WO2012118492A1

WO2012118492A1 - Heterocyclic sulfonamides as raf inhibitors

Info

Publication number: WO2012118492A1
Application number: PCT/US2011/026700
Authority: WO
Inventors: Jonas Grina; Joshua D. Hansen; Ellen Laird; Simon Mathieu; David Moreno; Li Ren; Joachim Rudolph; Steven Mark Wenglowsky
Original assignee: Array Biopharma Inc.; Genentech, Inc.
Priority date: 2011-03-01
Filing date: 2011-03-01
Publication date: 2012-09-07

Abstract

Compounds of Formula (I) are useful for inhibition of Raf kinases. Methods of using compounds of Formula (I), stereoisomers, tautomers and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.

Description

HETEROCYCLIC SULFONAMIDES AS RAF INHIBITORS

BACKGROUND OF THE INVENTION

[0001] FIELD OF THE INVENTION

[0002] Compounds, pharmaceutical compositions comprising the compounds, a process for making the compounds and the use of the compounds in therapy are provided herein. More particularly, certain quinazolinone compounds useful for inhibiting Raf kinase and for treating disorders mediated thereby are provided herein.

[0003] DESCRIPTION OF THE STATE OF THE ART

[0004] The Raf/MEK/ERK pathway is critical for cell survival, growth, proliferation and tumorigenesis. Li, Nanxin, et al. "B-Raf kinase inhibitors for cancer treatment." Current Opinion in Investigational Drugs. Vol. 8, No. 6 (2007): 452-456. Raf kinases exist as three isoforms, A-Raf, B-Raf and C-Raf. Among the three isoforms, studies have shown that B- Raf functions as the primary MEK activator. B-Raf is one of the most frequently mutated genes in human cancers. B-Raf kinase represents an excellent target for anticancer therapy based on preclinical target validation, epidemiology and drugability.

[0005] Small molecule inhibitors of B-Raf are being developed for anticancer therapy. Nexavar® (sorafenib tosylate) is a multikinase inhibitor, which includes inhibition of B-Raf, and is approved for the treatment of patients with advanced renal cell carcinoma and unresectable hepatocellular carcinoma. Other Raf inhibitors have also been disclosed or have entered clinical trials, for example SB-590885, RAF-265, PLX-4032, XL-281 and GS - 2118436.

SUMMARY OF THE INVENTION

[0006] Compounds that are inhibitors of Raf kinase are described herein. Certain hyperproliferative disorders are characterized by the over activation of Raf kinase function, for example by mutations or over expression of the protein. Accordingly, the compounds are useful in the treatment of hyperproliferative disorders, such as cancer.

[0007] More specifically, one aspect provides compounds of Formula I:

I

and stereoisomers and pharmaceutically acceptable salts thereof, wherein W, X, Y, Z, L, R¹, R², R³, R⁴ and R⁵ are as defined herein and the dashed lines represent optional double bonds.

[0008] Another aspect of the present invention provides methods of preventing or treating a disease or disorder modulated by B-Raf, comprising administering to a mammal in need of such treatment an effective amount of a compound of this invention or a stereoisomer, tautomer, solvate, prodrug or pharmaceutically acceptable salt thereof. Examples of such diseases and disorders include, but are not limited to, hyperproliferative disorders (such as cancer, including melanoma and other cancers of the skin), neurodegeneration, cardiac hypertrophy, pain, migraine and neurotraumatic disease.

[0009] Another aspect of the present invention provides methods of preventing or treating cancer, comprising administering to a mammal in need of such treatment an effective amount of a compound of this invention, or a stereoisomer, tautomer, solvate, prodrug or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds having anti-cancer properties.

[0010] Another aspect of the present invention provides methods of preventing or treating cancer, comprising administering to a mammal in need of such treatment an effective amount of a compound of this invention, or a stereoisomer, tautomer, solvate, prodrug or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds having anti-cancer properties.

[0011] Another aspect of the present invention provides a method of treating a hyperproliferative disease in a mammal comprising administering a therapeutically effective amount of a compound of this invention to the mammal.

[0012] Another aspect of the present invention provides methods of preventing or treating kidney disease, comprising administering to a mammal in need of such treatment an effective amount of a compound of this invention, or a stereoisomer, tautomer, solvate, prodrug or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds. Another aspect of the present invention provides methods of preventing or treating polycystic kidney disease, comprising administering to a mammal in need of such treatment an effective amount of a compound of this invention, or a stereoisomer, tautomer, solvate, prodrug or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds.

[0013] Another aspect of the present invention provides the compounds of the present invention for use in therapy.

[0014] Another aspect of the present invention provides the compounds of the present invention for use in the treatment of a hyperproliferative disease. In a further embodiment, the hyperproliferative disease may be cancer (or still further, a specific cancer as defined herein).

[0015] Another aspect of the present invention provides the compounds of the present invention for use in the treatment of a kidney disease. In a further embodiment, the kidney disease may be polycystic kidney disease.

[0016] Another aspect of the present invention provides the use of a compound of this invention in the manufacture of a medicament for the treatment of a hyperproliferative disease. In a further embodiment, the hyperproliferative disease may be cancer (or still further, a specific cancer as defined herein).

[0017] Another aspect of the present invention provides the use of a compound of this invention in the manufacture of a medicament for the treatment of a kidney disease. In a further embodiment, the kidney disease may be polycystic kidney disease.

[0018] Another aspect of the present invention provides the use of a compound of the present invention in the manufacture of a medicament, for use as a B-Raf inhibitor in the treatment of a patient undergoing cancer therapy.

[0019] Another aspect of the present invention provides the use of a compound of the present invention in the manufacture of a medicament, for use as a B-Raf inhibitor in the treatment of a patient undergoing polycystic kidney disease therapy.

[0020] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the treatment of a hyperproliferative disease.

[0021] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the treatment of cancer.

[0022] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention for use in the treatment of polycystic kidney disease. [0023] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of this invention, a stereoisomer, tautomer, solvate, prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0024] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of this invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0025] Another aspect of the present invention provides intermediates for preparing compounds of Formulas I, II, III, IV, V, VI, and VII. Certain compounds of Formulas I, II, III, IV, V, VI, and VII may be used as intermediates for other compounds of Formulas I, II, III, IV, V, VI, and VII.

[0026] Another aspect of the present invention includes methods of preparing, methods of separation, and methods of purification of the compounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

[0027] Reference will now be made in detail to certain embodiments, examples of which are illustrated in the accompanying structures and formulas. While enumerated embodiments will be described, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.

[0028] DEFINITIONS

[0029] The term "alkyl" includes linear or branched-chain radicals of carbon atoms.

Some alkyl moieties have been abbreviated, for example, methyl ("Me"), ethyl ("Et"), propyl ("Pr") and butyl ("Bu"), and further abbreviations are used to designate specific isomers of compounds, for example, 1 -propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1- butyl or n-butyl ("n-Bu"), 2-methyl-l -propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu") and the like. The abbreviations are sometimes used in conjunction with elemental abbreviations and chemical structures, for example, methanol ("MeOH") or ethanol ("EtOH"). [0030] Additional abbreviations used throughout the application may include, for example, benzyl ("Bn"), phenyl ("Ph") and acetate ("Ac").

[0031] The following terms are abbreviated: dimethylsulfoxide ("DMSO"), dimethylformamide ("DMF"), dichloromethane ("DCM"), ethyl acetate ("EtOAc") and tetrahydrofuran ("THF").

[0032] The term "alkenyl" refers to linear or branched-chain monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon double bond, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. In one example, the alkenyl radical is two to six carbon atoms (C₂- C₆). In other examples, the alkenyl radical is C₂-C₅, C₂-C₄ or C₂-C₃.

[0033] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein. In one example, the alkynyl radical is two to six carbon atoms (C₂-C₆). In other examples, the alkynyl radical is C₂-C₅, C₂-C₄ or C₂-C₃.

[0034] The term "cycloalkyl" refers to a non-aromatic, saturated or partially unsaturated hydrocarbon ring group, wherein the cycloalkyl group may be optionally substituted independently with one or more substituents described herein. In one example, the cycloalkyl group is 3 to 6 carbon atoms (C₃-C₆). In other examples, cycloalkyl is C₃-C₄ or C₃-C₅. In other examples, the cycloalkyl group, as a monocycle, is C₃-C₆ or C₅-C₆. In another example, the cycloalkyl group, as a bicycle, is C₇-C₁₂.

[0035] The term "halogen" refers to F, CI, Br or I.

[0036] The terms "heterocyclic" or "heterocycle" or "heterocyclyl" refers to a saturated or a partially unsaturated (i.e., having one or more double and/or triple bonds within the ring) cyclic group in which at least one ring atom is a heteroatom independently selected from nitrogen, oxygen, and sulfur, the remaining ring atoms being carbon. In one embodiment, heterocyclyl includes saturated or partially unsaturated 3-7 membered heterocyclyl groups, another embodiment includes 4-6 membered heterocyclyl groups, and another embodiment includes 5-6 membered heterocyclyl groups. The heterocyclyl group may be optionally substituted with one or more substituents described herein. Heterocycles include 3 to 7 membered rings containing one or two heteroatoms selected from oxygen, nitrogen and sulfur.

[0037] The term "heteroaryl" refers to an aromatic cyclic group in which at least one ring atom is a heteroatom independently selected from nitrogen, oxygen and sulfur, the remaining ring atoms being carbon. Heteroaryl groups may be optionally substituted with one or more substituents described herein. In one example, heteroaryl includes 5-6 membered heteroaryl groups. Heteroaryls includes 5 to 6 membered aromatic rings containing one, two, three or four heteroatoms selected from oxygen, nitrogen and sulfur.

[0038] A "solvate" refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to the complex where the solvent molecule is water.

[0039] The abbreviation "TLC" stands for thin layer chromatography.

[0040] The terms "treat" or "treatment" refer to therapeutic, prophylactic, palliative or preventative measures. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.

[0041] The phrases "therapeutically effective amount" or "effective amount" mean an amount of a compound described herein that, when administered to a mammal in need of such treatment, sufficient to (i) treat or prevent the particular disease, condition, or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.

[0042] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by abnormal or unregulated cell growth. A "tumor" comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small- cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, skin cancer, including melanoma, as well as head and neck cancer.

[0043] The phrase "pharmaceutically acceptable" indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.

[0044] The phrase "pharmaceutically acceptable salt," as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound described herein.

[0045] The compounds described herein also include other salts of such compounds that are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds described herein and/or for separating enantiomers of compounds described herein.

[0046] The term "mammal" means a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.

[0047] The terms "compound of this invention," and "compounds of the present invention", unless otherwise indicated, include compounds of Formulas I, II, III, IV, V, VI, and VII, stereoisomers, tautomers, solvates, prodrugs and salts (e.g., pharmaceutically acceptable salts) thereof. Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds of Formulas I, II, III, IV, V, VI, and VII, wherein one or more hydrogen atoms are replaced deuterium or tritium, or one or more carbon atoms are replaced by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention.

[0048] RAF INHIBITORS

[0049] Provided herein are compounds, and pharmaceutical formulations thereof, that are potentially useful in the treatment of diseases, conditions and/or disorders modulated by B-Raf.

[0050] One embodiment provides compounds of Formula I:

I

and stereoisomers, tautomers, solvates, prodrugs and pharmaceutically acceptable salts thereof, wherein:

the dashed lines represent optional double bonds;

W is selected from N, NR⁶, C(=0), CR⁷ and CHR⁷;

X is selected from N, NR⁸, C(=0), CR⁹ and CHR⁹, provided when:

(i) W is N, then X is CR⁹,

(ii) W is NR⁶, then X is C(=0) or CHR⁹,

(iii) W is C(=0), then X is NR⁸ or CHR⁹,

(iv) W is CR⁷, then X is N or CR⁹, and

(v) W is CHR⁷, then X is NR⁸, C(=0) or CHR⁹;

Y is selected from N, NR¹⁰, CR¹¹ and CHR¹¹;

Z is selected from N, NR¹², CR¹³ and CHR¹³;

L is selected from O, NR¹⁴, S, C(-O) and CR¹⁵R¹⁶;

R and R" are independently selected from hydrogen, halogen, CN, Ci-C₃ alkyl, C1-C3 alkoxy and C₂-C₃ alkynyl;

R is selected from hydrogen, halogen and C1-C3 alkyl;

R⁴ is selected from C₃-C₅ cycloalkyl, C C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, phenyl, a 5-6 membered heteroaryl, or NR^aR^b, wherein the cycloalkyl, alkyl, alkenyl, alkynyl, phenyl and heteroaryl are optionally substituted with OR⁰, halogen, phenyl, C₃-C₄ cycloalkyl, or C C4 alkyl optionally substituted with halogen;

R⁵ is selected from hydrogen, C1-C3 alkyl and Ci-C₃ alkoxy, wherein the alkyl and alkoxy are optionally substituted with R^d;

R⁶ is selected from hydrogen, Ci-C6 alkyl, Ci-Ce alkenyl, Q-C6 alkynyl, C₃-C₆ cycloalkyl, phenyl, a 3 to 6 membered heterocyclyl, and a 5 to 6 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl and heteroaryl are optionally substituted with halogen, oxo (not on phenyl or heteroaryl), OR^e, SR^e, NR^fR^g, phenyl, Ci-C₄ alkyl, C1-C4 alkoxy, and cyclopropyl, wherein the alkyl, alkoxy and cyclopropyl are optionally substituted with R^p; R⁷ is selected from hydrogen, C C₆ alkyl, Ci-C alkenyl, Ci-C^ alkynyl, Q-Q alkoxy, C₃-C₆ cycloalkyl, phenyl, a 3 to 6 membered heterocyclyl, a 5 to 6 membered heteroaryl, and NR^hR', wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, phenyl, heterocyclyl and heteroaryl are optionally substituted with halogen, oxo (not on phenyl or heteroaryl), OR^e, SR^e, NR^fR^g, Q- i alkyl, C C₄ alkoxy, and cyclopropyl, wherein the alkyl, alkoxy and cyclopropyl are optionally substituted with R ;

Q

R is selected from hydrogen, Q-Q alkyl, C C₆ alkenyl, C C₆ alkynyl, C₃-C₆ cycloalkyl, phenyl, a 3 to 6 membered heterocyclyl, and a 5 to 6 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl and heteroaryl are optionally substituted with halogen, oxo (not on phenyl or heteroaryl), OR", SR^J, NR^kR*, phenyl, Q-C4 alkyl, Q-C4 alkoxy, and cyclopropyl, wherein the alkyl, alkoxy and cyclopropyl are optionally substituted with R^p;

R⁹ is selected from hydrogen, C!-C₆ alkyl, Ci-C₆ alkenyl, C!-C₆ alkynyl, Ci-Ce alkoxy, C₃-C₆ cycloalkyl, phenyl, a 3 to 6 membered heterocyclyl, a 5 to 6 membered heteroaryl, and NR^mRⁿ, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, phenyl, heterocyclyl and heteroaryl are optionally substituted with halogen, oxo (not on phenyl or heteroaryl), OR^J, SR^J, NR^kR*, C C₄ alkyl, d-C₄ alkoxy, and cyclopropyl, wherein the alkyl, alkoxy and cyclopropyl are optionally substituted with R^p;

R¹⁰ is selected from hydrogen and halogen;

R¹¹ is selected from hydrogen and halogen, or

R¹¹ and R¹⁴ together with the atoms to which they are attached form a 5-6 membered heterocyclyl or heteroaryl optionally substituted with oxo, or

R¹¹ and R¹⁵ together with the atoms to which they are attached form a 5-6 membered carbocyclyl;

R¹² is hydrogen;

R¹³ is selected from hydrogen and halogen;

R¹⁴ is selected from hydrogen and C C₄ alkyl;

R¹⁵ and R¹⁶ are independently selected from hydrogen and Q-C3 alkyl;

R^a and R^b are independently selected from hydrogen or C Cs alkyl optionally substituted by halogen, or

R^a and R^b are taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C!-C₃ alkyl;

R^c is selected from hydrogen and C!-C₆ alkyl optionally substituted by halogen;

each R^d is selected from halogen and OH; R^e is selected from hydrogen and Q-C4 alkyl;

R^f and R⁸ are independently selected from hydrogen and Q-C4 alkyl optionally substituted with halogen;

R^h and R¹ are independently selected from hydrogen and C₁-C4 alkyl optionally substituted with halogen;

R^J is selected from hydrogen and C₁-C₄ alkyl;

R^k and R¹ are independently selected from hydrogen and Q-C₄ alkyl optionally substituted with halogen;

R^m and R" are independently selected from hydrogen and C!-C4 alkyl optionally substituted with halogen; and

each R^p is independently selected from halogen, oxo, Q-C₄ alkyl and Q-C4 alkoxy, wherein the alkyl and alkoxy are optionally substituted with halogen.

[0051] One embodiment provides compounds of Formula II:

1 2 3 and stereoisomers and pharmaceutically acceptable salts thereof, wherein W, X, L, R , R , R , R⁴, R⁵ and Rⁿ are as defined herein and the dashed lines represent optional double bonds.

[0052] One embodiment provides compounds of Formula III:

1 2 3 and stereoisomers and pharmaceutically acceptable salts thereof, wherein W, X, L, R , R , R , R⁴, R⁵ and R¹¹ are as defined herein and the dashed line between W and X represents an optional double bond.

[0053] One embodiment provides compounds of Formula IV:

IV

and stereoisomers and pharmaceutically acceptable salts thereof, wherein L, R¹, R², R³, R⁴, R⁵, R⁶ and Rⁿ are as defined herein.

[0054] One embodiment provides compounds of Formula V:

V

and stereoisomers and pharmaceutically acceptable salts thereof, wherein L, R¹, R², R³, R⁴, R⁵, R⁷ and R¹¹ are as defined herein.

[0055] One embodiment provides compounds of Formula VI:

VI

and stereoisomers and pharmaceutically acceptable salts thereof, wherein L, R¹, R², R³, R⁴, R⁵, R⁹ and Rⁿ are as defined herein.

[0056] One embodiment provides compounds of Formula VII:

VII

and stereoisomers and pharmaceutically acceptable salts thereof, wherein L, R¹, R², R³, R⁴, R⁵, R⁷, R⁸ and R¹¹ are as defined herein. [0057] In certain embodiments, W is selected from N, NR⁶, C(=0), CR⁷ and CHR⁷.

In certain embodiments, W is selected from N,

.

[0058] In certain embodiments, R⁶ is selected from hydrogen, C!-C₆ alkyl, C C₆ alkenyl, C C₆ alkynyl, C₃-C₆ cycloalkyl, phenyl, a 3 to 6 membered heterocyclyl, and a 5 to 6 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl and heteroaryl are optionally substituted with halogen, oxo (not on phenyl or heteroaryl), OR^e, SR^e, NR^fR⁸, phenyl, Q-Q alkyl, C C₄ alkoxy, and cyclopropyl, wherein the alkyl, alkoxy and cyclopropyl are optionally substituted with R^p. In certain embodiments, R⁶ is selected from C_\- e alkyl, phenyl, and a 5 to 6 membered heteroaryl, wherein the alkyl, phenyl and heteroaryl are optionally substituted with phenyl or C1-C₄ alkyl optionally substituted with R^p. In certain embodiments, R⁶ is methyl, benzyl, phenyl or 1 -methyl- 1H- pyrazol-4-yl.

[0059] In certain embodiments, R is selected from hydrogen, C_\-C(, alkyl, Q-Ce alkenyl, Q-Q alkynyl, Ci-C₆ alkoxy, C₃-C₆ cycloalkyl, phenyl, a 3 to 6 membered heterocyclyl, a 5 to 6 membered heteroaryl, and NR^hR', wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, phenyl, heterocyclyl and heteroaryl are optionally substituted with halogen, oxo (not on phenyl or heteroaryl), OR^e, SR^e, NR^fR^g, Q-C4 alkyl, C1-C4 alkoxy, and cyclopropyl, wherein the alkyl, alkoxy and cyclopropyl are optionally substituted with R^p. In certain embodiments, R⁷ is selected from hydrogen, C_\-C(, alkoxy and NR^hR'. In certain embodiments, R^h and R¹ are independently selected from hydrogen and C₁-C₄ alkyl optionally substituted with halogen. In certain embodiments, R⁷ is hydrogen, OCH₃ or NHCH3.

[0060] In certain embodiments, X is selected from N, NR⁸, C(=0), CR⁹ and CHR⁹.

Q

In certain embodiments, X is selected from N, NR , C(=0) and CR .

o

[0061] In certain embodiments, R is selected from hydrogen, Q-Q alkyl, Q-C6 alkenyl, C_!-C₆ alkynyl, C₃-C₆ cycloalkyl, phenyl, a 3 to 6 membered heterocyclyl, and a 5 to 6 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl and heteroaryl are optionally substituted with halogen, oxo (not on phenyl or heteroaryl), OR^J, SR^J, NR^kR*, phenyl, Q-C4 alkyl, Q-C4 alkoxy, and cyclopropyl, wherein the alkyl, alkoxy and cyclopropyl are optionally substituted with R^p. In certain embodiments, R⁸ is C - C₆ alkyl. In certain embodiments, R is methyl, ethyl or isopropyl.

[0062] In certain embodiments, R⁹ is selected from hydrogen, C_\-C(, alkyl, C C₆ alkenyl, C C₆ alkynyl, C C₆ alkoxy, C₃-C₆ cycloalkyl, phenyl, a 3 to 6 membered heterocyclyl, a 5 to 6 membered heteroaryl, and NR^mRⁿ, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, phenyl, heterocyclyl and heteroaryl are optionally substituted with halogen, oxo (not on phenyl or heteroaryl), OR^J, SR^J, NR^kR', Q-C4 alkyl, Q-C4 alkoxy, and cyclopropyl, wherein the alkyl, alkoxy and cyclopropyl are optionally substituted with R^p. In certain embodiments, R⁹ is selected from hydrogen, Cy-Ce alkoxy, a 3 to 6 membered heterocyclyl, and NR^mRⁿ, wherein the alkoxy and heterocyclyl are optionally substituted with C C₄ alkyl optionally substituted R^p. In certain embodiments, R^m and Rⁿ are independently selected from hydrogen and C1-C4 alkyl optionally substituted with halogen. In certain embodiments, each R^p is independently selected from halogen, oxo, Ct-Q alkyl and C₁-C₄ alkoxy, wherein the alkyl and alkoxy are optionally substituted with halogen. In certain embodiments, R⁹ is hydrogen, OCH₃, OCH₂CH₃, NHCH₃, N(CH₃)₂, piperazin-l-yl, 4- methylpirperazin-l-yl or tert-butyl 4-piperazine-l-carboxylate.

[0063] In the present invention, when:

(i) W is N, then X is CR⁹,

(ii) W is NR⁶, then X is C(=0) or CHR⁹,

(iii) W is C(=0), then X is NR⁸ or CHR⁹,

(iv) W is CR⁷, then X is N or CR⁹, and

(v) W is CHR⁷, then X is NR⁸, C(=0) or CHR⁹.

[0064] In certain embodiments, when:

(i) W is N, then X is CR⁹,

(ii) W is NR⁶, then X is C(=0),

(iii) W is C(=0), then X is NR⁸, and

(iv) W is CR⁷, then X is N or CR⁹.

[0065] In certain embodiments, Y is selected from N, NR¹⁰, CR¹¹ and CHR¹¹. In certain embodiments, Y is CR¹¹. In certain embodiments, R¹¹ is selected from hydrogen and halogen. In certain embodiments, Y is CH or CC1.

[0066] In certain embodiments, Z is selected from N, NR¹², CR¹³ and CHR¹³. In

13 12

certain embodiments, Z is CR . In certain embodiments, R is hydrogen. In certain embodiments, R is selected from hydrogen and halogen. In certain embodiments, R is hydrogen. In certain embodiments, Z is CH.

[0067] In certain embodiments the residue:

wherein the wavy line represents the point of attachment of the residue to L, is selected from:



wherein the wav line represents the point of attachment of the residue to L, is selected from:

[0069] In certain embodiments, L is selected from O, NR. , S, C(=0) and CR R .

In certain embodiments, L is selected from O and NR¹⁴. In certain embodiments, R¹⁴ is selected from hydrogen and Ci-C₄ alkyl. In certain embodiments, L is O, NH, N(CH₃) or N(CH₂CH₃).

[0070] In certain embodiments, L is O.

[0071] In certain embodiments, L is NR¹⁴. In certain embodiments, R¹⁴ is selected from hydrogen and C C₄ alkyl. In certain embodiments, R¹⁴ is hydrogen. In certain embodiments, R¹⁴ is Ci-C₄ alkyl. In certain embodiments, L is NH, N(CH₃) or N(CH₂CH₃). In certain embodiments, L is N(CH₃) or N(CH₂CH₃). In certain embodiments, L is NH.

1

[0072] In certain embodiments, R and R are independently selected from hydrogen, halogen, CN, Ci-C₃ alkyl, Ci-C₃ alkoxy or C₁-C₃ alkynyl. In certain embodiments, R¹ and R² are independently selected from hydrogen, halogen, CN, C C₃ alkyl or C C₃ alkoxy.

1 9

[0073] In certain embodiments, R , R and R are independently selected from hydrogen, halogen or 1 2 3

C1-C3 alkyl. In certain embodiments, R , R and R are independently selected from hydrogen, F, CI or methyl.

[0074] In certain embodiments, R¹ is hydrogen, halogen, CN, C C₃ alkyl, C1-C3 alkoxy or C₂-C₃ alkynyl. In certain embodiments, R¹ is hydrogen, halogen, CN, Q-C3 alkyl or Ci-C₃ alkoxy. In certain embodiments, R¹ is hydrogen or halogen. In certain embodiments, R¹ is hydrogen, CI or F.

[0075] In certain embodiments, R¹ is hydrogen.

[0076] In certain embodiments, R¹ is halogen. In certain embodiments, R¹ is F or CI.

[0077] In certain embodiments, R¹ is C!-C₃ alkyl. In certain embodiments, R¹ is methyl.

[0078] In certain embodiments, R is hydrogen, halogen, CN, C C₃ alkyl, Q-C3 alkoxy or C₂-C₃ alkynyl. In certain embodiments, R is hydrogen, halogen, CN, Ci-C₃ alkyl

2 2 or C C3 alkoxy. In certain embodiments, R is halogen or CN. In certain embodiments, R is CI, F or CN. In certain embodiments, R² is CI or CN.

[0079] In certain embodiments, R is hydrogen.

9 9

[0080] In certain embodiments, R is halogen. In certain embodiments, R is F or CI.

In certain embodiments, R is CI.

[0081] In certain embodiments, R is C1-C3 alkyl. In certain embodiments, R is methyl.

[0082] In certain embodiments, R is hydrogen, halogen or C1-C3 alkyl. In certain embodiments, R is hydrogen.

[0083] In certain embodiments, R is halogen. In certain embodiments, R is F or CI.

1 9 '

[0084] In certain embodiments, R and R are F and R is hydrogen.

1 9 ^

[0085] In certain embodiments, R is hydrogen and R and R are F.

[0086] In certain embodiments, R is hydrogen, R is F and R is CI.

[0087] In certain embodiments, R is F and R is CI and R is hydrogen.

[0088] In certain embodiments, R¹ is CI and R² is F and R³ is hydrogen.

1 9

[0089] In certain embodiments, R is F and R and R are hydrogen.

[0090] In certain embodiments, R and R are hydrogen and R is F.

[0091] In certain embodiments, R and R are hydrogen and R is CI.

1 9

[0092] In certain embodiments, R is CI and R and R are hydrogen.

[0093] In certain embodiments, R¹, R² and R³ are F.

1 9 "X

[0094] In certain embodiments, R is F and R is methyl and R is hydrogen.

1 9 "X

[0095] In certain embodiments, R is methyl and R is F and R is hydrogen.

[0096] In certain embodiments, R² is F and R¹ and R³ are hydrogen.

1 9 "X

[0097] In certain embodiments, R is CI, R is ethynyl and R is hydrogen.

1 9 "

[0098] In certain embodiments, R is F, R is ethynyl and R is hydrogen.

[0099] In certain embodiments, R¹ and R³ are hydrogen and R² is CN. [00100] In certain embodiments, R¹ is F, R² is CN and R³ is hydrogen.

[00101] In certain embodiments, R¹ is CI, R² is CN and R³ is hydrogen.

[00102] In certain embodiments, R is methyl and R and R are hydrogen.

[00103] In certain embodiments, the residue:

[00104] In certain embodiments, R⁴ is selected from C₃-C₅ cycloalkyl, C_!-C₆ alkyl, C₂- C₆ alkenyl, C₂-C₆ alkynyl, phenyl, a 5-6 membered heteroaryl, or NR^aR^b, wherein the cycloalkyl, alkyl, alkenyl, alkynyl, phenyl and heteroaryl are optionally substituted with OR^c, halogen, phenyl, C₃-C cycloalkyl, or Ci-C₄ alkyl optionally substituted with halogen. In certain embodiments, R⁴ is selected from Ci-Ce alkyl, a 5-6 membered heteroaryl, or NR^aR^b, wherein the alkyl and heteroaryl are optionally substituted with halogen or C₃-C₄ cycloalkyl. In certain embodiments, R^a and R^b are independently selected from hydrogen or C Cs alkyl optionally substituted by halogen. In certain embodiments, R^a and R^b are Q-Cs alkyl. In certain embodiments, R^a and R^b are taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or Ci- C₃ alkyl. In certain embodiments, R^a and R^b are taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclyl. In certain embodiments, R^a and R^b are taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclyl, wherein the heterocyclyl contains one nitrogen heteroatom. In certain embodiments, R^a and R^b are taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclyl, wherein the heterocyclyl is pyrrolidine. In certain embodiments, R⁴ is propyl, isobutyl, -CH₂CH₂CH₂F, cyclopropylmethyl, -N(CH₃)₂, pyrrolidine, or furan-2-yl.

