WO2015184405A1 - Aromatic compounds, compositions and uses thereof - Google Patents

Aromatic compounds, compositions and uses thereof Download PDF

Info

Publication number
WO2015184405A1
WO2015184405A1 PCT/US2015/033407 US2015033407W WO2015184405A1 WO 2015184405 A1 WO2015184405 A1 WO 2015184405A1 US 2015033407 W US2015033407 W US 2015033407W WO 2015184405 A1 WO2015184405 A1 WO 2015184405A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
phenyl
alkyl
methyl
hydroxy
Prior art date
Application number
PCT/US2015/033407
Other languages
French (fr)
Inventor
Roopa Rai
Son Minh Pham
Anil Kumar AGARWAL
Sarvajit Chakravarty
Original Assignee
Medivation Technologies, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Medivation Technologies, Inc. filed Critical Medivation Technologies, Inc.
Publication of WO2015184405A1 publication Critical patent/WO2015184405A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/26—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a saturated carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/27—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/33—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/44—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/19—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same saturated acyclic carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/23—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same unsaturated acyclic carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/11—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
    • C07C317/40—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • This invention relates to new compounds that are bromodomain inhibitors and may find use in treating diseases and conditions, such as certain cancers, in which bromodomain is implicated.
  • Acetylation of histone lysines is important for regulation of chromatin-based gene transcription.
  • Histone acetylation is typically associated with activation of gene transcription by loosening the interaction of duplex DNA histone proteins. Not only does histone acetylation alter the three-dimensional chromatin structure, specific proteins also bind to acetylated lysine residues within histones to read the epigenetic code.
  • Bromodomains a conserved structural motif in chromatin-associated proteins and histone acetyltransferases, recognize acetyl-lysine residues on proteins. Bromodomain-containing proteins have a variety of cellular functions.
  • the bromodomain and extra-C terminal domain (BET) protein family consists of four members (BRD2, BRD3, BRD4, and BRDT), all of which contain two bromodomains. These proteins bind to acetylated lysine residues on the tails of histones H3 and H4 and regulate chromatin structure and gene expression. BRD2 and BRD3 may be involved in facilitating transcriptional elongation. BRD4 may be involved in recruitment of the pTEF- ⁇ complex to inducible genes, thereby playing a role in increasing transcriptional output.
  • BRD3 and BRD4 may also form fusion oncogenes with NUT (nuclear protein in testis), which may play a role in carcinogenesis.
  • NUT nuclear protein in testis
  • BRDT is a testis-specific chromatin protein that specifically binds histone H4 and plays a role in spermatogenesis.
  • BET bromodomain-containing proteins Due to the role of BET bromodomain-containing proteins in chromosomal regulation and cell division, small molecule inhibitors of these proteins have therapeutic potential for diseases such as cancer, in which these proteins may have a role. While certain small molecule inhibitors of BET bromodomain proteins are known (see, e.g., WO
  • New bromodomain inhibitors are provided herein, as are methods of using the compounds in therapy, such as in the treatment of cancer.
  • W is 0 r S0 2 , and Y is a bond, CH 2 or NH; or W is NH, and Y is C(0);
  • R 1 is hydrogen, Ci-C ⁇ alkyl, C 2 -C6 alkenyl, C6-Q4 aryl, heteroaryl, C(0)(R z ), C(0)OR z , C(0)NHR z , C(0)NR n R z , NHC(0)(R z ), N(R n )C(0)(R z ) or S(0) 2 R z , wherein the C1-C6 alkyl, C 2 -C6 alkenyl, C6-Q4 aryl, or heteroaryl of R 1 are independently optionally substituted with 1-3 Rc groups which may be the same or different; each R z is independently d-d alkyl, C3-C6 cycloalkyl, C6-C14 aryl or heteroaryl, each of which is optionally substituted with 1-3 R c groups which may be the same or different;
  • R 2 when present, is hydrogen, d-d alkyl, C3-C6 cycloalkyl, C(0)(R z ), aryl or heteroaryl, wherein the d-d alkyl or C3-C6 cycloalkyl of R 2 is optionally substituted with 1- 3 R c groups which may be the same or different, and wherein the aryl or heteroaryl of R 2 is optionally substituted with 1-3 R e groups which may be the same or different, or ZR 2 is taken together with R 5 to form an oxo group;
  • R 3 is hydrogen,Ci-C6 alkyl or C3-C6 cycloalkyl, wherein the d-d alkyl or C3-C6 cycloalkyl of R 3 is optionally substituted with 1-3 R c groups which may be the same or different;
  • R 5 when present, is hydrogen, d-d alkyl or C3-C6 cycloalkyl, wherein the d-d alkyl or C3-C6 cycloalkyl of R 5 is optionally substituted with 1-3 R c groups which may be the same or different, or R 5 is taken together with ZR 2 to form an oxo group;
  • R 7 is hydrogen or d-d alkyl, wherein the d-d alkyl of R 7 is optionally substituted with 1-3 R c groups which may be the same or different;
  • R 8 is hydrogen or d-d alkyl, wherein the d-d alkyl of R 8 is optionally substituted with 1-3 R c groups which may be the same or different;
  • R 9 is hydrogen, cyano ord-d alkyl, wherein the d-d alkyl of R 9 is optionally substituted with 1-3 R c groups which may be the same or different;
  • R 10 is hydrogen ord-d alkyl, wherein the d-d alkyl of R 10 is optionally substituted with 1-3 R c groups which may be the same or different;
  • R 11 is d-d alkyl, wherein the d-d alkyl of R 11 is optionally substituted with 1-3 R c groups which may be the same or different;
  • Q is N or CR 10 ;
  • X is a bond, CH 2 , CHOR 12 , NH, NR 11 or O;
  • Z when present, is NH, NR 2 , O, S, S(O) or S0 2 , or ZR 2 and R 5 are taken together to form an oxo;
  • each R a and R b is independently halo, OR 12 , NR 13 R 14 , CN, CONR 13 R 14 , S0 2 CH 3 , S0 2 NR 13 R 14 , d-d alkyl or d-d cycloalkyl, wherein each d-d alkyl of R a and R b and each d-d cycloalkyl of R a and R b is optionally substituted with 1-3 R d groups which may be the same or different; each , d-Ce alkyl, 12 Rc is independently halo, phenyl, heteroaryl C3-C6 cycloalkyl, OR or NR 13 R 14 , wherein the phenyl or heteroaryl of Rc is optionally substituted with 1-3 Re groups which may be the same or different;
  • each Ra is independently halo, OR 12 or NR 13 R 14 ;
  • each Re is independently halo, trifluoromethyl, C1-C4 alkyl, OR 12 or NR 13 R 14 ;
  • each R 12 is independently hydrogen, trifluoromethyl, C1-C4 alkyl or C3-C6 cycloalkyl
  • each R 13 is independently hydrogen, trifluoromethyl, C1-C4 alkyl or C3-C6 cycloalkyl
  • each R 14 is independently hydrogen, trifluoromethyl, C1-C4 alkyl or C3-C6 cycloalkyl
  • m is an integer from 0-3;
  • n is an integer from 0-5.
  • the compound is of the formula (I). In some embodiments of
  • the compo is of the formula (II). In some embodiments,
  • W is .
  • the compound is of the formula (B):
  • Y is a bond. In some of these embodiments, Y is NH. In some embodiments of the compounds of formula (I) or (II), W is S0 2 and Y is a bond.
  • Z is O.
  • R 2 is hydrogen or C(0)(R z ).
  • R 5 is hydrogen or C ⁇ -Ce alkyl (e.g., methyl).
  • R z is Ci-C alkyl (e.g., tert-b tyl).
  • m is 0. In some embodiments, m is 1 and R a is halo (e.g., chloro). In some embodiments, n is 0. In some embodiments, n is 1 and Rb is halo (e.g., chloro) or OR 12 . In some embodiments, R 12 is C1-C4 alkyl (e.g., methyl).
  • X is a bond and R 1 is hydrogen. In some embodiments, X is a bond and R 1 is C1-C6 alkyl optionally substituted with 1-3 Rc groups which may be the same or different. In some embodiments, Rc is NR 13 R 14 where R 13 and R 14 are independently hydrogen or C1-C4 alkyl. In some embodiments, X is a bond and R 1 is tert- butylaminomethyl.
  • X is O.
  • R 1 is hydrogen, C1-C6 alkyl, C 2 -C6 alkenyl, C6-Q4 aryl, heteroaryl, or C(0)(R z ), wherein the C1-C6 alkyl, C 2 -C6 alkenyl, C6-C14 aryl, or heteroaryl of R 1 are independently optionally substituted with 1-3 Rc groups which may be the same or different.
  • R 1 is hydrogen.
  • R 1 is C 2 -C6 alkenyl (e.g., allyl).
  • R 1 is heteroaryl (e.g., pyridyl). In some of these embodiments, R 1 is d-d alkyl optionally substituted with 1-3 Rc groups which may be the same or different (e.g., cyclopropylmethyl or benzyl). In some of these embodiments, R 1 is C(0)(R z ). In some embodiments, R z is Q- alkyl, C3-C6 cycloalkyl or -d 4 aryl, each of which is optionally substituted with 1-3 Rc groups which may be the same or different. In some embodiments, R z is d-d alkyl (e.g., tert-b tyl).
  • R z is C3-C6 cycloalkyl (e.g., cyclopropyl). In some embodiments, R z is phenyl optionally substituted with 1-3 Rc groups which may be the same or different (e.g., hydroxyphenyl).
  • X is NH or NR 11 .
  • R 11 is d-d alkyl.
  • R 11 is d-d alkyl substituted with 1-3 Rc groups which may be the same or different (e.g., benzyl or 2-hydroxyethyl).
  • R 1 is hydrogen, C1-C6 alkyl, - alkenyl, d-d 4 aryl, heteroaryl, or C(0)(R z ), wherein the d-d alkyl, C 2 - alkenyl, C6-C14 aryl, or heteroaryl of R 1 are independently optionally substituted with 1-3 Rc groups which may be the same or different.
  • R 1 is d-d alkyl optionally substituted with 1-3 Rc groups which may be the same or different.
  • R 1 is cyclopropylmethyl, 2-hydroxyethyl or benzyl.
  • R 1 is heteroaryl optionally substituted with 1-3 Rc groups which may be the same or different.
  • R 1 is pyridyl (e.g., pyridin-4-yl), quinolinyl (e.g., quinolin-6-yl) or pyrazolyl substituted with 1-3 Rc groups which may be the same or different (e.g., l-methyl-2-cyclopropylpyrazol-5-yl).
  • R 1 is phenyl optionally substituted with 1-3 Rc groups which may be the same or different (e.g., 3 -hydroxyphenyl or 4-hydroxyphenyl).
  • X is CH 2 or CHOR 12 .
