% Triton X-100 in water (0.25 nM final ENPP-1 concentration). Enzyme was omitted in control wells reserved to define maximum inhibition (max). Control wells were reserved to define no inhibition (min), and DMSO was used in place of compound solution. The plate was centrifuged for 30 s, and the mixture was incubated for 30 min. 2.5 μL of 2,3-cGAMP in Assay Buffer (final conc: 24 μM; KM=24 μM) was added and the plate was centrifuged and incubated for 30 min. AMP-Glom Reagent I (Promega Corp.; 5 μL) was added, the plate was centrifuged for 1 min and incubated for 60 min. AMP Detection solution (10 μL) was added to each well, the plate centrifuged and incubated for 60 min. Luminescence was measured with an Envision plate reader, and % Inhibition was calculated for each well as: (([max −min]−[test−min])/[max−min]. IC50 values were calculated from concentration vs. % Inhibition data via a four-parameter variable slope model and converted to KI values via the Cheng/Prusoff Equation (KI=(IC50+[E]/2)/(1+[substrate]/KM). Known inhibitors of ENPP1 have the following KIs in Assay 2:

    8-(3-cyano-6-fluoro-7-methoxyquinolin-4-yl)-2,8-diazaspiro[4.5]decane-2-sulfonamide, 0.47 nM
    4-[(6,7-dimethoxyquinolin-4-yl)oxy]benzene-1-sulfonamide, 32 nM
    N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}aminosulfonamide, 70 nM
    N-{[4-(7-methoxyquinolin-4-yl)phenyl]methyl}aminosulfonamide, 4.9 nM
    N-{2-[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]ethyl}aminosulfonamide, 2.3 nM


Results are summarized in Table 17 and Table 18.
Biological Example B-2
Inhibition of ENPP1 Hydrolysis of AMP p-Nitrophenyl Ester on MDA-MB-231 Cells (Assay 3)
ENPP1 is normally expressed on the human metastatic breast cancer cell line MDA-MB-231. Hydrolysis of the p-nitrophenyl ester of AMP (pNP-AMP), an isostere of ATP, is selectively catalyzed by ENPP1 in the supernatant of MDA-MB-231 cell cultures. Inhibition of the hydrolysis of pNP-AMP by MDA-MB-231 at pH 7.4 and 37° C., is a good model of physiologically relevant activity of membrane-bound ENPP1 at disease-relevant expression levels.
MDA-MB-231 cells were harvested using TypLE Express Enzyme digestion and suspended in 100 μL of Leibovitz's L-15 Medium, 20% FBS, seeding the cells in a 96-well assay plate with 4.5×104 cells/well. Cells were incubated at 37° C. with 1% CO2 for 24 h. In a separate dilution plate, 2× of top dose of compound was prepared in phenol-red free 1640 medium without FBS and then 1:3 serial diluted in the same medium. The cell culture medium of L15 medium was aspirated carefully and cells were washed with PBS once, and 50 μL per well of test compound or DMSO blank were added to the assay plate. Substrate mix (50 μL; 0.5 mM pNP-AMP in phenol-red free 1640 media without FBS) was added for a pNP-AMP final concentration of 0.25 mM. The system was incubated at 37° C. for 3 h. Release of para-nitrophenol was measured by absorbance at 405 nM on an Envision plate reader, and % Inhibition was calculated for each well as: (([max−min]−[test−min])/[max−min]. IC50 values were calculated from concentration vs. % Inhibition data via a four-parameter variable slope model and converted to apparent KI (KI,app) values via the Cheng/Prusoff Equation (KI,app=IC50/(1+[substrate]/KM)). Known ENPP1 inhibitors have the following apparent KIs in Assay 3:

    8-(3-cyano-6-fluoro-7-methoxyquinolin-4-yl)-2,8-diazaspiro[4.5]decane-2-sulfonamide, 24 nM
    4-[(6,7-dimethoxyquinolin-4-yl)oxy]benzene-1-sulfonamide, 380 nM
    N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}aminosulfonamide, 920 nM
    7-(6,7-dimethoxyquinazolin-4-yl)-1,2,3,4-tetrahydroisoquinoline-2-sulfonamide, 23 nM
    N-{[4-(7-methoxyquinolin-4-yl)phenyl]methyl}aminosulfonamide, 330 nM
    N-{2-[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]ethyl}aminosulfonamide, 120 nM


Results for Assays 1 and 2 are summarized in Table 17 below. Table 17 Legend: Assay 1 IC50 values, A: >1000 nM; B: ≤1000 but >10 nM; C: ≤10 nM; Assay 2 KI values, D: >300 nM; E: ≤300 but >3 nM; F: ≤3 nM.
A more detailed and expanded summary of results for Assays 1, 2, and 3 is provided below in Table 18.