[00105] In certain embodiments, R⁴ is C₃-C₄ cycloalk l, Q-Q alkyl optionally substituted with halogen or C₃-C₄ cycloalkyl, or NR^aR^b. In certain embodiments, R^a and R^b are independently selected from hydrogen and Q-Cs alkyl.

[00106] In certain embodiments, R⁴ is C₃-C₅ cycloalkyl, C C6 alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, wherein the cycloalkyl, alkyl, alkenyl and alkynyl are optionally substituted with OR^c, halogen or C3-C4 cycloalkyl.

[00107] In certain embodiments, R⁴ is cyclopropyl, ethyl, propyl, butyl, isobutyl, -CH₂C1, -CH₂CF₃, -CH₂CH₂CH₂F, ^CH₂CH₂CF₃, phenylmethyl, cyclopropylmethyl, phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 4-chloro-3- trifluoromethylphenyl, 1 -methyl- lH-imidazol-4-yl, furan-2-yl, pyridin-2-yl, pyridin-3-yl, thiophen-2-yl, -NHCH₂CH₃, -NHCH₂CH₂CH₃, -N(CH₃)CH₂CH₃, -N(CH₃)₂, or pyrrolidine.

[00108] In certain embodiments, R⁴ is cyclopropyl, propyl, butyl, isobutyl, -CH₂C1, -CH₂CF₃, -CH₂CH₂CH₂F, -CH₂CH₂CF₃, cyclopropylmethyl, -NHCH₂CH₂CH₃, -N(CH₃)CH₂CH₃, -N(CH₃)₂, or pyrrolidine.

[00109] In certain embodiments, R⁴ is cyclopropyl, propyl, butyl, isobutyl, -CH₂C1, -€H₂CF₃, -CH₂CH₂CH₂F, -CH₂CH₂CF₃, cyclopropylmethyl or -NHCH₂CH₂CH₃.

[00110] In certain embodiments, R⁴ is propyl, butyl, isobutyl, -CH₂CH₂CH₂F, -CH₂CH₂CF₃ or cyclopropylmethyl.

[00111] In certain embodiments, R⁴ is C₃-C₅ cycloalkyl or C C₆ alkyl optionally substituted with OH, halogen or C₃-C₄ cycloalkyl.

[00112] In certain embodiments, R⁴ is C₃-C₅ cycloalkyl. In certain embodiments, R⁴ is C₃-C₄ cycloalkyl. In certain embodiments, R⁴ is cyclopropyl or cyclobutyl. In certain embodiments, R⁴ is cyclopropyl.

[00113] In certain embodiments, R⁴ is Ci-C₆ alkyl. In certain embodiments, R⁴ is ethyl, propyl, butyl or isobutyl. In certain embodiments, R⁴ is propyl or isobutyl.

[00114] In certain embodiments, R⁴ is C C₆ alkyl optionally substituted with halogen. In certain embodiments, R⁴ is -CF₃, -CH₂C1, -CH₂CF₃, -CH₂CH₂CH₂F, -CH₂CH₂CF₃, -CF₂CF₃ or -CF₂CF₂CF₃. In certain embodiments, R⁴ is -CH₂CH₂CH₂F or -CH₂CH₂CF₃. In certain embodiments, R⁴ is -CH₂CH₂CH₂F.

[00115] In certain embodiments, R⁴ is Ci-Ce alkyl optionally substituted with OH, halogen or C₃-C₄ cycloalkyl. In certain embodiments, R⁴ is cyclopropylmethyl (-CH₂- cyclopropyl) or cyclobutylmethyl (-CH₂-cyclobutyl). In certain embodiments, R⁴ is cyclopropylmethyl .

[00116] In certain embodiments, R⁴ is Q-C₆ alkyl optionally substituted with phenyl. In certain embodiments, R⁴ is phenylmethyl.

[00117] In certain embodiments, R⁴ is phenyl optionally substituted with OR^c, halogen, C₃-C₄ cycloalkyl, or C₁-C₄ alkyl optionally substituted with halogen. In certain embodiments, R⁴ is phenyl optionally substituted with halogen. In certain embodiments, R⁴ is phenyl optionally substituted with C C₄ alkyl optionally substituted with halogen. In certain embodiments, R⁴ is phenyl optionally substituted with halogen and Q-C₄ alkyl optionally substituted with halogen. In certain embodiments, R⁴ is phenyl. In certain embodiments, R⁴ is phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,5- difluorophenyl or 4-chloro-3-trifluoromethylphenyl.

[00118] In certain embodiments, R⁴ is a 5-6 membered heteroaryl optionally substituted with OR^c, halogen, C₃-C₄ cycloalkyl or C_t-C4 alkyl optionally substituted with halogen. In certain embodiments, R⁴ is a 5-6 membered heteroaryl optionally substituted with C!-C₄ alkyl. In certain embodiments, R⁴ is a 5-6 membered heteroaryl, wherein the heteroaryl contains one or two heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. In certain embodiments, R⁴ is a 5-6 membered heteroaryl, wherein the heteroaryl is imidazolyl, furanyl, pyridinyl or thiophenyl. In certain embodiments, R⁴ is 1- methyl-lH-imidazol-4-yl, furan-2-yl, pyridin-2-yl, pyridin-3-yl or thiophen-2-yl. In certain embodiments, R⁴ is furan-2-yl.

[00119] In certain embodiments, R⁴ is NR^aR^b. In certain embodiments, R^a and R^b are independently selected from hydrogen and Q-Cs alkyl. In certain embodiments, R^a is hydrogen. In certain embodiments, R^a is Ci-C₆ alkyl. In certain embodiments, R^a is ethyl or propyl. In certain embodiments, R⁴ is selected from the group consisting of -NHCH₂CH₃, -NHCH₂CH₂CH₃, -N(CH₃)CH₂CH₃ and -N(CH₃)₂. In certain embodiments, R⁴ is -N(CH₃)₂.

[00120] In certain embodiments, R^a and R^b together with the nitrogen to which they are attached form a 3 to 6 membered heterocyclyl ring. In certain embodiments, R^a and R^b together with the nitrogen to which they are attached form a 3 to 6 membered heterocyclic ring, wherein the heterocyclic ring contains one nitrogen heteroatom. In certain embodiments, R⁴ is pyrrolidine. In certain embodiments, R⁴ is pyrrolidin-l-yl.

[00121] In certain embodiments, R⁴ is selected from propyl, cyclopropylmethyl, -CH₂CH₂CH₂F and phenyl. In a further embodiment, R⁴ is selected from propyl, cyclopropylmethyl and -CH₂CH₂CH₂F.

[00122] In certain embodiments, R⁵ is selected from hydrogen, Q-C₃ alkyl and C_!-C₃ alkoxy, wherein the alkyl and alkoxy are optionally substituted with R^d. In certain embodiments, R⁵ is hydrogen.

[00123] In certain embodiments, R¹¹ and R¹⁴ together with the atoms to which they are attached form a 5-6 membered heterocyclyl or heteroaryl optionally substituted with oxo. This embodiment includes the following formula:

wherein V is O, N or CH; x is 1 or 2; the dashed lines represent optional double bonds, and W, X, Z, R¹, R², R³, R⁴ and R⁵ are as defined herein. In certain embodiments, compounds of the present invention have the following formulas:

[00124] In certain embodiments, R¹¹ and R¹⁵ together with the atoms to which they are attached form a 5-6 membered carbocyclyl. This embodiment includes the following formula:

[00125] In certain embodiments,

W is selected from N, NR⁶, C(=0) and CR⁷;

X is selected from N, NR⁸, C(=0) and CR⁹;

Y is CR¹¹;

Z is CH; and

R⁵ is hydrogen.

[00126] In certain embodiments,

W is selected from N, NR⁶, C(=0) and CR⁷;

X is selected from N, NR⁸, C(=0) and CR⁹, provided when:

(i) W is N, then X is CR⁹, (ii) W is NR.⁶, then X is C(=0),

(iii) W is C(=0), then X is NR⁸, and

(iv) W is CR⁷, then X is N or CR⁹;

Y is CR¹¹;

Z is CH;

L is selected from O and NR¹⁴;

R⁵ is hydrogen;

R⁶ is selected from C C₆ alkyl, phenyl, and a 5 to 6 membered heteroaryl, wherein the alkyl, phenyl and heteroaryl are optionally substituted with phenyl or C1-C4 alkyl optionally substituted with R^p;

R⁷ is selected from hydrogen, CrC₆ alkoxy and NR^hR';

R⁸ is Ci-Ce alkyl;

R⁹ is selected from hydrogen, Ci-C , alkoxy, a 3 to 6 membered heterocyclyl, and NR^mR", wherein the alkoxy and heterocyclyl are optionally substituted with C C₄ alkyl optionally substituted R ;

R¹¹ is selected from hydrogen and halogen; and

R is hydrogen.

[00127] It will be appreciated that certain compounds described herein may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds described herein, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present compounds.

[00128] In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds described herein. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.

[00129] It will also be appreciated that certain compounds of Formulas I, II, III, IV, V, VI, and VII may be used as intermediates for further compounds of Formulas I, II, III, IV, V, VI, and VII.

[00130] It will be further appreciated that the compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the compounds embrace both solvated and unsolvated forms.

[00131] SYNTHESIS OF COMPOUNDS [00132] Compounds described herein may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Sigma-Aldrich (St. Louis, MO), Alfa Aesar (Ward Hill, MA), or TCI (Portland, OR), or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, New York: Wiley 1967-2006 ed. (also available via the Wiley InterScience® website), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer- Verlag, Berlin, including supplements (also available via the Beilstein online database)).

[00133] In preparing compounds of Formula I, II, III, IV, V, VI, and VII, protection of remote functionalities (e.g., primary or secondary amines, etc.) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, t-butyloxycarbonyl ("Boc"), benzyloxycarbonyl ("CBz") and 9-fluorenylmethyleneoxycarbonyl ("Fmoc"). The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, et al. Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006.

[00134] For illustrative purposes, Schemes 1-18 show general methods for preparing the compounds described herein, as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds. Although specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

1.6

Scheme 1

[00135] Scheme 1 shows a general method for preparing a compound 1.6, wherein R , R², R³ and R⁴ are as defined herein. A benzoic acid 1.1 is esterified to an alkyl benzoate 1.2 (wherein R is alkyl), e.g., by treatment with tnmethylsilyl diazomethane in MeOH or via Fischer esterification conditions, such as treatment with trimethylsilyl chloride ("TMSC1") in MeOH. Reduction of nitro intermediate 1.2 to its amino analog 1.3 is performed using a standard condition, such as treatment with Pd/C and H₂. Bis-sulfonamide 1.4 is obtained by treatment of the aniline 1.3 with a sulfonyl chloride, R⁴S0₂C1, in the presence of a base, such as NEt₃, in an organic solvent, such as dichloromethane ("DCM"). Hydrolysis of compound 1.4 is accomplished under basic conditions, such as aqueous NaOH, in the appropriate solvent system, such as THF and/or MeOH, to provide a carboxylic acid 1.5. This compound in a suitable solvent, such as THF, is treated with diphenylphosphonic azide ("DPP A") and a base such as triethylamine, and subsequently hydrolyzed to form an amine 1.6.

Scheme 2

[00136] Scheme 2 describes the synthesis of aniline intermediates 2.7, wherein R¹, R²', R³, R⁴ and R" are as defined herein. A benzoic acid ester 2.1 is treated with an alkoxide,

2' 2'

NaOR (wherein R is C1-C3 alkyl), in an appropriate solvent, such as methanol, to form the ether intermediate 2.2. Reduction of the nitro group affords aniline 2.3, which is reacted with a sulfonyl chloride, R⁴S0₂C1, in the presence of base, such as pyridine, to give a sulfonamide intermediate 2.4. Benzylation with an optionally substituted benzyl halide, for example p- methoxybenzyl chloride, (wherein LG is a leaving group such as chloro, bromo, iodo, triflate, tosylate; and R" is hydrogen, C C₃ alkyl or Ci-C alkoxy; and in one example, R" is hydrogen, in another example, R" is OMe) in the presence of a base, such as sodium hydride, yields the protected sulfonamide ester 2.5, which is hydrolyzed with aqueous base, such as NaOH, to form the acid 2.6. In the last step, application of Curtius rearrangement conditions and subse uent hydrolysis gives the amino intermediate 2.7.

Scheme 3

[00137] Scheme 3 shows a procedure for generating the aniline intermediate 3.1, wherein R" and LG are defined in Scheme 2 and R¹, R², R³ and R⁴ are as defined herein, through protection of the sulfonamide moiety of aniline 1.6. This transformation can be accomplished by treatment with an optionally substituted benzyl halide (e.g., p- methox benzyl chloride) and a base, such as sodium hydride.

4.1 4.2 4.3 1.3

Scheme 4

[00138] Scheme 4 describes the synthesis of an aniline ester of Formula 1.3, wherein R , R and R^J are defined herein and R is alkyl, such as methyl or ethyl, or benzyl. The amino group of an aniline 4.1 is protected by reacting with hexane-2,5-dione in the presence of a catalytic amount of an acid, such as p-toluenesulfonic acid, in a solvent, such as toluene, to form the 2,5-dimethylpyrrole derivative 4.2. Reaction with a carbamoyl chloride, RO(C=0)Cl, in the presence of n-butyllithium or a comparable agent in a suitable solvent, such as THF, leads to formation of the ester analog 4.3. The amino function of compound 4.3 is deprotected by reaction with hydroxylamine in a suitable solvent, such as ethanol, leading to formation of intermediate 1.3.

4 1 5.1 5.2

Scheme 5

[00139] Scheme 5 describes the synthesis of an aniline ester of Formula 1.3, wherein

R 1', R2", and R 3^J are defined herein and R is small alkyl, such as methyl or ethyl, or benzyl. The amino group of an aniline 4.1 is protected by reacting with 1,2- bis(chlorodimethylsilyl)ethane in the presence of a strong base, such as n-butyllithium, in a suitable solvent, such as THF, at low temperatures, e.g., -78°C, to form the l-aza-2,5- disilacyclopentane intermediate 5.1. Compound 5.1 is immediately reacted with a carbamoyl chloride, RO(C=0)Cl, in the presence of n-butyllithium or a comparable agent in a suitable solvent, such as THF, leading to formation of the ester analog 5.2. The amino function of compound 5.2 is deprotected by reaction with an acid, such as HC1, in a suitable solvent, leadin to formation of intermediate 1.3.

Scheme 6

[00140] Scheme 6 describes another way of synthesizing an intermediate of Formula 1.6, wherein R¹, R², R³ and R⁴ are as defined herein. Bis-sulfonamide 6.2 is obtained by treatment of the aniline 6.1 with a sulfonyl chloride, R⁴S0₂C1, in the presence of a base, such as NEt₃, in an organic solvent, such as dichloromethane. Hydrolysis of compound 6.2 is accomplished under basic conditions, such as aqueous NaOH, in the appropriate solvent system, such as THF and/or MeOH, to provide the mono-sulfonamide 6.3. This compound in a suitable solvent, such as ethanol, is treated with a reducing agent, such as iron, and additional reagents, such as ammonium chloride, to form an amine 1.6.

Scheme 7

[00141] Scheme 7 shows another way of preparing an intermediate of Formula 1.6. This transformation is accomplished by mono-sulfonylation of a diamino derivative 7.1 with a sulfonyl chloride, R⁴S0₂C1, in the presence of a base, such as pyridine, in an organic solvent, such as dichloromethane.

8.2

Scheme 8

[00142] Scheme 8 describes the synthesis of an intermediate of Formula 8.2, a subset of Formula 1.6 compounds, wherein R¹, R³ and R⁴ are as defined herein and R² is hydrogen. This transformation is accomplished by reduction of the chloro atom of compound 8.1 using reducing conditions, such as hydrogen in the presence of a palladium catalyst in a suitable solvent, such as ethanol.

Scheme 9

[00143] Scheme 9 describes the synthesis of an intermediate of Formula 9.2, a subset of Formula 1.6 compounds, wherein R², R³ and R⁴ are as defined herein and R¹ is hydrogen. This transformation is accomplished by reduction of the chloro atom of compound 9.1 using reducing conditions, such as hydrogen in the presence of a palladium catalyst in a suitable solvent, such as ethanol.

Scheme 10

[00144] Scheme 10 shows a method for preparing nitrile-substituted aniline intermediates 10.2. Reaction of fluoronitrile 10.1 with the sodium salt of H₂NS0₂R⁴ (generated by a strong base, such as sodium hydride) in a suitable solvent, such as dimethylsulfoxide or N-methylpyrrolidone, at elevated temperature, results in the formation of intermediate 10.2.

11.6 11 .5

Scheme 11

[00145] Scheme 11 shows a general method for preparing compounds 11.2 and 11.6, wherein W, X, Y, Z, R¹, R², R³, R⁴ and R⁸ are as defined herein. Amino heterocycle 11.1 can be coupled with aniline 1.6 under standard Buchwald coupling conditions utilizing a Pd catalyst, such as Pd(dba)₂, and a ligand, such as BINAP, to give biarylamine 11.2. Alternatively, aniline 1.6 can be protected with a suitable protecting group, for example PMB, with a suitable base, such as NaH, in a solvent, such as DMF, to give 11.3, and then coupled to give 11.4 and deprotected, for example with neat TFA at room temperature or DCM/TFA at elevated temperatures to provide 11.2. Biaryl amine 11.4 may also be alkylated on nitrogen utilizing a suitable base, preferably NaH, and an alkylating agent, such as Mel, Etl, allyl bromide or cyclopropylmethyl methanesulfonate. Subsequent deprotection provides compound 11.6.

Scheme 12

[00146] Scheme 12 shows a general method for preparing compound 12.2, wherein R¹, R², R³, R⁴, R⁶ and R¹⁴ are as defined herein. Biaryl amine 12.1 can be chlorinated in the presence of a chlorinating reagent, such as n-chlorosuccinimide, in a variety of solvents, including THF, DMF or CHC1₃, to provide compound 12.2. Alternatively, protected sulfonamide 12.3, where PG is a protecting group, can be chlorinated and then deprotected with TFA to provide compound 12.2.

Scheme 13

[00147] Scheme 13 shows a general method for preparing compounds 13.2 and 13.3, wherein R and R is as defined herein. Quinoxalinone 13.1 can be alkylated with an alkylating agent, such as Mel, EtI, allyl bromide or cyclopropylmethyl methanesulfonate, utilizing a base, such as NaH, in a solvent, such as DMF, giving a mixture of heterocycles 13.2 and 13.3. Heterocycles 13.2 and 13.3 can be separated and coupled separately in the Buchwald reaction according to Scheme 11.

14.1 14.2 14.3

Scheme 14

[00148] Scheme 14 describes the preparation of nitriles 14.3, wherein W, X, R¹, R³, R⁴ and R¹¹ are as defined herein. An alkali metal salt of a hydroxyl-containing heterocycle 14.1 is generated using a suitable base, such as sodium hydride, in an appropriate solvent, such as THF, DMF or NMP. The resulting phenoxide is treated with an optionally substituted difluorobenzonitrile at ambient or elevated temperature to afford ether intermediate 14.2. Nitrile 14.3 is obtained by reacting, at elevated temperature, intermediate 14.2 with an anion of an optionally protected sulfonamide or sulfamide, formed by the action of a strong base, such as sodium hydride, in a solvent, such as NMP, DMF, or DMSO.

Scheme 15

[00149] Scheme 15 describes the preparation of nitriles 15.3, wherein W, X, R¹, R³, R⁴ and R¹¹ are as defined herein. An aniline is coupled to a heterocycle 15.1 under standard Buchwald coupling conditions utilizing a Pd catalyst, such as Pd(dba)₂, and a ligand, such as ΒΓΝΑΡ, to give biarylamine 15.2. Nitrile 15.3 is obtained by reacting, at elevated temperature, intermediate 15.2 with an anion of an optionally protected sulfonamide or sulfamide, formed by the action of a strong base, such as sodium hydride, in a solvent, such as NMP DMF, or DMSO.

Scheme 16

[00150] Scheme 16 shows a general method for preparing compounds 16.2 and 16.3, wherein R⁶, R^m and Rⁿ are as defined herein. A quinazolinone such as 16.1 can be treated with a coupling agent, such as BOP, in a suitable solvent, such as DMF or acetonitrile, and subsequently treated with an amine to provide quinazoline amines 16.3. Alternatively, 16.1 can be treated with the coupling agent FLATU in a suitable solvent, such as DMF or acetonitrile, and subsequently treated with an amine to provide quinazolines 16.2.

Scheme 17

[00151] Scheme 17 shows a general method for preparing sulfamides 17.2, wherein W, X, R¹, R², R³, R⁴, R¹¹, R^a and R^b are as defined herein. A sulfonamide 17.1 is treated with a sulfamoyl chloride in a solvent, such as DMF, and subsequently hydrolyzed to a sulfamide 17.2 by addition of a base and water, such as sodium h droxide.

Scheme 18

[00152] Scheme 18 shows a general method for preparing compounds 18.2, wherein R^z is Ci-C₆ alkyl optionally substituted with halogen, oxo, OR^J, SR^j, NR^kR', phenyl, d-C₄ alkyl, C_!-C₄ alkoxy, and cyclopropyl, wherein the alkyl, alkoxy and cyclopropyl are optionally substituted with R^p. 4-Chloroquinazolinone 18.1 can be treated with a nucleophile, such as NaOR^z, in a suitable solvent, such as R^zOH, to provide 4-alkoxyquinazole 18.2.

[00153] METHODS OF SEPARATION

[00154] It may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography. One skilled in the art will apply techniques most likely to achieve the desired separation.

[00155] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.

[00156] A single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C. H., et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr., 113(3) (1975): pp. 283-302). Racemic mixtures of chiral compounds described herein may be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[00157] Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl- β-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid, can result in formation of the diastereomeric salts.

[00158] Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer. A method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, a-methoxy-a- (trifluoromethyl)phenyl acetate (Jacob III, Peyton. "Resolution of (±)-5-Bromonornicotine. Synthesis of (R)- and (S)-Nornicotine of High Enantiomeric Purity." J. Org. Chem. Vol. 47, No. 21 (1982): pp. 4165-4167), of the racemic mixture, and analyzing the 1H NMR spectrum for the presence of the two atropisomeric enantiomers or diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (WO 96/15111).

[00159] By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (Lough, W.J., Ed. Chiral Liquid Chromatography. New York: Chapman and Hall, 1989; Okamoto, Yoshio, et al. "Optical resolution of dihydropyridine enantiomers by high-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase." J. of Chromatogr. Vol. 513 (1990): pp. 375-378). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.

[00160] BIOLOGICAL EVALUATION

[00161] B-Raf mutant protein 447-717 (V600E) was co-expressed with the chaperone protein Cdc37, complexed with Hsp90 (Roe, S. Mark, et al. "The Mechanism of Hsp90 Regulation by the Protein Kinase-Specific Cochaperone p50cdc37." Cell. Vol. 116 (2004): pp. 87-98; Stancato, LF, et al. "Raf exists in a native heterocomplex with Hsp90 and p50 that can be reconstituted in a cell free system." J. Biol. Chem. 268(29) (1993): pp. 21711-21716).

[00162] Determining the activity of Raf in the sample is possible by a number of direct and indirect detection methods (US 2004/0082014). Activity of human recombinant B-Raf protein may be assessed in vitro by assay of the incorporation of radio labeled phosphate to recombinant MAP kinase (MEK), a known physiologic substrate of B-Raf, according to US 2004/0127496 and WO 03/022840. The activity/inhibition of V600E full-length B-Raf was estimated by measuring the incorporation of radio labeled phosphate from [γ-33Ρ]ΑΤΡ into FSBA-modified wild-type MEK (see Example A).

[00163] ADMINISTRATION AND PHARMACEUTICAL FORMULATIONS

[00164] The compounds described herein may be administered by any convenient route appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal.

[00165] The compounds may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion.

[00166] A typical formulation is prepared by mixing a compound described herein and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound described herein or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[00167] One embodiment includes a pharmaceutical composition comprising a compound of Formulas I, II, III, IV, V, VI, or VII, or a stereoisomer or pharmaceutically acceptable salt thereof. A further embodiment provides a pharmaceutical composition comprising a compound of Formulas I, II, III, IV, V, VI, or VII, or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient. [00168] Another embodiment of the present invention provides a pharmaceutical composition comprising a compound of Formulas I, II, III, IV, V, VI, or VII for use in the treatment of a hyperproliferative disease.

[00169] Another embodiment of the present invention provides a pharmaceutical composition comprising a compound of Formulas I, II, III, IV, V, VI, or VII for use in the treatment of cancer.

[00170] Another embodiment of the present invention provides a pharmaceutical composition comprising a compound of Formulas I, II, III, IV, V, VI, or VII for use in the treatment of kidney disease. A further embodiment of the present invention provides a pharmaceutical composition comprising a compound of Formulas I, II, III, IV, V, VI, or VII for use in the treatment of polycystic kidney disease.

[00171] METHODS OF TREATMENT WITH COMPOUNDS OF THE INVENTION

[00172] The invention includes methods of treating or preventing disease or condition by administering one or more compounds of this invention, or a stereoisomer or pharmaceutically acceptable salt thereof. In one embodiment, a human patient is treated with a compound of Formulas I, II, III, IV, V, VI, or VII, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle in an amount to detectably inhibit B-Raf activity.

[00173] In another embodiment, a human patient is treated with a compound of Formulas I, II, III, IV, V, VI, or VII, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle in an amount to detectably inhibit B-Raf activity.

[00174] In another embodiment of the present invention, a method of treating a hyperproliferative disease in a mammal comprising administering a therapeutically effective amount of the compound of Formulas I, II, III, IV, V, VI, or VII, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, to the mammal is provided.

[00175] In another embodiment of the present invention, a method of treating kidney disease in a mammal comprising administering a therapeutically effective amount of the compound of Formulas I, II, III, IV, V, VI, or VII, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, to the mammal is provided. In a further embodiment, the kidney disease is polycystic kidney disease.

[00176] In another embodiment, a method of treating or preventing cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of Formulas I, II, III, IV, V, VI, or VII, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. The cancer is selected from breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, NSCLC, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin's and leukemia. Another embodiment of the present invention provides the use of a compound of Formulas I, II, III, IV, V, VI, or VII, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

[00177] In another embodiment, a method of treating or preventing cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of Formulas I, II, III, IV, V, VI, or VII, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[00178] Another embodiment of the present invention provides the use of a compound of Formulas I, II, III, IV, V, VI, or VII, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

[00179] Another embodiment of the present invention provides the use of a compound of Formulas I, II, III, IV, V, VI, or VII, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of kidney disease. In a further embodiment, the kidney disease is polycystic kidney disease.

[00180] In another embodiment, a method of preventing or treating cancer, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formulas I, II, III, IV, V, VI, or VII, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds having anti-cancer properties.

[00181] In another embodiment, a method of preventing or treating cancer, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formulas I, II, III, IV, V, VI, or VII, or a stereoisomer or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds having anti-cancer properties.

[00182] In one further embodiment, the cancer is a sarcoma. [00183] In another further embodiment, the cancer is a carcinoma. In one further embodiment, the carcinoma is squamous cell carcinoma. In another further embodiment, the carcinoma is an adenoma or adenocarcinoma.

[00184] In another embodiment, a method of treating or preventing a disease or disorder modulated by B-Raf, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formulas I, II, III, IV, V, VI, or VII, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. Examples of such diseases and disorders include, but are not limited to, cancer. The cancer is selected from breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, NSCLC, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin's and leukemia.

[00185] In another embodiment, a method of treating or preventing a disease or disorder modulated by B-Raf, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formulas I, II, III, IV, V, VI, or VII, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[00186] In another embodiment of the present invention, a method of preventing or treating kidney disease, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formulas I, II, III, IV, V, VI, or VII, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds. In another embodiment of the present invention, a method of preventing or treating polycystic kidney disease, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formulas I, II, III, IV, V, VI, or VII, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, alone or in combination with one or more additional compounds.

[00187] Another embodiment of the present invention provides the use of a compound of Formulas I, II, III, IV, V, VI, or VII, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. The cancer is selected from breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, NSCLC, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, Hodgkin's and leukemia. In a further embodiment, the use of a compound of Formulas I, II, III, IV, V, VI, or VII in the manufacture of a medicament, for use as a B-Raf inhibitor in the treatment of a patient undergoing cancer therapy.

[00188] Another embodiment of the present invention provides the use of a compound of Formulas I, II, III, IV, V, VI, or VII, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.

[00189] Another embodiment of the present invention provides the use of a compound of Formulas I, II, III, IV, V, VI, or VII, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of polycystic kidney disease. In a further embodiment, the kidney disease is polycystic kidney disease.

[00190] Another embodiment of the present invention provides the compounds of

Formulas I, II, III, IV, V, VI, or VII for use in therapy.