  • R 12 is hydrogen.
  • R 1 is hydrogen, d-d alkyl, C 2 -C6 alkenyl, C6-C14 aryl, heteroaryl, C(0)OR z , C(0)NHR z , C(0)NR n R z , NHC(0)(R z ), or N(R n )C(0)(R z ), wherein the d-d alkyl, -d alkenyl, -d4 aryl and heteroaryl of R 1 are independently optionally substituted with 1-3 Rc groups which may be the same or different.
  • R 1 is phenyl.
  • R 1 is C(0)OR z where R z is d-d alkyl (e.g., tert-butyl). In some of these embodiments, R 1 is C(0)NHR z where R z is d-d alkyl (e.g., ethyl). In some of these embodiments, R 1 is NHC(0)(R z ) where R z is d-d alkyl (e.g., ethyl, isopropyl or tert-butyl). In some of these embodiments, R z is d-d alkyl (e.g., methyl, ethyl, isopropyl or tert-butyl).
  • R 3 is hydrogen or d-Ce alkyl optionally substituted with 1-3 R c groups which may be the same or different. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is Q-C6 alkyl (e.g., methyl).
  • a pharmaceutical composition comprising a compound described herein, such as a compound of the formula (I), (II), (A), or (B), or variations thereof, or a compound selected from Compound Nos. 1, la, lb and 2-53, or a salt thereof, and a pharmaceutically acceptable carrier.
  • a method of treating cancer in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound described herein, such as a compound of the formula (I), (II), (A), or (B), or variations thereof, or a compound selected from Compound Nos. 1, la, lb and 2-53, or a pharmaceutically acceptable salt thereof.
  • a compound described herein such as a compound of the formula (I), (II), (A), or (B), or variations thereof, or a compound selected from Compound Nos. 1, la, lb and 2-53, or a pharmaceutically acceptable salt thereof.
  • a compound described herein such as a compound of the formula (I), (II), (A), or (B), or variations thereof, or a compound selected from Compound Nos. 1, la, lb and 2-53, or a salt thereof, for use in a method of treating cancer in an individual in need thereof.
  • a compound described herein such as a compound of the formula (I), (II), (A), or (B), or variations thereof, or a compound selected from Compound Nos. 1, la, lb and 2-53, or a salt thereof, in the manufacture of a medicament for the treatment of cancer.
  • a compound described herein such as a compound of the formula (I), (II), (A), or (B), or variations thereof, or a compound selected from Compound Nos. 1, la, lb and 2-53, or a salt thereof, in the treatment of cancer.
  • a compound described herein such as a compound of the formula (I), (II), (A), or (B), or variations thereof, or a compound selected from Compound Nos. 1, la, lb and 2-53, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in an individual in need thereof.
  • a compound described herein such as a compound of the formula (I), (II), (A), or (B), or variations thereof, or a compound selected from Compound Nos. 1, la, lb and 2-53, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
  • a compound described herein such as a compound of the formula (I), (II), (A), or (B), or variations thereof, or a compound selected from Compound Nos. 1, la, lb and 2-53, or a pharmaceutically acceptable salt thereof, in the treatment of cancer.
  • kits comprising a compound described herein, such as a compound of the formula (I), (II), (A), or (B), or variations thereof, or a compound selected from Compound Nos. 1, la, lb and 2-53, or a pharmaceutically acceptable salt thereof, optionally comprising instructions for use in treating cancer.
  • a compound described herein such as a compound of the formula (I), (II), (A), or (B), or variations thereof, or a compound selected from Compound Nos. 1, la, lb and 2-53, or a pharmaceutically acceptable salt thereof, optionally comprising instructions for use in treating cancer.
  • W is or S0 2 , and Y is a bond, CH 2 or NH; or W is NH, and Y is C(0);
  • R 1 is hydrogen, Q-C6 alkyl, C 2 -C6 alkenyl, C6-Q4 aryl, heteroaryl, C(0)(R z ), C(0)OR z , C(0)NHR z , C(0)NR n R z , NHC(0)(R z ), N(R n )C(0)(R z ) or S(0) 2 R z , wherein the C1-C6 alkyl, C 2 -C6 alkenyl, C6-Q4 aryl, or heteroaryl of R 1 are independently optionally substituted with 1-3 Rc groups which may be the same or different;
  • R z is C1-C6 alkyl, C3-C6 cycloalkyl, C6-Q4 aryl or heteroaryl, each of which is optionally substituted with 1-3 Rc groups which may be the same or different;
  • R 2 when present, is hydrogen, Q-C6 alkyl, C3-C6 cycloalkyl, C(0)(R z ), aryl or heteroaryl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl of R 2 is optionally substituted with 1- 3 Rc groups which may be the same or different, and wherein the aryl or heteroaryl of R 2 is optionally substituted with 1-3 Re groups which may be the same or different, or ZR 2 is taken together with R 5 to form an oxo group;
  • R 3 is hydrogen, d-d alkyl or C3-C6 cycloalkyl, wherein the d-d alkyl or C3-C6 cycloalkyl of R 3 is optionally substituted with 1-3 Rc groups which may be the same or different;
  • R 5 when present, is hydrogen, d-d alkyl or C3-C6 cycloalkyl, wherein the d-d alkyl or C3-C 6 cycloalkyl of R 5 is optionally substituted with 1-3 Rc groups which may be the same or different, or R 5 is taken together with ZR 2 to form an oxo group;
  • R 7 is hydrogen or d-d alkyl, wherein the d-d alkyl of R 7 is optionally substituted with 1-3 Rc groups which may be the same or different;
  • R 8 is hydrogen or d-d alkyl, wherein the d-d alkyl of R 8 is optionally substituted with 1-3 R c groups which may be the same or different;
  • R 9 is hydrogen, cyano ord-d alkyl, wherein the d-d alkyl of R 9 is optionally substituted with 1-3 Rc groups which may be the same or different;
  • R 10 is hydrogen ord-d alkyl, wherein the d-d alkyl of R 10 is optionally substituted with 1-3 Rc groups which may be the same or different;
  • R 11 is d-d alkyl, wherein the d-d alkyl of R 11 is optionally substituted with 1-3 Rc groups which may be the same or different;
  • Q is N or CR 10 ;
  • X is a bond, CH 2 , CHOR 12 , NH, NR 11 or O;
  • Z when present, is NH, NR 2 , O, S, S(O) or S0 2 , or ZR 2 and R 5 are taken together to form an oxo;
  • each R a and R b is independently halo, OR 12 , NR 13 R 14 , CN, CONR 13 R 14 , S0 2 CH 3 , S0 2 NR 13 R 14 , d-d alkyl or d-d cycloalkyl, wherein each d-d alkyl of R a and R b and each d-d cycloalkyl of R a and Rb is optionally substituted with 1-3 Rd groups which may be the same or different;
  • each Rc is independently halo, phenyl, heteroaryl, d-d alkyl, d-d cycloalkyl, OR 12 or NR 13 R 14 , wherein the phenyl or heteroaryl of Rc is optionally substituted with 1-3 Re groups which may be the same or different;
  • each Rd is independently halo, OR 12 or NR 13 R 14 ;
  • each Re is independently halo, trifluoromethyl, d-d alkyl, OR 12 or NR 13 R 14 ; each R is independently hydrogen, trifluoromethyl, C1-C4 alkyl or C3-C6 cycloalkyl;
  • n is an integer from 0-5.
  • n is 0 or 1 and R b is halo or OR 12 .
  • W is ; Y is a bond or NH, provided that Y is NH only when ZR 2 and R 5 are taken together to form an oxo; Z is O or ZR 2 and R 5 are taken together to form an oxo; R 2 is hydrogen, acyl or ZR 2 and R 5 are taken together to form an oxo; and R 5 is hydrogen or C1-C6 alkyl or ZR 2 and R 5 are taken together to form an oxo.
  • m is 0 or 1 and R a is halo.
  • R 3 is hydrogen or methyl.
  • each of the variables of the formula (II) are as defined in the formula (I).
  • Alkyl refers to and includes, unless otherwise stated, a saturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having the number of carbon atoms designated (i.e. , Q-Cio means one to ten carbon atoms).
  • Particular alkyl groups are those having 1 to 20 carbon atoms (a "C1-C20 alkyl"), having 1 to 8 carbon atoms (a “Ci-C 8 alkyl”), having 1 to 6 carbon atoms (a “C1-C6 alkyl”), having 2 to 6 carbon atoms (a “C2-C6 alkyl”), or having 1 to 4 carbon atoms (a "C1-C4 alkyl”).
  • alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n- pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An alkenyl group may have "cis” or "trans” configurations, or alternatively have "E” or "Z” configurations.
  • Particular alkenyl groups are those having 2 to 20 carbon atoms (a "C2-C20 alkenyl"), having 2 to 8 carbon atoms (a “Ci-C 8 alkenyl”), having 2 to 6 carbon atoms (a “C2-C6 alkenyl”), or having 2 to 4 carbon atoms (a "C2-C4 alkenyl”).
  • alkenyl group examples include, but are not limited to, groups such as ethenyl (or vinyl), prop-l-enyl, prop-2-enyl (or allyl), 2-methylprop-l-enyl, but-l-enyl, but-2-enyl, but-3-enyl, buta-l,3-dienyl, 2-methylbuta-l,3-dienyl, homologs and isomers thereof, and the like.
  • groups such as ethenyl (or vinyl), prop-l-enyl, prop-2-enyl (or allyl), 2-methylprop-l-enyl, but-l-enyl, but-2-enyl, but-3-enyl, buta-l,3-dienyl, 2-methylbuta-l,3-dienyl, homologs and isomers thereof, and the like.
  • Alkynyl refers to and includes, unless otherwise stated, an unsaturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e. , having at least one moiety of the formula C ⁇ C) and having the number of carbon atoms designated (i.e. , C2-C10 means two to ten carbon atoms).
  • Particular alkynyl groups are those having 2 to 20 carbon atoms (a "C2- C20 alkynyl"), having 2 to 8 carbon atoms (a "Ci-C 8 alkynyl”), having 2 to 6 carbon atoms (a “C2-C6 alkynyl”), or having 2 to 4 carbon atoms (a "C2-C4 alkynyl”).
  • alkynyl group examples include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-l-ynyl, prop-2-ynyl (or propargyl), but-l-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof, and the like.
  • Alkylene refers to the same residues as alkyl, but having bivalency.
  • alkylene groups are those having 1 to 6 carbon atoms (a "d-Ce alkylene"), 1 to 5 carbon atoms (a “C1-C5 alkylene”), 1 to 4 carbon atoms (a “C1-C4 alkylene”) or 1 to 3 carbon atoms (a "C1-C3 alkylene”).