TABLE 17








Assay 1
Assay 2



Compound
(IC50)
(KI)









 1
B
E



 1R
A
D



 1S
B
F



 6
A
—



 8
C
F



 10
B
F



 12
B
E



 14
B
E



 18
B
E



 22
A
D



 26
A
—



 37
C
F



 37a
—
E



 37b
—
F



 43
C
F



 44
B
F



 44a
B
F



 44b
A
D



 47
B
—



 50
A
—



 52
B
E



 52a
—
E



 52b
—
E



 53
B
E



 54
C
F



 54a
C
F



 54b
C
F



 55
C
F



 55a
C
F



 55b
B
E



 57
B
E



 58
B
—



 60
C
F



 60a
C
F



 60b
B
E



 69
B
E



 72
B
E



 74
B
F



 75
C
F



 75a
C
F



 75b
A
E



 76
A
—



 77
B
—



 78
—
E



 79
B
E



 80
C
F



 80a
C
F



 80b
B
E



 84
A
E



 88
B
—



 94
C
F



 94a
—
F



 94b
—
E



 98
B
E



101
B
E



103
C
F



103a
A
D



103b
C
F



114
C
F



114a
C
F



114b
B
E



115
B
E



116
B
E



117
B
E



118
B
E



119
B
E



120
C
F



120a
C
F



120b
B
E



121
—
E



122
—
F



123
—
F



124
—
F



125
B
—



126
B
E



127
B
E



128
B
—



129
B
E



130
A
—



131
A
—



132
—
F



133
C
F



133a
C
F



133b
A
E



134
A
—



135
C
F



136
C
F



137
B
E



138
B
E



139
B
F



140
B
E



141
C
F



141a
—
F



141b
—
E



142
C
F



142a
—
E



142b
—
F



143
—
F



144
—
F



145
—
E



146
—
F



147
—
E



148
—
E



149
A
D



150
C
F



151
C
F



152
C
F



153
B
E



154
A
—



155
A
—



156
—
F



156a
—
F



156b
—
F



157
—
F



158
—
F



159
—
F



160
—
F



161
C
F



161a
—
F



161b
—
F



162
B
E



163
—
E



164
—
E



165
A
D






















TABLE 18








Assay 1
Assay 2
Assay 3



Compound
(IC50)
(KI)
(KI, app)





