[00191] Another embodiment of the present invention provides the compounds of Formulas I, II, III, IV, V, VI, or VII for use in the treatment of a hyperproliferative disease. In a further embodiment, the hyperproliferative disease is cancer (as further defined and may be individually selected from those above).

[00192] Another embodiment of the present invention provides the compounds of Formulas I, II, III, IV, V, VI, or VII for use in the treatment of kidney disease. In a further embodiment, the kidney disease is polycystic kidney disease.

[00193] COMBINATION THERAPY

[00194] The compounds described herein and stereoisomers and pharmaceutically acceptable salts thereof may be employed alone or in combination with other therapeutic agents for treatment. The compounds described herein may be used in combination with one or more additional drugs, for example an anti-hyperproliferative (or anti-cancer) agent that works through action on a different target protein. The second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound described herein, such that they do not adversely affect each other. Such molecules are suitably present in combination in amounts that are effective for the purpose intended. The compounds may be administered together in a unitary pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. Such sequential administration may be close in time or remote in time.

[00195] A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer, regardless of mechanism of action. Chemotherapeutic agents include compounds used in "targeted therapy" and conventional chemotherapy. A number of suitable chemotherapeutic agents to be used as combination therapeutics are contemplated for use in the methods of the present invention. The present invention contemplates, but is not limited to, administration of numerous anticancer agents, such as: agents that induce apoptosis; polynucleotides (e.g., ribozymes); polypeptides (e.g., enzymes); drugs; biological mimetics; alkaloids; alkylating agents^antitumor antibiotics; antimetabolites; hormones; platinum compounds; monoclonal antibodies conjugated with anticancer drugs, toxins, and/or radionuclides; biological response modifiers (e.g., interferons [e.g., IFN-a, etc.] and interleukins [e.g., IL-2, etc.], etc.); adoptive immunotherapy agents; hematopoietic growth factors; agents that induce tumor cell differentiation (e.g., all-trans-retinoic acid, etc.); gene therapy reagents; antisense therapy reagents and nucleotides; tumor vaccines; inhibitors of angiogenesis, and the like.

[00196] Examples of chemotherapeutic agents include Erlotinib (TARCEVA®, Genentech/OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sunitinib (SUTENT®, Pfizer), Letrozole (FEMARA®, Novartis), Imatinib mesylate (GLEEVEC®, Novartis), PTK787/ZK 222584 (Novartis), Oxaliplatin (Eloxatin®, Sanofi), 5-FU (5-fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafarnib (SCH 66336), Sorafenib (NEXAVAR®, Bayer), Irinotecan (CAMPTOSAR®, Pfizer) and Gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomo holino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6- mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE™ (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Illinois), and TAXOTERE® (doxetaxel; Rhone-Poulenc Rorer, Antony, France); chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

[00197] Also included in the definition of "chemotherapeutic agent" are: (i) anti- hormonal agents that act to regulate or inhibit hormone action on tumors such as anti- estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4- hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RTVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Raf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; a topoisomerase 1 inhibitor such as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such as bevacizumab (AVASTIN®, Genentech); (x) PI3k/AKT/mTOR pathway inhibitors, including GDC-0941 (2-( 1 H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin- 1 -ylmethyl)-4- morpholin-4-yl-thieno[3,2-d]pyrimidine), XL-147, GSK690693 and temsirolimus; (xi) Ras/Raf MEK/ERK pathway inhibitors; and (xii) pharmaceutically acceptable salts, acids and derivatives of any of the above.

[00198] Also included in the definition of "chemotherapeutic agent" are therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idee), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).

[00199] Humanized monoclonal antibodies with therapeutic potential as chemotherapeutic agents in combination with the Raf inhibitors of the invention include: alemtuzumab, apolizumab, aselizumab, atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, and visilizumab.

EXAMPLES

[00200] For illustrative purposes, the following Examples are included. However, it is to be understood that these Examples do not limit the invention and are only meant to suggest a method of practicing the invention. Persons skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare a number of other compounds described herein, and alternative methods for preparing the compounds are deemed to be within the scope of this invention. For example, the synthesis of non- exemplified compounds may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds described herein.

[00201] In the Examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and were used without further purification unless otherwise indicated. [00202] The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.

[00203] Column chromatography was done on a Biotage system (Manufacturer: Dyax Corporation) having a silica gel column or on a silica SepPak cartridge (Waters) (unless otherwise stated). 1H NMR spectra were recorded on a Varian instrument operating at 400 MHz. 1H-NMR spectra were obtained as CDC1₃, CD₃OD, D₂0, (CD₃)₂SO, (CD₃)₂CO, C₆D₆, CD₃CN solutions (reported in ppm), using tetramethylsilane (0.00 ppm) or residual solvent (CDC1₃: 7.26 ppm; CD₃OD: 3.31 ppm; D₂0: 4.79 ppm; (CD₃)₂SO: 2.50 ppm; (CD₃)₂CO: 2.05 ppm; C₆D₆: 7.16 ppm; CD₃CN: 1.94 ppm) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).

Example A

B-Raf ICsn Assay Protocol

[00204] Activity of human recombinant B-Raf protein may be assessed in vitro by assay of the incorporation of radio labeled phosphate to recombinant MAP kinase (MEK), a known physiologic substrate of B-Raf, according to US 2004/0127496 and WO 03/022840. Catalytically active human recombinant B-Raf protein is obtained by purification from sf9 insect cells infected with a human B-Raf recombinant baculovirus expression vector.

[00205] The activity/inhibition of V600E full-length B-Raf was estimated by measuring the incorporation of radio labeled phosphate from [γ-³³Ρ] ATP into FSBA-modified wild-type MEK. The 30-μΙ_< assay mixtures contained 25mM Na Pipes, pH 7.2, lOOmM KC1, lOmM MgCl₂, 5mM β-glycerophosphate, ΙΟΟμΜ Na Vanadate, 4μΜ ATP, 500 nCi [γ- ³³P]ATP, Ι μΜ FSBA-MEK and 20nM V600E full-length B-Raf. Incubations were carried out at 22°C in a Costar 3365 plate (Corning). Prior to the assay, the B-Raf and FSBA-MEK were preincubated together in assay buffer at 1.5x (20 μΐ_^ of 30nM and 1.5μΜ, respectively) for 15 minutes, and the assay was initiated by the addition of 10 μΐ, of 10μΜ ATP. Following the 60-minute incubation, the assay mixtures were quenched by the addition of 100 \iL of 25% TCA, the plate was mixed on a rotary shaker for 1 minute, and the product was captured on a Perkin-Elmer GF/B filter plate using a Tomtec Mach III Harvester. After sealing the bottom of the plate, 35 μί_^ of Bio-Safe II (Research Products International) scintillation cocktail were added to each well and the plate was top-sealed and counted in a Topcount NXT (Packard).

[00206] The compounds of Examples 1-49 were tested in the above assay and found to have an IC₅₀ of less than 900 nM. The compounds of Examples 1-14, 17-29, 31-43 and 45- 49 were tested in the above assay and found to have an IC₅₀ of less than 100 nM.

Example B

Methyl 2,6-difluoro-3-(N-(propylsulfonyl)propylsulfonamido^')benzoate

[00207] Step A: A 1 L flask was charged with 2,6-difluoro-3-nitrobenzoic acid (17.0 g, 83.7 mmol) and MeOH (170 mL, 0.5M). The flask was placed in a cold water bath, and an addition funnel charged with a 2M solution of trimethylsilyl ("TMS") diazomethane in hexanes (209 mL, 419 mmol) was attached to the flask. The TMS diazomethane solution was added slowly to the reaction flask over the course of 2 hours. A large excess of reagent was required in order for the reaction to reach completion as determined by the ceased evolution of N₂ upon further addition of reagent. The volatiles were removed in vacuo to afford crude methyl 2,6-difluoro-3-nitrobenzoate as a solid (18.2 g). The material was taken directly to Step B.

[00208] Step B: 10% (wt.) Pd on activated carbon (4.46 g, 4.19 mmol) was added to a 1 L flask charged with methyl 2,6-difluoro-3-nitrobenzoate (18.2 g, 83.8 mmol) under a nitrogen atmosphere. To the flask was added EtOH (350 mL, 0.25 M), and H₂ gas was passed through the mixture for 15 minutes. The reaction mixture was stirred under two H₂ balloons overnight. The balloons were recharged with H₂ gas and the mixture was stirred an additional 4 hours. Upon consumption of the starting material and intermediate hydroxylamine as determined by TLC, N₂ gas was flushed through the reaction mixture. The mixture was then filtered through glass microfibre filter ("GF/F") paper twice. The volatiles were removed to afford crude methyl 3-amino-2,6-difluorobenzoate as an oil (15.66 g). The material was taken directly onto the next step.

[00209] Step C: Propane- 1-sulfonyl chloride (23.46 mL, 209.3 mmol) was slowly added to a solution of methyl 3-amino-2,6-difluorobenzoate (15.66 g, 83.7 mmol) and triethylamine (35.00 mL, 251.1 mmol) in CH₂C1₂ (175 mL, 0.5M) maintained in a cool water bath. The reaction mixture was stirred for 1 hour at room temperature. Water (300 mL) was added and the organic layer was separated, washed with water (2 X 300 mL) and brine (200 mL), then dried (Na₂S04), filtered and concentrated to an oil. The crude product was purified by column chromatography, eluting with 15% ethyl acetate ("EtOAc")/hexane. The isolated fractions were triturated with hexanes to afford methyl 2,6-difluoro-3-(N- (propylsulfonyl)propylsulfonamido)benzoate as a solid (24.4 g, 73% yield for 3 steps). 1H NMR (400 MHz, CDC1₃) δ 7.52-7.45 (m, 1H), 7.08-7.02 (m, 1H), 3.97 (s, 3H), 3.68-3.59 (m, 2H), 3.53-3.45 (m, 2H), 2.02-1.89 (m, 4H), 1.10 (t, J = 7.4 Hz, 6H). m/z (APCI-neg) M- (S0₂Pr) = 292.2.

Example C

2,6-Difluoro-3-(propylsulfonamido)benzoic acid

[00210] A IN aqueous NaOH solution (150 mL, 150 mmol) was added to a solution of methyl 2,6-difluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate (20.0 g, 50.1 mmol) in 4:1 THF/MeOH (250 mL, 0.2M). The reaction mixture was stirred at room temperature overnight. The majority of the organic solvents were removed in vacuo (water bath temperature 35°C). IN HC1 (150 mL) was slowly added to the mixture, and the resulting solid was filtered and rinsed with water (4 X 50 mL). The material was washed with Et₂0 (4 X 15 mL) to give 2,6-difluoro-3-(propylsulfonamido)benzoic acid as a solid (10.7 g, 77% yield). 1H NMR (400 MHz, (CD₃)₂SO) δ 9.74 (s, 1H), 7.57-7.50 (m, 1H), 7.23-7.17 (m, 1H), 3.11-3.06 (m, 2H), 1.79-1.69 (m, 2H), 0.98 (t, J - 7.4 Hz, 3H). m/z (APCI-neg) M-l = 278.0.

Example D

2,6-Difluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoic acid

[00211] Propane- 1-sulfonyl chloride (1.225 mL, 10.92 mmol) was added to a mixture of 3-amino-2,6-difluorobenzoic acid (0.573 g, 3.310 mmol), triethylamine (2.030 mL, 14.56 mmol) and CH₂C1₂ (17 mL, 0.2M) cooled to 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was then partitioned between saturated NaHC0₃ (100 mL) and ethyl acetate (75 mL). The aqueous layer was washed with ethyl acetate (50 mL) and then acidified with concentrated HC1 to a pH of about 1. The acidified aqueous layer was extracted with ethyl acetate (2 x 50 mL), and the combined ethyl acetate extracts were dried (over Na₂S0₄), filtered and concentrated. The resulting residue was triturated with hexanes to afford 2,6-difluoro-3-(N-(propylsulfonyl)propyl- sulfonamido)benzoic acid as a solid (0.948 g, 74% yield). 1H NMR (400 MHz, (CD₃)₂SO) δ 7.90-7.84 (m, 1H), 7.39-7.34 (m, 1H), 3.73-3.58 (m, 4H), 1.88-1.74 (m, 4H), 1.01 (t, J = 7.5 Hz, 6H). m/z (APCI-neg) M-(S0₂Pr) = 278.1.

Example E

2-Chloro-6-fluoro-3 -(propylsulfonamido)benzoic acid

[00212] Step A: Into a 20-L 4-neck round flask was placed a solution of 2-chloro-4- fluorobenzenamine (1300 g, 8.82 mol, 1.00 equiv, 99%) in toluene (10 L), 4- methylbenzenesulfonic acid (3.1 g, 17.84 mmol, 99%), and hexane-2,5-dione (1222.5 g, 10.62 mol, 1.20 equiv, 99%). The resulting solution was heated to reflux for 1 hour in an oil bath and cooled. The pH value of the solution was adjusted to 8 with sodium carbonate (1 mol/L). The resulting mixture was washed with water (5000 mL) and concentrated under vacuum. The crude product was purified by distillation and the fraction was collected at 140°C to afford l-(2-chloro-4-fluorophenyl)-2,5-dimethyl-lH-pyrrole as a solid (1700 g, yield: 85%).

[00213] Step B: Into a 5000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of l-(2-chloro-4-fluorophenyl)- 2,5-dimethyl-lH-pyrrole (390 g, 1.65 mol, 1.00 equiv, 95%) in tetrahydrofuran (2000 mL). The reaction vessel was cooled to -78°C. n-BuLi (800 mL, 1.10 equiv, 2.5%) was added dropwise with stirring to the reaction vessel over 80 minutes, and methyl carbonochloridate (215.5 g, 2.27 mol, 1.20 equiv, 99%) was added dropwise with stirring over 90 minutes. The reaction solution was further stirred for 60 minutes at -78°C and quenched by the addition of NH₄Cl/water (1000 mL). The resulting solution was extracted with ethyl acetate (1500 mL). The organic layers were combined, washed with water (1500 mL) and aqueous sodium chloride (1500 mL), dried over anhydrous magnesium sulfate, and concentrated under vacuum to afford methyl 2-chloro-3-(2,5-dimethyl-lH-pyrrol-l-yl)-6-fluorobenzoate as an oil (crude, 566.7 g).

[00214] Step C: A solution of methyl 2-chloro-3-(2,5-dimethyl-lH-pyrrol-l-yl)-6- fluorobenzoate (1500 g, 5.05 mol, 1.00 equiv, 95%) in ethanol/H₂0 (7500/2500 mL), NH₂OH-HCl (5520 g, 79.20 mol, 15.00 equiv, 99%), and triethylamine (2140 g, 20.98 mol, 4.00 equiv, 99%) was placed into five 5000-mL 4-neck round-bottom flasks. The resulting solution was refluxed for 18 hours in an oil bath, cooled to room temperature, concentrated, and extracted with ethyl acetate (3 X 3000 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column eluting with PE:EA (20:1-10:1) to afford methyl 3-amino-2-chloro- 6-fluorobenzoate as an oil (980 g, yield: 95%).

[00215] Step D: A solution of methyl 3-amino-2-chloro-6-fluorobenzoate (980 g, 4.76 mol, 1.00 equiv, 99%) in dichloromethane (8000 mL) was placed into four 5000-mL 4-neck round-bottom flasks. Triethylamine (1454 g, 14.25 mol, 3.00 equiv, 99%) was added dropwise to this reaction vessel with stirring at 0°C over 80 minutes followed by the addition of propane- 1-sulfonyl chloride (1725 g, 11.94 mol, 2.50 equiv, 99%). The resulting solution was stirred at room temperature for 2 hours, diluted with water (1000 mL). The organic layer was washed with hydrogen chloride (1000 mL) and water (1000 mL), dried over sodium sulfate, and concentrated to afford methyl 2-chloro-6-fluoro-3-(propylsulfonamido)benzoate as a solid (1500 g, 97%).

[00216] Step E: A solution of methyl 2-chloro-6-fluoro-3-

(propylsulfonamido)benzoate (1500 g, 4.61 mol, 1.00 equiv, 95%) in tetrahydrofuran/H₂0 (3000/3000 mL) and potassium hydroxide (1000 g, 17.68 mol, 4.50 equiv, 99%) was placed into a 10000-mL 4-necked round-bottom flask. The resulting solution was refluxed for 2 hours, cooled to room temperature and extracted with ethyl acetate (3 X 2000 mL). The aqueous layers were combined, and the pH was adjusted to 2 with hydrogen chloride (2 mol/L). The resulting solution was extracted with dichloromethane (2 X 3000 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated to afford 2-chloro-6-fluoro-3-(propylsulfonamido)benzoic acid as a solid (517.5 g, yield: 37%). (ES, m/z): [M+H]⁺ 296. 1H NMR (400 MHz, CDC1₃): δ 1.058-1.096 (3H, m, J = 15.2Hz), 1.856-1.933 (2H, m, J = 30.8 Hz), 3.073-3.112 (2H, m, J = 15.6 Hz); 6.811 (1H, s), 7.156- 7.199 (1H, d, J= 17.2 Hz), 7.827-7.863 (1H, d, J= 14.4Hz).

Example F

6-Chloro-2-fluoro-3 -(^'propylsulfonarnido)benzoic acid

[00217] Step A: A flame dried flask equipped with a stir bar and rubber septum was charged with 4-chloro-2-fluoroaniline (5.00 g, 34.35 mmol) and anhydrous THF (170 mL). This solution was chilled to -78°C, and n-BuLi (14.7 mL, 1.07 eq. of 2.5M solution in hexanes) was then added over a 15 minute period. This mixture was stirred at -78°C for 20 minutes, and then a THF solution (25 mL) of l,2-bis(chlorodimethylsilyl)ethane (7.76 g, 1.05 eq.) was added slowly (over a 10 minute period) to the reaction mixture. This was stirred for 1 hour, and then 2.5M n-BuLi in hexanes (15.11 mL, 1.1 eq.) was added slowly. After allowing the mixture to warm to room temperature for one hour, the mixture was chilled back to -78°C. A third allotment of n-BuLi (15.66 mL, 1.14 eq.) was added slowly, and the mixture was stirred at -78°C for 75 minutes. Benzyl chloroformate (7.40 g, 1.2 eq.) was then added slowly, and the mixture was stirred at -78°C for one hour. The cooling bath was then removed. The mixture was allowed to warm for 30 minutes and then quenched with water (70 mL) and concentrated HC1 (25 mL). The mixture was allowed to continue to warm to room temperature. The mixture was then extracted with EtOAc. The extracts were washed twice with a saturated Na₂HC0₃ solution, once with water, dried over sodium sulfate and concentrated. The resulting residue was flashed on a 65 Biotage (30% ethyl acetate/hexane) to produce benzyl 3-amino-6-chloro-2-fluorobenzoate (4.3 g, 45%) as an oil.

1H NMR ((CD₃)₂SO, 400 MHz) δ 7.37-7.48 (m, 5H), 7.07 (dd, 1H, J = 8, 2), 6.87 (t, 1H, J = 8), 5.61 (br s, 2H), 5.40 (s, 2H).

[00218] Step B: Benzyl 3-amino-6-chloro-2-fluorobenzoate (4.3 g, 15.37 mmol) was dissolved in dry dichloromethane (270 mL). Triethylamine (5.36 mL, 2.5 eq.) was added, and the mixture was chilled to 0°C. Propane- 1-sulfonyl chloride (3.63 mL, 32.3 mmol, 2.1 eq.) was then added via syringe, and a precipitate resulted. Once the addition was complete, the mixture was allowed to warm to room temperature, and the starting material was consumed as determined by TLC (3:1 hexanerethyl acetate). The mixture was then diluted with dichloromethane (200 mL), washed with 2M aqueous HC1 (2 X 100 mL), saturated Na₂HC0₃ solution, dried over sodium sulfate and concentrated. The resulting residue was purified on a 65 Biotage chromatography system (40% ethyl acetate/hexane) to produce benzyl 6-cliloro-2-fluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate (5.5 g, 72%») as an oil that slowly solidified upon standing. NMR (CDC1₃, 400 MHz) δ 7.28-7.45 (m, 7H), 5.42 (s, 2H), 3.58-3.66 (m, 2H), 3.43-3.52 (m, 2H), 1.08 (t, 6H, J=8).

[00219] Step C: Benzyl 6-chloro-2-fluoro-3-(N-(propylsulfonyl)propylsulfonamido) benzoate (5.4 g, 10.98 mmol) was dissolved in THF (100 mL) and 1M aqueous KOH (100 mL). This mixture was refluxed for 16 hours and then allowed to cool to room temperature. The mixture was then acidified to a pH of 2 with 2M aqueous HCl and extracted with EtOAc (2 X). The extracts were washed with water, dried over sodium sulfate and concentrated to a solid that was triturated with hexanes/ether to give 6-chloro-2-fluoro-3- (propylsulfonamido)benzoic acid (2.2 g, 68%) as a solid. 1H NMR ((CD₃)₂SO, 400 MHz) δ 9.93 (s, 1H), 7.49 (t, 1H, J=8), 7.38 (dd, 1H, J = 8, 2), 3.11-3.16 (m, 2H), 1.68-1.78 (m, 2H), 0.97 (t, 3H, J = 8).

Exam le G

N-(3 - Amino-2,4-difluorophenyl)propane- 1 -sulfonamide

[00220] Triethylamine (4.68 mL, 33.59 mmol) and diphenylphosphonic azide (3.73 mL, 16.79 mmol) were added to a solution of 2,6-difluoro-3-(propylsulfonamido)benzoic acid (4.078 g, 14.6 mmol) in THF (60 mL). The reaction mixture was stirred at room temperature for 3 hours and then warmed to 80°C for 2 hours. Water (10 mL) was added, and the mixture was stirred at 80°C for 15 hours. The reaction mixture was diluted with EtOAc (300 mL), and the organic layer was washed with saturated aqueous NaHC0₃ solution and brine. The solvent was removed under reduced pressure, and the residual purified via silica gel column chromatography eluting with 30/70 EtOAc/hexane to obtain 2.03 g (55%) of the title compound. 1H NMR (400 MHz, DMSO-d₆) δ 9.32 (s, 1H), 6.90-^.80 (m, 1H), 6.51 (td, J=8.7, 5.5, 1H), 5.28 (s, 2H), 3.05-2.96 (m, 2H), 1.82-1.64 (m, 2H), 1.01-0.90 (m, 3H). LC/MS: w/z 251.1 [M+l].

Exam le H

N-(3 - Amino-4-chloro-2-fluorophenyl)propane- 1 -sulfonamide

[00221] Triethylamine (1.84 mL, 13.2 mmol) and diphenylphosphonic azide (1.43 mL, 6.61 mmol) were added to a solution of 6-chloro-2-fluoro-3-(propylsulfonamido)benzoic acid (1.70 g, 5.75 mmol) in THF (23 mL). The reaction mixture was stirred at room temperature for 1 hour, warmed to 70°C and stirred for 1 hour. Water (6 mL) was added, after which the reaction mixture was stirred again at 70°C for 3 hours. The mixture was cooled to room temperature, ethyl acetate was added, and the layers were separated. The organic phase was dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography using 0-50% EtO Ac/heptane gradient to afford N-(3- amino-4-chloro-2-fluorophenyl)propane-l -sulfonamide (1.01 g, 66%) as a solid. 1H NMR (500 MHz, (CD₃)₂SO) δ 9.54 (s, 1H), 7.02 (d, 1H), 6.58 (t, 1H), 5.50 (s, 2H), 3.09-2.95 (t, 2H), 1.81-1.64 (m, 2H), 0.96 (t, 3H). LC/MS: m/z 267.1 [M+l].

Example I

N-(3-Amino-2-chloro-4-fluorophenvnpropane-l-sulfonamide

[00222] The compound was prepared using the procedure described in Example G using 2-chloro-6-fluoro-3-(propylsulfonamido)benzoic acid instead 2,6-difluoro-3 -(propyl - sulfonamido)benzoic acid as starting material. 1H NMR (400 MHz, (CD₃)₂SO) δ 9.20 (s, 1H), 7.28-6.99 (m, 1H), 6.63 (td, J=8.7, 5.5, 1H), 5.45 (s, 2H), 3.07-2.99 (m, 2H), 1.88-1.69 (m, 2H), 1.03-0.95 (m, 3H). LC/MS: m/z 267.1 [M+l].

Exam le J

N-(3-Amino-2,4-difluorophenyl)ethanesulfonamide

[00223] Triethylamine (8.02 mL, 57.61 mmol) and diphenylphosphonic azide (6.21 mL, 28.81 mmol) were added to a solution of 2,6-difluoro-3-(propylsulfonamido)benzoic acid (6.643 g, 25.1 mmol) in THF (50 mL). The reaction mixture was stirred at room temperature for 3 hours and then warmed to 80°C for 2 hours. Water (15 mL, 830 mmol) was added, and the mixture stirred at 80°C for 15 hours. The reaction mixture was diluted with EtOAc (500 mL), and the organic layer was washed with saturated aqueous NaHC0₃ solution and brine. The solvent was removed under reduced pressure, and the residual purified via silica gel column chromatography eluting with EtOAc/hexane (30/70) to obtain 3.03 g (50%) of the title compound. 1H NMR (400 MHz, (CD₃)₂SO) δ 9.37 (d, J=29.6, 1H), 6.86 (dd, J=10.7, 9.1, 1.9, 1H), 6.52 (td, J=8.7, 5.5, 1H), 5.28 (s, 2H), 3.03 (q, J=7.3, 2H), 1.25 (td, J=7.3, 2.5, 3H). LC/MS: m/z 237.1 [M+l].

Exam le K

N-(3-Amino-4-chloro-2-fluorophenyl ethanesulfonamide

[00224] Triethylamine (9.10 mL, 65.3 mmol) and diphenylphosphonic azide (7.04 mL, 32.7 mmol) was added to a solution of 6-chloro-3-(ethylsulfonamido)-2-fluorobenzoic acid (8.00 g, 28.4 mmol) in THF (115 mL). The reaction mixture was stirred at room temperature for 4 hours, warmed to 70°C and stirred for 2 hours. Water (27 mL) was then added, after which the reaction mixture was stirred again at 70°C for 16 hours. The mixture was cooled to room temperature, ethyl acetate and a saturated solution of NaHC0₃ were added, and the layers were separated. The organic phase was dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography using 30-50% EtOAc/heptane gradient to afford N-(3-amino-4-chloro-2- fluorophenyl)ethanesulfonamide (4.24 g, 59%) as a solid. 1H NMR (500 MHz, (CD₃)₂SO) δ 9.48 (s, 1H), 7.02 (dd, J=8.8, 1.7 Hz, 1H), 6.59 (t, J=8.3 Hz, 1H), 5.44 (s, 2H), 3.07 (q, J=7.3 Hz, 2H), 1.24 (t, J=7.3 Hz, 3H). LC/MS: m/z 253.2 [M+l].

Exam le L

N-(3-Amino-2-chloro-4-fluorophenyl)ethanesulfonamide

[00225] 2-Chloro-6-fluoro-3-(ethylsulfonamido)benzoic acid (3.3 g, 12.0 mmol) was treated with thionyl chloride (21.0 mL, 0.29 mmol) and heated at reflux for 15 hours. The reaction mixture was concentrated and then azeotrophed with toluene (2 X 20 mL). The residue was treated with a solution of sodium azide (3.1 g, 48.0 mmol) dissolved in water (20 mL) and acetone (20 mL). After stirring at room temperature for 1 hour, the intermediate acyl azide was extracted into ethyl acetate (2 X 25 mL), dried with magnesium sulfate and concentrated. The residue was dissolved in dioxane (40 mL) and water (5 mL) and heated to reflux for 3 hours. After cooling to room temperature, the product was extracted into methylene chloride (2 X 25 mL), dried with magnesium sulfate and concentrated. The residue was purified by flash silica gel chromatography (2-30% isopropanol in methylene chloride) to afford N-(3-amino-2-chloro-4-fluorophenyl)ethanesulfonamide (2.0 g, 66%). 1H NMR (400 MHz, (CD₃)₂SO) 6 9.15 (s, 1H), 7.02 (dd, J= 10.7, 8.8 Hz, 1H), 6.64 (dd, J= 8.8, 5.1 Hz, 1H), 5.45 (s, 2H), 3.06 (q, J = 7.3 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H). LC/MS: m/z 253.0 [M+l].

Example M

N-(3 - Amino-2-chloro-4-fluorophenyl)- 1 -cyclopropylmethanesulfonamide

[00226] Step A: Cyclopropylmethanesulfonyl chloride (4.74 g, 30.6 mmol) was added dropwise to a solution of methyl 3-amino-2-chloro-6-fluorobenzoate (2.97 g, 14.6 mmol) in THF (26 mL) and triethylamine (6.10 mL, 43.8 mmol) at 0°C. The reaction mixture was stirred at 0°C for 90 minutes, after which 8N NaOH (18.2 mL, 140 mmol) was added. The reaction mixture was then warmed up at 40°C and stirred for 16 hours. The volatiles were removed in vacuo, and the mixture acidified with concentrated HC1 at 0°C to pH 1. The acidified mixture was extracted with ethyl acetate twice. The organic phases were combined, dried with sodium sulfate, filtered and concentrated in vacuo to obtain crude 2-chloro-3- (cyclopropylmethylsulfonamido)-6-fluorobenzoic acid, which was used directly in the next step without further purification.