  • alkylene include, but are not limited to, groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene
  • Cycloalkyl refers to and includes, unless otherwise stated, cyclic univalent hydrocarbon structures, which may be fully saturated, mono- or polyunsaturated, having the number of carbon atoms designated (i.e., C 3 -C10 means three to ten carbon atoms). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl, but excludes aryl groups. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. Particular cycloalkyl groups are those having from 3 to 12 annular carbon atoms.
  • a preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C 3 -C8 cycloalkyl"), or having 3 to 6 carbon atoms (a "C 3 -C6 cycloalkyl”).
  • Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornyl, and the like.
  • a preferred cycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C 3 -C8 cycloalkenyl”).
  • Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.
  • Aryl or “Ar” as used herein refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic.
  • Particular aryl groups are those having from 6 to 14 annular carbon atoms (a "C6-C14 aryl”).
  • An aryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, an aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.
  • Heteroaryl or “HetAr” as used herein refers to an unsaturated aromatic carbocyclic group having from 1 to 14 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur.
  • a heteroaryl group may have a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl) which condensed rings may or may not be aromatic.
  • the heteroaryl group may be optionally substituted independently with one or more substituents described herein.
  • heteroaryl groups are 5 to 14-membered rings having 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 5 to 10-membered rings having 1 to 8 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5, 6 or 7- membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • heteroaryl includes monocyclic aromatic 5-, 6- or 7-membered rings having from 1 to 6 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • heteroaryl includes polycyclic aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • a heteroaryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position.
  • a heteroaryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.
  • Heterocycle refers to a saturated or an unsaturated non-aromatic cyclic group having a single ring or multiple condensed rings, and having from 1 to 14 annular carbon atoms and from 1 to 6 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like.
  • a heterocycle comprising more than one ring may be fused, spiro or bridged, or any combination thereof.
  • fused ring systems one or more of the fused rings can be cycloalkyl, aryl or heteroaryl.
  • the heterocyclyl group may be optionally substituted independently with one or more substituents described herein.
  • Particular heterocyclyl groups are 3 to 14-membered rings having 1 to 13 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 12-membered rings having 1 to 11 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 10-membered rings having 1 to 9 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 8-membered rings having 1 to 7 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3 to 6-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7-membered rings having from 1 to 2, 1 to 3, 1 to 4, 1 to 5 or 1 to 6 annular carbon atoms and 1 to 2, 1 to 3 or 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • heterocyclyl includes polycyclic non-aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • a heterocycle having more than one ring where at least one ring is aromatic is connected to the parent structure at a non-aromatic ring position.
  • Halo refers to elements of the Group 17 series having atomic number 9 to 85.
  • Preferred halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two ("di") or three ("tri") halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3- fluorophenyl is within the scope of dihaloaryl.
  • perhaloalkyl An alkyl group in which each hydrogen is replaced with a halo group is referred to as a "perhaloalkyl.”
  • a preferred perhaloalkyl group is trifluoroalkyl (-CF 3 ).
  • perhaloalkoxy refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group.
  • An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).
  • Geminal refers to the relationship between two moieties that are attached to the same atom.
  • R 1 and R 2 are geminal and R 1 may be referred to as a geminal R group to R 2 .
  • Vicinal refers to the relationship between two moieties that are attached to adjacent atoms.
  • R 1 and R2 are vicinal and R 1 may be referred to as a vicinal R group to R 2 .
  • Optionally substituted unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same of different.
  • an optionally substituted group has one substituent.
  • an optionally substituted group has two substituents.
  • an optionally substituted group has three substituents.
  • an optionally substituted group has four substituents.
  • an optionally substituted group has 1 to 2, 1 to 3, 1 to 4 or 1 to 5 substituents.
  • an individual as used herein intends a mammal, including but not limited to a primate, human, bovine, horse, feline, canine, or rodent.
  • treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread (e.g., metastasis) of the disease, preventing or delaying the occurrence or recurrence of the disease, delay or slowing the progression of the disease, ameliorating the disease state, providing a remission (whether partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
  • treatment is a reduction of pathological consequence of cancer. The methods of the invention contemplate any one or more of these aspects of treatment.
  • “delaying" the development of cancer means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease.
  • a method that "delays" development of cancer is a method that reduces probability of disease development in a given time frame and/or reduces the extent of the disease in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects. Cancer development can be detectable using standard methods, such as routine physical exams, mammography, imaging, or biopsy. Development may also refer to disease progression that may be initially undetectable and includes occurrence, recurrence, and onset.
  • an "at risk” individual is an individual who is at risk of developing cancer.
  • An individual “at risk” may or may not have detectable disease, and may or may not have displayed detectable disease prior to the treatment methods described herein.
  • At risk denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of cancer, which are described herein. An individual having one or more of these risk factors has a higher probability of developing cancer than an individual without these risk factor(s).
  • combination therapy is meant a therapy that includes two or more different compounds.
  • a combination therapy comprising a compound detailed herein and another compound is provided.
  • the combination therapy optionally includes one or more pharmaceutically acceptable carriers or excipients, non-pharmaceutically active compounds, and/or inert substances.
  • an effective amount intends such amount of a compound of the invention which in combination with its parameters of efficacy and toxicity, should be effective in a given therapeutic form.
  • an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint.
  • An effective amount may be considered in the context of administering one or more therapeutic agents (e.g., a compound, or pharmaceutically acceptable salt thereof), and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
  • an effective amount of the composition or therapy may (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent, and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (e.g., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of a tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer.
  • the amount is sufficient to ameliorate, palliate, lessen, and/or delay one or more of symptoms of cancer.
  • a “therapeutically effective amount” refers to an amount of a compound or salt thereof sufficient to produce a desired therapeutic outcome (e.g., reducing the severity or duration of, stabilizing the severity of, or eliminating one or more symptoms of cancer).
  • beneficial or desired results include, e.g., decreasing one or more symptoms resulting from the disease (biochemical, histologic and/or behavioral), including its complications and intermediate pathological phenotypes presenting during development of the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication, delaying the progression of the disease, and/or prolonging survival of patients.
  • a “prophylactically effective amount” refers to an amount of a compound, or pharmaceutically acceptable salt thereof, sufficient to prevent or reduce the severity of one or more future symptoms of cancer when administered to an individual who is susceptible and/or who may develop cancer.
  • beneficial or desired results include, e.g., results such as eliminating or reducing the risk, lessening the severity of future disease, or delaying the onset of the disease (e.g., delaying biochemical, histologic and/or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presenting during future development of the disease).
  • an effective amount of a compound or pharmaceutically acceptable salt thereof, including a prophylactically effective amount may be given to an individual in the adjuvant setting, which refers to a clinical setting in which an individual has had a history of cancer, and generally (but not necessarily) has been responsive to therapy, which includes, but is not limited to, surgery (e.g., surgical resection), radiotherapy, and chemotherapy. However, because of their history of the cancer, these individuals are considered at risk of developing cancer. Treatment or administration in the "adjuvant setting" refers to a subsequent mode of treatment.
  • unit dosage form refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • Unit dosage forms may contain a single or a combination therapy.
  • controlled release refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate, i.e., with a "controlled release” formulation, administration does not result in immediate release of the drug into an absorption pool.
  • the term encompasses depot formulations designed to gradually release the drug compound over an extended period of time.
  • Controlled release formulations can include a wide variety of drug delivery systems, generally involving mixing the drug compound with carriers, polymers or other compounds having the desired release characteristics ⁇ e.g., pH- dependent or non-pH-dependent solubility, different degrees of water solubility, and the like) and formulating the mixture according to the desired route of delivery ⁇ e.g., coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, and the like).
  • desired release characteristics e.g., pH- dependent or non-pH-dependent solubility, different degrees of water solubility, and the like
  • pharmaceutically acceptable or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • “Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • coordinates with an organic base e.
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
  • Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the invention in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.
  • excipient means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient.
  • a drug or pharmaceutical such as a tablet containing a compound of the invention as an active ingredient.
  • Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent.
  • lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.
  • materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.;
  • suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.
  • X is O.
  • X is O and RSS H.
  • X is O and R 1 is C(0)(R z ).
  • X is O and R 1 is C(0)C(CH 3 ) 3 .
  • X is CH 2 and R 1 is H.
  • X is O and R 1 is alkenyl.
  • X is O and R 1 is alkyl (e.g., methyl) substituted with phenyl or C 3 -C6 cycloalkyl (e.g., cyclopropyl).
  • X is O and R 1 is heteroaryl (e.g., pyridyl).
  • X is NH.
  • X is NH and R 1 is substituted or unsubstituted heteroaryl (e.g., pyridyl, quinolinyl, pyrazolyl).
  • X is NH and R 1 is substituted or unsubstituted C6-C14 aryl (e.g., substituted or unsubstituted phenyl).
  • X is NH and R 1 is alkyl (e.g., methyl) substituted with C3-C6 cycloalkyl (e.g., cyclopropyl).
  • X is NH and R 1 is C(0)(R z ).
  • X is NR 11 , and R 11 is alkyl (e.g., methyl).
  • X is CH 2 .
  • X is CHz and RSs H.
  • X is CH 2 and R is C(0)OR z , C(0)NHR z , or NHC(0)(R z ).
  • R z is C1-C4 alkyl (e.g., CH 3 , CH2CH 3 , or C(CH 3 ) 3 ).
  • W is or S0 2
  • Y is a bond
  • W is , and Y is a bond.
  • W is , and Y is CH 2 . In some embodiments, W is , and Y is NH. In some embodiments, W is S0 2 , and Y is a bond. In some embodiments, W is S0 2 and Y is NH.
  • W is NH and Y is C(O).
  • Z is O and Y is a bond.
  • Z is O and R 2 is H. In some embodiments, Z is O, R 2 is H, and R 5 is H. In some embodiments, Z is O, R 2 is H, and R 5 is Q-C6 alkyl (e.g., methyl). In some embodiments, Z is O, and R 2 is C(0)(R z ). In a particular embodiment, R 2 is C(0)C(CH 3 )3.
  • ZR 2 and R 5 are taken together to form an oxo, and Y is NH.
  • Z is S0 2 and Y is a bond.
  • m and n are both 0. In another aspect, m and n are both 1. In another aspect, m is 1 and n is 0. In another aspect, m is 0 and n is 1. In some embodiments, R a is halo (e.g., chloro). In some embodiments, R b is halo (e.g., chloro). In some embodiments, R b is alkoxy (e.g., methoxy). In some embodiments, n is 1, m is 0, and R b is chloro or alkoxy. In some embodiments, n is 0, m is 1, and R a is chloro.
  • R 3 is Q-C6 alkyl or hydrogen. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is methyl.
  • R 4 is R 6 C(0)-.
  • R 4 is N ⁇ CCH 2 C(0)-.
  • R 4 is R 6 S(0) 2 -.