 1
17
3.5
61



 1R
3200
330
—



 1S
13
0.87
45



 6
>30000
—
—



 8
4.1
0.69
27



 10
23
2.8
—



 12
30
8.6
190



 14
110
15
—



 18
180
24
—



 22
1200
310
—



 26
8800
—
—



 37
2.9
0.41
28



 37a
—
21
—



 37b
—
0.28
21



 43
3.9
0.49
29



 44
15
1.6
110



 44a
11
1
110



 44b
1900
350
—



 47
180
—
—



 50
2600
—
—



 52
35
6.3
280



 52a
—
110
—



 52b
—
3.5
—



 53
44
4.6
160



 54
0.71
0.014
0.88



 54a
0.34
0.0075
0.32



 54b
7.6
1.3
130



 55
2
0.14
25



 55a
0.76
0.09
8.7



 55b
45
7.3
—



 57
31
5.3
120



 58
51
—
—



 60
2.8
0.34
23



 60a
1.3
0.099
11



 60b
520
93
—



 69
55
10
—



 72
120
18
430



 74
11
1.7
—



 75
4.4
0.49
31



 75a
3
0.38
22



 75b
—
98
—



 76
23000
—
—



 77
57
—
—



 78
—
150
—



 79
740
220
—



 80
6.2
1.1
29



 80a
2.2
0.26
13



 80b
180
13
—



 84
1300
210
—



 88
920
—
—



 94
6.6
1.3
83



 94a
—
0.78
46



 94b
—
9
—



 98
140
25
—



101
40
5.4
300



103
9
1.3
49



103a
1600
450
—



103b
2.2
0.31
30



107
—
80
—



107a
—
27
—



107b
—
74
—



114
2.8
0.27
19



114a
0.94
0.088
6.3



114b
77
>25
—



115
85
13
—



116
220
25
—



117
180
94
—



118
160
36
—



119
66
17
—



120
1.1
0.12
6.2



120a
0.46
0.05
6.5



120b
37
4.8
—



121
—
4.2
250



122
—
1.6
—



123
—
1.5
60



124
—
0.73
30



125
340
110
—



126
39
11
—



127
30
5
380



128
310
—
—



129
260
39
—



130
8100
—
—



131
>30000
—
—



132
—
1.1
45



133
1.4
0.12
13



133a
0.5
0.055
4.1



133b
>100
49
—



134
1100
—
—



135
7.8
1.4
110



136
2
0.32
29



137
200
38
—



138
37
4.6
140



139
15
2.4
—



140
880
180
—



141
2.1
0.25
16



141a
—
0.26
28



141b
—
31
—



142
6.3
1.2
86



142a
—
25
—



142b
—
0.8
52



143
—
1
180



144
—
0.28
19



145
—
8.7
—



146
—
0.36
15



146a
—
0.12
4.5



146b
—
66
—



147
—
9.9
—



148
—
56
—



149
1400
410
—



150
8.6
1.3
62



151
6.2
0.57
59



152
2.4
0.41
26



153
54
12
—



154
1800
—
—



155
14000
—
—



156
—
0.03
4.1



156a
—
0.016
1.7



156b
—
2.9
—



157
—
2.7
—



158
—
0.44
—



159
—
0.025
3.6



160
—
0.021
0.45



160a
—
0.007
0.22



160b
—
1.7
—



161
1.3
0.051
3.7



161a
—
0.015
5.2



161b
—
0.64
—



162
40
6.9
—



163
—
21
—



164
—
97
—



165
>30000
1400
—



166
—
3.1
230



167
—
7.9
—



168
—
0.84
40



169
—
0.051
1.5



169a
—
15
>190



169b
—
0.018
1.5



170
—
0.7
25



171
—
49
—



172
—
11
—



173
—
0.17
9.2



174
—
5.2
240



175
—
0.037
3.5



175a
—
0.011
0.53



175b
—
4.1
—



176
—
0.094
7.2



177
—
0.03
1.5



177a
—
20
—



177b
—
0.0085
0.48



178
—
2.6
—



178a
—
—
—



178b
—
34
—



179
—
0.048
3.3



179a
—
9.1
—



179b
—
0.014
0.63



180
—
16
—



181
—
0.16
28



182
—
3.1
—



183
—
5.2
—



183a
—
2.9
—



183b
—
>150
—



184
—
0.13
5.5



184a
—
0.1
1.7



184b
—
2.5
58



185
—
0.028
0.45



185a
—
0.013
0.32



185b
—
2.8
—



186
—
0.38
17



187
—
0.19
4.4



188
—
0.074
6.5



189
—
0.033
0.45



189a
—
8.8
—



189b
—
0.0075
0.31



190
—
0.19
7.3



191
—
0.34
15



192
—
0.58
—



193
—
0.023
0.62



193a
—
54
—



193b
—
0.012
0.36



194
—
40
—



195
—
0.2
—



195a
—
0.052
—



195b
—
7.7
—



196
—
0.091
2.3



197
—
0.04
2.3



198
—
0.014
0.2



198a
—
0.0025
0.086



198b
—
1.2
—



199
—
0.43
8.8



200
—
0.019
0.41



201
—
0.69
12



202
—
370
—



203
—
1.7
—



204
—
28
—



205
—
0.032
2.2



205a
—
5
—



205b
—
0.0057
0.12



206
—
17
—



207
—
0.037
3.3



208
—
0.021
0.21



208a
—
1.1
55



208b
—
0.0078
0.16



209
—
17
—



210
—
0.024
2.5



211
—
0.022
0.97



211a
—
0.023
2.2



211b
—
0.5
—



212
—
0.047
4.4



213
—
0.058
2.8



214
—
110
—



215
—
3.8
—



216
—
5.5
—



217
—
0.29
8



218
—
0.022
0.69



218a
—
0.0078
0.29



218b
—
1.5
—



219
—
0.091
—



219a
—
0.071
1.2



219b
—
2
—



220
—
0.25
11



221
—
0.12
4.6



222
—
0.07
1.1



222a
—
0.034
1.2



222b
—
1.3
—



223
—
0.11