[00227] Step B: Triethylamine (2.05 mL, 14.7 mmol) was added to a solution of 2- chloro-3-(cyclopropylmethylsulfonamido)-6-fluorobenzoic acid (4.11 g, 13.4 mmol) in 1,4- dioxane (30 mL), followed by diphenylphosphonic azide (3.12 mL, 14.0 mmol) at room temperature. The reaction was stirred at room temperature for 4 hours, and the resulting mixture added dropwise, via an addition funnel, over 15 minutes in a round-bottom flask containing 1,4-dioxane (16 mL) and water (1.20 mL, 66.8 mmol) at 95°C. The reaction mixture was stirred at this temperature for 16 hours. Half of the reaction mixture was concentrated in vacuo, then the rest of the solution was diluted with ethyl acetate and a saturated solution of NaHC0₃. The layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The organic phases were combined, dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to afford N-(3-amino-2-chloro-4-fluorophenyl)-l- cyclopropylmethanesulfonamide (2.05 g, 55%). m/z (ES-MS) M+l = 279.2. 1H NMR (500 MHz, (CD₃)₂SO) δ 9.07 (s, 1H), 7.01 (dd, J = 10.7, 8.9 Hz, 1H), 6.66 (dd, J = 8.8, 5.1 Hz, 1H), 5.43 (s, 2H), 3.04 (d, J = 7.1 Hz, 2H), 1.12 - 0.99 (m, 1H), 0.59 - 0.52 (m, 2H), 0.36 - 0.30 (m, 2H).

Example N

N-(3 - Amino-2-chloro-4-fluorophenyl)-2-methylpropane- 1 -sulfonamide

[00228] Step A: 2-Methylpropane-l-sulfonyl chloride (4.80 g, 30.6 mmol) was added dropwise to a solution of methyl 3-amino-2-chloro-6-fluorobenzoate (2.97 g, 14.6 mmol) in THF (20 mL) and triethylamine (6.10 mL, 43.8 mmol) at 0°C. The reaction mixture was stirred at 0°C for 90 minutes, after which 8N aqueous NaOH (18.2 mL, 140 mmol) was added. The reaction mixture was warmed up at 40°C and stirred for 16 hours. The volatiles were then removed in vacuo, and the mixture was acidified with concentrated HCl at 0°C to pH 1. The acidified mixture was extracted with ethyl acetate twice. The organic phases were combined, dried with sodium sulfate, filtered and concentrated in vacuo to obtain crude 2- chloro-6-fluoro-3-(2-methylpropylsulfonamido)benzoic acid, which was used directly in the next step without further purification.

[00229] Step B: N-(3-Amino-2-chloro-4-fluorophenyl)-2-methylpropane-l- sulfonamide was prepared according to the general procedure for Example A, Step B, substituting 2-chloro-6-fluoro-3-(2-methylpropylsulfonamido)benzoic acid for 2-chloro-3- (cyclopropylmethylsulfonamido)-6-fluorobenzoic acid, m/z (ES-MS) M+l = 281.2. 1H NMR (500 MHz, (CD₃)₂SO) δ 9.14 (s, 1H), 7.02 (dd, 7 = 10.7, 8.9 Hz, 1H), 6.64 (dd, J = 8.8, 5.1 Hz, 1H), 5.44 (s, 2H), 2.96 (d, J= 6.4 Hz, 2H), 2.20-2.10 (m, 1H), 1.01 (d, J= 6.7 Hz, 6H).

Example O

N-(3-Amino-2,5-difluorophenyl)propane-l-sulfonamide

[00230] Propane- 1-sulfonyl chloride (1.867 mL, 16.65 mmol) at 0°C was added to a solution of 2,5-difluorobenzene-l,3-diamine (2.00 g, 13.9 mmol) (described in Moilliet, J. S. et al., EP415595, 1989, 4) in THF (40 mL) and pyridine (1.571 mL, 19.43 mmol). The reaction mixture was stirred at 50°C for 90 minutes, and DCM and a saturated solution of NaHC0₃ were then added. The layers were separated, and the aqueous layer was extracted twice with DCM. The organic layers were combined, dried with sodium sulfate, filtered and concentrated in vacuo. The crude mixture was re-submitted to exact same reaction conditions, and the reaction was stirred at 55°C for 16 hours. Ethyl acetate and a saturated solution of NaHC0₃ were then added. The layers were separated, and the aqueous layer extracted twice with ethyl acetate. The organic layers were combined, dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to afford N-(3-amino-2,5-difluorophenyl)propane-l -sulfonamide (485 mg, 14%).

Example P

N-(3-Amino-2,4-difluorophenyl)-2-methylpropane- 1 -sulfonamide

[00231] Step A: 2,6-Difluoro-3-(2-methylpropylsulfonamido)benzoic acid was prepared according to the general procedure for Example N, Step A, substituting methyl 3- amino-2,6-difluorobenzoate for methyl 3-amino-2-chloro-6-fluorobenzoate.

[00232] Step B: N-(3-Amino-2,4-difluorophenyl)-2-methylpropane-l -sulfonamide was prepared according to the general procedure for Example M, Step B, substituting 2,6- difluoro-3-(2-methylpropylsulfonamido)benzoic acid for 2-chloro-3-(cyclopropylmethyl- sulfonamido)-6-fluorobenzoic acid, m/z (ES-MS) M+l = 265.2. 1H NMR (400 MHz, (CD₃)₂SO) δ 9.36 (s, 1H), 6.86 (t, J= 9.8 Hz, 1H), 6.55-6.47 (m, 1H), 5.32 (s, 2H), 2.93 (d, J = 6.4 Hz, 2H), 2.21-2.10 m, 1H), 1.01 (d, J= 6.7 Hz, 6H).

Example Q

N-(3 - Amino-2,4-difluorophenylV 1 -cvclopropylmethanesulfonamide

[00233] Step A: 3-(Cyclopropylmethylsulfonamido)-2,6-difluorobenzoic acid was prepared according to the general procedure for Example M, Step A, substituting methyl 3- amino-2,6-difluorobenzoate for methyl 3-amino-2-chloro-6-fluorobenzoate.

[00234] Step B: N-(3-Amino-2,4-difluorophenyl)-l -cyclopropylmethanesulfonamide was prepared according to the general procedure for Example M, Step B, substituting 3- (cyclopropylmethylsulfonamido)-2,6-difluorobenzoic acid for 2-chloro-3-(cyclopropyl- methylsulfonamido)-6-fluorobenzoic acid, m/z (ES-MS) M+l = 263.2. 1H NMR (400 MHz, (CD₃)₂SO) δ 9.37 (s, 1H), 6.84 (t, J= 9.8 Hz, 1H), 6.57-6.50 (m, 1H), 5.30 (s, 2H), 3.01 (d, J = 7.1 Hz, 2H), 1.11 - 0.98 (m, 1H), 0.59 - 0.51 (m, 2H), 0.35 - 0.27 (m, 2H).

Example R

N-(3-Amino-5-chloro-2-fluorophenyl)propane-l-sulfonamide

[00235] Step A: Fuming nitric acid (4.98 mL, 119 mmol) was added to a solution of methyl 5-chloro-2-fluorobenzoate (16.0 g, 84.8 mmol) in sulfuric acid (100 mL) at 0°C. The reaction mixture was stirred at room temperature for 3 hours, poured into ice/water, and the resulting precipitate was filtered. The obtained solid was purified by flash chromatography to afford methyl 5-chloro-2-fluoro-3-nitrobenzoate (6.78 g, 30%), contaminated with 10% of an undesired regioisomer.

[00236] Step B: A round-bottom flask was charged with 5-chloro-2-fluoro-3- nitrobenzoate (6.78 g, 29.0 mmol), iron (16.2 g, 290 mmol), ammonium chloride (5.43 g, 102 mmol), ethanol (100 mL) and water (30 mL). The reaction mixture was stirred at 85°C for 2 hours and then cooled to room temperature. The mixture was diluted with ethyl acetate and a saturated solution of NaHC0₃, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to afford methyl 3-amino-5-chloro-2-fluorobenzoate (3.7 g, 63%), contaminated with 10% of an undesired regioisomer.

[00237] Step C: Propane- 1-sulfonyl chloride (3.12 mL, 27.8 mmol) was added dropwise to a solution of methyl 3-amino-5-chloro-2-fluorobenzoate (2.71 g, 13.3 mmol) in THF (25 mL) and triethylamine (5.54 mL, 39.8 mmol) at 0°C. The reaction mixture was stirred at 0°C for 90 minutes, after which 8N aqueous NaOH (16.6 mL, 130 mmol) was added. The reaction mixture was then warmed up at 40°C and stirred for 16 hours. The volatiles were removed in vacuo, and the mixture was then acidified with concentrated HCl at 0°C to pH 1. The acidified mixture was extracted with ethyl acetate twice. The organic layers were combined, dried with sodium sulfate, filtered and concentrated in vacuo to obtain crude 5-chloro-2-fluoro-3-(propylsulfonamido)benzoic acid, which was used in the next step without further purification. [00238] Step D: N-(3-Amino-5-chloro-2-fluorophenyl)propane-l -sulfonamide was prepared according to the general procedure for Example M, Step B, substituting 5-chloro-2- fluoro-3-(propylsulfonamido)benzoic acid for 2-chloro-3-(cyclopropylmethylsulfonamido)-6- fluorobenzoic acid, m/z (ES-MS) M+l = 267.0. 1H NMR (400 MHz, (CD₃)₂SO) δ 9.58 (s, 1H), 6.59 (dd, J = 7.1, 2.6 Hz, 1H), 6.53 (dd, J= 5.9, 2.6 Hz, 1H), 5.56 (s, 2H), 3.11 - 3.03 (m, 2H), 1.78 - 1.65 (m, 2H), 0.97 (t, J= 7.4 Hz, 3H).

Example S

N-(3-Arnmo-4-c oro-2-fluorophenyl)-2-methylpropane-l-sulfonamide

[00239] Step A: Benzyl 6-chloro-2-fluoro-3-(N-(isobutylsulfonyl)-2-methylpropyl- sulfonamido)benzoate was prepared according to the general procedure for Example F, Step B, substituting 2-methylpropane-l-sulfonyl chloride for propane- 1-sulfonyl chloride.

[00240] Step B: 6-Chloro-2-fluoro-3-(2-methylpropylsulfonamido)benzoic acid was prepared according to the general procedure for Example F, Step C, substituting benzyl 6- cUoro-2-fluoro-3-(N-(isobutylsulfonyl)-2-methylpropylsulfonamido)benzoate for benzyl 6- chloro-2-fluoro-3 -(N-(propylsulfonyl)propylsulfonamido) benzoate.

[00241] Step C: N-(3-Amino-4-chloro-2-fluorophenyl)-2-methylpropane-l- sulfonamide was prepared according to the general procedure for Example M, Step B, substituting 6-chloro-2-fluoro-3-(2-methylpropylsulfonamido)benzoic acid for 2-chloro-3- (cyclopropylmethylsulfonamido)-6-fluorobenzoic acid, m/z (ES-MS) M+l = 281.2. 1H NMR (400 MHz, (CD₃)₂SO) δ 9.50 (s, 1H), 7.02 (dd, J = 8.8, 1.8 Hz, 1H), 6.62 - 6.54 (m, 1H), 5.45 (s, 2H), 2.97 (d, J- 6.4 Hz, 2H), 2.21-2.10 (m, 1H), 1.01 (d, J= 6.7 Hz, 6H).

Example T

N-(3-Amino-2-chloro-5-fluorophenvDpropane- 1 -sulfonamide

[00242] Propane- 1-sulfonyl chloride (1.41 mL, 12.6 mmol) at 0°C was added to a solution of 2-chloro-5-fluorobenzene-l,3-diamine (1.01 g, 6.29 mmol; 70% purity) (described in Frutos, R. P. et al., US 2006/0258888, 2006, 3) in DCM (30 mL) and triethylamine (1.93 mL, 13.8 mmol). The reaction mixture was stirred at room temperature for 1 hour. An aqueous saturated solution of NaHC0₃ and ethyl acetate were added, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic phases were combined, dried with sodium sulfate, filtered and concentrated in vacuo. The crude mixture was dissolved in tetrahydrofuran (15 mL) and methanol (5 mL), and then 1.0M of sodium hydroxide in water (6.3 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes. An aqueous saturated solution of NaHC0₃ and ethyl acetate were added, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to afford N- (3-amino-2-chloro-5-fluorophenyl)propane-l-sulfonamide (0.17 g, 7%). m/z (ES-MS) M+l = 281.2.

Exam le U

N-(3-Amino-2,4-dichlorophenyl)propane- 1 -sulfonamide

[00243] Step A: 2,6-Dichloro-3-nitrobenzoic acid (2.13 g, 9.03 mmol) was dissolved in 2:1 THF:saturated aqueous N¾C1 and cooled to 0°C. The mixture was treated with zinc (11.8 g, 181 mmol) and then allowed to warm to ambient temperature and stir for 24 hours. The reaction mixture was filtered through GF/F paper while rinsing with THF. The mixture was acidified to a pH of 1 using 1.0 M HC1 and extracted with 15% 2-propanol/DCM (3 X). The extracts were washed with water and brine, dried over sodium sulfate and concentrated to afford 3-amino-2,6-dichlorobenzoic acid (1.40 g, 6.82 mmol, 75.5% yield). MS (APCI- neg) w/z =203.6 (M-H).

[00244] Step B: 3-Amino-2,6-dichlorobenzoic acid (1.40 g, 6.82 mmol) was dissolved in dry dichloromethane (66.7 mL). Triethylamine (4.09 mL, 29.4 mmol) was added, and the mixture was chilled to 0°C. Propane- 1-sulfonyl chloride (2.48 mL, 22 mmol) was then added using a syringe. When the addition was complete, the mixture was allowed to warm to ambient temperature and stir for 1 hour. The mixture was concentrated in vacuo and diluted with diethyl ether. The mixture was washed with 0.25 M NaOH (80 mL), and the aqueous layer acidified to a pH of 1 using 1.0M HC1. The aqueous layer was extracted with 15% 2- propano DCM (2 X 300 mL). The organic layer was collected, dried over sodium sulfate, and concentrated to afford 2,6-dichloro-3-(propylsulfonamido)benzoic acid (1.55 g, 4.96 mmol, 74.4% yield). 1H NMR (400 MHz, (CD₃)₂SO) δ 9.77-9.75 (s, IH), 7.84-7.80 (d, IH), 7.71-7.68 (d, IH), 3.82-3.72 (m, 2H), 1.89-1.70 (m, 2H), 1.05-1.03 (m, 3H).

[00245] Step C: Triethylamine (2.863 mL, 20.5 mmol) and diphenylphosphonic azide (2.282 mL, 10.2 mmol) was added to a solution of 2,6-dichloro-3- (propylsulfonamido)benzoic acid (2.788 g, 8.93 mmol in THF (40 mL). The reaction mixture was stirred for 6 hours at room temperature. Then water (8 mL, 400 mmol) was added, and the reaction mixture was heated under reflux overnight. Ethyl acetate (300 mL) was added, followed by washing with saturated aqueous NaHC0₃ solution and brine. The solvent was removed under reduced pressure, and the crude product purified via silica gel flash chromatography using ethyl acetate/hexane (1 :1) as eluent to yield N-(3-amino-2,4- dichlorophenyl)propane-l -sulfonamide (834 mg, 33%). 1H NMR (500 MHz, (CD₃)₂SO) δ 9.24 (s, 1H), 7.20 (d, J - 8.7 Hz, 1H), 6.71 (d, J= 8.7 Hz, 1H), 5.55 (s, 2H), 3.13 - 2.92 (m, 2H), 1.73 (dd, J= 15.2, 7.6 Hz, 2H), 0.96 (t, J= 7.4 Hz, 3H). LC-MS [M+l] mJz 284.1.

Example V

2,6-Difluoro-3-(3-fluoropropylsulfonamido)benzoic acid

[00246] Step A: Methyl 2,6-difluoro-3-(N-(3-fluoropropylsulfonyl)-3-fluoropropyl- sulfonamido)benzoate was prepared according to the general procedure described in Example B, Step C, substituting 3-fluoropropyl sulfonyl chloride for propane- 1-sulfonyl chloride. 1H NMR (400 MHz, (CD₃)₂SO) δ 8.05-7.99 (m, 1H), 7.44 (t, 1H), 4.62 (t, 2H), 4.50 (t, 2H), 3.93 (s, 3H), 3.89-3.74 (m, 4H), 2.26-2.11 (m, 4H).

[00247] Step B: 2,6-Difluoro-3-(3-fluoropropylsulfonamido)benzoic acid was prepared according to the general procedure in Example C, substituting methyl 2,6-difluoro- 3-(N-(3-fluoropropylsulfonyl)-3-fluoropropylsulfonamido)benzoate for methyl 2,6-difluoro- 3-(N-(propylsulfonyl)-propylsulfonamido)benzoate. 1H NMR (400 MHz, CD₃OD) δ 7.64 (m, 1H), 7.07 (m, 1H), 4.58 (m, 1H), 4.47 (m, 1H), 3.22 (m, 2H), 2.26-2.12 (m, 2H). MS m/z 296.1 [M-l].

Example W

6-Chloro-2-fluoro-3 -(3 -fluoropropylsulfonamido)benzoic acid [00248] Step A: Benzyl 6-chloro-2-fluoro-3-(3-fiuoro-N-(3-fluoropropylsulfonyl)- propylsulfonamido)benzoate (92%) was prepared according to the general procedure described in Example F, Step B, substituting 3-fluoropropane-l-sulfonyl chloride for propane- 1-sulfonyl chloride.

[00249] Step B: 6-Chloro-2-fluoro-3-(3-fluoropropylsulfonamido)benzoic acid (71%) was prepared according to the general procedure for Example F, Step C, substituting benzyl 6-chloro-2-fluoro-3 -(3 -fluoro-N-(3 -fluoropropylsulfonyl)propylsulfonamido)benzoate for benzyl 6-chloro-2-fluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate. 1H NMR (400 MHz, (CD₃)₂SO) δ 9.65 (br s, 1H), 7.03 (m, 1H), 6.58 (m, 1H), 4.59 (m, 1H), 4.47 (m, 1H), 3.18 (m, 2H), 2.22-2.02 (m, 2H). MS m/z 312.1, 314.1 [M-l].

Example X

2-Chloro-6-fluoro-3 -(3 -fluoropropylsulfonamido)benzoic acid

[00250] Step A: Methyl 2-chloro-6-fluoro-3-(3-fluoro-N-(3-fluoropropylsulfonyl)- propylsulfonamido)benzoate was prepared according to the general procedure in Example B, Step C, substituting 3-fluoropropyl sulfonyl chloride for propane- 1-sulfonyl chloride.

[00251] Step B: 2-Chloro-6-fiuoro-3-(3-fluoropropylsulfonamido)benzoic acid (93% over 2 steps) was prepared according to the general procedure for Example F, Step C, substituting methyl 2-chloro-6-fluoro-3-(3-fiuoro-N-(3- fluoropropylsulfonyl)propylsulfonamido)benzoate for benzyl 6-chloro-2-fluoro-3-(N- (propylsulfonyl)propylsulfonamido)benzoate. 1H NMR (400 MHz, CD₃OD) δ 7.63 (m, 1H), 7.19 (m, 1H), 4.56 (m, 1H), 4.44 (m, 1H), 3.21 (m, 2H), 2.25-2.12 (m, 2H). MS m/z 312.1, 314.1 [M-l].

Example Y

N-(3 - Amino-2,4-difluorophenvD-3 -fluoropropane- 1 -sulfonamide

[00252] Triethylamine (0.682 mL, 4.89 mmol) and diphenylphosphoryl azide (0.547 mL, 2.45 mmol) were added to a solution of 2,6-difluoro-3-(3- fluoropropylsulfonamido)benzoic acid (0.485 g, 1.63 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 1 hour. Water (1.18 mL, 65.2 mmol) was added, and the mixture was stirred at 80°C for 15 hours. The reaction mixture was diluted with ethyl acetate (100 mL), and the organic layer was washed with saturated aqueous NaHC0₃, dried over sodium sulfate and concentrated. The crude product was purified via silica gel chromatography, eluting with hexanes/ethyl acetate (4:1) to give the title compound (0.34 g, 77%). 1H NMR (400 MHz, (CD₃)₂SO) δ 9.49 (br s, 1H), 6.87 (m, 1H), 6.52 (m, 1H), 5.33 (br s, 2H), 4.60 (m, 1H), 4.48 (m, 1H), 3.14 (m, 2H), 2.16-2.03 (m, 2H). LC/MS: m/z 267.1 [M- 1]·

Example Z

N-(3 - Amino-4-chloro-2-fluorophenyl)-3 -fluoropropane- 1 -sulfonamide

[00253] N-(3-Amino-4-chloro-2-fluorophenyl)-3 -fluoropropane- 1 -sulfonamide (8.8 g, 52%) was prepared according to the general procedure in Example Y, substituting 6-chloro- 2-fluoro-3-(3-fluoropropylsulfonamido)benzoic acid for 2,6-difluoro-3-(3-fluoropropyl- sulfonamido)benzoic acid. 1H NMR (400 MHz, (CD₃)₂SO) δ 9.65 (br s, 1H), 7.03 (m, 1H), 6.58 (m, 1H), 5.50 (br s, 2H), 4.59 (m, 1H), 4.48 (m, 1H), 3.17 (m, 2H), 2.16-2.03 (m, 2H). LC/MS: m/z 283.1, 285.1 [M-1J.

Example AA

N-(3 -Amino-2-chloro-4-fluorophenyl -3 -fluoropropane- 1 -sulfonamide

[00254] N-(3-Amino-2-chloro-4-fluorophenyl)-3-fluoropropane-l-sulfonamide

(0.88 g, 42%) was prepared according to the general procedure in Example Y, substituting 2- chloro-6-fluoro-3-(3-fluoropropylsulfonamido)benzoic acid for 2,6-difluoro-3-(3-fluoro- propylsulfonamido)benzoic acid. 1H NMR (400 MHz, (CD₃)₂SO) δ 9.35 (br s, 1H), 7.03 (m, 1H), 6.63 (m, 1H), 5.50 (br s, 2H), 4.59 (m, 1H), 4.48 (m, 1H), 3.17 (m, 2H), 2.16-2.03 (m, 2H). LC/MS: m/z 283.1, 285.1 [M-l].

Exam le AB

(3-Amino-4-methylphenyl)propane- 1 -sulfonamide [00255] Step A: TEA (4.58 mL, 32.9 mmol) was added to 4-methyl-3-nitroaniline (1.0 g, 6.57 mmol) in DCM (30 mL) at 0°C, followed by propane- 1-sulfonyl chloride (1.84 mL, 16.4 mmol). The solution was allowed to warm to ambient temperature and stirred for 2 hours. The solution was diluted with aqueous bicarbonate (100 mL) and extracted with EtOAc (3 X 40 mL). The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford N-(4-methyl-3-nitrophenyl)-N-(propylsulfonyl)propane-l- sulfonamide (2.4 g, 100%).

[00256] Step B: 2M NaOH (16 mL, 33 mmol) was added to N-(4-methyl-3- nitrophenyl)-N-(propylsulfonyl)propane-l -sulfonamide (2.4 g, 6.6 mmol) in 4:1 THF:MeOH (75 mL). The solution was warmed to 50°C for 3 hours. The cooled solution was concentrated under reduced pressure, and the residue was diluted with aqueous ammonium chloride (100 mL) and extracted with EtOAc (3 X 40 mL). The combined organics were washed with aqueous bicarbonate (2 X 50 mL), then dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford N-(4-methyl-3-nitrophenyl)propane-l- sulfonamide (1.6 g, 94%).

[00257] Step C: 10% Pd/C (1.32 g, 1.24 mmol) was added to N-(4-methyl-3- nitrophenyl)propane-l -sulfonamide (1.6 g, 6.19 mmol) in EtOH (30 mL). The suspension was stirred under a balloon of hydrogen at ambient temperature for 16 hours. The suspension was filtered and concentrated to afford (3 -amino-4-methylphenyl)propane-l -sulfonamide (1.38 g, 97.6%). Ή NMR (400 MHz, CD₃OD) δ 6.96-6.99 (m, 1H), 6.63-6.65 (m, 1H), 6.45- 6.49 (m, 1H), 6.38 (br s, 1H), 3.02-3.07 (m, 2H), 2.13 (s, 3H), 1.75-1.90 (m, 2H), 0.98-1.04 (m, 3H). LCMS: m/z 229.1 [M+l].

xample AC

N-(3 - Amino-4-chlorophenyl)propane- 1 -sulfonamide

[00258] Step A: Triethylamine (4.19 mL, 29.0 mmol) and propane- 1-sulfonyl chloride (1.63 mL, 14.5 mmol) was added to 4-chloro-3-nitroaniline (29.0 mL, 5.79 mmol) in DCM (30 mL) at 0°C. The solution was allowed to warm to ambient temperature and stirred for 1 hour before dilution with aqueous bicarbonate (50 mL) and extraction with EtOAc (3 X 40 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford N-(4-chloro-3-nitrophenyl)-N-(propylsulfonyl)propane-l -sulfonamide (2.4 g, 107%), which was used without further purification. [00259] Step B: 2M NaOH (16 mL, 33 mmol) was added to N-(N-(4-chloro-3- nitrophenyl)-N-(propylsulfonyl)propane-l -sulfonamide (2.4 g, 6.6 mmol) in 4:1 THF:MeOH (75 mL). The solution was warmed to 50°C for 3 hours. The cooled solution was concentrated under reduced pressure, and the residue was diluted with aqueous ammonium chloride (100 mL) and extracted with EtOAc (3 X 40 mL). The combined organic extracts were washed with aqueous bicarbonate (2 X 50 mL), then dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford N-(4-chloro-3-nitrophenyl)propane-l- sulfonamide (1.5 g, 88%).

[00260] Step C: 2M HC1 (2 mL) and Fe (0) (0.301 g, 5.38 mmol) were added to N-(4- chloro-3-nitrophenyl)propane-l -sulfonamide (0.50 g, 1.79 mmol) in MeOH (10 mL). The suspension was warmed to reflux for 4 hours, then cooled and filtered through GF/F paper. The filtrate was concentrated under reduced pressure to afford N-(3-amino-4- chlorophenyl)propane-l -sulfonamide (0.40 g, 89%). 1H NMR (400 MHz, CD₃OD) δ 7.16- 7.21 (m, 1H), 6.90 (s, 1H), 6.58-6.63 (m, 1H), 3.02-3.08 (m, 2H), 2.13 (s, 3H), 1.73-1.84 (m, 2H), 0.97-1.05 (m, 3H). LC/MS: m/z 247.1 [M-l].

Example AD

N-(3 - Amino-2-chlorophenyl)propane- 1 -sulfonamide

[00261] Step A: 2-Chloro-3-nitroaniline (Sienkowska, et. al, Tetrahedron 56 (2000) 165) (0.36 g, 2.086 mmol) was dissolved in DCM (20 mL) and cooled to 0°C. Triethylamine (0.8723 mL, 6.258 mmol) was added followed by propane- 1-sulfonyl chloride (0.5847 mL, 5.215 mmol) and the reaction was stirred at room temperature overnight. The reaction was quenched with 0.1N HC1 (10 mL), and the layers were separated. The organic layer was dried over Na₂S0₄, and concentrated to give N-(2-chloro-3-nitrophenyl)-N- (propylsulfonyl)propane-l -sulfonamide as an oil, which was used directly in the next step.

[00262] Step B: N-(2-Chloro-3-nitrophenyl)-N-(propylsulfonyl)propane-l- sulfonamide (0.8028 g, 2.086 mmol) was dissolved in 3:1 THF/MeOH (4.0 mL). NaOH (2.0 M, 2.086 mL, 4.172 mmol) was added, and the reaction was stirred for five minutes at room temperature. The reaction was quenched with 0.1N HC1 (5 mL), and the volatiles were removed by rotary evaporation. EtOAc (10 mL) was added, and the organic layer was washed with water and brine, dried with Na₂S0₄ and concentrated to give N-(2-chloro-3- nitrophenyl)propane-l -sulfonamide as an oil, which was used directly in the next step. [00263] Step C: N-(2-Chloro-3-nitrophenyl)propane-l -sulfonamide (0.580 g, 2.08 mmol) was dissolved in 4:1 EtOH/water (10 mL). Fe (0) (1.16 g, 20.8 mmol) was added, followed by a catalytic amount of NH4CI (5 mg), and the reaction was heated to 80°C for 3 hours. The reaction was cooled to room temperature, filtered through Celite®, concentrated, dissolved in EtOAc, washed with water, dried over Na₂S0₄ and concentrated. Purification by silica gel chromatography (10% to 90% EtOAc/hexanes) gave N-(3-amino-2- chlorophenyl)propane-l -sulfonamide (259 mg, 1.04 mmol, 51%) as an oil. 1H NMR (400 MHz, (CD₃)₂SO) δ 9.06 (br s, 1H), 6.96-6.99 (d, 1H), 6.63-6.66 (m, 2H), 5.43 (br s, 1H), 3.03-3.07 (t, 1H), 1.71-1.77 (m, 2H), 0.94-0.98 (t, 3H); m/z (APCI-neg) M-l = 247.1, 249.0.