  • the -W-Y- moiety is selected from:
  • the -XR 1 moiety is selected from:
  • the -N(R 3 )R 4 moiety is selected from:
  • the compound is of the formula (I-A-1), (I-A-2), (I- A-3), or (I-A-4):
  • each of the variables of the formulae (I-A-1), (I-A-2), (I-A-3), and (I-A-4) are as defined in the formula (I) or any variation thereof.
  • the compound is of the formula (I-B-1), (I-B-2), (I- B-3), (I-B-4), (I-B-5), (I-B-6), (I-B-7), or (I-B-8):
  • each of the variables of the formulae (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-B-5), (I-B- 6), (I-B-7), and (I-B-8) are as defined in the formula (I) or any variation thereof.
  • the compound is of the formula (I-C-1), (I-C-2), (I- C-3), (I-C-4), (I-C-5), or (I-C-6):
  • each of the variables of the formulae (I-C-1), (I-C-2), (I-C-3), (I-C-4), (I-C-5), and (I-C-6) are as defined in the formula (I) or any variation thereof.
  • the compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter.
  • the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.
  • a particular enantiomer of a compound may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers.
  • diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization, and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
  • Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
  • Solvates and/or polymorphs of a compound provided herein or a pharmaceutically acceptable salt thereof are also contemplated. Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are often formed during the process of
  • Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and/or solubility. Various factors such as the
  • recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
  • the invention relates to Compounds described in Table 1, and uses thereof.
  • tautomeric forms may be present for any of the compounds described herein, each and every tautomeric form is intended even though only one or some of the tautomeric forms may be explicitly depicted.
  • the tautomeric forms specifically depicted may or may not be the predominant forms in solution or when used according to the methods described herein.
  • the invention also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms of the compounds described.
  • the structure or name is intended to embrace all possible stereoisomers of a compound depicted, and each unique stereoisomer has a compound number bearing a suffix "a", "b", etc. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds.
  • Compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof, or a composition comprising mixtures of compounds of the invention in any ratio, including two or more stereochemical forms, such as in a racemic or non-racemic mixture.
  • the invention also intends isotopically-labeled and/or isotopically-enriched forms of compounds described herein.
  • the compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compound is isotopically-labeled, such as an isotopically-labeled compound of the formula (I) or variations thereof described herein, where a fraction of one or more atoms are replaced by an isotope of the same element.
  • Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2 H, 3 H, n C, 13 C, 14 C 13 N, 15 0, 17 0, 32 P, 35 S, 18 F, and 36 C1.
  • Certain isotope-labeled compounds e.g. 3 H and 14 C
  • Incorporation of heavier isotopes such as deuterium ( 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements and, hence may be preferred in some instances.
  • Isotopically-labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described in the accompanying Examples, substituting appropriate isotopically- labeled reagents in place of the corresponding non-labeled reagent.
  • the invention also includes any or all metabolites of any of the compounds described.
  • the metabolites may include any chemical species generated by a
  • Articles of manufacture comprising a compound of the invention, or a salt or solvate thereof, in a suitable container are provided.
  • the container may be a vial, jar, ampoule, preloaded syringe, i.v. bag, and the like.
  • the compounds detailed herein are orally bioavailable.
  • the compounds may also be formulated for parenteral (e.g. , intravenous) administration.
  • One or several compounds described herein can be used in the preparation of a medicament by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier, which are known in the art.
  • a pharmacologically acceptable carrier which are known in the art.
  • the carrier may be in various forms.
  • the manufacture of a medicament is for use in any of the methods disclosed herein, e.g., for the treatment of cancer.
  • compositions of any of the compounds detailed herein are embraced by this invention.
  • the invention includes pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a
  • compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
  • a compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein.
  • compositions comprising a compound as detailed herein or a salt thereof are provided, such as
  • compositions of substantially pure compounds are in substantially pure form.
  • substantially pure intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof.
  • a composition of substantially pure compound 1 intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than compound 1 or a salt thereof.
  • a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25% impurity.
  • a composition of substantially pure compound or a salt thereof wherein the composition contains or no more than 20% impurity. In still another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 10% impurity. In a further variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 5% impurity. In another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3% impurity. In still another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 1% impurity.
  • a composition of substantially pure compound or a salt thereof wherein the composition contains or no more than 0.5% impurity.
  • a composition of substantially pure compound means that the composition contains no more than 15% or preferably no more than 10% or more preferably no more than 5% or even more preferably no more than 3% and most preferably no more than 1% impurity, which impurity may be the compound in a different stereochemical form.
  • a composition of substantially pure (S) compound means that the composition contains no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the (R) form of the compound.
  • the compounds herein are synthetic compounds prepared for administration to an individual.
  • compositions are provided containing a compound in substantially pure form.
  • the invention embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier.
  • methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
  • the compound may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g.,
  • a compound may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g. , aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.
  • suitable carriers include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices
  • One or several compounds described herein can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above.
  • a pharmaceutically acceptable carrier such as those mentioned above.
  • the carrier may be in various forms.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • Formulations comprising the compound may also contain other substances which have valuable therapeutic properties.
  • Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington 's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20 th ed. (2000), which is incorporated herein by reference.
  • Compounds as described herein may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions.
  • carriers which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc.
  • Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • any of the compounds described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein or a pharmaceutically acceptable salt thereof can be formulated as a 10 mg tablet.
  • compositions comprising a compound provided herein are also described.
  • the composition comprises a compound and a pharmaceutically acceptable carrier or excipient.
  • a composition of substantially pure compound is provided.
  • Compounds and compositions of the invention such as a pharmaceutical composition containing a compound of any formula provided herein or a salt thereof and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein.
  • the compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality control assays.
  • a method of inhibiting a bromodomain protein comprising administering to an individual in need thereof a compound or composition as provided herein or a salt thereof.
  • the compound may inhibit one or more of the bromodomains of BRD2, BRD3, BRD4, and BRDT.
  • bromodomain is implicated, comprising administering to an individual in need thereof a compound or composition as provided herein, or a salt thereof. Also provided is a method of treating a cancer in which bromodomain is implicated, comprising administering to the individual a compound or composition as provided herein, or a salt thereof.
  • the cancer that may be treated is a solid tumor such as sarcomas and carcinomas.
  • the cancer that may be treated is a liquid tumor such as leukemia.
  • cancers that may be treated by methods of the invention include, but are not limited to, breast cancer, prostate cancer, ovarian cancer, lung cancer, colon cancer, brain tumors, gastric cancer, liver cancer, thyroid cancer, endometrial cancer, gallbladder cancer, kidney cancer, adrenocortical cancer, sarcoma, skin cancer, head and neck cancer, leukemia, bladder cancer, colorectal cancer, hematopoietic cancer and pancreatic cancer.
  • the breast cancer is breast carcinoma (ER negative or ER positive), primary breast ductal carcinoma, mammary adenocarcinoma, mammary ductal carcinoma (ER positive, ER negative or HER2 positive), HER2 positive breast cancer, luminal breast cancer or triple negative breast cancer (TNBC).
  • the breast cancer is unclassified.
  • the triple negative breast cancer is a basal-like TNBC, a mesenchymal TNBC (mesenchymal or mesenchymal stem-like), an immunomodulatory TNBC, or a luminal androgen receptor TNBC.
  • the prostate cancer is prostate adenocarcinoma.
  • the ovarian cancer is ovary adenocarcinoma.
  • the lung cancer is lung carcinoma, non-small lung carcinoma, adenocarcinoma, mucoepidermoid, anaplastic, large cell, or unclassified.
  • the colon cancer is colon adenocarcinoma, colon adenocarcinoma from a metastatic site lymph node, metastatic colorectal cancer, or colon carcinoma.
  • a brain tumor is glioblastoma, astrocytoma, meduloblastoma, meningioma or neuroblastoma.
  • gastric cancer is stomach cancer.
  • the liver cancer is hepatocellular carcinoma, hepatoblastoma or
  • the liver cancer is hepatitis B virus-derived. In some embodiments, the liver cancer is virus negative.
  • the thyroid cancer is papillary thyroid carcinoma, follicular thyroid cancer or medullary thyroid cancer.
  • the endometrial cancer is high grade endometroid cancer, uterine papillary serous carcinoma or uterine clear cell carcinoma.
  • the gallbladder cancer is gallbladder adenocarcinoma or squamous cell gallbladder carcinoma.
  • the kidney cancer is renal cell carcinoma or urothelial cell carcinoma.
  • the adrenocortical cancer is adrenal cortical carcinoma.
  • the sarcoma is synovial sarcoma, osteosarcoma, rhabdomyosarcoma, fibrosarcoma or Ewing's sarcoma.
  • the skin cancer is basal cell carcinoma, squamous carcinoma or melanoma.
  • the head and neck cancer is oropharyngeal cancer, nasopharyngeal cancer, laryngeal cancer and cancer of the trachea.
  • the leukemia is acute promyelocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, mantle cell lymphoma or multiple myeloma. In some embodiments, the leukemia is acute promyelocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, mantle cell lymphoma or multiple myeloma.
  • the invention additionally provides a method for treating a tumor comprising contacting the tumor with an effective amount of one or more compounds of the invention, or a salt thereof.
  • a compound or salt thereof is administered to an individual in need of tumor treatment.
  • Exemplary tumors are derived from carcinomas of the breast, prostate, ovary, lung, or colon.
  • the treatment results in a reduction of the tumor size.
  • the treatment slows or prevents tumor growth and/or metastasis.
  • Any of the methods of treatment provided herein may be used to treat a primary tumor. Any of the methods of treatment provided herein may also be used to treat a metastatic cancer (that is, cancer that has metastasized from the primary tumor). Any of the methods of treatment provided herein may be used to treat cancer at an advanced stage. Any of the methods of treatment provided herein may be used to treat cancer at a locally advanced stage. Any of the methods of treatment provided herein may be used to treat early stage cancer. Any of the methods of treatment provided herein may be used to treat cancer in remission. In some of the embodiments of any of the methods of treatment provided herein, the cancer has reoccurred after remission. In some embodiments of any of the methods of treatment provided herein, the cancer is progressive cancer.
  • a method of treating cancer in an individual comprising administering to the individual an effective around of a compound described herein or a pharmaceutically acceptable salt thereof, wherein in the cancer is dependent on BRD2.
  • a method of treating cancer in an individual comprising administering to the individual an effective around of a compound described herein or a pharmaceutically acceptable salt thereof, wherein in the cancer is dependent on BRD3.
  • a method of treating cancer in an individual comprising administering to the individual an effective around of a compound described herein or a pharmaceutically acceptable salt thereof, wherein in the cancer is dependent on BRD4.
  • a method of treating cancer in an individual comprising administering to the individual an effective around of a compound described herein or a pharmaceutically acceptable salt thereof, wherein in the cancer is dependent on BRDT.