3.2



223a
—
0.047
3.1



223b
—
19
460



224
—
0.019
1.1



225
—
0.096
6.8



226
—
1.2
43



227
—
0.018
0.51



228
—
0.25
8.7



229a
—
39
—



229b
—
0.37
3.6



230a
—
11
—



230b
—
0.38
6.6



231
—
1.2
56



232
—
3.3
—



233
—
>500
—



234
—
>500
—



235
—
8
—



236
—
86
>580



237
—
0.028
1.2



237a
—
2.4
—



237b
—
0.005
0.17



238a
—
66
260



238b
—
13
—



239
—
0.81
15



239a
—
0.43
5.4



239b
—
83
—



240
—
0.069
5.4



241
—
0.031
1.2



242
—
>500
—



243
—
4.3
—



244
—
0.018
0.55



245
—
0.23
5.7



246
—
19
—










Biological Example B-3
Evaluation of Effect of ENPP1 Inhibitors on Mouse Model of Tumor Growth
EMT6 cells (ATCC, CRL-2755TM) are maintained in vitro as a monolayer culture in Waymouth's medium supplemented with 15% heat inactivated fetal bovine serum, 100 U/mL penicillin and 100 μg/mL streptomycin at 37° C. in an atmosphere of 5% CO2 in air. The tumor cells are routinely subcultured twice weekly by trypsin-EDTA treatment. The cells growing to a confluency around 70%-80% are harvested and counted for tumor inoculation. Each mouse is inoculated subcutaneously at the right flank with 2×105 EMT6 cells suspended in 0.1 mL base medium for tumor development, with n=10 mice inoculated per treatment group. Once primary tumor size reaches an average of 50 mm3, animals are randomized using block randomization by Excel based on tumor size. Animals are then dosed once daily by oral gavage (10 mL/kg) with vehicle control (0.5% methylcellulose and 1% Tween-80 in water) or test compound as suspension in vehicle. Mice are dosed continuously, for example once daily or twice daily, until individual tumors reached the experimental endpoint of 1,500 mm3 in size, after which animals are euthanized and tumors harvested for downstream analysis.
While the foregoing written description of the compounds, uses, and methods described herein enables one of ordinary skill to make and use the compounds, uses, and methods described herein, those of ordinary skill will understand and appreciate the existence of variations, combinations, and equivalents of the specific embodiments, methods, and examples herein. The compounds, uses, and methods provided herein should therefore not be limited by the above-described embodiments, methods, or examples, but rather encompasses all embodiments and methods within the scope and spirit of the compounds, uses, and methods provided herein.
All references disclosed herein are incorporated by reference in their entirety.

## Claims

1. A compound of Formula (I):




or a pharmaceutically acceptable salt thereof, wherein W is



R2a is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, or optionally substituted C1-6 haloalkyl;
X1 is —CR1b— or —N—;
X2 is —CR2b— or —N—;
X3 is —CR3b— or —N—;
X4 is —CR4b— or —N—;
X5 is —CR5b— or —N—;
X6 is —CR6b— or —N—;
R1b-R6b are each independently hydrogen, halogen, hydroxyl, C1-4 alkoxy optionally substituted with one or more halo substituents, cyano, C1-3 alkyl, C1-3 haloalkyl, nitro, —NR1cR2c, —NHC(O)R3c, or —C(O)NR4cR5c;
L is a bond, —O—, —C(O)—, —NR6c—, or —OCR7c—*, wherein * represents the point of attachment to




R1c-R7c are each independently hydrogen or C1-3 alkyl; and
a1 and a2 are each independently 0, 1, 2, or 3.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2a is C1-6 alkyl.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R2a is methyl.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the




portion of Formula (I) is

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the




portion of Formula (I) is

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is a bond.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is —O—.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein a1 is 0 and a2 is 0.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of

10. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.