Example AE

N-(3 - Amino-4-fluorophenyl) propane- 1 -sulfonamide

[00264] N-(3-Amino-2-chloro-4-fluorophenyl) propane- 1 -sulfonamide (668 mg, 2.5 mmol) was dissolved in methanol (100 mL), and the solution was run through an H-Cube hydrogenator at 50°C and 10 bar H₂ pressure at a 1 mL/min flow rate. After removal of the solvent, 481 mg (83%) of N-(3-amino-4-fluorophenyl) propane- 1 -sulfonamide were obtained. 1H NMR (500 MHz, (CD₃)₂SO) δ 9.37 (s, 1H), 6.89 (dd, J= 11.2, 8.7, 1H), 6.67 (dd, J= 8.1, 2.6, 1H), 6.49 - 6.24 (m, 1H), 5.19 (s, 2H), 3.09 - 2.86 (m, 2H), 1.67 (dq, J= 15.0, 7.5, 2H), 0.93 (t, J= 7.4, 3H). LC-MS [M+l] m/z 233.1.

Example AF

N-(3-Amino-2 -fluorophenyl) propane- 1 -sulfonamide

[00265] N-(3-Amino-4-chloro-2-fluorophenyl) propane- 1 -sulfonamide (477 mg, 1.8 mmol) was dissolved in methanol (100 mL), and the solution was run through an H-Cube hydrogenator at room temperature and ambient pressure at a 1 mL/min flow rate. After removal of the solvent, N-(3-amino-2-fluorophenyl) propane- 1 -sulfonamide was obtained (251 mg, 60%). 1H NMR (500 MHz, (CD₃)₂SO) δ 9.29 (s, 1H), 6.79 (t, J= 8.0, 1H), 6.58 (td, J = 8.1, 1.4, 1H), 6.55 - 6.49 (m, 1H), 5.17 (s, 2H), 3.02 (dd, J = 8.7, 6.7, 2H), 1.85 - 1.60 (m, 2H), 0.96 (t, J= 7.4, 3H). LC-MS [M+l] m/z 233.1.

Example AG

N-(3 - Amino-2 ,4,5 -trifluorophenyPpropane- 1 -sulfonamide

[00266] 2,4,5-Trifluorobenzene-l,3-diamine (1116 mg, 6.88 mmol) was dissolved in methylene chloride (27 mL, 420 mmol), and pyridine (557 μί, 6.88 mmol) was added. After cooling the mixture to 0°C, propane- 1-sulfonyl chloride (772 μί, 6.88 mmol) was added dropwise through a syringe. The ice bath was removed, and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the crude product purified via chromatography eluting with 1:1 ethyl acetate/hexane to afford N-(3- amino-2,4,5-trifluorophenyl)propane-l -sulfonamide (1847 mg, 83.6%). 1H NMR (400 MHz, (CD₃)₂SO) δ 9.58 (s, 1H), 6.53 (dt, J= 11.8, 7.5 Hz, 1H), 5.75 (s, 2H), 3.10 - 2.91 (m, 2H), 1.72 (dd, J= 15.1, 7.5 Hz, 2H), 0.96 (t, J= 7.4 Hz, 3H). LC-MS [M+l] m/z 269.0.

Exam le AH

N-(3-Amino-2-cyano-4-fluorophenyl)propane- 1 -sulfonamide

[00267] Step A: Concentrated ammonium hydroxide (5.16 mL, 76.4 mmol) was added to 2,3,6-trifluorobenzonitrile (2.0 g, 12.7 mmol) in isopropanol (5 mL). The colorless solution was heated at 80°C in a sealed vial overnight. The reaction mixture was concentrated, and the residue partitioned between EtOAc and water. The EtOAc was washed with brine, dried over MgS0₄, filtered, and evaporated to yield 2-amino-3,6- difluorobenzonitrile (1.93 g, 12.5 mmol, 98.4% yield) as a solid.

[00268] Step B: 60% sodium hydride (0.558 g, 14.0 mmol) was added slowly in portions to propane- 1 -sulfonamide (1.68 g, 13.6 mmol) in DMSO (10 mL) with water bath cooling. After gas evolution ceased, the mixture was diluted with DMSO (5 mL) to aid in dissolution, and was stirred an additional 30 minutes at ambient temperature. A solution of 2-amino-3,6-difluorobenzonitrile (1.00 g, 6.49 mmol) in DMSO (20 mL) was added to the reaction, and the resulting mixture was heated at 100°C for 20 hours, then 120°C for 16 hours. The reaction mixture was diluted with 0.5M NaOH and washed with 2 portions EtOAc. The aqueous layer was acidified with 12M HC1 to pH 4 and extracted twice with EtOAc. The organic layer was washed with brine (3 X), dried over MgS0₄, filtered, and evaporated to yield a thick oil (0.41 g). This was chromatographed on a 50 g Biotage SNAP column with 1 :1 hexane:EtOAc to afford N-(3-amino-2-cyano-4-fluorophenyl)propane-l- sulfonamide (0.33 g, 1.28 mmol, 19.8% yield). 1H NMR (400 MHz, CDC1₃) δ 7.12-7.18 (m, 1H), 6.90-6.94 (m, 1H), 6.50 (br s, 1H), 4.58 (br s, 2H), 3.11-3.15 (m, 2H), 1.85-1.95 (m, 2H), 1.06 (t, 3H). m/z 256.1 (LC/MS negative ionization) [M-l].

Exam le AI

N-(3 -Amino-4-chloro-2-cvanophenyl)propane- 1 -sulfonamide

[00269] Step A: 14.8M ammonium hydroxide (4.67 mL, 69.1 mmol) was added to 3- chloro-2,6-difluorobenzonitrile (2.00 g, 11.5 mmol) in isopropanol (5 mL). The colorless solution was heated at 80°C in a sealed vial. After 2 hours, the reaction mixture was concentrated, and the residue partitioned between EtOAc and water. The EtOAc was washed with brine, dried over MgS0₄, filtered, and evaporated to yield 2-amino-3-chlorO_'6- fluorobenzonitrile (1.63 g, 9.56 mmol, 82.9% yield) as a solid.

[00270] Step B: 60% sodium hydride (0.252 g, 6.30 mmol) was added slowly in portions to propane- 1 -sulfonamide (0.740 g, 6.01 mmol) in NMP (10 mL) with water bath cooling. Gas evolution continued as the mixture was stirred an additional 30 minutes at ambient temperature and then heated 1 hour at 40°C. The mixture was cooled to room temperature, and 2-amino-3-chloro-6-fluorobenzonitrile (0.50 g, 2.93 mmol) was added. The resulting mixture was heated in a sealed vial at 120°C overnight. The reaction mixture was diluted with 0.5M NaOH and washed twice with EtOAc. The aqueous layer was acidified with 12M HC1 to pH 5 and extracted with 2 portions of EtOAc. The combined EtOAc extracts were washed twice with brine, dried over MgS0₄, filtered, and evaporated to afford a thick oil (0.65 g). This was chromatographed on a 50g Biotage SNAP column with DCM to yield N-(3-amino-4-chloro-2-cyanophenyl)propane-l -sulfonamide (0.29 g, 1.06 mmol, 36.1% yield) as a solid. 1H NMR (400 MHz, CDC1₃) δ 7.40 (d, 1H), 6.97 (d, 1H), 6.62 (br s, 1H), 4.90 (br s, 2H), 3.13-3.17 (m, 2H), 1.85-1.94 (m, 2H), 1.06 (t, 3H). m/z 272.1 (LC/MS negative ionization) [M-l].

Example AJ

N-(3 -Amino-2-cvanophenyl)propane- 1 -sulfonamide

[00271] 60% sodium hydride (0.194 g, 8.08 mmol) was added to propane-1- sulfonamide (0.950 g, 7.71 mmol) in N-methylpyrrolidone (7 mL) in a vial. After gas evolution ceased, the mixture was stirred 30 minutes at 40°C. 2-Amino-6-fluorobenzonitrile (0.500 g, 3.67 mmol) was added, and the sealed vial was heated at 120°C overnight, then 150°C overnight, then for 3 days at 150°C. The reaction mixture was partitioned between 0.5M NaOH and EtOAc. The aqueous layer was acidified to pH 5 with concentrated HCl and extracted with EtOAc. The EtOAc extract was washed with brine (2 X), dried over MgS0₄, filtered, and evaporated to yield an oil (0.73 g). This material was dissolved in ether and washed with 3 portions water to remove NMP, dried over MgS0₄, filtered, and evaporated to yield N-(3-amino-2-cyanophenyl)propane-l -sulfonamide (0.34 g, 1.42 mmol, 38.7% yield) as a film. 1H NMR (400 MHz, CDC1₃) δ 7.29 (t, 1H), 6.98 (dd, 1H), 6.70 (br s, 1H), 6.51 (dd, 1H), 4.52 (br s, 2H), 3.18-3.14 (m, 2H), 1.95-1.85 (m, 2H), 1.06 (t, 3H). m/z 238.1 (LC/MS negative ionization) [M-l].

Exam le AK

N-(3 -Amino-2,4-difluorophenyl pyrrolidine- 1 -sulfonamide

[00272] Potassium carbonate (0.414 g, 3.00 mmol) and pyrrolidine- 1-sulfonyl chloride (0.196 mL, 1.50 mmol) were added to N-(3-amino-2,4-difluorophenyl)propane-l- sulfonamide (0.250 g, 0.999 mmol) in DMF (4.5 mL). The suspension was stirred at ambient temperature for 18 hours. 2M NaOH (1 mL) was added to the suspension, which stirred at ambient temperature for 1 hour. The resulting solution was diluted with water (20 mL) and brought to pH 9 with HCl, followed by extraction with EtOAc (3 X 15 mL). The concentrated organics were purified via silica gel chromatography eluting with 1 : 1 hexane- EtOAc to provide N-(3-amino-2,4-difluorophenyl)pyrrolidine-l -sulfonamide (184 mg, 66%). 1H NMR (400 MHz, CD₃OD) δ 6.86-6093 (m, 1H), 6.75-9.82 (m, 1H), 6.34 (br s, 1H), 3.78 (br s, 2 H), 3.28-3.33 (m, 4H), 1.82-1.87 (m, 4H). LC/MS: m/z 276.1 [M-l].

Example AL

N-(3 -Amino-4-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)propane- 1 -sulfonamide

[00273] Step A: A 250 mL round bottom flask was charged with methyl 2,6-difluoro- 3-nitrobenzoate (10.03 g, 46.18 mmol) and methanol (60 mL, 1000 mmol) and was then cooled over a brine / ice bath at -4°C for 20 minutes. A 5M solution of sodium methoxide in methanol (11.98 mL, 59.88 mmol) was added dropwise to this solution over 20 minutes, while maintaining the reaction temperature at -4°C over the course of the addition. The reaction mixture was allowed to stir overnight, gradually rising to room temperature. The methanol was removed under reduced pressure, and the residual oil quenched with a saturated aqueous solution of potassium bicarbonate (250 mL). The organic layer was saved, and the aqueous layer was extracted twice with ethyl acetate (250 mL). The combined organic layers were washed once with brine, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified via flash chromatography (330 g ISCO column) using a gradient of 0 - 50% ethyl acetate: heptane to yield methyl 6-fluoro-2-methoxy-3-nitrobenzoate (3.37 g. 32%) as an oil. 1H NMR (400 MHz, (CD₃)₂SO) δ = 8.23 (dd, J=9.3, 5.9, 1H), 7.39 (t, J=8.9, 1H), 3.94 (s, 3H), 3.89 (s, 3H).

[00274] Step B: A 250 mL round bottom flask was charged with methyl 6-fluoro-2- methoxy-3-nitrobenzoate (3.37 g, 14.71 mmol) dissolved in methanol (125 mL, 3080 mmol). Nitrogen was passed through the reaction mixture, and 10% palladium on activated carbon (1.3 g, 1.2 mmol) was added. The flask was capped and evacuated and then allowed to stir for 60 hours under an atmosphere of hydrogen at ambient temperature and pressure. The mixture was then filtered through Celite® to remove the solid catalyst and washed with methanol (500 mL). The filtrate was concentrated to give methyl 3-amino-6-fluoro-2- methoxybenzoate as an oil (2.95 g, 100%). 1H NMR (400 MHz, (CD₃)₂SO) δ = 6.74-6.84 (m, 2H), 4.98 (s, 2H), 3.85 (s, 3H), 3.68 (s, 3H).

[00275] Step C: A 250 mL round bottom flask was charged with a solution of methyl 3-amino-6-fluoro-2-methoxybenzoate (3.656 g, 18.36 mmol) in methylene chloride (100 mL). A solution of 4-dimethylaminopyridine (113 mg, 0.925 mmol), pyridine (7.45 mL, 92.1 mmol) and propane- 1-sulfonyl chloride (8.25 mL, 73.6 mmol) in methylene chloride (10 mL) was added to the reaction mixture over the course of five minutes. The reaction mixture was stirred at room temperature for 14 hours. After removing the organic solvent under reduced pressure, saturated aqueous sodium bicarbonate (100 mL) was added followed by stirring for 10 minutes. The aqueous mixture was extracted twice with ethyl acetate (200 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified using flash chromatography, eluting with 0- 30% ethyl acetate/heptanes to give methyl 6-fluoro-2-methoxy-3-(propylsulfonamido)- benzoate as an oil (4.914 g, 85%). 1H NMR (400 MHz, (CD₃)₂SO) δ = 9.27 (s, 1H), 7.48 (dd, J=9.1, 6.1, 1H), 7.09 (t, J=9.0, 1H), 3.89 (s, 3H), 3.85 - 3.74 (m, 3H), 3.29 (s, 15H).

[00276] Step D: A 100 mL round bottom flask was charged with methyl 6-fluoro-2- methoxy-3-(propylsulfonamido)benzoate (4.91 g, 16.1 mmol) dissolved in N,N- dimethylformamide (16 mL, 210 mmol) and was cooled over an ice/ brine bath. Sodium hydride (0.676 g, 16.9 mmol) was added in four portions. After the vigorous bubbling subsided, the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was cooled over an ice/brine bath, and p-methoxybenzyl chloride (2.646 g, 16.90 mmol) was added. The reaction was allowed to warm to room temperature over the next three hours and then quenched by adding a semi-saturated aqueous ammonium chloride solution (200 mL) at 0°C. After stirring at room temperature overnight, the aqueous layer was discarded, and the remaining oil washed with heptanes to remove the mineral oil. The residual oil was dissolved in ethyl acetate, dried over magnesium sulfate, filtered and concentrated to remove the ethyl acetate. The crude product was purified by flash chromatography (120 g column), using a gradient of 0-100% ethyl acetate: heptanes to give methyl 6-fluoro-2-methoxy-3-(N-(4-methoxybenzyl)propylsulfonamido)benzoate (3.71 g, 57%) as an oil. 1H NMR (400 MHz, (CD₃)₂SO) δ = 7.28 (dd, J=9.0, 6.3, 1H), 7.12 (d, J=8.7, 2H), 6.98 (t, J=8.9, 1H), 6.84 (dd, J=6.8, 4.8, 2H), 4.65 (s, 2H), 3.90 (d, J=7.6, 3H), 3.73 (s, 3H), 3.70 (s, 3H), 3.28 - 3.21 (m, 2H), 1.84 - 1.70 (m, 2H), 1.00 (q, J=7.2, 3H).

[00277] Step E: A 250 mL round bottom flask was charged with methyl 6-fluoro-2- methoxy-3-(N-(4-methoxybenzyl)propylsulfonamido)benzoate (4.42 g, 10.4 mmol) dissolved in tetrahydrofuran (70 mL, 900 mmol). 1M of sodium hydroxide in water (67.8 mL, 67.8 mmol) was added, and the mixture was stirred at 60°C for 48 hours. After cooling, the THF was removed under reduced pressure. The basic aqueous solution was diluted with water to a volume of 100 mL and then extracted once with ethyl acetate (200 mL). The aqueous layer was acidified with concentrated hydrochloric acid (5 mL) to a pH of 2 and extracted three times with ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford 6-fluoro-2-methoxy-3-(N-(4- methoxybenzyl)propylsulfonamido)benzoic acid as a solid (4.253 g, 99%). ^!H NMR (400 MHz, (CD₃)₂SO) 6 = 13.86 (s, 1H), 7.19 (dd, J=8.9, 6.3, 1H), 7.12 (d, J=8.6, 2H), 6.93 (t, J=8.8, 1H), 6.83 (d, J=8.7, 2H), 4.65 (s, 2H), 3.80 (s, 3H), 3.70 (s, 3H), 3.27 - 3.19 (m, 2H), 1.78 (dd, J-15.3, 7.5, 2H), 1.01 (t, J=7.4, 3H).

[00278] Step F: Under a nitrogen atmosphere, a dry 100 mL round bottom, stir bar and reflux condenser were charged with 6-fluoro-2-methoxy-3-(N-(4-methoxybenzyl)- propylsulfonamido)benzoic acid (379 mg, 0.921 mmol) dissolved in 1,4-dioxane (10 mL, 83 mmol). Triethylamine (295.3 μί, 2.12 mmol) and then diphenylphosphonic azide (228.3 μί, 1.06 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours and then heated to reflux for 1 hour. Water (10 mL, 36 mmol) was added to reaction mixture and heating to reflux continued for 2 hours. The reaction mixture was concentrated to remove the 1,4-dioxane. Residual material was stirred with a saturated aqueous solution of sodium bicarbonate for thirty minutes, and the aqueous layer was decanted and discarded. The residual oil was purified by flash chromatography (40 g column) using a gradient of 0- 100% ethyl acetate:heptanes to give N-(3-amino-4-fluoro-2-methoxyphenyl)-N-(4- methoxybenzyl)propane-l -sulfonamide (108 mg, 31%) as an oil. 1H NMR (400 MHz, (CD₃)₂SO) δ = 7.11 (d, J=8.7, 2H), 6.82 (d, J-8.7, 2H), 6.73 (dd, J=10.4, 8.9, 1H), 6.33 (dd, J=8.9, 5.8, 1H), 4.95 (s, 2H), 4.63 (s, 2H), 3.69 (s, 3H), 3.62 (s, 3H), 3.25 - 3.17 (m, 2H), 1.77 (dq, J=15.0, 7.4, 2H), 1.00 (t, J-7.4, 3H). MS m/z 383.2 [M+l].

Example AM

N-(3 -Amino-2-chloro-4-fluorophenyl)-N-(4-methoxybenzyl)propane- 1 -sulfonamide

[00279] N-(3-Amino-2-chloro-4-fluorophenyl)propane-l -sulfonamide (75 g, 280 mmol) was dissolved in N,N-dimethylformamide (200 mL, 2000 mmol). A 60% sodium hydride suspension in mineral oil (6:4, sodium hydride:mineral oil, 11.85 g, 296 mmol) was added in multiple portions over a period of fifteen minutes. The reaction mixture was stirred at room temperature for 90 minutes and was then warmed to 40°C for two hours. This homogeneous mixture was cooled to 0°C, and p-methoxybenzyl chloride (40.03 mL, 295.25 mmol) was added over 5 minutes. The reaction was left to stir and warm to room temperature. After 14 hours, the reaction mixture was poured into a dilute ammonium chloride solution (1750 mL), and the water layer was decanted to leave an oil. This oil was triturated three times with water (2 L). The remaining product was transferred into a 1 L beaker, diluted with water (800 mL), sonicated for 30 minutes and then stirred at room temperature for 1 hour. The resulting solid was collected via filtration and dried by lyophilization to give N-(3-amino-2-chloro-4-fluorophenyl)-N-(4-methoxybenzyl)propane-l- sulfonamide (111.9 g, 99 %). 1H NMR (500 MHz, (CD₃)₂SO) 5 = 7.11 (d, J=8.6, 2H), 6.96 (dd, J=10.6, 8.8, 1H), 6.81 (t, J=5.7, 2H), 6.51 (dd, J=8.7, 5.1, 1H), 5.42 (s, 2H), 4.71 (d, J=14.4, 1H), 4.57 (d, J=14.4, 1H), 3.70 (s, 3H), 3.21 (td, J=6.7, 1.4, 2H), 1.77 (dd, J=15.3, 7.5, 2H), 1.00 (t, J=7.4, 3H). MS m/z 387.2 [M+l].

Example AN

7-Bromoquinoxalin-2( 1 HVone

[00280] Bromine (3.56 mL, 68.63 mmol) was slowly added to a solution of quinoxalin-2(lH)-one (10.03 g, 68.63 mmol) in 0.1M acetic acid (686.3 mL). The reaction mixture was stirred at ambient temperature for 1.5 hours. The resulting solids were collected by filtration and washed with hexanes to afford 7-bromoquinoxalin-2(lH)-one (4.02 g, 17.86 mmol, 26.0% yield). 1H NMR (400 MHz, (CD₃)₂SO) δ = 12.466 (s, 1H), 8.191 (s, 1H), 7.724-7.700 (d, 1H), 7.470-7.444 (m, 2H).

Example AO

N-(3-Amino-4-chloro-2-((triisopropylsilyl)ethvnyl)phenyl)propane-l -sulfonamide

[00281] Step A: 2-Chloro-l,3-dinitrobenzene (0.500 g, 2.47 mmol), Cul (0.0940 g, 0.494 mmol), P(t-Bu)₃ (1.51 mL, 0.494 mmol) and ethynyltriisopropylsilane (0.658 mL, 2.96 mmol) were dissolved in 5:1 acetonitrile/TEA (10 mL). Nitrogen gas was bubbled through for 5 minutes, and PdCl₂(MeCN)₂ (0.0640 g, 0.247 mmol) was added. Nitrogen gas was bubbled though for another 10 minutes. The reaction was stirred at room temperature for 2 hours, diluted with EtOAc and filtered through Celite®. The filtrate was concentrated, dissolved in EtOAc, and washed with 0.1N HC1, water and brine, and dried over Na₂S0₄ and concentrated. The product was purified by Biotage chromatography eluting with hexanes/EtOAc to give ((2,6-dinitrophenyl)ethynyl)triisopropylsilane (310 mg, 36%) as an oil. m/z (APCI-neg) M-l = 348.1.

[00282] Step B: ((2,6-Dinitrophenyl)ethynyl)triisopropylsilane (0.310 g, 0.890 mmol) was dissolved in 1:1 DCM/DMF (30 mL). SnCl₂ dihydrate (10.0 g, 44.5 mmol) was added and stirred for one hour at room temperature. The reaction was poured into saturated aqueous NaHC0₃ (200 mL) giving a precipitate, which was stirred at room temperature for 30 minutes and filtered through Celite®. The layers were separated, the aqueous was extracted with DCM, and the combined organics washed with water (2 X) and brine, dried over Na₂S0₄ and concentrated. The product was purified by Biotage chromatography eluting with hexanes/EtOAc to give 2-((triisopropylsilyl)ethynyl)benzene- 1,3 -diamine as an oil. 1H NMR (400 MHz, CDC1₃) δ 6.89 (t, 1H), 6.09 (d, 2H), 4.17 (br s, 4H), 1.14 (s, 21H). m/z (APCI- pos) M+l = 389.2.

[00283] Step C: 2-((Triisopropylsilyl)ethynyl)benzene-l,3-diamine (0.072 g, 0.249 mmol) was dissolved in THF (5 mL), and n-chlorosuccinimide (0.036 g, 0.286 mmol) was added and stirred at room temperature for one hour. The crude reaction was diluted with EtOAc, washed with water (3 X) and brine, and then dried over Na₂S0₄ and concentrated. The product was purified by Biotage chromatography eluting with hexanes/DCM to give 4- chloro-2-((triisopropylsilyl)ethynyl)benzene- 1,3 -diamine (55 mg, 64% for two steps) as an oil. m/z (APCI-pos) M+l = 323.1, 325.2.

[00284] Step D: 4-Chloro-2-((triisopropylsilyl)ethynyl)benzene- 1,3 -diamine (0.0554 g, 0.172 mmol) was dissolved in 10:1 dichloroethane/pyridine (1 mL) and cooled to 0°C. Propane- 1-sulfonyl chloride (0.0193 mL, 0.172 mmol) was added, and the reaction was stirred at 50°C overnight. The reaction was concentrated, dissolved in EtOAc and washed with 0.1N HC1, water, and brine, dried over Na₂S0₄ and concentrated. The product was purified by Biotage chromatography eluting with hexanes/DCM to give N-(3-amino-4- chloro-2-((triisopropylsilyl)ethynyl)phenyl)propane-l -sulfonamide (30 mg, 41%) as an oil. 1H NMR (400 MHz, CDC1₃) δ 7.17-7.19 (d, 1H), 6.93-6.95 (d, 1H), 6.89 (br s, 1H), 4.69 (br s, 2H), 3.04-3.08 (m, 2H), 1.77-1.87 (m, 2H), 1.14-1.16 (m, 21 H), 0.98-1.02 (t, 3H). m/z (APCI-neg) M-l = 427.2, 429.2.

Exam le 1

N-(4-Chloro-2-fluoro-3 -(3 -methyl-4-oxo-3 ,4-dihvdroquinazolin-6-ylamino)phenyl)propane-

1 -sulfonamide

[00285] 6-Bromo-3-methylquinazolin-4(3H)-one (0.100 g, 0.418 mmol), N-(3-amino- 4-chloro-2-fluorophenyl)propane-l -sulfonamide (0.112 g, 0.418 mmol), NaOtBu (0.121 g, 1.25 mmol), Binap-rac (0.0260 g, 0.0418 mmol) and Pd₂dba₃.CHCl₃ (0.0216 g, 0.0209 mmol) were suspended in toluene (8 mL). Ar was bubbled through for 10 minutes, and the reaction was heated to 100°C for 16 hours under an Ar balloon. The next morning the reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL) and water (30 mL). The pH of the aqueous layer was adjusted to about 6 with AcOH. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was transferred to a separatory funnel, and the layers were separated. The aqueous layer was extracted with ethyl acetate (1 X 50 mL). The combined organics were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with DCM/ ethyl acetate (2:1), DCM/ ethyl acetate (1:1) to give N-(4-chloro-2-fluoro- 3 -(3 -methyl-4-oxo-3 ,4-dihydroquinazolin-6-ylamino)phenyl)propane- 1 -sulfonamide (0.020 g, 11%) as a solid. 1H NMR (400 MHz, (CD₃)₂SO) δ 9.83 (br s, 1H), 8.42 (br s, 1H), 8.16 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.42 (d, J=8.6 Hz, 1H), 7.32-7.24 (m, 2H), 7.15 (s, 1H), 3.44 (s, 3H), 3.12 (m, 2H), 1.73 (m, 2H), 0.96 (t, J=7.4 Hz, 3H). LC/MS: m/z 425.1, 427.1 [M+l].

Exam le 2

N-(2 ,4-Difluoro-3 -(3 -methyl-4-oxo-3 ,4-dihydroquinazolin-6-ylamino)phenyl)propane- 1 - sulfonamide

[00286] Step A: 6-Bromo-3-methylquinazolin-4(3H)-one (0.200 g, 0.837 mmol), N- (3-amino-2,4-difluorophenyl)-N-(4-methoxybenzyl)propane-l-sulfonamide (0.310 g, 0.837 mmol), NaOtBu (0.241 g, 2.51 mmol), and Binap-rac (0.0521 g, 0.0837 mmol) were taken up in toluene as a slurry in a sealed vial. Nitrogen gas was bubbled through for 5 minutes, and Pd₂dba₃ CHCI3 (0.0433 g, 0.0418 mmol) was added. Nitrogen gas was bubbled through for another 10 minutes, and the reaction was heated to 100°C overnight. The reaction was concentrated and partitioned between EtOAc and 0.1N HC1. The organic layer was washed with water and brine, dried over Na₂S0 , filtered and concentrated. The crude product was purified by Biotage chromatography with 1% MeOH/EtOAc to give N-(2,4-difluoro-3-(3- methyl-4-oxo-3 ,4-dihydroquinazolin-6-ylamino)phenyl)-N-(4-methoxybenzyl)propane- 1 - sulfonamide (28 mg, 6.3%) as a solid, m/z (APCI-pos) M+l = 429.2.

[00287] Step B: N-(2,4-difluoro-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6- ylamino)phenyl)-N-(4-methoxybenzyl)propane-l -sulfonamide (0.010 g, 0.019 mmol) was dissolved in neat TFA with one drop of water and stirred at room temperature for 30 minutes. The reaction was concentrated, and the residual solid was taken up in EtOAc and washed with saturated NaHC0₃ and brine, dried over Na₂S0₄, and concentrated. Biotage chromatography (hexanes/EtOAc) provided N-(2,4-difluoro-3-(3-methyl-4-oxo-3,4- dihydroquinazolin-6-ylamino)phenyl)propane-l -sulfonamide (5.6 mg, 72%) as a solid. ^lH NMR (400 MHz, (CD₃)₂SO) 6 9.68 (s, 1H), 8.46 (s, 1H), 8.16 (s, 1H), 7.53-7.56 (d, 1H), 7.27-7.30 (m, 1H), 7.20-7.23 (m, 2H), 3.45 (s, 3H), 3.06-3.10 (m, 2H), 1.72-1.78 (m, 2H), 0.95-0.99 (t, 3H); m/z (APCI-pos) M+l = 409.1.