  • any of the methods of treatment provided herein may be used to treat an individual (e.g., human) who has been diagnosed with or is suspected of having cancer.
  • the individual may be a human who exhibits one or more symptoms associated with cancer.
  • the individual may have advanced disease or a lesser extent of disease, such as low tumor burden.
  • the individual is at an early stage of a cancer.
  • the individual is at an advanced stage of cancer.
  • the individual may be a human who is genetically or otherwise predisposed (e.g., has one or more so-called risk factors) to developing cancer who has or has not been diagnosed with cancer.
  • these risk factors include, but are not limited to, age, sex, race, diet, history of previous disease, presence of precursor disease, genetic (e.g., hereditary) considerations, and environmental exposure.
  • the individuals at risk for cancer include, e.g., those having relatives who have experienced this disease, and those whose risk is determined by analysis of genetic or biochemical markers.
  • any of the methods of treatment provided herein may be practiced in an adjuvant setting.
  • any of the methods of treatment provided herein may be used to treat an individual who has previously been treated for cancer, e.g., with one or more other therapies such as radiation, surgery or chemotherapy.
  • Any of the methods of treatment provided herein may be used to treat an individual who has not previously been treated for cancer.
  • Any of the methods of treatment provided herein may be used to treat an individual at risk for developing cancer, but who has not been diagnosed with cancer.
  • Any of the methods of treatment provided herein may be used as a first-line therapy.
  • Any of the methods of treatment provided herein may be used as a second- or subsequent-line therapy.
  • the amount of the compound or pharmaceutically acceptable salt thereof that is administered to an individual is an amount sufficient to decrease the size of a tumor, decrease the number of cancer cells, or decrease the growth rate of a tumor by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% compared to the corresponding tumor size, number of cancer cells, or tumor growth rate in the same subject prior to treatment or compared to the corresponding activity in other subjects not receiving the treatment. Standard methods can be used to measure the magnitude of this effect, such as in vitro assays with purified enzyme, cell-based assays, animal models, or human testing.
  • Any of the methods of treatment provided herein in one aspect reduce the severity of one or more symptoms associated with cancer by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% compared to the corresponding symptom in the same subject prior to treatment or compared to the corresponding symptom in other subjects not receiving a compound or composition of the invention.
  • the compounds and compositions of the invention may be used to treat or prevent cancer in conjunction with a second therapy useful for cancer treatment.
  • the second therapy includes, but is not limited to, surgery, radiation, and/or chemotherapy.
  • Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein or a salt thereof and a pharmaceutically acceptable excipient.
  • a compound or composition of the invention may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual's life.
  • the compound is administered on a daily or intermittent schedule.
  • the compound can be administered to an individual continuously (for example, at least once daily) over a period of time.
  • the dosing frequency can also be less than once daily, e.g., about a once weekly dosing.
  • the dosing frequency can be more than once daily, e.g., twice or three times daily.
  • the dosing frequency can also be intermittent, including a 'drug holiday' (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.
  • a 'drug holiday' e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more.
  • the compounds provided herein or a salt thereof may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral and transdermal.
  • a compound provided herein can be administered frequently at low doses, known as 'metronomic therapy,' or as part of a maintenance therapy using compound alone or in combination with one or more additional drugs.
  • Metronomic therapy or maintenance therapy can comprise administration of a compound provided herein in cycles.
  • Metronomic therapy or maintenance therapy can comprise intra-tumoral administration of a compound provided herein.
  • the invention provides a method of treating cancer in an individual by parenterally administering to the individual (e.g., a human) an effective amount of a compound or salt thereof.
  • the route of administration is intravenous, intra-arterial, intramuscular, or subcutaneous. In some embodiments, the route of
  • administration is oral. In still other embodiments, the route of administration is transdermal.
  • compositions including pharmaceutical compositions as described herein for the use in treating, preventing, and/or delaying the onset and/or development of cancer and other methods described herein.
  • the composition comprises a pharmaceutical formulation which is present in a unit dosage form.
  • articles of manufacture comprising a compound of the invention or a salt thereof, composition, and unit dosages described herein in suitable packaging for use in the methods described herein.
  • suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like.
  • An article of manufacture may further be sterilized and/or sealed.
  • kits for carrying out the methods of the invention which comprises one or more compounds described herein or a pharmacological composition comprising a compound described herein.
  • the kits may employ any of the compounds disclosed herein.
  • the kit employs a compound described herein or a pharmaceutically acceptable salt thereof.
  • the kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for use in the treatment of cancer.
  • Kits generally comprise suitable packaging.
  • the kits may comprise one or more containers comprising any compound described herein.
  • Each component if there is more than one component
  • One or more components of a kit may be sterile and/or may be contained within sterile packaging.
  • kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses.
  • kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or a second pharmaceutically active compound useful for a disease detailed herein (e.g., cancer) to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
  • Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g. , hospital pharmacies and compounding pharmacies).
  • kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g. , magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present invention.
  • the instructions included with the kit generally include information as to the components and their administration to an individual.
  • TLC thin layer chromatography
  • hour hour
  • minute minute
  • second sec
  • ethanol EtOH
  • DMSO dimethylsulfoxide
  • DMF N,N- dimethylformamide
  • TFA trifluoroacetic acid
  • THF tetrahydroiuran
  • Normal N
  • aqueous aq.
  • methanol MeOH
  • DCM dichloromethane
  • EtOAc ethyl acetate
  • Rf room temperature
  • RT room temperature
  • Step-3 Synthesis of l-bromo-3-(methoxymethoxy)-5-((methoxymethoxy)( phenyl)methyl)benzene :
  • Step-4 Synthesis of 3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl)- N-methylaniline :
  • Step-6 Synthesis of N-(3-hydroxy-5-(hydroxy(phenyl)methyl)phenyl)-N- methylacrylamide : [0140] To a solution of 3-bromo-5-(hydroxy(phenyl)methyl)phenol (120 mg, 0.323 mmol) in THF (5 mL) was added 6 N hydrochloric acid (5 mL). The reaction mixture was stirred at RT for 48 h. The reaction mixture was neutralized with saturated sodium bicarbonate solution (5 mL) and extracted with EtOAc (3x30 mL).
  • Step-1 Synthesis of 3-bromo-5-hydroxybenzaldehyde:
  • Step-3 Synthesis of l-bromo-3-(methoxymethoxy)-5-((methoxymethoxy)
  • Step-4 Synthesis of 3-(methoxymethoxy)-5-((methoxymethoxy)
  • Step-5 Synthesis of l-(3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl)phenyl)-N-methylmethanamine: [0145] To a solution of 3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl) benzaldehyde (184 mg, 0.581 mmol) in methanol (10 mL) was added lithium hydroxide monohydrate (49 mg, 1.162 mmol). The reaction mixture was stirred at RT for 20 min followed by addition of 40% aqueous methylamine solution (0.45 mL, 5.81 mmol). The reaction mixture was allowed to stir at RT for 1 h.
  • Step-6 Synthesis of N-(3-(methoxymethoxy)-5- ((memoxymethoxy)(phenyl)methyl)benzyl)-N-me1hylacrylamide:
  • Step-7 Synthesis of N-(3-hydroxy-5-(hydroxy(phenyl)methyl)benzyl)-N- methylacrylamide :
  • Step-3 Synthesis of l-bromo-3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl) benzene :
  • Step-4 Synthesis of 3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl)- N-methylaniline :
  • Step-5 Synthesis of N-(3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl)phenyl)-N-methyl methacrylamide :
  • Step-3 Synthesis of l-bromo-3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl) benzene :
  • Step-4 Synthesis of 3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl)- N-methylaniline :
  • Step-5 Synthesis of N-(3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl)phenyl)-N-methylethenesulfonamide:
  • Step-6 Synthesis of N-(3-hydroxy-5-(hydroxy(phenyl)methyl)phenyl)-N- methylethene sulfonamide:
  • Step-3 Synthesis of l-bromo-3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl) benzene :
  • Step-4 Synthesis of 3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl)aniline:
  • Step-5 Synthesis of N-(3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl)phenyl)-methacryl amide:
  • Step-6 Synthesis of N-(3-hydroxy-5- (hydroxy(phenyl)methyl)phenyl)methacrylamide:
  • Step-3 Synthesis of l-bromo-3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl) benzene :
  • Step-5 Synthesis of N-(3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl)phenyl)-N-methyl acrylamide :
  • Step-6 Synthesis of N-(3-hydroxy-5-(hydroxy(phenyl)methyl)phenyl)-N- methylacrylamide :
  • Step-7 Synthesis of 3-[hydroxy(phenyl)methyl]-5-(N-methylprop-2- enamido)phenyl 2,2 -dimethylpropanoate :
  • Step-1 Synthesis of 3-bromo-5-hydroxybenzaldehyde:
  • Step-4 Synthesis of 2-cyano-N-(3-hydroxy-5-(hydroxy(phenyl)methyl)phenyl)-N- methylacetamide :
  • Step-1 Synthesis of 3-bromo-N-(4-chlorophenyl)-5-hydroxybenzamide:
  • Step-2 Synthesis of N-(4-chlorophenyl)-3 -hydroxy-5 -(methylamino)benzamide :
  • Step-3 Synthesis ofN-(4-chlorophenyl)-3-hydroxy-5-(N- me1hylvinylsulfonamido)benzamide :
  • Step-1 Synthesis of 3-bromo-5-hydroxybenzaldehyde:
  • Step-3 Synthesis of l-bromo-3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl) benzene :
  • Step-4 Synthesis of 3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl)- N-methylaniline :
  • Step-5 Synthesis of N-(3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl)phenyl)-N-methyl acrylamide :
  • Step-6 Synthesis of N-(3-hydroxy-5-(hydroxy(phenyl)methyl)phenyl)-N- methylacrylamide :
  • Step-7 N-(3 -benzoyl-5 -hydroxyphenyl)-N-methylacrylamide :
  • Step-1 Synthesis of 3-bromo-5-((4-chlorophenyl)(hydroxy)methyl)phenol:
  • Step-2 Synthesis of 3-((4-chlorophenyl)(hydroxy)memyl)-5-(memylamino)phenol:
  • Step-3 Synthesis of N-(3-((4-chlorophenyl)(hydroxy)methyl)-5-hydroxyphenyl)-N- methylacrylamide :
  • Step-1 Synthesis of 3-bromo-5-((3-chlorophenyl)(hydroxy)methyl)phenol:
  • Step-2 Synthesis of 3-((3-chlorophenyl)(hydroxy)memyl)-5-(memylamino)phenol:
  • Step-3 Synthesis of N-(3-((3-chlorophenyl)(hydroxy)methyl)-5-hydroxyphenyl)-N- methylacrylamide :
  • Step-1 Synthesis of 3-bromo-5-(hydroxy(2-methoxyphenyl)methyl)phenol:
  • Step-2 Synthesis of 3-(hydroxy(2-methoxyphenyl)methyl)-5-(methylamino)phenol:
  • Step-3 Synthesis of N-(3-hydroxy-5-(hydroxy(2-methoxyphenyl)methyl)phenyl)- N-methy lacrylamide :
  • Compounds of the present invention may be assessed for bromodomain activity according to standard methods. Examples B1-B4 describe inhibition assessments for certain compounds.