Exam le 3

N-(2,4-Difluoro-3-(methyl(3-methyl-4-oxo-3,4-dihydroquinazolin-6- yl)arnino)phenyl)propane- 1 -sulfonamide

[00288] Step A: N-(2,4-Difluoro-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6- ylamino)phenyl)-N-(4-methoxybenzyl)propane-l -sulfonamide (0.015 g, 0.0284 mmol) was dissolved in DMF (1 mL) and cooled to 0°C. NaH (0.00170 g, 0.0426 mmol) was added and stirred for 10 minutes. Mel (0.00195 mL, 0.0312 mmol; d 2.275) was added and stirred for 10 minutes at room temperature. The reaction was partitioned between EtOAc and water. The organic layer was washed with water (2 X) and brine, dried over Na₂S0₄ and concentrated to provide N-(2,4-difluoro-3-(methyl(3-methyl-4-oxo-3,4-dihydroquinazolin-6- yl)amino)phenyl)-N-(4-methoxybenzyl)propane-l -sulfonamide, which was used in the next step without further purification, m/z (APCI-pos) M+l = 543.2.

[00289] Step B: N-(2,4-Difluoro-3-(methyl(3-methyl-4-oxo-3,4-dihydroquinazolin-6- yl)amino)phenyl)-N-(4-methoxybenzyl)propane-l -sulfonamide (0.0154 g, 0.0284 mmol) was dissolved in neat TFA with a few drops of water and stirred at room temperature for 30 minutes. The reaction was concentrated, and the residual solid was taken up in EtOAc and washed with saturated NaHC0₃ and brine, and dried over Na₂S0₄ and concentrated. Biotage chromatography (hexanes/EtOAc) provided N-(2,4-difiuoro-3-(methyl(3-methyl-4-oxo-3,4- dihydroquinazolin-6-yl)amino)phenyl)propane-l -sulfonamide as an oil (7.7 mg, 64%). 1H NMR (400 MHz, (CD₃)₂SO) δ 9.73 (s, 1H), 8.18 (s, 1H), 7.54-7.56 (d, 1H), 7.41-7.47 (m, 1H), 7.27-7.32 (m, 1H), 7.21-7.22 (d, 1H), 7.13-7.16 (m, 1H), 3.46 (s, 3H), 3.33 (s, 3H), 3.07-3.11 (m, 2H), 1.70-1.76 (m, 2H), 0.93-0.96 (t, 3H); m/z (APCI-pos) M+l = 423.3.

xample 4

N-(2-CMoro-4-fluoro-3-(3-methyl-4-oxo-3^-dih^

1 -sulfonamide

[00290] N-(2-Chloro-4-fluoro-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6- ylamino)phenyl)propane-l -sulfonamide (0.050 g, 28% yield) was prepared according to the general procedure of Example 1, substituting N-(3-amino-2-chloro-4-fluorophenyl)propane- 1-sulfonamide for N-(3-amino-4-chloro-2-fluorophenyl)propane-l -sulfonamide. 1H NMR (400 MHz, (CD₃)₂SO) δ 9.54 (br s, 1H), 8.40 (br s, 1H), 8.15 (s, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.37 (m, 2H), 7.25 (d, J=8.6 Hz, 1H), 7.14 (s, 1H), 3.44 (s, 3H), 3.11 (m, 2H), 1.77 (m, 2H), 0.98 (t, J=7.4 Hz, 3H). LC/MS: m/z 425.1, 427.1 [M+l].

Example 5

N-(2-Chloro-4-fluoro-3-(3-methyl-4-oxo-3,4-dihvdroquinazolin-6-ylamino)phenyl)-l- cyclopropylmethanesulfonamide

[00291] N-(2-Chloro-4-fluoro-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6- ylamino)phenyl)-l-cyclopropylmethanesulfonamide (0.082 g, 48% yield) was prepared according to the general procedure of Example 1, substituting N-(2-chloro-4-fluoro-3-(3- methyl-4-oxo-3 ,4-dihydroquinazolin-6-ylamino)phenyl)- 1 -cyclopropylmethanesulfonamide for N-(3-amino-4-chloro-2-fluorophenyl)propane-l -sulfonamide. 1H NMR (400 MHz, (CD₃)₂SO) δ 9.43 (br s, 1H), 8.34 (br s, 1H), 8.1 1 (s, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.34 (m, 2H), 7.22 (m, 1H), 7.09 (s, 1H), 3.40 (s, 3H), 3.09 (d, J=7.1 Hz, 2H), 1.07 (m, 1H), 0.53 (m, 2H), 0.32 (m, 2H). LC/MS: m/z 437.1, 439.1 [M+l].

Example 6

N-(2-Chloro-4-fluoro-3 -(methyl(3 -methyl-4-oxo-3 ,4-dihvdroquinazolin-6- yl amino)phenyl)propane- 1 -sulfonamide

[00292] Step A: N-(2-Chloro-4-fluoro-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6- ylamino)phenyl)-N-(4-methoxybenzyl)propane-l -sulfonamide (0.45 g, 49% yield) was prepared according to the general procedure of Example 1, substituting N-(3-amino-2-chloro- 4-fluorophenyl)-N-(4-methoxybenzyl)propane- 1 -sulfonamide for N-(3 -amino-4-chloro-2- fluorophenyl)propane-l -sulfonamide. LC/MS: m/z 545.2, 547.2 [M+l].

[00293] Step B: N-(2-Chloro-4-fluoro-3-(methyl(3-methyl-4-oxo-3,4- dihydroquinazolin-6-yl)amino)phenyl)-N-(4-methoxybenzyl)propane- 1 -sulfonamide was prepared according to the general procedure of Example 3, Step A, substituting N-(2-chloro- 4-fluoro-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)-N-(4- methoxybenzyl)propane- 1 -sulfonamide for N-(2,4-difluoro-3-(3-methyl-4-oxo-3,4- dihydroquinazolin-6-ylamino)phenyl)-N-(4-methoxybenzyl)propane- 1 -sulfonamide. LC/MS : m/z 559.2, 561.2 [M+l].

[00294] Step C: N-(2-Chloro-4-fluoro-3-(methyl(3-methyl-4-oxo-3,4- dihydroquinazolin-6-yl)amino)phenyl)propane-l -sulfonamide (0.025 g, 74% yield over 2 steps) was prepared according to the general procedure of Example 3, Step B substituting N- (2-chloro-4-fluoro-3 -(methyl(3 -methyl-4-oxo-3 ,4-dihydroquinazolin-6-yl)amino)phenyl)-N- (4-methoxybenzyl)propane- 1 -sulfonamide for N-(2,4-difluoro-3 -(methyl(3 -methyl-4-oxo- 3,4-dihydroquinazolin-6-yl)amino)phenyl)-N-(4-methoxybenzyl)propane- 1 -sulfonamide. 1H NMR (400 MHz, (CD₃)₂SO) δ 9.56 (br s, 1H), 8.15 (s, 1H), 7.55-7.50 (m, 2H), 7.43 (m, 1H), 7.08 (d, J=3.0 Hz, 1H), 7.08 (m, 1H), 3.44 (s, 3H), 3.27 (s, 3H), 3.11 (m, 2H), 1.73 (m, 2H), 0.94 (t, J=7.4 Hz, 3H). LC/MS: m/z 439.1, 441.1 [M+l].

Exam le 7

N-(2-Chloro-4-fluoro-3 -(quinoxalin-6-ylamino)phenvDpropane- 1 -sulfonamide

[00295] N-(2-Chloro-4-fiuoro-3 -(quinoxalin-6-ylamino)phenyl)propane- 1 -sulfonamide (53%) was prepared according to Example 1, using 6-bromoquinoxaline and N-(3-amino-2- chloro-4-fluorophenyl)propane-l -sulfonamide. 1H NMR (400 MHz, (CD₃)₂SO) 5 9.57 (s, 1H), 8.72 (s, 1H), 8.70 (s, 1H), 8.61 (s, 1H), 7.91-7.93 (d, 1H), 7.42-7.48 (m, 3H), 6.73-6.76 (m, 1H), 3.12-3.16 (m, 2H), 1.75-1.80 (m, 2H), 0.96-1.00 (t, 3H); m/z (APCI-neg) M-l = 393.0, 395.0.

Example 8

N-(2-Chloro-4-fluoro-3 -(4-memoxyquinazolin-6-ylamino)phenyl)propane- 1 -sulfonamide

[00296] Step A: 6-Bromo-4-chloroquinazoline (1.00 g, 4.11 mmol) was treated with 0.5M NaOMe (82.1 mL, 41.1 mmol) at room temperature for 2 hours. The reaction mixture was concentrated, and the crude solids were washed with water and dried in vacuo to give 6- bromo-4-methoxyquinazoline (0.83 g, 84% yield) as a solid. LC/MS: m/z 239.0, 241.0 [M+l].

[00297] Step B: N-(2-Chloro-4-fluoro-3-(4-methoxyquinazolin-6- ylamino)phenyl)propane-l -sulfonamide (0.100 g, 55% yield) was prepared according to the general procedure of Example 1, substituting 6-bromo-4-methoxyquinazoline for 6-bromo-3- methylquinazolin-4(3H)-one. 1H NMR (400 MHz, (CD₃)₂SO) δ 9.57 (br s, IH), 8.57 ( s, IH), 8.54 (s, IH), 7.78 (d, J=9.2 Hz, IH), 7.50 (m, IH), 7.40 (m, 2H), 6.91 (s, IH), 4.03 (s, 3H), 3.13 (m, 2H), 1.77 (m, 2H), 0.97 (t, J=7.0 Hz, 3H). LC/MS: m/z 425.1, 427.1 [M+l].

Exam le 9

N-(2-Chloro-3 -(4-ethoxyquinazolin-6-ylamino)-4-fluorophenyl)propane- 1 -sulfonamide

[00298] Step A: 6-Bromo-4-ethoxyquinazoline (0.61 g, 59% yield) was prepared according to the general procedure in Example 8, Step A, substituting NaOEt for NaOMe. LC/MS: m/z 253.1, 255.1 [M+l].

[00299] Step B: N-(2-Chloro-3-(4-ethoxyquinazolin-6-ylamino)-4- fluorophenyl)propane-l -sulfonamide (0.100 g, 55% yield) was prepared according to the general procedure in Example 1, substituting 6-bromo-4-ethoxyquinazoline for 6-bromo-3- methylquinazolin-4(3H)-one. 1H NMR (400 MHz, (CD₃)₂SO) δ 9.56 (br s, IH), 8.55 ( s, 2H), 7.76 (d, J=8.6 Hz, IH), 7.42-7.38 (m, 3H), 7.02 (s, IH), 4.53 (q, J=7.0 Hz, 2H), 3.13 (m, 2H), 1.77 (m, 2H), 1.37 (t, J=7.0 Hz, 3H), 0.97 (t, J=7.0 Hz, 3H). LC/MS: m/z 439.1, 441.1 [M+l].

Example 10

N-(2-Chloro-4-fluoro-3 -(3 -Π -methyl- 1 H-pyrazol-4- vD-4-oxo-3 ,4-dihydroquinazolin-6- ylamino)phenyQpropane- 1 -sulfonamide

[00300] Step A: HATU (0.329 g, 0.867 mmol), DBU (0.152 g, 1.000 mmol) and 1- methyl-lH-pyrazol-4-amine hydrochloride (0.0745 mL, 0.800 mmol) were added to 6- bromoquinazolin-4(3H)-one (0.150 g, 0.667 mmol) in MeCN (3.5 mL). The solution was aged for 25 hours at ambient temperature before it was diluted with EtOAc and washed with brine-water. The concentrated organics were purified via silica gel chromatography eluting with 2% MeOH-EtOAc to yield 6-bromo-3-(l-methyl-lH-pyrazol-4-yl)quinazolin-4(3H)-one (0.018 g, 0.059 mmol, 18% yield).

[00301] Step B: N-(2-Chloro-4-fluoro-3-(3-(l-methyl-lH-pyrazol-4-yl)-4-oxo-3,4- dihydroquinazolin-6-ylamino)phenyl)propane-l -sulfonamide (0.005 g, 17% yield) was prepared according to the general procedure in Example 1, substituting N-(3-amino-2-chloro- 4-fluorophenyl)propane- 1 -sulfonamide for N-(3 -amino-4-chloro-2-fluorophenyl)propane- 1 - sulfonamide and 6-bromo-3-methylquinazolin-4(3H)-one for 6 -bromo-3-(l -methyl- 1H- pyrazol-4-yl)quinazolin-4(3H)-one. ^!H NMR (400 MHz, CD₃OD) δ 9.22 (s, 1H), 8.12 (s, 1H), 7.81 (s, 1H), 7.67-7.71 (m, 1H), 7.51-7.56 (m, 1H), 7.43-7.47 (m, 1H), 7.34-7.36 (m, 1H), 7.24-7.30 (m, 1H), 3.98 (s, 3H), 3.09-3.15 (m, 2H), 1.81-1.91 (m, 2H), 1.01-1.06 (m, 3H). LC/MS: m/z 491.2 [M+l].

Example 11

N-(2,4-Difluoro-3 -(3 -( 1 -methyl- 1 H-pyrazol-4-yl)-4-oxo-3 ,4-dihydroquinazolin-6- ylamino)phenyl)propane- 1 -sulfonamide

[00302] N-(2,4-Difluoro-3-(3-(l-methyl-lH-pyrazol-4-yl)-4-oxo-3,4- dihydroquinazolin-6-ylamino)phenyl)propane-l -sulfonamide (0.006 g, 21% yield) was prepared according to the Example 10, Step B, substituting N-(3-amino-4-chloro-2- fluorophenyl)propane-l -sulfonamide for N-(3-amino-2,4-difIuorophenyl)propane-l - sulfonamide. 1H NMR (400 MHz, CD₃OD) δ 8.20 (s, 1H), 8.07 (s, 1H), 7.79 (s, 1H), 7.59- 7.63 (m, 1H), 7.29-7.41 (m, 3H), 7.05-7.12 (m, 1H), 3.96 (s, 3H), 3.07-3.12 (m, 2H), 1.80- 1.91 (m, 2H), 1.00-1.05 (m, 3H). LC/MS: m/z 475.2 [M+l].

Example 12

N-(2-CMoro-4-fluoro-3-(4-oxo-3-phenyl-3,4-dihvo^oquinazolin-6-ylamino)phenyl)propane-

1 -sulfonamide

[00303] Step A: HATU (0.329 g, 0.867 mmol), DBU (0.152 g, 1.000 mmol) and aniline (0.0745 mL, 0.800 mmol) were added to 6-bromoquinazolin-4(3H)-one (0.150 g, 0.667 mmol) in MeCN (3.5 mL). The solution was aged for 25 hours at ambient temperature before it was diluted with EtOAc and washed with brine-water. The concentrated organics were purified via silica gel chromatography eluting with 2% MeOH-EtOAc to yield 6-bromo- 3-phenylquinazolin-4(3H)-one (0.042 g, 0.139 mmol, 20.9% yield).

[00304] Step B: N-(2-Chloro-4-fluoro-3-(4-oxo-3-phenyl-3,4-dihydroquinazolin-6- ylamino)phenyl)propane-l -sulfonamide (0.005 g, 7.4% yield) was prepared according to the general procedure in Example 1, substituting N-(3-amino-2-chloro-4-fluorophenyl)propane- 1 -sulfonamide for N-(3-amino-4-chloro-2-fluorophenyl)propane-l -sulfonamide and 6-bromo- 3-methylquinazolin-4(3H)-one for 6-bromo-3-phenylquinazolin-4(3H)-one. 1H NMR (400 MHz, CD₃OD) δ 8.09 (s, 1H), 7.61-7.64 (m, 1H), 7.43-7.58 (m, 6H), 7.34-7.38 (m, 1H), 7.30-7.32 (m, 1H), 7.18-7.24 (m, 1H), 3.07-3.13 (m, 2H), 1.80-1.90 (m, 2H), 0.99-1.04 (m, 3H). LC/MS: m/z 487.1 [M+l].

Example 13

N-(3-(3-Benzyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)-2-chloro-4-fluorophenyl)propane-

1 -sulfonamide

[00305] Step A: HATU (0.329 g, 0.867 mmol), DBU (0.152 g, 1.000 mmol) and phenylmethanamine (0.0902 mL, 0.800 mmol) were added to 6-bromoquinazolin-4(3H)-one (0.150 g, 0.667 mmol) in MeCN (3.5 mL). The solution was aged for 25 hours at ambient temperature before it was diluted with EtOAc and washed with brine-water. The concentrated organics were purified via silica gel chromatography eluting with 2% MeOH- EtOAc to yield 3-benzyl-6-bromoquinazolin-4(3H)-one (0.020 g, 0.0635 mmol, 9.5% yield).

[00306] Step B: N-(3-(3-Benzyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)-2-chloro-4- fluorophenyl)propane-l -sulfonamide (0.020 g, 36% yield) was prepared according to the general procedure in Example 1, substituting N-(3-amino-2-chloro-4-fluorophenyl)propane- 1 -sulfonamide for N-(3-amino-4-chloro-2-fluorophenyl)propane-l -sulfonamide and 6-bromo- 3-methylquinazolin-4(3H)-one for 3-benzyl-6-bromoquinazolin-4(3H)-one. 1H NMR (400 MHz, CD₃OD) δ 8.43 (s, IH), 8.34 (s, IH), 7.54-7.58 (m, IH), 7.25-7.39 (m, 7H), 7.09-7.11 (m, IH), 5.14 (s, IH), 3.07-3.13 (m, 2H), 1.70-1.79 (m, 2H), 0.94-0.99 (m, 3H). LC/MS: m/z 501.2 [M+l].

Example 14

N-(2-Chloro-4-fluoro-3 -(4-(methylamino)quinazolin-6- ylamino)phenyl propane- 1 - sulfonamide

[00307] Step A: PyBOP (0.347 g, 0.667 mmol), DBU (0.152 g, 1.000 mmol), and methylamine (0.400 mL, 0.800 mmol) were added to 6-bromoquinazolin-4(3H)-one (0.150 g, 0.667 mmol) in MeCN (3.5 mL). The solution was aged for 25 hours at ambient temperature before it was diluted with EtOAc and washed with brine-water. The concentrated organics were purified via trituration with DCM to provide 6-bromo-N-methylquinazolin-4-amine (0.055 g, 0.231 mmol, 35.7% yield).

[00308] Step B: N-(2-Chloro-4-fluoro-3-(4-(methylamino)quinazolin-6- ylamino)phenyl)propane-l -sulfonamide (0.003 g, 3.1% yield) was prepared according to the general procedure in Example 1, substituting N-(3-amino-2-chloro-4-fluorophenyl)propane- 1 -sulfonamide for N-(3-amino-4-chloro-2-fluorophenyl)propane-l -sulfonamide and 6-bromo- 3-methylquinazolin-4(3H)-one for 6-bromo-N-methylquinazolin-4-amine. 1H NMR (400 MHz, CD₃OD) δ 8.43 (s, IH), 8.34 (s, IH), 8.20-8.25 (br s, 2H), 7.60-7.64 (m, IH), 7.46-7.52 (m, 2H), 7.22-7.28 (m, IH), 7.02-7.05 (m, IH), 3.11 (s, 3H), 3.11-3.16 (m, 2H), 1.84-1.92 (m, 2H), 1.02-1.07 (m, 3H). LC/MS: m/z 424.1 [M+l].

Example 15

N-(2-Chloro-3 -(4-(dimethylamino)quinazolin-6-ylamino)-4-fluorophenyl)propane- 1 - sulfonamide

[00309] Step A: PyBOP (0.347 g, 0.667 mmol), DBU (0.152 g, 1.000 mmol), and dimethylamine (0.400 mL, 0.800 mmol) were added to 6-bromoquinazolin-4(3H)-one (0.150 g, 0.667 mmol) in MeCN (3.5 mL). The solution was aged for 25 hours at ambient temperature before it was diluted with EtOAc and washed with brine-water. The concentrated organics were purified via silica gel chromatography eluting with EtOAc to provide 6-bromo-N,N-dimethylquinazolin-4-amine (0.042 g, 0.167 mmol, 25% yield).

[00310] Step B: N-(2-Chloro-3-(4-(dimethylamino)quinazolin-6-ylamino)-4- fluorophenyl)propane-l -sulfonamide (0.005 g, 6.9% yield) was prepared according to the general procedure in Example 1, substituting N-(3-amino-2-chloro-4-fluorophenyl)propane- 1 -sulfonamide for N-(3-amino-4-chloro-2-fluorophenyl)propane-l -sulfonamide and 6-bromo- 3-methylquinazolin-4(3H)-one for 6-bromo-N,N-dimethylquinazolin-4-amine. 1H NMR (400 MHz, CD₃OD) 5 8.32 (s, 1H), 7.62-7.66 (m, 1H), 7.42-7.47 (m, 1H), 7.36-7.40 (m, 1H), 7.20-7.26 (m, 1H), 7.09-7.11 (m, 1H), 3.23 (s, 6H), 3.10-3.16 (m, 2H), 1.82-1.92 (m, 2H), 1.01-1.07 (m, 3H). LC/MS: m/z 438.2 [M+l].

Example 16

N-(2-Chloro-4-fluoro-3 -(4-(4-methylpiperazin- 1 -yl)quinazolin-6-ylamino)phenyl)propane- 1 - sulfonamide

[00311 ] N-(2-Chloro-4-fluoro-3 -(4-(4-methylpiperazin- 1 -yl)quinazolin-6- ylamino)phenyl)propane-l -sulfonamide (0.002 g, 2.5% yield) was prepared according to the general procedure in Example 14, substituting methylamine for methyl piperazine and substituting 6-bromo-N-methylquinazolin-4-amine for 6-bromo-4-(4-methylpiperazin-l- yl)quinazoline. 1H NMR (400 MHz, CD₃OD) δ 8.71 (s, 1H), 7.80-7.83 (m, 1H), 7.62-7.66 (m, 1H), 7.46-7.52 (m, 1H), 7.29-7.34 (m, 1H), 6.97-6.99 (m, 1H), 3.29-3.32 (m, 8H), 3.18- 3.23 (m, 2H), 2.96 (s, 3H), 1.87-1.97 (m, 2H), 1.06-1.11 (m, 3H). LC/MS: m/z 493.2 [M+l].

Example 17

tert-Butyl 4-(6-(2-chloro-6-fluoro-3-(propylsulfonamido)phenylamino)quinazolin-4- vOpiperazine- 1 -carboxylate

[00312] tert-Butyl 4-(6-(2-cMoro-6-fluoro-3- ( ropylsulfonarnido)phenylamino)quinazolin-4-yl)piperazine- 1 -carboxylate sulfonamide (0.020 g, 27% yield) was prepared according to the general procedure in Example 14, substituting methylamine for tert-butyl piperazine-l-carboxylate and substituting 6-bromo-N- methylquinazolin-4-amine for tert-butyl 4-(6-bromoquinazolin-4-yl)piperazine-l -carboxylate. 1H NMR (400 MHz, CDC1₃) δ 8.68 (s, 1H), 7.84-7.87 (m, 1H), 7.47-7.53 (m, 1H), 7.34-7.38 (m, 1H), 7.15-7.20 (m, 1H), 6.97-7.0 (m, 1H), 6.67-6.71 (br s, 1H), 5.97-5.99 (br s, 1H), 3.54-3.61 (m, 8H), 3.10-3.15 (m, 2H), 1.85-1.95 (m, 2H), 1.50 (s, 9H), 1.04-1.09 (m, 3H). LC/MS: m/z 579.3 [M+l].

Example 18

N-(2-Chloro-4-fluoro-3 -(4-(piperazin- 1 -yl)quinazolin-6-ylamino phenyl)propane- 1 - sulfonamide

[00313] tert-Butyl 4-(6-(2-chloro-6-fluoro-3- (propylsulfonamido)phenylamino)quinazolin-4-yl)piperazine-l -carboxylate (0.020 g, 0.035 mmol) was taken up in DCM (1 mL) and cooled to 0°C. TFA (1 mL) was added, and after 1 hour at 0°C, the solution was concentrated under reduced pressure. The residue was then taken up in 1M HCl-dioxane (2 mL) and re-concentrated to provide N-(2-chloro-4-fluoro-3- (4-(piperazin- 1 -yl)quinazolin-6-ylamino)phenyl)propane- 1 -sulfonamide hydrochloride (0.015 g, 0.030 mmol, 90% yield). 1H NMR (400 MHz, CD₃OD) δ 8.70 (s, 1H), 7.78-7.82 (m, 1H), 7.60-7.64 (m, 1H), 7.48-7.53 (m, 1H), 7.29-7.35 (m, 1H), 7.06-7.09 (m, 1H), 4.35-4.40 (m, 4H), 3.44-3.49 (m, 4H), 3.16-3.22 (m, 2H), 1.85-1.95 (m, 2H), 1.04-1.09 (m, 3H). LC/MS: m/z 47902 [M+l].

Example 19

N-(2-Chloro-4-fluoro-3 -(quinazolin-6-ylamino)phenyl)propane- 1 -sulfonamide

[00314] N-(2-Chloro-4-fluoro-3-(quinazolin-6-ylamino)phenyl)propane-l -sulfonamide (0.050 g, 26.5% yield) was prepared according to the general procedure in Example 1, substituting N-(3-amino-2-chloro-4-fluorophenyl)propane-l -sulfonamide for N-(3-amino-4- chloro-2-fluorophenyl)propane-l -sulfonamide and 6-bromo-3-methylquinazolin-4(3H)-one for 6-bromoquinazoline. 1H NMR (400 MHz, CDC1₃) δ 9.18 (s, 1H), 9.21 (s, 1H), 7.96-7.99 (m, 1H), 7.54-7.59 (m, 1H), 7.49-7.54 (m, 1H), 7.17-7.23 (m, 1H), 6.93-6.96 (m, 1H), 6.74- 6.77 (br s, 1H), 5.99-6.02 (br s, 1H), 3.10-3.15 (m, 2H), 1.85-1.96 (m, 2H), 1.04-1.09 (m, 3H). LC/MS: m/z 395.1 [M+l].

Example 20

N-(2,4-Difluoro-3-(quinazolin-6-ylarnino)phenyl)propane-l-sulfonamide

[00315] Step A: N-(2,4-Difluoro-3-(quinazolin-6-ylamino)phenyl)-N-(4- methoxybenzyl)propane-l -sulfonamide (0.050 g, 28% yield) was prepared according to the general procedure in Example 1, substituting N-(3-amino-2-chloro-4-fluorophenyl)propane- 1 -sulfonamide for N-(3 -amino-2,4-difluorophenyl)-N-(4-methoxybenzyl)propane- 1 - sulfonamide and 6-bromo-3-methylquinazolin-4(3H)-one for 6-bromoquinazoline. LC/MS: m/z 499.2 [M+l].

[00316] Step B: N-(2,4-Difluoro-3-(quinazolin-6-ylamino)phenyl)-N-(4- methoxybenzyl)propane-l -sulfonamide (0.010 g, 0.020 mmol) was taken up in TFA (1 mL) and warmed to 50°C for 30 minutes. Concentration under reduced pressure and trituration of the residue with DCM provided N-(2,4-difluoro-3-(quinazolin-6-ylamino)phenyl)propane-l- sulfonamide (0.004 g, 0.011 mmol, 53% yield). 1H NMR (400 MHz, CDC1₃) δ 9.21 (s, 1H), 9.18 (s, 1H), 7.96-8.00 (m, 1H), 7.50-7.55 (m, 1H), 7.37-7.43 (m, 1H), 7.04-7.10 (m, 1H), 6.99-7.01 (m, 1H), 6.43-6.47 (br s, 1H), 5.82-5.86 (br s, 1H), 3.10-3.15 (m, 2H), 1.86-1.96 (m, 2H), 1.05-1.09 (m, 3H). LC/MS: m/z 377.7 [M+l].

Example 21

N-(2^-Difluoro-3-(memyl(quinazolin-6-yl amm^

[00317] Step A: N-(2,4-Difluoro-3-(quinazolin-6-ylamino)phenyl)-N-(4- methoxybenzyl)propane-l -sulfonamide (0.050 g, 28% yield) was prepared according to the general procedure in Example 1, substituting N-(3-amino-2-chloro-4-fluorophenyl)propane- 1 -sulfonamide for N-(3 -amino-2,4-difluorophenyl)-N-(4-methoxybenzyl)propane- 1 - sulfonamide and 6-bromo-3-methylquinazolin-4(3H)-one for 6-bromoquinazoline. LC MS: m/z 499.2 [M+l].

[00318] Step B: NaH (0.00882 g, 0.221 mmol) was added to N-(2,4-difluoro-3- (quinazolin-6-ylamino)phenyl)-N-(4-methoxybenzyl)propane-l -sulfonamide (0.044 g, 0.0883 mmol) in DMF (1 mL) at ambient temperature. After 10 minutes, Mel (0.0275 mL, 0.441 mmol; d 2.275) was added and stirred for 1 hour. The suspension was diluted with EtOAc and washed with brine-water. The organics were concentrated under reduced pressure to afford N-(2,4-difluoro-3-(methyl(quinazolin-6-yl)amino)phenyl)-N-(4- methoxybenzyl)propane-l -sulfonamide (0.040 g, 0.0780 mmol, 88.4% yield).