  • Examples B1-B4 employed the reader assay, which is a binding assay using AlphaScreen technology FRET assay.
  • the biotinylated peptide binding to the reader domain of His-tagged protein is monitored by the singlet oxygen transfer from the Streptavidin-coated donor beads to the AlphaScreen Ni-chelate acceptor beads.
  • Examples B1-B4 employed the following reagents: reaction buffer: 50 mM Hepes, pH7.5, 100 mM NaCl, 0.05% CHAPS, 0.1 % BSA, and 1% DMSO; histone H4 peptide (1- 21) K5/8/12/16Ac-Biotin.
  • the assays were performed by delivering 4X BRD in the wells of a reaction plate except for the control wells in which buffer was added instead.
  • Test compounds were delivered in 100% DMSO into the BRD mixture by Acoustic technology (Echo550; nanoliter range), followed by spin down and pre-incubation for 30 min.
  • 4X ligand Histone H4 peptide (1-21) K5/8/12/16Ac-Biotin) was delivered, followed by spin and shake. The samples were allowed to incubate for 30 min at RT with gentle shaking.
  • 4X donor beads Streptavidin Donor beads
  • 4X acceptor beads AlphaScreen Ni acceptor beads
  • the samples were gently shaken in the dark for 60 min. Detection was assessed via alpha measurement
  • the 4 Ac peptide ligand has C-terminus biotin, and BRD domains have His-Tag.
  • BRD binds peptide
  • energy transfer occurs and high signals are detected. If compounds interrupt the binding of BRD and peptide, the signals will be decreased.
  • IC50 values mean 50% inhibition of the binding of BRD and peptide.
  • BRD2-1 refers to the BDl domain of BRD2
  • BRD2-2 refers to the BD2 domain of BRD2.
  • BRD3-1 refers to the BDl domain of BRD3
  • BRD3-2 refers to the BD2 domain of BRD3.
  • BRD4-1 refers to the BDl domain of BREW
  • BRD4-2 refers to the BD2 domain of BRD4.
  • BRDT-1 refers to the BDl domain of BRDT.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Aromatic compounds that are bromodomain inhibitors are provided. The compounds may be used in a method of treating cancer. Pharmaceutical compositions comprising an aromatic compound as detailed herein are provided, as are kits comprising a compound or a salt thereof and instructions for use, e.g., in a method of treating cancer.

Description

AROMATIC COMPOUNDS, COMPOSITIONS AND USES THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority benefit of Indian Patent Application No.
1433/DEL/2014, filed May 30, 2014, the disclosure of which is hereby incorporated herein by reference in its entirely.
FIELD OF THE INVENTION
[0002] This invention relates to new compounds that are bromodomain inhibitors and may find use in treating diseases and conditions, such as certain cancers, in which bromodomain is implicated.
BACKGROUND OF THE INVENTION
[0003] Acetylation of histone lysines is important for regulation of chromatin-based gene transcription. Histone acetylation is typically associated with activation of gene transcription by loosening the interaction of duplex DNA histone proteins. Not only does histone acetylation alter the three-dimensional chromatin structure, specific proteins also bind to acetylated lysine residues within histones to read the epigenetic code. Bromodomains, a conserved structural motif in chromatin-associated proteins and histone acetyltransferases, recognize acetyl-lysine residues on proteins. Bromodomain-containing proteins have a variety of cellular functions.
[0004] The bromodomain and extra-C terminal domain (BET) protein family consists of four members (BRD2, BRD3, BRD4, and BRDT), all of which contain two bromodomains. These proteins bind to acetylated lysine residues on the tails of histones H3 and H4 and regulate chromatin structure and gene expression. BRD2 and BRD3 may be involved in facilitating transcriptional elongation. BRD4 may be involved in recruitment of the pTEF-β complex to inducible genes, thereby playing a role in increasing transcriptional output.
BRD3 and BRD4 may also form fusion oncogenes with NUT (nuclear protein in testis), which may play a role in carcinogenesis. BRDT is a testis-specific chromatin protein that specifically binds histone H4 and plays a role in spermatogenesis.
[0005] Due to the role of BET bromodomain-containing proteins in chromosomal regulation and cell division, small molecule inhibitors of these proteins have therapeutic potential for diseases such as cancer, in which these proteins may have a role. While certain small molecule inhibitors of BET bromodomain proteins are known (see, e.g., WO
2011/054864, WO 2011/054843, US2013/0184264), there remains a need for small molecule inhibitors with pharmacological properties that are suitable for therapeutic applications.
BRIEF SUMMARY OF THE INVENTION
[0006] New bromodomain inhibitors are provided herein, as are methods of using the compounds in therapy, such as in the treatment of cancer.
[0007] In one aspect, provided is a compound of the formula (I) or (II):
Figure imgf000003_0001
or a salt thereof, wherein:
W is 0r S02, and Y is a bond, CH2 or NH; or W is NH, and Y is C(0);
R1 is hydrogen, Ci-C^ alkyl, C2-C6 alkenyl, C6-Q4 aryl, heteroaryl, C(0)(Rz), C(0)ORz, C(0)NHRz, C(0)NRnRz, NHC(0)(Rz), N(Rn)C(0)(Rz) or S(0)2Rz, wherein the C1-C6 alkyl, C2-C6 alkenyl, C6-Q4 aryl, or heteroaryl of R1 are independently optionally substituted with 1-3 Rc groups which may be the same or different; each Rz is independently d-d alkyl, C3-C6 cycloalkyl, C6-C14 aryl or heteroaryl, each of which is optionally substituted with 1-3 Rc groups which may be the same or different;
R2, when present, is hydrogen, d-d alkyl, C3-C6 cycloalkyl, C(0)(Rz), aryl or heteroaryl, wherein the d-d alkyl or C3-C6 cycloalkyl of R2 is optionally substituted with 1- 3 Rc groups which may be the same or different, and wherein the aryl or heteroaryl of R2 is optionally substituted with 1-3 Re groups which may be the same or different, or ZR2 is taken together with R5 to form an oxo group;
R3 is hydrogen,Ci-C6 alkyl or C3-C6 cycloalkyl, wherein the d-d alkyl or C3-C6 cycloalkyl of R3 is optionally substituted with 1-3 Rc groups which may be the same or different;
R4 is R6C(0)- or R6S(0)2-, where each R6 is independently (R7)(R8)C=C(R9)- or
Figure imgf000004_0001
R5, when present, is hydrogen, d-d alkyl or C3-C6 cycloalkyl, wherein the d-d alkyl or C3-C6 cycloalkyl of R5 is optionally substituted with 1-3 Rc groups which may be the same or different, or R5 is taken together with ZR2 to form an oxo group;
R7is hydrogen or d-d alkyl, wherein the d-d alkyl of R7 is optionally substituted with 1-3 Rc groups which may be the same or different;
R8 is hydrogen or d-d alkyl, wherein the d-d alkyl of R8 is optionally substituted with 1-3 Rc groups which may be the same or different;
R9 is hydrogen, cyano ord-d alkyl, wherein the d-d alkyl of R9 is optionally substituted with 1-3 Rc groups which may be the same or different;
R10 is hydrogen ord-d alkyl, wherein the d-d alkyl of R10 is optionally substituted with 1-3 Rc groups which may be the same or different;
R11 is d-d alkyl, wherein the d-d alkyl of R11 is optionally substituted with 1-3 Rc groups which may be the same or different;
Q is N or CR10;
X is a bond, CH2, CHOR12, NH, NR11 or O;
Z, when present, is NH, NR2, O, S, S(O) or S02, or ZR2 and R5 are taken together to form an oxo;
each Ra and Rb is independently halo, OR12, NR13R14, CN, CONR13R14, S02CH3, S02NR13R14, d-d alkyl or d-d cycloalkyl, wherein each d-d alkyl of Ra and Rb and each d-d cycloalkyl of Ra and Rb is optionally substituted with 1-3 Rd groups which may be the same or different; each , d-Ce alkyl, 12 Rc is independently halo, phenyl, heteroaryl C3-C6 cycloalkyl, OR or NR13R14, wherein the phenyl or heteroaryl of Rc is optionally substituted with 1-3 Re groups which may be the same or different;
each Ra is independently halo, OR12 or NR13R14;
each Re is independently halo, trifluoromethyl, C1-C4 alkyl, OR12 or NR13R14;
each R12 is independently hydrogen, trifluoromethyl, C1-C4 alkyl or C3-C6 cycloalkyl; each R13 is independently hydrogen, trifluoromethyl, C1-C4 alkyl or C3-C6 cycloalkyl; each R14 is independently hydrogen, trifluoromethyl, C1-C4 alkyl or C3-C6 cycloalkyl; m is an integer from 0-3; and
n is an integer from 0-5.
[0008] In some embodiments, the compound is of the formula (I). In some embodiments of
the compounds of the formula (I), W is
Figure imgf000005_0001
, and the compound is of the formula (A):
Figure imgf000005_0002
wherein X, Y, Z, R1, R2, R3, R4, R5, Ra, Rb, m, and n are as described for formula (I).
[0009] In some embodiments, the compo is of the formula (II). In some embodiments
of the compounds of the formula (II), W is
Figure imgf000005_0003
. In some embodiments of the compounds of the formula (II), the compound is of the formula (B):
Figure imgf000006_0001
wherein X, Y, Z, R1, R2, R3, R4, R5, Ra, Rb, m, and n are as described for formula (II).
.
Figure imgf000006_0002
these embodiments, Y is a bond. In some of these embodiments, Y is NH. In some embodiments of the compounds of formula (I) or (II), W is S02 and Y is a bond.
[0012] In some embodiments, Z is O. In some embodiments, R2 is hydrogen or C(0)(Rz). In some embodiments, R5 is hydrogen or C\-Ce alkyl (e.g., methyl). In some embodiments, Rz is Ci-C alkyl (e.g., tert-b tyl).
[0013] In some embodiments, m is 0. In some embodiments, m is 1 and Ra is halo (e.g., chloro). In some embodiments, n is 0. In some embodiments, n is 1 and Rb is halo (e.g., chloro) or OR12. In some embodiments, R12 is C1-C4 alkyl (e.g., methyl).
[0014] In some embodiments, X is a bond and R1 is hydrogen. In some embodiments, X is a bond and R1 is C1-C6 alkyl optionally substituted with 1-3 Rc groups which may be the same or different. In some embodiments, Rc is NR13R14 where R13 and R14 are independently hydrogen or C1-C4 alkyl. In some embodiments, X is a bond and R1 is tert- butylaminomethyl.