[00319] Step C: N-(2,4-Difluoro-3-(methyl(quinazolin-6-yl)amino)phenyl)-N-(4- methoxybenzyl)propane-l -sulfonamide (0.010 g, 0.020 mmol) was taken up in TFA (1 mL) and warmed to 50°C for 30 minutes. Concentration under reduced pressure and trituration of the residue with DCM provided N-(2,4-difluoro-3-(methyl(quinazolin-6- yl)amino)phenyl)propane-l -sulfonamide (0.004 g, 0.010 mmol, 52% yield). 1H NMR (400 MHz, CDC1₃) δ 9.25 (s, 1H), 9.14 (s, 1H), 7.84-7.88 (m, 1H), 7.53-7.60 (m, 1H), 7.23-7.25 (m, 1H), 7.05-7.11 (m, 1H), 7.01-7.03 (m, 1H), 6.61-6.65 (br s, 1H), 3.44 (s, 3H), 3.09-3.15 (m, 2H), 1.88-1.95 (m, 2H), 1.03-1.09 (m, 3H). LC/MS: m/z 393.2 [M+l].

Example 22

N-(2-Chloro-4-fluoro-3 -(methyl(quinazolin-6- yl)amino)phenyl)propane- 1 -sulfonamide

[00320] N-(2-Chloro-4-fluoro-3 -(methyl(quinazolin-6-yl)amino)phenyl)propane- 1 - sulfonamide (0.004 g, 52% yield) was prepared according to the procedure in Example 21, substituting N-(3-amino-2,4-difluorophenyl)-N-(4-methoxybenzyl)propane- 1 -sulfonamide for N-(3-amino-2-chloro-4-fluorophenyl)-N-(4-methoxybenzyl)propane-l -sulfonamide. 1H NMR (400 MHz, CDC1₃) δ 9.26 (s, 1H), 9.13 (s, 1H), 7.85-7.88 (m, 1H), 7.70-7.75 (m, 1H), 7.20-7.25 (m, 1H), 7.12-7.16 (m, 1H), 6.94-6.97 (m, 1H), 6.77-6.80 (br s, 1H), 3.41 (s, 3H), 3.11-3.16 (m, 2H), 1.85-1.95 (m, 2H), 1.05-1.10 (m, 3H). LC/MS: m/z 409.1 [M+l].

Example 23

N-(2-C yano-3 -(quinazolin-6- ylamino)phenyl propane- 1 -sulfonamide

[00321] Step A: 2-Fluoro-6-(quinazolin-6-ylamino)benzonitrile (0.100 g, 26.4% yield) was prepared according to the general procedure in Example 1, substituting N-(3-amino-2- chloro-4-fluorophenyl)propane-l -sulfonamide for 2-amino-6-fluorobenzonitrile and 6- bromo-3-methylquinazolin-4(3H)-one for 6-bromoquinazoline. LC/MS: m/z 265.1 [M+l].

[00322] Step B: NaH (0.020 g, 0.50 mmol) was added to propane- 1 -sulfonamide (0.062 g, 0.50 mmol) in DMA (0.7 mL). After 20 minutes, a solution of 2-fluoro-6- (quinazolin-6-ylamino)benzonitrile (0.066 g, 0.25 mmol) in DMA (1 mL) was slowly added. The mixture was sealed and placed in a microwave for 6 hours at 210°C. The resulting solution was diluted with EtOAc and washed with NRjCl-brine-water. The concentrated residue was then partitioned between EtAOc and aqueous sodium bicarbonate. The aqueous was washed with EtOAc, then acidified to pH 6 and extracted with EtOAc. The organics were dried over sodium sulfate and concentrated under reduce pressure. The residue was purified via silica gel chromatography eluting with 1% MeOH-EtOAc to provide N-(2-cyano- 3-(quinazolin-6-ylamino)phenyl)propane-l -sulfonamide (0.010 g, 0.027 mmol, 11% yield). 1H NMR (400 MHz, CD₃OD) δ 9.33 (s, 1H), 9.07 (s, 1H), 7.94-7.98 (m, 1H), 7.84-7.88 (m, 1H), 7.60-7.61 (m, 1H), 7.53-7.58 (m, 1H), 7.31-7.34 (m, 1H), 7.21-7.24 (m, 1H), 3.19-3.24 (m, 2H), 1.87-1.97 (m, 2H), 1.05-1.10 (m, 3H). LC/MS: m/z 368.1 [M+l].

Example 24

N-(2-Cyano-3 -(methyl(quinazolin-6-yl)amino)phenyl)propane- 1 -sulfonamide

[00323] Step A: 2-Fluoro-6-(quinazolin-6-ylamino)benzonitrile (0.100 g, 26.4% yield) was prepared according to the general procedure in Example 1, substituting N-(3-amino-2- chloro-4-fluorophenyl)propane-l -sulfonamide for 2-amino-6-fluorobenzonitrile and 6- bromo-3-methylquinazolin-4(3H)-one for 6-bromoquinazoline. LC/MS: m/z 265.1 [M+l].

[00324] Step B: NaH (0.00568 g, 0.142 mmol) was added to 2-fIuoro-6-(quinazolin-6- ylamino)benzonitrile (0.592 mL, 0.118 mmol) in DMF at 0°C. After 10 minutes at ambient temperature, Mel (0.0148 mL, 0.237 mmol) was added and stirred for 20 minutes. The suspension was diluted with EtOAc and washed with brine-water. The organics were concentrated under reduced pressure to afford 2-fluoro-6-(methyl(quinazolin-6- yl)amino)benzonitrile (0.035 g, 0.126 mmol, 106%).

[00325] Step C: NaH (0.010 g, 0.25 mmol) was added to propane- 1 -sulfonamide (0.031 g, 0.25 mmol) in DMA (0.5 mL). After 20 minutes, a solution of 2-fluoro-6- (methyl(quinazolin-6-yl)amino)benzonitrile (0.035 g, 0.13 mmol) in DMA (1 mL) was slowly added. The mixture was sealed and placed in a microwave for 6 hours at 210°C. The resulting solution was diluted with EtOAc and washed with NFL_tCl-brine-water. The concentrated residue was then partitioned between EtAOc and aqueous sodium bicarbonate. The aqueous was washed with EtOAc, then acidified to pH 6 and extracted with EtOAc. The organics were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via silica gel chromatography eluting with 1% MeOH-EtOAc to provide N-(2-cyano-3-(methyl(quinazolin-6-yl)amino)phenyl)propane-l -sulfonamide (0.005 g, 0.013 mmol, 10% yield). ¹H NMR (400 MHz, CD₃OD) δ 9.35 (s, 1H), 9.02 (s, 1H), 7.83-7.86 (m, 1H), 7.69-7.74 (m, 1H), 7.49-7.54 (m, 2H), 7.34-7.36 (m, 1H), 7.27-7.31 (m, 2H), 3.53 (s, 3H), 3.20-3.25 (m, 2H), 1.85-1.95 (m, 2H), 1.04-1.09 (m, 3H). LC/MS: m/z 382.3 [M+l].

Example 25

O CN

N-(2-Cvano-4-fluoro-3-(3-methyl-4-oxo-3,4-dihvdroquinazolin-6-yloxy phenyl)propane-l- sulfonamide

[00326] Step A: 60% Sodium hydride (0.0522 g, 1.31 mmol) was slowly added to 6- hydroxy-3-methylquinazolin-4(3H)-one (0.2 g, 1.14 mmol; Maillard, Jacques, et al. "(3H)- Quinazolin-4-one derivatives with antiinflammatory activity. II. Derivatives substituted in the aromatic nucleus, and related compounds." Chim. Ther. 2(4) (1967): 231-9) in DMF (4 mL) cooled in ice. When gas evolution ceased, the mixture was stirred at room temperature for 15 minutes, then cooled in ice, and a solution of 2,3,6-trifluorobenzonitrile (0.178 g, 1.14 mmol) in DMF (1 mL) was added. The mixture was allowed to stir at ambient temperature. After 1 hour, the reaction mixture was diluted with water, and the resulting solid was collected by vacuum filtration, washed with water and a small amount of hexane. Ή NMR and LC/MS were consistent with the desired 3,6-difluoro-2-(3-methyl-4-oxo-3,4- dihydroquinazolin-6-yloxy)benzonitrile (0.294 g, 0.939 mmol, 82.7% yield). Ή NMR (400 MHz, CDC1₃) δ 8.01 (s, 1H), 7.77 (d, 1H), 7.55-7.61 (m, 2H), 7.41-7.48 (m, 1H), 7.09-7.14 (m, 1H), 3.58 (s, 3H). LC/MS: m/z 314.1 [M+l].

[00327] Step B: 60% Sodium hydride (0.0287 g, 0.718 mmol) was slowly added to propane- 1 -sulfonamide (0.0826 g, 0.670 mmol) in NMP (5 mL) cooled in ice. After addition, the mixture was stirred at 50°C for 30 minutes. 3,6-Difluoro-2-(3-methyl-4-oxo-3,4- dihydroquinazolin-6-yloxy)benzonitrile (0.10 g, 0.319 mmol; Step A) was added to the mixture. The reaction was stirred at 120°C overnight. The cooled reaction mixture was partitioned between 0.1M NaOH and EtOAc. The aqueous layer was washed with EtOAc, acidified to pH 4 with 6M HC1, and extracted with 2 portions of EtOAc. The combined EtOAc extracts were washed with 3 portions water, brine, dried over MgS0₄, filtered, and evaporated to yield a solid. This was absorbed on silica gel, dry-loaded on a 10 g Biotage SNAP column, and chromatographed with EtOAc. Fractions 16-24 contained solid. ^!H NMR and LC/MS were consistent with the desired N-(2-cyano-4-fluoro-3-(3-methyl-4-oxo- 3, 4-dihydroquinazolin-6-yloxy)phenyl)propane-l -sulfonamide (0.0136 g, 0.0327 mmol, 10.2% yield). 1H NMR (400 MHz, CD₃OD) δ 8.27 (s, 1H), 7.77 (d, 1H), 7.62-7.67 (m, 2H), 7.54-7.57 (m, 2H), 3.58 (s, 3H), 3.19-3.23 (m, 2H), 1.86-1.96 (m, 2H), 1.07 (t, 3H). LC/MS: m/z AM 2 [M+l].

Exam le 26

N-(2-Cvano-3-(3-methyl-4-oxo-3,4-dihvdroquinazolin-6-yloxy)phenyl)propane-l- sulfonamide

[00328] Step A: 60% Sodium hydride (0.0522 g, 1.31 mmol) was slowly added to 6- hydroxy-3-methylquinazolin-4(3H)-one (0.200 g, 1.14 mmol) in DMF (3 mL) cooled in ice. When gas evolution ceased, the mixture was stirred 15 minutes at room temperature, then 2,6-difluorobenzonitrile (0.158 g, 1.14 mmol) was added, and the mixture was stirred at 80°C. After 1 hour, the reaction mixture was allowed to cool and was diluted with water. The resulting solid was collected by vacuum filtration, washed with water and some hexane. 1H NMR and LC/MS were consistent with the desired 2-fluoro-6-(3-methyl-4-oxo-3,4- dihydroquinazolin-6-yloxy)benzonitrile (0.297 g, 1.01 mmol, 88.6% yield). Ή NMR (400 MHz, CDC1₃) δ 8.05 (s, 1H), 7.92 (d, 1H), 7.80 (d, 1H), 7.48-7.56 (m, 2H), 6.98 (t, 1H), 6.72 (d, 1H), 3.61 (s, 3H). LC/MS: m/z 296.1 [M+l].

[00329] Step B: 60% Sodium hydride (0.0291 g, 0.728 mmol) was slowly added to propane- 1 -sulfonamide (0.0876 g, 0.711 mmol) in NMP (5 mL) cooled in ice. After addition, the mixture was stirred at 50°C for 30 minutes. 2-Fluoro-6-(3-methyl-4-oxo-3,4- dihydroquinazolin-6-yloxy)benzonitrile (0.10 g, 0.339 mmol) was added to the mixture. The reaction mixture was stirred at 140°C overnight, then at 180°C for 8 hours. The cooled reaction mixture was partitioned between 0.5M NaOH and EtOAc. The aqueous layer was washed with EtOAc, acidified to pH 5 with 6M HC1, and extracted with 2 portions of EtOAc. The combined EtOAc extracts were washed with twice with brine, dried over MgS0₄, filtered, and evaporated to yield solid (0.09 g). This was absorbed on silica gel, dry-loaded on a 10 g Biotage SNAP column, and chromatographed with 10:1 DCM:MeOH to afford N- (2-cyano-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yloxy)phenyl)propane-l-sulfonamide (0.0166 g, 0.0417 mmol, 12.3% yield) as a solid. 1H NMR (400 MHz, CD₃OD) δ 8.29 (s, 1H), 7.80 (d, 1H), 7.79 (s, 1H), 7.58-7.65 (m, 2H), 7.40-7.47 (m, 2H), 3.59 (s, 3H), 3.21-3.27 (m, 2H), 1.82-1.86 (m, 2H), 1.08 (t, 3H). LC MS: m/z 399.2 [M+l].

Exam le 27

N-(4-Chloro-2-cyano-3 -(3 -methyl-4-oxo-3 ,4-dihvdroquinazolin-6-yloxy)phenyl)propane- 1 - sulfonamide

[00330] Step A: 60% Sodium hydride (0.0522 g, 1.31 mmol) was slowly added to 6- hydroxy-3-methylquinazolin-4(3H)-one (0.200 g, 1.14 mmol) in DMF (4 mL). When gas evolution ceased, a solution of 3-chloro-2,6-difluorobenzonitrile (0.197 g, 1.14 mmol) in DMF (1 mL) was added, and the mixture was stirred at ambient temperature. After 30 minutes, the reaction mixture was diluted with water, stirred for 20 minutes, and the resulting solid was collected by vacuum filtration, washed with water then a small amount of hexane, and dried under high vacuum to afford 3-chloro-6-fluoro-2-(3-methyl-4-oxo-3,4- dihydroquinazolin-6-yloxy)benzonitrile (0.279 g, 0.846 mmol, 74.5% yield). 1H NMR (400 MHz, CDC1₃) δ 8.01 (s, 1H), 7.78 (d, 1H), 7.72 (q, 1H), 7.56 (dd, 1H), 7.45 (d, 1H), 7.16 (dd, 1H), 3.58 (s, 3H). LC/MS: m/z 330.1 [M+l].

[00331] Step B: 60% Sodium hydride (0.0255 g, 0.637 mmol) was added to propane-

1 - sulfonamide (0.0785 g, 0.637 mmol) in NMP (4 mL) in a vial cooled in ice. After gas evolution ceased, the mixture was stirred at 40°C for 15 minutes, and then 3-chloro-6-fluoro-

2- (3-methyl-4-oxo-3,4-dihydroquinazolin-6-yloxy)benzonitrile (0.100 g, 0.303 mmol) was added. The mixture was stirred and heated at 120°C for 4 hours. The cooled reaction mixture was partitioned between 0.5M NaOH and EtOAc. The aqueous layer was washed with EtOAc, acidified to pH 5 with 6 M HCl, and extracted with 2 portions of EtOAc. The combined EtOAc extracts were washed twice with brine, dried over MgS0₄, filtered, and evaporated to yield glass (0.21 g). This was chromatographed on a 10 g Biotage SNAP column with 20:1 EtOAc:MeOH to afford impure desired product (0.0098 g). This was triturated with Et₂0 to provide N-(4-chloro-2-cyano-3-(3-methyl-4-oxo-3,4- dihydroquinazolin-6-yloxy)phenyl)propane-l -sulfonamide (0.0063 g, 0.0146 mmol, 4.80% yield). 1H NMR (400 MHz, CD₃OD) δ 8.26 (s, 1H), 7.83 (d, 1H), 7.77 (d, 1H), 7.59 (dd, 1H), 7.42 (d, 1H), 3.57 (s, 3H), 3.20-3.24 (m, 2H), 1.85-1.94 (m, 2H), 1.06 (t, 3H). LC/MS: m/z 433.1 [M+l].

Ex mple 28

N-(4-Chloro-2-cyano-3 -(3 -methyl-4-oxo-3 ,4-dihvdroquinazolin-6-ylamino)phenyl)propane-

1 -sulfonamide

[00332] N-(4-Chloro-2-cyano-3 -(3 -methyl-4-oxo-3 ,4-dihydroquinazolin-6- ylamino)phenyl)propane-l -sulfonamide (0.024 g, 22% yield) was prepared according to the general procedure in Example 1, substituting N-(3-amino-4-chloro-2-cyanophenyl)propane- 1-sulfonamide for N-(3-amino-4-chloro-2-fluorophenyl)propane-l -sulfonamide. 1H NMR

(400 MHz, CD₃OD) δ 8.16 (s, 1H), 7.76 (d, 1H), 7.61 (d, 1H), 7.39-7.44 (m, 3H), 3.57 (s, 3H), 3.18-3.22 (m, 2H), 1.84-1.94 (m, 2H), 1.05 (t, 3H). LC/MS: m/z 432.1 [M+l].

Example 29

N-(2-Cvano-3-(3-methyl-4-oxo-3^-dihydroquinazolin-6-ylarnino phenyl)propane-l- sulfonamide

[00333] N-(2-Cyano-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6- ylamino)phenyl)propane-l -sulfonamide (0.0295 g, 18.7% yield) was prepared according to the general procedure in Example 1, substituting N-(3-amino-2-cyanophenyl)propane-l- sulfonamide for N-(3 -amino-4-chloro-2-fluorophenyl)propane- 1 -sulfonamide . ¹ H NMR (400 MHz, CD₃OD) δ 8.20 (s, 1H), 7.89 (d, 1H), 7.60-7.67 (m, 2H), 7.49 (dd, 1H), 7.21 (d, 1H), 7.15 (d, 1H), 3.59 (s, 3H), 3.18-3.22 (m, 2H), 1.87-1.96 (m, 2H), 1.07 (t, 3H). LC/MS: m/z 398.2 [M+l].

Exam le 30

N-(4-Chloro-2-fluoro-3 -(3 -methyl-4-oxo-3 ,4-dihydroquinazolin-6- ylammo)phenyl)dimethylsulfamide

[00334] Potassium carbonate (0.035 g, 0.25 mmol) and dimethylsulfarnoyl chloride (0.014 mL, 0.13 mmol) were added to N-(4-chloro-2-fiuoro-3-(3-methyl-4-oxo-3,4- dihydroquinazolin-6-ylamino)phenyl)propane-l -sulfonamide (0.036 g, 0.085 mmol) in DMF (0.75 mL). The suspension was aged at ambient temperature for 48 hours before addition of 2M NaOH (1 mL). After an additional 2 hours, the solution was diluted with EtOAc and washed with brine-water. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with DCM then EtOAc to provide N-(4-chloro-2-fluoro-3 -(3 -methyl-4-oxo-3 ,4-dihydroquinazolin-6- ylamino)phenyl)dimethylsulfamide (0.010 g, 0.023 mmol, 28% yield). 1H NMR (400 MHz, CD₃OD) δ 8.12 (s, 1H), 7.55-7.58 (m, 1H), 7.40-7.45 (m, 1H), 7.29-7.36 (m, 2H), 7.24-7.27 (m, 1H), 3.55 (s, 3H), 2.81 (s, 6H). LC/MS: m/z 426.1, [M+l].

Exam le 31

N-(4-Chloro-2-fluoro-3-(3-methyl-4-oxo-3,4-dihvdroquinazolin-6- ylamino phenyl)pyrrolidine- 1 -sulfonamide

[00335] Potassium carbonate (0.037 g, 0.27 mmol) and pyrrolidine- 1-sulfonyl chloride (0.018 mL, 0.13 mmol) were added to N-(4-chloro-2-fluoro-3-(3-methyl-4-oxo-3,4- dihydroquinazolin-6-ylamino)phenyl)propane-l -sulfonamide (0.038 g, 0.089 mmol) in DMF (0.75 mL). The suspension was aged at ambient temperature for 48 hours before addition of 2M NaOH (1 mL). After an additional 2 hours, the solution was diluted with EtOAc and washed with brine-water. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with DCM then EtOAc to provide N-(4-chloro-2-fluoro-3 -(3 -methyl-4-oxo-3 ,4-dihydroquinazolin-6- ylamino)phenyl)pyrrolidine-l -sulfonamide (0.006 g, 0.013 mmol, 15% yield). 1H NMR (400 MHz, CD₃OD) δ 8.11 (s, 1H), 7.54-7.57 (m, 1H), 7.42-7.47 (m, 1H), 7.29-7.35 (m, 2H), 7.24-7.27 (m, 1H), 3.55 (s, 3H), 2.27-2.30 (m, 4H), 1.83-1.87 (m, 4H). LC/MS: m/z 452.1, [M+l].

Exam le 32

N-(2,4-Difluoro-3 -(3 -methyl-4-oxo-3 ,4-dihvdroquinazolin-6-ylamino)phenyl)-3 - fluoropropane- 1 -sulfonamide

[00336] Step A: N-(2,4-Difluoro-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6- ylamino)phenyl)-3-fluoro-N-(4-methoxybenzyl)propane-l -sulfonamide (32%) was prepared according to the general procedure of Example 2, Step A, substituting N-(3-amino-2,4- difluorophenyl)-3 -fluoro-N-(4-methoxybenzyl)propane- 1 -sulfonamide for N-(3 -amino-2,4- difluorophenyl)-N-(4-methoxybenzyl)propane-l -sulfonamide, m/z (APCI-pos) M+l = 547.1.

[00337] Step B: N-(2,4-Difluoro-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6- ylamino)phenyl)-3 -fluoropropane- 1 -sulfonamide (74%) was prepared according to the general procedure of Example 2, Step B, using N-(2,4-difluoro-3-(3-methyl-4-oxo-3,4- dihydroquinazolin-6-ylamino)phenyl)-3 -fluoro-N-(4-methoxybenzyl)propane- 1 -sulfonamide for N-(2,4-difluoro-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)-3-fluoro-N- (4-methoxybenzyl)propane-l-sulfonamide. 1H NMR (400 MHz, (CD₃)₂SO) δ 9.82 (s, 1H), 8.48 (s, 1H), 8.17 (s, 1H), 7.53-7.56 (d, 1H), 7.22-7.30 (m, 4H), 4.59-4.62 (t, 1H), 4.47-4.50 (t, 1H), 3.45 (s, 3H), 3.20-3.24 (m, 2H), 2.05-2.18 (m, 2H); m/z (APCI-neg) M-l = 425.1.

Example 33

N-(2,4-Difluoro-3-(methylQ-meth^

fluoropropane- 1 -sulfonamide

[00338] Step A: N-(2,4-Difluoro-3-(methyl(3-methyl-4-oxo-3,4-dihydroquinazolin-6- yl)amino)phenyl)-3 -fluoro-N-(4-methoxybenzyl)propane- 1 -sulfonamide ( 100%) was prepared according to the general procedure of Example 3, Step A, substituting N-(2,4- difluoro-3 -(3 -methyl-4-oxo-3 ,4-dihydroquinazolin-6-ylamino)phenyl)-3 -fluoro-N-(4- methoxybenzyl)propane- 1 -sulfonamide for N-(2,4-difluoro-3 -(3-methyl-4-oxo-3 ,4- dihydroquinazolin-6-ylamino)phenyl)-N-(4-methoxybenzyl)propane-l-sulfonamide.

[00339] Step B: N-(2,4-Difluoro-3-(methyl(3-methyl-4-oxo-3,4-dihydroquinazolin-6- yl)amino)phenyl)-3 -fluoropropane- 1 -sulfonamide (33%) was prepared according to the general procedure of Example 3, Step B, substituting N-(2,4-difluoro-3-(methyl(3-methyl-4- oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-3-fluoro-N-(4-methoxybenzyl)propane-l- sulfonamide for N-(2,4-difluoro-3 -(methyl(3 -methyl-4-oxo-3 ,4-dihydroquinazolin-6- yl)amino)phenyl)-N-(4-methoxybenzyl)propane-l -sulfonamide. 1H NMR (400 MHz, (CD₃)₂SO) δ 9.88 (s, 1H), 8.18 (s, 1H), 7.42-7.48 (m, 1H), 7.27-7.33 (m, 1H), 7.22-7.23 (d, 1H), 7.13-7.16 (m, 1H), 4.57-4.59 (t, 1H), 4.45-4.48 (t, 1H), 3.46 (s, 3H), 3.33 (s, 3H), 3.20- 3.24 (m, 2H), 2.03-2.16 (m, 2H); m/z (APCI-neg) M-l = 439.1.

mple 34

N-(2-Chloro-4-fluoro-3-(3-methyl-4-oxo-3,4-dihvdroquinazolin-6-ylamino)phenyl)-3- fluoropropane- 1 -sulfonamide

[00340] Step A: N-(2-Chloro-4-fluoro-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6- ylamino)phenyl)-3 -fluoropropane- 1 -sulfonamide (44%) was prepared according to the general procedure of Example 4, Step A, substituting N-(3-amino-2-chloro-4-fluorophenyl)- 3 -fluoro-N-(4-methoxybenzyl)propane- 1 -sulfonamide for N-(3 -amino-2,4-difluorophenyl)- N-(4-methoxybenzyl)propane- 1 -sulfonamide.

[00341] Step B: N-(2-Chloro-4-fluoro-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6- ylamino)phenyl)-3 -fluoropropane- 1 -sulfonamide (37%) was prepared according to the general procedure of Example 4, Step B, substituting N-(2-chloro-4-fluoro-3-(3-methyl-4- oxo-3 ,4-dihydroquinazolin-6-ylamino)phenyl)-3 -fluoro-N-(4-methoxybenzyl)propane- 1 - sulfonamide for N-(2,4-difluoro-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6- ylamino)phenyl)-3-fluoro-N-(4-methoxybenzyl)propane-l -sulfonamide. ^!H NMR (400 MHz, (CD₃)₂SO) δ 9.71 (s, 1H), 8.42 (s, 1H), 8.15 (s, 1H), 7.52-7.55 (d, 1H), 7.37-7.39 (m, 2H), 7.24-7.27 (m, 1H), 7.14 (s, 1H) 4.60-4.63 (t, 1H), 4.48-4.51 (t, 1H), 3.45 (s, 3H), 3.23- 3.27 (m, 2H), 2.08-2.21 (m, 2H); m/z (APCI-pos) M+l = 441.0, 443.0.

Example 35

N-(4-Chloro-2-fluoro-3 -(methyl(3 -methyl-4-oxo-3 ,4-dihydroquinazolin-6- yl amino)phenyl)propane- 1 -sulfonamide

[00342] Step A: N-(4-Chloro-2-fluoro-3-(methyl(3-methyl-4-oxo-3,4- dihydroquinazolin-6-yl)amino)phenyl)-N-(4-methoxybenzyl)propane- 1 -sulfonamide ( 100%) was prepared according to the general procedure of Example 3, Step A, substituting N-(4- chloro-2-fluoro-3 -(3 -methyl-4-oxo-3 ,4-dihydroquinazolin-6-ylamino)phenyl)-N-(4- methoxybenzyl)propane- 1 -sulfonamide for N-(2,4-difluoro-3-(3 -methyl-4-oxo-3 ,4- dihydroquinazolin-6-ylammo)phenyl)-3-fluoro-N-(4-methoxybenzyl)propane-l-sulfonamide.

[00343] Step B: N-(4-Chloro-2-fluoro-3-(methyl(3-methyl-4-oxo-3,4- dihydroquinazolin-6-yl)amino)phenyl)propane-l -sulfonamide (71%) was prepared according to the general procedure of Example 3, Step B, substituting N-(4-chloro-2-fluoro-3- (methyl(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-N-(4- methoxybenzyl)propane- 1 -sulfonamide for N-(2,4-difluoro-3-(methyl(3-methyl-4-oxo-3,4- dihydroquinazolin-6-yl)amino)phenyl)-N-(4-methoxybenzyl)propane- 1 -sulfonamide. ^!H NMR (400 MHz, (CD₃)₂SO) δ 9.90 (s, 1H), 8.17 (s, 1H), 7.53-7.55 (d, 1H), 7.46-7.50 (m, 2H), 7.12-7.13 (d, 1H), 7.03-7.06 (m, 1H), 3.46 (s, 3H), 3.30 (s, 3H), 3.11-3.15 (m, 2H), 1.66-1.76 (m, 2H), 0.92-0.95 (t, 3H); m/z (APCI-pos) M+l = 439.9.

Exam le 36

N-(4-C oro-3-(5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)-2- fluorophenvDpropane- 1 -sulfonamide

[00344] Step A: N-(4-Chloro-2-fluoro-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6 ylamino)phenyl)-N-(4-methoxybenzyl)propane-l -sulfonamide (0.0235 g, 0.0431 mmol) was dissolved in THF. N-Chlorosuccinimide (0.00576 g, 0.0431 mmol) was added and stirred at room temperature for 3 days. The reaction was concentrated and partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over Na₂S0₄, filtered and concentrated. The crude product was purified by Biotage chromatography eluting with DCM/acetone to give N-benzyl-N-(4-chloro-3-(5-chloro-3-methyl-4-oxo-3,4- dihydroquinazolin-6-ylamino)-2-fluorophenyl)propane-l -sulfonamide (0.010 g, 40%) as an oil.

[00345] Step B: N-Benzyl-N-(4-chloro-3-(5-chloro-3-methyl-4-oxo-3,4- dihydroqumazolin-6-ylamino)-2-fluorophenyl)propane-l -sulfonamide was dissolved in neat TFA with one drop of water and stirred at room temperature for 30 minutes. The reaction was concentrated, and the residual solid was taken up in EtOAc and washed with saturated NaHC0₃ and brine, dried over Na₂S0₄, and concentrated. Biotage chromatography (hexanes/EtO Ac) provided N-(4-chloro-3 -(5 -chloro-3 -methyl-4-oxo-3 ,4-dihydroquinazolin- 6-ylamino)-2-fiuorophenyl)propane-l -sulfonamide (0.0056g, 71%) as a solid. 1H NMR (400 MHz, CDC1₃) δ 7.95 (s, 1H), 7.51-7.49 (d, 1H), 7.41-7.45 (t, 1H), 7.29-7.32 (m, 1H), 6.96- 6.99 (m, 1H), 6.76 (br s, 1H), 6.47 (br s, 1H), 3.58 (s, 3H), 3.10-3.14 (m, 2H), 1.84-1.93 (m, 2H), 1.04-1.08 (t, 3H); m/z (APCI-neg) M-l = 459.3, 461.3.

Example 37

N-(2-CMoro-3-(5-cMoro-3-methyl-4-oxo-3^-dihvdroquinazolin-6-ylamino -4-fluorophenyl)-

3-fluoropropane- 1 -sulfonamide

[00346] N-(2-Chloro-4-fluoro-3 -(3 -methyl-4-oxo-3 ,4-dihydroquinazolin-6- ylamino)phenyl)-3-fluoropropane-l -sulfonamide (0.0207 g, 0.0467 mmol) was dissolved in THF. N-Chlorosuccinimide (0.00624 g, 0.0467 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction was concentrated and partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over Na₂S0₄, filtered and concentrated. The crude product was purified by Biotage chromatography eluting with DCM/acetone to give N-(2-chloro-3-(5-chloro-3-methyl-4-oxo- 3 ,4-dihydroquinazolin-6-ylamino)-4-fluorophenyl)-3-fluoropropane-l -sulfonamide (0.0131 g, 59%) as a solid. 1H NMR (400 MHz, CDC1₃) δ 7.94 (s, 1H), 7.54-7.58 (dd, 1H), 7.49-7.51 (d, 1H), 7.16-7.21 (t, 1H), 6.96-6.98 (dd, 1H), 6.86 (br s, 1H), 6.48 (br s, 1H), 4.60-4.63 (t, 2H), 4.49-4.51 (t, 2H), 3.57 (s, 3H), 3.26-3.30 (m, 2H), 2.19-2.32 (m, 2H); m/z (APCI-neg) M-l = 475.0, 477.0.

Example 38

N-(2-CMoro-4-fluoro-3-(3-(methylamino quinoxalin-6-ylamino)phenyl)propane-l- sulfonamide

[00347] Step A: 7-Bromoquinoxalin-2(lH)-one (145.0 mg, 0.644 mmol) was dissolved in 0.1M MeCN (6.4 mL) and treated sequentially with 2.0M methylamine in tetrahydrofuran (354.4 μί, 0.709 mmol), l,8-diazabicyclo[5.4.0]undec-7-ene (115.6 μί, 0.773 mmol), and benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (342.0 mg, 0.773 mmol). The reaction mixture was stirred at ambient temperature for 16 hours and then concentrated in vacuo. Biotage chromatography (hexanes/EtOAc) provided 7-bromo-N-methylquinoxalin-2-amine (31.4 mg, 0.132 mmol, 20.5% yield). LC/MS: m/z 240.0 [M+l].

[00348] Step B: N-(2-Chloro-4-fluoro-3-(3-(methylamino)quinoxalin-6- ylamino)phenyl)propane-l -sulfonamide (10.0 mg, 0.024 mmol, 17.9% yield) was prepared according to the general procedure in Example 1 , substituting 7-bromo-N-methylquinoxalin- 2-amine for 6-bromo-3-methylquinazolin-4(3H)-one. 1H NMR (400 MHz, (CD₃)₂SO) δ = 9.548 (s, 1H), 8.258 (s, 1H), 7.970 (s, 1H), 7.563-7.541 (d, 1H), 7.395-7.344 (m, 3H), 6.907- 6.880 (d, 1H), 6.352 (s, 1H), 3.145-3.107 (t, 2H), 2.825-2.813 (d, 3H), 1.799-1.742 (m, 2H), 1.000-0.963 (t, 3H). LC/MS: m/z 424.1, 426.1 [M+l].

Exam le 39

N-(2-Chloro-4-fluoro-3-(3-methoxyquinoxalin-6-ylamino phenvnpropane-l-sulfonamide

[00349] Step A: 7-Bromoquinoxalin-2(lH)-one (313.1 mg, 1.391 mmol) was dissolved in 0.15M DMF (9.2 mL) and treated with potassium carbonate (288.4 mg, 2.087 mmol) and iodomethane (95.5 iL, 1.530 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was then diluted with water and extracted with EtOAc (2 X). The organics were washed with water (3 X) and brine (1 X), dried over Na₂S0₄, filtered and concentrated. Biotage chromatography (hexanes/EtOAc) provided 7- bromo-2-methoxyquinoxaline (25.2 mg, 0.105 mmol, 7.6% yield). 1H NMR (400 MHz, (CD₃)₂SO) δ = 8.642 (s, 1H), 8.070-8.064 (d, 1H), 7.971-7.950 (d, 1H), 7.801-7.774 (dd, 1H), 4.045 (s, 3H).

[00350] Step B: N-(2-Chloro-4-fluoro-3-(3-methoxyquinoxalin-6- ylamino)phenyl)propane-l -sulfonamide (12.1 mg, 0.029 mmol, 27.0% yield) was prepared according to the general procedure in Example 1, substituting 7-bromo-2- methoxyquinoxaline for 6-bromo-3-methylquinazolin-4(3H)-one. ^]H NMR (400 MHz, (CD₃)₂SO) δ = 9.583 (s, 1H), 8.590 (s, 1H), 8.250 (s, 1H), 7.822-7.799 (d, 1H), 7.459-7.389 (m, 2H), 7.231-7.203 (dd, 1H), 6.541 (s, 1H), 3.935 (s, 3H), 3.157-3.119 (t, 2H), 1.824-1.729 (m, 2H), 1.004-0.967 (t, 3H). LC MS: m/z 425.1, 427.1 [M+l].

Example 40

N-f 2-Chloro-4-fluoro-3 -(4-methyl-3 -oxo-3 ,4-dihvdroquinoxalin-6-ylamino)phenyl)propane-

1 -sulfonamide

[00351] Step A: 7-Bromoquinoxalin-2(lH)-one (313.1 mg, 1.391 mmol) was dissolved in 0.15M DMF (9.2 mL) and treated with potassium carbonate (288.4 mg, 2.087 mmol) and iodomethane (95.5 μΐ,, 1.530 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was then diluted with water and extracted with EtOAc (2 X). The organics were washed with water (3 X) and brine (1 X), dried over Na₂S04, filtered and concentrated. Biotage chromatography (hexanes/EtOAc) provided 7- bromo-l-methylquinoxalin-2(lH)-one (87.6 mg, 0.366 mmol, 26.3% yield). 1H NMR (400 MHz, (CD₃)₂SO) δ = 8.257 (s, 1H), 7.824 (s, 1H), 7.768-7.746 (d, 1H), 7.569-7.543 (dd, 1H), 3.591 (s, 3H).

[00352] Step B: N-(2-Chloro-4-fluoro-3-(4-methyl-3-oxo-3,4-dihydroquinoxalin-6- ylamino)phenyl)propane-l -sulfonamide (1.8 mg, 0.004 mmol, 1.2% yield) was prepared according to the general procedure in Example 1, substituting 7-bromo-l-methylquinoxalin- 2(lH)-one for 6-bromo-3-methylquinazolin-4(3H)-one. 1H NMR (400 MHz, (CD₃)₂SO) δ = 9.560 (s, 1H), 8.734 (s, 1H), 7.909 (s, 1H), 7.612-7.591 (d, 1H), 7.430-7.361 (m, 2H), 6.656- 6.635 (d, 1H), 6.578 (s, 1H), 3.457 (s, 3H), 3.147-3.109 (t, 2H), 1.817-1.724 (m, 2H), 0.999- 0.962 (t, 3H). LC/MS: m/z 425.2, 427.1 [M+l].

Example 41

N-(2,4-Difluoro-3 -(3 -methyl-4-oxo-3 ,4-dihydroquinazolin-6-ylamino)phenyl)f\iran-2- sulfonamide

[00353] Step A: Methyl 3-amino-2,6-difluorobenzoate (652.8 mg, 3.488 mmol) was dissolved in 0.2M DCM (17.4 mL), chilled to 0°C, and then treated sequentially with triethylamine (1.42 mL, 10.46 mmol) and furan-2-sulfonyl chloride (1.16 mg, 6.98 mmol). The reaction mixture was warmed to ambient temperature and stirred for 16 hours. The reaction mixture was diluted with EtOAc, washed with water (2 X) and brine (1 X), dried over Na₂S0₄, filtered and concentrated. The crude reaction mixture was then dissolved in 4:1 THF:MeOH (17.5 mL) and treated with 2.0M KOH (8.70 mL, 17.45 mmol) at ambient temperature for 2 hours. The organic solvent was then concentrated off in vacuo, and the reaction mixture was diluted with water and extracted with EtOAc (2 X). The aqueous layer was then acidified to pH 3 using 6.0M HC1 and extracted with EtOAc (2 X). The organics were washed with water (2 X) and brine (1 X), dried over Na₂S0₄, filtered and concentrated to afford 2,6-difluoro-3-(furan-2-sulfonamido)benzoic acid (475.0 mg, 1.57 mmol, 44.9% yield). LC MS: m/z 302.0 [M-l].

[00354] Step B: 2,6-Difluoro-3-(furan-2-sulfonamido)benzoic acid (475.0 mg, 1.57 mmol) was dissolved in 0.1M DMF (15.7 mL) and treated with triethylamine (637.4 μΕ, 4.70 mmol) and then diphenylphosphoryl azide (523.7 μί, 2.350 mmol) at ambient temperature for 1 hour. The reaction mixture was then treated with deionized water (5.0 mL) and heated to 80°C for 16 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc and washed with water (3 X) and brine (1 X), dried over Na₂S0₄, filtered and concentrated. Biotage chromatography (hexanes/EtOAc) provided N-(3-amino-2,4- difiuorophenyl)furan-2-sulfonamide (152.6 mg, 0.56 mmol, 35.5% yield). LC/MS: m/z 273.1 [M-l].

[00355] Step C: N-(2,4-Difluoro-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6- ylamino)phenyl)furan-2-sulfonamide (4.5 mg, 0.010 mmol, 9.6% yield) was prepared according to the general procedure in Example 1, substituting N-(3-amino-2,4- difluorophenyl)furan-2-sulfonamide for N-(3-amino-4-chloro-2-fluorophenyl)propane-l - sulfonamide. 1H NM (400 MHz, (CD₃)₂SO) δ =10.534 (s, 1H), 8.394 (s, 1H), 8.167 (s, 1H), 7.997 (s, 1H), 7.546-7.524 (d, 1H), 7.221-7.134 (m, 2H), 7.089-7.031 (m, 2H), 6.652 (s, 1H), 3.459 (s, 3H). LC/MS: m/z 431.1 [M-l].

N-(2-Chloro-3 -(4-ethyl-3 -oxo-3 -άίΙινάΓο ηίηοχ-ΐΙίη-ό-νΐ ηιΐηο^^-ίΙ^ΓορΙιεηνΠρΓο εηε- 1 - sulfonamide

[00356] Step A: 7-Bromo-l-ethylquinoxalin-2(lH)-one: 7-bromoquinoxalin-2(lH)- one (313.6 mg, 1.39 mmol) was dissolved in 0.2M DMF (7.0 mL) and treated with potassium carbonate (288.9 mg, 2.09 mmol) and iodoethane (123.7 \L, 1.53 mmol) at ambient temperature for 1 hour. The reaction mixture was then diluted with water and extracted with EtOAc (2 X). The organics were washed with water (3 X) and brine (1 X), dried over Na₂S0₄, filtered and concentrated. Biotage chromatography (hexanes/EtOAc) provided 7- bromo-l-ethylquinoxalin-2(lH)-one (169.2 mg, 0.67 mmol, 48.0% yield). 1H NMR (400 MHz, (CD₃)₂SO) δ = 8.611 (s, 1H), 8.038 (s, 1H), 7.954-7.937 (d, 1H), 7.787-7.764 (d, 1H), 4.517-4.474 (q, 2H), 1.431-1.402 (t, 3H).

[00357] Step B: N-(2-Chloro-3-(4-ethyl-3-oxo-3,4-dihydroquinoxalin-6-ylamino)-4- fluorophenyl)propane-l -sulfonamide (5.4 mg, 0.012 mmol, 1.9% yield) was prepared according to the general procedure in Example 1, substituting 7-bromo-l-ethylquinoxalin- 2(lH)-one for 6-bromo-3-methylquinazolin-4(3H)-one. 1H NMR (400 MHz, (CD₃)₂SO) δ = 9.568 (s, 1H), 8.700 (s, 1H), 7.901 (s, 1H), 7.624-7.602 (d, 1H), 7.406-7.386 (d, 2H), 6.677- 6.627 (t, 2H), 4.103-4.049 (q, 2H), 3.150-3.1 12 (t, 2H), 1.821-1.727 (m, 2H), 1.207-1.171 (t, 3H), 1.001-0.964 (t, 3H). LC/MS: m/z 437.1, 439.1 [M-l].

Example 43

N-(2-Chloro-4-fluoro-3 -(4-isopropyl-3 -oxo-3 ,4-dihydroquinoxalin-6- ylamino)phenvDpropane- 1 -sulfonamide

[00358] Step A: 7-Bromoquinoxalin-2(lH)-one (322.6 mg, 1.43 mmol) was dissolved in 0.1 M DMF (14.4 mL) and treated with potassium carbonate (297.2 mg, 2.15 mmol) and 2- iodopropane (157.7 ih, 1.58 mmol) at 50°C for 2 hours. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with EtOAc (2 X). The organics were washed with water (3 X) and brine (1 X), dried over Na₂S0₄, filtered and concentrated. Biotage chromatography (hexanes/EtOAc) provided 7-bromo-l-isopropylquinoxalin-2(lH)- one (1 1.5 mg, 0.043 mmol, 3.0% yield). 1H NMR (400 MHz, (CD₃)₂SO) 5 = 8.144 (s, 1H), 8.015 (s, 1H), 7.757-7.736 (d, 1H), 7.552-7.526 (dd, 2H), 5.133 (m, 1H), 1.531-1.515 (d, 6H).

[00359] Step B: N-(2-Chloro-4-fluoro-3-(4-isopropyl-3-oxo-3,4-dihydroquinoxalin-6- ylamino)phenyl)propane-l -sulfonamide (5.4 mg, 0.012 mmol, 27.7% yield) was prepared according to the general procedure in Example 1, substituting 7-bromo-l- isopropylquinoxalin-2(lH)-one for 6-bromo-3-methylquinazolin-4(3H)-one. 1H NMR (400 MHz, (CD₃)₂SO) δ = 9.576 (s, 1H), 8.648 (s, 1H), 7.831 (s, 1H), 7.601-7.578 (d, 1H), 7.412- 7.394 (d, 2H), 6.849 (s, 1H), 6.638-6.615 (d, 1H), 5.190 (m, 1H), 3.145-3.107 (t, 2H), 1.815- 1.722 (m, 2H), 1.472-1.454 (d, 6H), 0.997-0.959 (t, 3H). LC/MS: m/z 453.2, 455.1 [M+l].

Exam le 44

N-(4-Mefhyl-3 -(3 -mefhyl-4-oxo-3 ,4-dihydroquinazolin-6-ylamino)phenyl)propane- 1 - sulfonamide

[00360] Step A: DMAP (0.096 g, 0.79 mmol), pyridine (1.67 mL, 20.7 mmol) and propane- 1-sulfonyl chloride (2.32 mL, 20.7 mmol) were added to a solution of 4-mefhyl-3- nitroaniline (3 g, 19.7 mmol) in DCM (25 mL). The reaction was stirred at 45°C for 18 hours. The reaction mixture was then diluted with ethyl acetate and washed with water. The organics were dried with sodium sulfate, filtered and concentrated in vacuo to obtain a crude mixture of N-(4-methyl-3-nitrophenyl)propane-l -sulfonamide (5 g). Half of this crude mixture (2.5 g) was dissolved in ethanol (35 mL) and water (15 mL). Iron (5.4 g, 96.8 mmol) and ammonium chloride (2.1 g, 38.7 mmol) were subsequently added. The reaction was heated at reflux for 2 hours, after which salts were filtered off. The filtrate was diluted with ethyl acetate and water, and the layers were partitioned and washed with a saturated solution of NaCl. The aqueous layer was extracted twice with ethyl acetate. The organics were dried with sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography to obtain N-(3-amino-4-methylphenyl)propane-l -sulfonamide (2.46 g, quantitative yield). 1H NMR (400 MHz, CDC1₃) δ 6.98 (d, J = 8.0 Hz, 1H), 6.63 (d, J = 2.2 Hz, 1H), 6.45 (dd, J = 8.0, 2.2 Hz, 1H), 6.29 (s, 1H), 3.08 - 3.01 (m, 2H), 2.13 (br s, 2H) 1.90 - 1.78 (m, 2H), 1.01 (t, J = 7.5 Hz, 3H); m/z (ES-MS) 229.3 (100%) [M+l].

[00361] Step B: A sealed microwave vial was charged with 6-bromo-3- methylquinazolin-4(3H)-one (0.075 g, 0.31 mmol), N-(3-amino-4-methylphenyl)propane-l- sulfonamide (0.079 g, 0.35 mmol), Pd₂(dba)₃ (0.014 g, 0.016 mmol), (R)-BINAP (0.020 g, 0.031 mmol), sodium tert-butoxide (0.106 g, 1.10 mmol) and toluene (2.3 mL). The mixture was heated in a microwave reactor at 120°C for 15 minutes. The reaction mixture was filtered, and the filtrate was directly concentrated in vacuo. The crude product was purified by reverse phase HPLC to give N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6- ylamino)phenyl)propane-l -sulfonamide (23 mg, 19%). 1H NMR (500 MHz, (CD₃)₂SO) δ 9.58 (s, 1H), 8.14 (s, 1H), 7.94 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 2.6 Hz, 1H), 7.39 (dd, J = 8.8, 2.7 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 7.14 (d, J = 2.1 Hz, 1H), 6.85 (dd, J = 8.1, 2.2 Hz, 1H), 3.46 (s, 3H), 3.02 (dd, J = 8.6, 6.7 Hz, 2H), 2.14 (s, 3H), 1.74 - 1.60 (m, 2H), 0.94 (t, J = 7.5 Hz, 3H); m/z (ES-MS) 387.2 (96.1%) [M+1], LCMS retention time: 3.78 minutes.

[00362] The following compounds in Table 1 were prepared according to the general procedure of the Example Number given in the Method column using appropriate intermediates.

Table 1

Ex. Structure Name MS / NMR Method

#

45

[M+l]

46 N-(3-(ethyl(3-methyl- ¾ NMR (400 6

4-oxo-3,4- MHz, CDC1₃) δ

dihydroquinazolin-6- 7.89 (s, 1H),

yl)amino)-2,4- 7.56-7.51 (m, difluorophenyl)propan 3H), 7.09-6.97

e-1 -sulfonamide (m, 2H), 6.43 (s,

1H), 3.80 (m, 2H), 3.57 (s,

3H), 3.09 (m, 2H), 1.88 (m, 2H), 1.27 (m, 3H), 1.05 (t,

J=7.4 Hz, 3H);

LC/MS: m/z

437.2, 439.2

[M+l]

47 N-(3-(ethyl(3-methyl- Ή NMR (400 1

4-oxo-3,4- MHz, (CD₃)₂SO)

0 CI dihydroquinazolin-6- δ 9.40 (br s, 1H),

yl)amino)-2,4- 8.26 (br s, 1H), difluorophenyl)propan 8.21 (s, 1H),

e-1 -sulfonamide 7.62 (s, 1H),

7.58 (d, J=8.4

Hz, 1H), 7.51

(m, 1H), 7.29- 7.20 (m, 2H), 7.14 (m, 1H), 3.47 (s, 3H),

3.13 (m, 2H), 1.79 (m, 2H), 0.99 (t, J=7.4

Hz, 3H); LC/MS: m/z

425.1, 427.1

[M+l]

1 -cyclopropyl-N-(2,4- 'H NMR (400 1 difluoro-3 -(3 -methyl- MHz, (CD₃)₂SO)

H _F H

4-oxo-3,4- δ 9.69 (s, 1H), dihydroquinazolin-6- 8.45 (s, 1H), ylamino)phenyl)metha 8.16 (s, 1H),

nesulfonamide 7.53-7.55 (d,

1H), 7.17-7.29 (m, 4H), 3.45 (s, 3H), 3.09-3.11 (d, 2H), 1.02- 1.13 (m, 1H), 0.58-0.53 (m, 2H), 0.33-0.36 (m, 2H); m/z

(APCI-pos) M+l

- 421.1

N-(2,4-difluoro-3-(3- 'H NMR (400 1 methyl-4-oxo-3,4- MHz, (CD₃)₂SO)

H _F H

dihydroquinazolin-6- 5 9.68 (s, 1H), ylamino)phenyl)-2- 8.46 (s, 1H), methylpropane- 1 - 8.16 (s, 1H),

sulfonamide 7.53-7.55 (d,

1H), 7.27-7.29

(m, 1H), 7.21- 7.23 (m, 3H), 3.45 (s, 3H),

3.00-3.02 (m,

2H), 2.15-2.21 (m, 1H), 1.01- 1.03 (d, 6H); m/z

[00363] It will be understood that the enumerated embodiments are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the present invention as defined by the claims. Thus, the foregoing description is considered as illustrative only of the principles of the invention.

[00364] The words "comprise," "comprising," "include," "including," and "includes" when used in this specification and in the following claims are intended to specify the presence of stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

Claims

What is claimed is:

1. A compound selected from Formula I:

and stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:

the dashed lines represent optional double bonds;

W is selected from N, NR⁶, C(=0), CR⁷ and CHR⁷;

X is selected from N, NR⁸, C(=0), CR⁹ and CHR⁹, provided when:

(i) W is N, then X is CR⁹,

(ii) W is NR⁶, then X is C(=0) or CHR⁹,

(iii) W is C(=0), then X is NR⁸ or CHR⁹,

(iv) W is CR⁷, then X is N or CR⁹, and

(v) W is CHR⁷, then X is NR⁸, C(=0) or CHR⁹;

Y is selected from N, NR¹⁰, CR¹¹ and CHR¹¹;

Z is selected from N, NR¹², CR¹³ and CHR¹³;

L is selected from O, NR¹⁴, S, C(=0) and CR¹⁵R¹⁶;

1 2

R' and R' are independently selected from hydrogen, halogen, CN, Q-C3 alkyl, Ci-Ca alkoxy and C₂-C₃ alkynyl;

R is selected from hydrogen, halogen and C C3 alkyl;

R⁴ is selected from C₃-C₅ cycloalkyl, Ci-C^ alkyl, C₂-C₆ alkenyl, C₂-C alkynyl, phenyl, a 5-6 membered heteroaryl, or NR^aR^b, wherein the cycloalkyl, alkyl, alkenyl, alkynyl, phenyl and heteroaryl are optionally substituted with OR^c, halogen, phenyl, C₃-C₄ cycloalkyl, or C C₄ alkyl optionally substituted with halogen;

R⁵ is selected from hydrogen, Cj-C3 alkyl and C!-C₃ alkoxy, wherein the alkyl and alkoxy are optionally substituted with R^d;

R⁶ is selected from hydrogen, Q-C6 alkyl, Ci-C₆ alkenyl, Ci-C^ alkynyl, C₃-C cycloalkyl, phenyl, a 3 to 6 membered heterocyclyl, and a 5 to 6 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl and heteroaryl are optionally substituted with halogen, oxo (not on phenyl or heteroaryl), OR^e, SR^e, NR^fR^g, phenyl, Q-C₄ alkyl, C1-C4 alkoxy, and cyclopropyl, wherein the alkyl, alkoxy and cyclopropyl are optionally substituted with R^p;

R is selected from hydrogen, Ci-Ce alkyl, C]-C6 alkenyl, C C₆ alkynyl, C!-C₆ alkoxy, C₃-C₆ cycloalkyl, phenyl, a 3 to 6 membered heterocyclyl, a 5 to 6 membered heteroaryl, and NR^hR', wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, phenyl, heterocyclyl and heteroaryl are optionally substituted with halogen, oxo (not on phenyl or heteroaryl), OR^e, SR^e, NR^fR⁸, C!-C₄ alkyl, C C₄ alkoxy, and cyclopropyl, wherein the alkyl, alkoxy and cyclopropyl are optionally substituted with R^p;

R is selected from hydrogen, Q-C6 alkyl, Ci-C alkenyl, C_\-Ce alkynyl, C₃-C₆ cycloalkyl, phenyl, a 3 to 6 membered heterocyclyl, and a 5 to 6 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl and heteroaryl are optionally substituted with halogen, oxo (not on phenyl or heteroaryl), OR", SR*, NR^kR^!, phenyl, Q-Gj alkyl, Q-Q alkoxy, and cyclopropyl, wherein the alkyl, alkoxy and cyclopropyl are optionally substituted with R^p;

R⁹ is selected from hydrogen, Q-Q alkyl, Ci-Ce alkenyl, C!-C₆ alkynyl, C^Ce alkoxy, C₃-C₆ cycloalkyl, phenyl, a 3 to 6 membered heterocyclyl, a 5 to 6 membered heteroaryl, and NR^mRⁿ, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, phenyl, heterocyclyl and heteroaryl are optionally substituted with halogen, oxo (not on phenyl or heteroaryl), OR^J, SR^j, NR^¹, C_rC₄ alkyl, C C₄ alkoxy, and cyclopropyl, wherein the alkyl, alkoxy and cyclopropyl are optionally substituted with R^p;

R¹⁰ is selected from hydrogen and halogen;

R¹¹ is selected from hydrogen and halogen, or

R is hydrogen;

R is selected from hydrogen and halogen;

R¹⁴ is selected from hydrogen and C C₄ alkyl;

R¹⁵ and R¹⁶ are independently selected from hydrogen and Q-C3 alkyl;

R^a and R^b are independently selected from hydrogen or Q-C5 alkyl optionally substituted by halogen, or

R^a and R^b are taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or Ci-C₃ alkyl; R^c is selected from hydrogen and C C₆ alkyl optionally substituted by halogen;

each R^d is selected from halogen and OH;

R^e is selected from hydrogen and C_!-C₄ alkyl;

R^f and R^g are independently selected from hydrogen and C C₄ alkyl optionally substituted with halogen;

R^h and R¹ are independently selected from hydrogen and Q-C4 alkyl optionally substituted with halogen;

R^J is selected from hydrogen and Q-C4 alkyl;

R^k and R¹ are independently selected from hydrogen and C1-C4 alkyl optionally substituted with halogen;

R^m and Rⁿ are independently selected from hydrogen and C1-C₄ alkyl optionally substituted with halogen; and

each R^p is independently selected from halogen, oxo, C]-C₄ alkyl and C!-C4 alkoxy, wherein the alkyl and alkoxy are optionally substituted with halogen.

2. The compound of Claim 1 wherein the residue:

4. The compound of any one of Claims 1 to 3, having the Formula II:

II

The compound of any one of Claims 1 to 4, having the Formula III:

III

The compound of any one of Claims 1 to 5, having the Formula IV:

IV

7. The compound of Claim 6, wherein R⁶ is methyl, benzyl, phenyl or 1 -methyl lH-pyrazol-4-yl.

8. The compound of any one of Claims 1 to 5, having the Formula V:

9. The compound of Claim 8, wherein R⁷ is hydrogen, OCH₃ or NHCH₃. The compound of any one of Claims 1 to 5, havin the Formula VI:

VI

11. The compound of Claim 10, wherein R⁹ is hydrogen, OCH₃, OCH₂CH₃, NHCH₃, N(CH₃)₂, piperazin-l-yl, 4-methylpirperazin-l-yl or tert-butyl 4-piperazine-l carboxylate.

12. The compound of any one of Claims 1 to 5, having the Formula VII:

VII

The compound of Claim 12, wherein R is methyl, ethyl or isopropyl.

The compound of any one of Claims 1 to 13, wherein L is selected from O and

NR 14

15. The compound of any one of Claims 1 to 14, wherein L is O, NH, N(CH₃) or N(CH₂CH₃).

16. The compound of any one of Claims 1 to 15, wherein the residue:

17. The compound of any one of Claims 1 to 15, wherein R¹ is hydrogen, CI or F; R² is CI, F or CN; and R³ is hydrogen.

18. The compound of any one of Claims 1 to 17, wherein R⁴ is propyl, isobutyl, -CH₂CH₂CH₂F, cyclopropylmethyl, -N(CH₃)₂, pyrrolidine, or furan-2-yl.

19. The compound of any one of Claims 1 to 18, wherein R⁵ is hydrogen.

20. A compound of Claim 1 and named in any one of Examples 1-49.

21. A pharmaceutical composition, comprising a compound of any one of Claims 1-20 and a pharmaceutically acceptable carrier or excipient.

22. A method of preventing or treating a disease or disorder modulated by b-Raf, comprising administering to a mammal in need of such treatment an effective amount of a compound of any one of Claims 1-20.

23. A compound of any one of Claims 1-20 for use in therapy.

24. Use of a compound of any one of Claims 1-20 in the manufacture of a medicament for the treatment of cancer.

25. A pharmaceutical composition comprising a compound of any one of Claims 1-20 for use in the treatment of cancer.