[0015] In some embodiments, X is O. In some embodiments, R1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C6-Q4 aryl, heteroaryl, or C(0)(Rz), wherein the C1-C6 alkyl, C2-C6 alkenyl, C6-C14 aryl, or heteroaryl of R1 are independently optionally substituted with 1-3 Rc groups which may be the same or different. In some of these embodiments, R1 is hydrogen. In some of these embodiments, R1 is C2-C6 alkenyl (e.g., allyl). In some of these embodiments, R1 is heteroaryl (e.g., pyridyl). In some of these embodiments, R1 is d-d alkyl optionally substituted with 1-3 Rc groups which may be the same or different (e.g., cyclopropylmethyl or benzyl). In some of these embodiments, R1 is C(0)(Rz). In some embodiments, Rz is Q- alkyl, C3-C6 cycloalkyl or -d4 aryl, each of which is optionally substituted with 1-3 Rc groups which may be the same or different. In some embodiments, Rz is d-d alkyl (e.g., tert-b tyl). In some embodiments, Rz is C3-C6 cycloalkyl (e.g., cyclopropyl). In some embodiments, Rz is phenyl optionally substituted with 1-3 Rc groups which may be the same or different (e.g., hydroxyphenyl).
[0016] In some embodiments, X is NH or NR11. In some embodiments, R11 is d-d alkyl. In some embodiments, R11 is d-d alkyl substituted with 1-3 Rc groups which may be the same or different (e.g., benzyl or 2-hydroxyethyl). In some embodiments, R1 is hydrogen, C1-C6 alkyl, - alkenyl, d-d4 aryl, heteroaryl, or C(0)(Rz), wherein the d-d alkyl, C2- alkenyl, C6-C14 aryl, or heteroaryl of R1 are independently optionally substituted with 1-3 Rc groups which may be the same or different. In some of these embodiments, R1 is d-d alkyl optionally substituted with 1-3 Rc groups which may be the same or different. In some of these embodiments, R1 is cyclopropylmethyl, 2-hydroxyethyl or benzyl. In some of these embodiments, R1 is heteroaryl optionally substituted with 1-3 Rc groups which may be the same or different. In some of these embodiments, R1 is pyridyl (e.g., pyridin-4-yl), quinolinyl (e.g., quinolin-6-yl) or pyrazolyl substituted with 1-3 Rc groups which may be the same or different (e.g., l-methyl-2-cyclopropylpyrazol-5-yl). In some of these embodiments, R1 is phenyl optionally substituted with 1-3 Rc groups which may be the same or different (e.g., 3 -hydroxyphenyl or 4-hydroxyphenyl).
[0017] In some embodiments, X is CH2 or CHOR12. In some embodiments, R12 is hydrogen. In some embodiments, R1 is hydrogen, d-d alkyl, C2-C6 alkenyl, C6-C14 aryl, heteroaryl, C(0)ORz, C(0)NHRz, C(0)NRnRz, NHC(0)(Rz), or N(Rn)C(0)(Rz), wherein the d-d alkyl, -d alkenyl, -d4 aryl and heteroaryl of R1 are independently optionally substituted with 1-3 Rc groups which may be the same or different. In some of these embodiments, R1 is phenyl. In some of these embodiments, R1 is C(0)ORz where Rz is d-d alkyl (e.g., tert-butyl). In some of these embodiments, R1 is C(0)NHRz where Rz is d-d alkyl (e.g., ethyl). In some of these embodiments, R1 is NHC(0)(Rz) where Rz is d-d alkyl (e.g., ethyl, isopropyl or tert-butyl). In some of these embodiments, Rz is d-d alkyl (e.g., methyl, ethyl, isopropyl or tert-butyl). [0018] In some embodiments, R3 is hydrogen or d-Ce alkyl optionally substituted with 1-3 Rc groups which may be the same or different. In some embodiments, R3 is hydrogen. In some embodiments, R3 is Q-C6 alkyl (e.g., methyl).
[0019] In some embodiments, R4 is R6C(0)- where R6 is (R7)(R8)C=C(R9)- or Q≡C(CH2)0- 1-. In some embodiments, R4 is R6S(0)2- where R6 is (R7)(R8)C=C(R9)- or Q≡C(CH2)0-i-. In some embodiments, R6 is (R7)(R8)C=C(R9)-. In some of these embodiments, R7 is hydrogen, R8 is hydrogen, and R9 is hydrogen, cyano or Q-C6 alkyl optionally substituted with 1-3 Rc groups which may be the same or different. In some embodiments, R6 is CH2=CH-, CH2=C(CH3)- or CH2=C(CN)-. In some embodiments, R6 is Q≡C(CH2)- where Q is N. In some embodiments, R6 is Q≡C- where Q is CR10.
[0020] In some embodiments, provided is a compound selected from Compound Nos. 1, la, lb and 2-53 in Table 1, or a salt thereof.
[0021] Also provided is a pharmaceutical composition comprising a compound described herein, such as a compound of the formula (I), (II), (A), or (B), or variations thereof, or a compound selected from Compound Nos. 1, la, lb and 2-53, or a salt thereof, and a pharmaceutically acceptable carrier.
[0022] In another aspect, provided is a method of treating cancer in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound described herein, such as a compound of the formula (I), (II), (A), or (B), or variations thereof, or a compound selected from Compound Nos. 1, la, lb and 2-53, or a pharmaceutically acceptable salt thereof.
[0023] Also provided is a compound described herein, such as a compound of the formula (I), (II), (A), or (B), or variations thereof, or a compound selected from Compound Nos. 1, la, lb and 2-53, or a salt thereof, for use in a method of treating cancer in an individual in need thereof. Further provided is use of a compound described herein, such as a compound of the formula (I), (II), (A), or (B), or variations thereof, or a compound selected from Compound Nos. 1, la, lb and 2-53, or a salt thereof, in the manufacture of a medicament for the treatment of cancer. Further provided is use of a compound described herein, such as a compound of the formula (I), (II), (A), or (B), or variations thereof, or a compound selected from Compound Nos. 1, la, lb and 2-53, or a salt thereof, in the treatment of cancer.
[0024] Also provided is a compound described herein, such as a compound of the formula (I), (II), (A), or (B), or variations thereof, or a compound selected from Compound Nos. 1, la, lb and 2-53, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in an individual in need thereof. Further provided is use of a compound described herein, such as a compound of the formula (I), (II), (A), or (B), or variations thereof, or a compound selected from Compound Nos. 1, la, lb and 2-53, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. Further provided is use of a compound described herein, such as a compound of the formula (I), (II), (A), or (B), or variations thereof, or a compound selected from Compound Nos. 1, la, lb and 2-53, or a pharmaceutically acceptable salt thereof, in the treatment of cancer.
[0025] Also provided is a kit comprising a compound described herein, such as a compound of the formula (I), (II), (A), or (B), or variations thereof, or a compound selected from Compound Nos. 1, la, lb and 2-53, or a pharmaceutically acceptable salt thereof, optionally comprising instructions for use in treating cancer.
DETAILED DESCRIPTION OF THE INVENTION
[0026] In one variation, provided are compounds of the formula (I):
Figure imgf000009_0001
or a salt thereof, wherein:
Figure imgf000009_0002
W is or S02, and Y is a bond, CH2 or NH; or W is NH, and Y is C(0);
R1 is hydrogen, Q-C6 alkyl, C2-C6 alkenyl, C6-Q4 aryl, heteroaryl, C(0)(Rz), C(0)ORz, C(0)NHRz, C(0)NRnRz, NHC(0)(Rz), N(Rn)C(0)(Rz) or S(0)2Rz, wherein the C1-C6 alkyl, C2-C6 alkenyl, C6-Q4 aryl, or heteroaryl of R1 are independently optionally substituted with 1-3 Rc groups which may be the same or different;
Rz is C1-C6 alkyl, C3-C6 cycloalkyl, C6-Q4 aryl or heteroaryl, each of which is optionally substituted with 1-3 Rc groups which may be the same or different;
R2, when present, is hydrogen, Q-C6 alkyl, C3-C6 cycloalkyl, C(0)(Rz), aryl or heteroaryl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl of R2 is optionally substituted with 1- 3 Rc groups which may be the same or different, and wherein the aryl or heteroaryl of R2 is optionally substituted with 1-3 Re groups which may be the same or different, or ZR2 is taken together with R5 to form an oxo group;
R3 is hydrogen, d-d alkyl or C3-C6 cycloalkyl, wherein the d-d alkyl or C3-C6 cycloalkyl of R3 is optionally substituted with 1-3 Rc groups which may be the same or different;
R4 is R6C(0)- or R6S(0)2-, where each R6 is independently (R7)(R8)C=C(R9)- or
Figure imgf000010_0001
R5, when present, is hydrogen, d-d alkyl or C3-C6 cycloalkyl, wherein the d-d alkyl or C3-C6 cycloalkyl of R5 is optionally substituted with 1-3 Rc groups which may be the same or different, or R5 is taken together with ZR2 to form an oxo group;
R7is hydrogen or d-d alkyl, wherein the d-d alkyl of R7 is optionally substituted with 1-3 Rc groups which may be the same or different;
R8 is hydrogen or d-d alkyl, wherein the d-d alkyl of R8 is optionally substituted with 1-3 Rc groups which may be the same or different;
R9 is hydrogen, cyano ord-d alkyl, wherein the d-d alkyl of R9 is optionally substituted with 1-3 Rc groups which may be the same or different;
R10 is hydrogen ord-d alkyl, wherein the d-d alkyl of R10 is optionally substituted with 1-3 Rc groups which may be the same or different;
R11 is d-d alkyl, wherein the d-d alkyl of R11 is optionally substituted with 1-3 Rc groups which may be the same or different;
Q is N or CR10;
X is a bond, CH2, CHOR12, NH, NR11 or O;
Z, when present, is NH, NR2, O, S, S(O) or S02, or ZR2 and R5 are taken together to form an oxo;
each Ra and Rb is independently halo, OR12, NR13R14, CN, CONR13R14, S02CH3, S02NR13R14, d-d alkyl or d-d cycloalkyl, wherein each d-d alkyl of Ra and Rb and each d-d cycloalkyl of Ra and Rb is optionally substituted with 1-3 Rd groups which may be the same or different;
each Rc is independently halo, phenyl, heteroaryl, d-d alkyl, d-d cycloalkyl, OR12 or NR13R14, wherein the phenyl or heteroaryl of Rc is optionally substituted with 1-3 Re groups which may be the same or different;
each Rd is independently halo, OR12 or NR13R14;
each Re is independently halo, trifluoromethyl, d-d alkyl, OR12 or NR13R14; each R is independently hydrogen, trifluoromethyl, C1-C4 alkyl or C3-C6 cycloalkyl;
13
each R is independently hydrogen, trifluoromethyl, C1-C4 alkyl or C3-C6 cycloalkyl; each R14 is independently hydrogen, trifluoromethyl, C1-C4 alkyl or C3-C6 cycloalkyl; m is an integer from 0-3; and
n is an integer from 0-5.
[0027] In one aspect of the formula (I), n is 0 or 1 and Rb is halo or OR12.
[0028] In another aspect of the formula (I), W is
Figure imgf000011_0001
; Y is a bond or NH, provided that Y is NH only when ZR2 and R5 are taken together to form an oxo; Z is O or ZR2 and R5 are taken together to form an oxo; R2 is hydrogen, acyl or ZR2 and R5 are taken together to form an oxo; and R5 is hydrogen or C1-C6 alkyl or ZR2 and R5 are taken together to form an oxo.
[0029] In another aspect of the formula (I), m is 0 or 1 and Ra is halo.
[0030] In another aspect of the formula (I), R3 is hydrogen or methyl.
[0031] In another aspect of the formula (I), R4 is H2C=C(R9)-C(0)- or H2C=C(R9)-S(0)2-, where each R9 is independently hydrogen, cyano or C1-C6 alkyl.
[0032] Compounds of the formula (II) are also provided:
Figure imgf000011_0002
or a salt thereof, wherein each of the variables of the formula (II) are as defined in the formula (I).
Definitions
[0033] For use herein, unless clearly indicated otherwise, use of the terms "a", "an" like refers to one or more. [0034] Reference to "about" a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to "about X" includes description of "X".
[0035] "Alkyl" as used herein refers to and includes, unless otherwise stated, a saturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having the number of carbon atoms designated (i.e. , Q-Cio means one to ten carbon atoms). Particular alkyl groups are those having 1 to 20 carbon atoms (a "C1-C20 alkyl"), having 1 to 8 carbon atoms (a "Ci-C8 alkyl"), having 1 to 6 carbon atoms (a "C1-C6 alkyl"), having 2 to 6 carbon atoms (a "C2-C6 alkyl"), or having 1 to 4 carbon atoms (a "C1-C4 alkyl"). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n- pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
[0036] "Alkenyl" as used herein refers to and includes, unless otherwise stated, an unsaturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of olefinic unsaturation (i.e. , having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e. , C2-C10 means two to ten carbon atoms). An alkenyl group may have "cis" or "trans" configurations, or alternatively have "E" or "Z" configurations. Particular alkenyl groups are those having 2 to 20 carbon atoms (a "C2-C20 alkenyl"), having 2 to 8 carbon atoms (a "Ci-C8 alkenyl"), having 2 to 6 carbon atoms (a "C2-C6 alkenyl"), or having 2 to 4 carbon atoms (a "C2-C4 alkenyl"). Examples of alkenyl group include, but are not limited to, groups such as ethenyl (or vinyl), prop-l-enyl, prop-2-enyl (or allyl), 2-methylprop-l-enyl, but-l-enyl, but-2-enyl, but-3-enyl, buta-l,3-dienyl, 2-methylbuta-l,3-dienyl, homologs and isomers thereof, and the like.
[0037] "Alkynyl" as used herein refers to and includes, unless otherwise stated, an unsaturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e. , having at least one moiety of the formula C≡C) and having the number of carbon atoms designated (i.e. , C2-C10 means two to ten carbon atoms). Particular alkynyl groups are those having 2 to 20 carbon atoms (a "C2- C20 alkynyl"), having 2 to 8 carbon atoms (a "Ci-C8 alkynyl"), having 2 to 6 carbon atoms (a "C2-C6 alkynyl"), or having 2 to 4 carbon atoms (a "C2-C4 alkynyl"). Examples of alkynyl group include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-l-ynyl, prop-2-ynyl (or propargyl), but-l-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof, and the like. [0038] "Alkylene" as used herein refers to the same residues as alkyl, but having bivalency. Particular alkylene groups are those having 1 to 6 carbon atoms (a "d-Ce alkylene"), 1 to 5 carbon atoms (a "C1-C5 alkylene"), 1 to 4 carbon atoms (a "C1-C4 alkylene") or 1 to 3 carbon atoms (a "C1-C3 alkylene"). Examples of alkylene include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene
(-CH2CH2CH2CH2-), and the like.
[0039] "Cycloalkyl" as used herein refers to and includes, unless otherwise stated, cyclic univalent hydrocarbon structures, which may be fully saturated, mono- or polyunsaturated, having the number of carbon atoms designated (i.e., C3-C10 means three to ten carbon atoms). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl, but excludes aryl groups. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. Particular cycloalkyl groups are those having from 3 to 12 annular carbon atoms. A preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C3-C8 cycloalkyl"), or having 3 to 6 carbon atoms (a "C3-C6 cycloalkyl"). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornyl, and the like.
[0040] "Cycloalkenyl" refers to an unsaturated cycloalkyl group having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C), which can consist of one ring, such as cyclohexyl, or multiple rings, such as norbornenyl. A preferred cycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C3-C8 cycloalkenyl"). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.
[0041] "Aryl" or "Ar" as used herein refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic. Particular aryl groups are those having from 6 to 14 annular carbon atoms (a "C6-C14 aryl"). An aryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, an aryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.
[0042] "Heteroaryl" or "HetAr" as used herein refers to an unsaturated aromatic carbocyclic group having from 1 to 14 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur. A heteroaryl group may have a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl) which condensed rings may or may not be aromatic. The heteroaryl group may be optionally substituted independently with one or more substituents described herein. Particular heteroaryl groups are 5 to 14-membered rings having 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 5 to 10-membered rings having 1 to 8 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5, 6 or 7- membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variation, heteroaryl includes monocyclic aromatic 5-, 6- or 7-membered rings having from 1 to 6 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variation, heteroaryl includes polycyclic aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. A heteroaryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, a heteroaryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position.
[0043] "Heterocycle", "heterocyclic", or "heterocyclyl" as used herein refers to a saturated or an unsaturated non-aromatic cyclic group having a single ring or multiple condensed rings, and having from 1 to 14 annular carbon atoms and from 1 to 6 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like. A heterocycle comprising more than one ring may be fused, spiro or bridged, or any combination thereof. In fused ring systems, one or more of the fused rings can be cycloalkyl, aryl or heteroaryl. The heterocyclyl group may be optionally substituted independently with one or more substituents described herein.
Particular heterocyclyl groups are 3 to 14-membered rings having 1 to 13 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 12-membered rings having 1 to 11 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 10-membered rings having 1 to 9 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 8-membered rings having 1 to 7 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3 to 6-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variation, heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7-membered rings having from 1 to 2, 1 to 3, 1 to 4, 1 to 5 or 1 to 6 annular carbon atoms and 1 to 2, 1 to 3 or 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variation, heterocyclyl includes polycyclic non-aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. A heterocycle having more than one ring where at least one ring is aromatic is connected to the parent structure at a non-aromatic ring position.
[0044] "Halo" or "halogen" refers to elements of the Group 17 series having atomic number 9 to 85. Preferred halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two ("di") or three ("tri") halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3- fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced with a halo group is referred to as a "perhaloalkyl." A preferred perhaloalkyl group is trifluoroalkyl (-CF3). Similarly, "perhaloalkoxy" refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).
[0045] "Carbonyl" refers to the group C=0.
[0046] "Thiocarbonyl" refers to the group C=S.
[0047] "Oxo" refers to the moiety =0.
[0048] "Geminal" refers to the relationship between two moieties that are attached to the same atom. For example, in the residue -Ctb-CHR'R2, R1 and R2 are geminal and R1 may be referred to as a geminal R group to R2.
[0049] "Vicinal" refers to the relationship between two moieties that are attached to adjacent atoms. For example, in the residue -CHR 1 -CH2R2 , R 1 and R2 are vicinal and R 1 may be referred to as a vicinal R group to R2.
[0050] "Optionally substituted" unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same of different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 1 to 3, 1 to 4 or 1 to 5 substituents.
[0051] Unless clearly indicated otherwise, "an individual" as used herein intends a mammal, including but not limited to a primate, human, bovine, horse, feline, canine, or rodent.
[0052] As used herein, "treatment" or "treating" is an approach for obtaining beneficial or desired results including clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread (e.g., metastasis) of the disease, preventing or delaying the occurrence or recurrence of the disease, delay or slowing the progression of the disease, ameliorating the disease state, providing a remission (whether partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival. Also encompassed by "treatment" is a reduction of pathological consequence of cancer. The methods of the invention contemplate any one or more of these aspects of treatment.
[0053] As used herein, "delaying" the development of cancer means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. A method that "delays" development of cancer is a method that reduces probability of disease development in a given time frame and/or reduces the extent of the disease in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects. Cancer development can be detectable using standard methods, such as routine physical exams, mammography, imaging, or biopsy. Development may also refer to disease progression that may be initially undetectable and includes occurrence, recurrence, and onset.
[0054] As used herein, an "at risk" individual is an individual who is at risk of developing cancer. An individual "at risk" may or may not have detectable disease, and may or may not have displayed detectable disease prior to the treatment methods described herein. "At risk" denotes that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of cancer, which are described herein. An individual having one or more of these risk factors has a higher probability of developing cancer than an individual without these risk factor(s).
[0055] As used herein, by "combination therapy" is meant a therapy that includes two or more different compounds. Thus, in one aspect, a combination therapy comprising a compound detailed herein and another compound is provided. In some variations, the combination therapy optionally includes one or more pharmaceutically acceptable carriers or excipients, non-pharmaceutically active compounds, and/or inert substances.
[0056] As used herein, the term "effective amount" intends such amount of a compound of the invention which in combination with its parameters of efficacy and toxicity, should be effective in a given therapeutic form. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents (e.g., a compound, or pharmaceutically acceptable salt thereof), and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action {e.g., additive or synergistic effects) of the compounds. In various embodiments, an effective amount of the composition or therapy may (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent, and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (e.g., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of a tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer. In various embodiments, the amount is sufficient to ameliorate, palliate, lessen, and/or delay one or more of symptoms of cancer.
[0057] A "therapeutically effective amount" refers to an amount of a compound or salt thereof sufficient to produce a desired therapeutic outcome (e.g., reducing the severity or duration of, stabilizing the severity of, or eliminating one or more symptoms of cancer). For therapeutic use, beneficial or desired results include, e.g., decreasing one or more symptoms resulting from the disease (biochemical, histologic and/or behavioral), including its complications and intermediate pathological phenotypes presenting during development of the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication, delaying the progression of the disease, and/or prolonging survival of patients. [0058] A "prophylactically effective amount" refers to an amount of a compound, or pharmaceutically acceptable salt thereof, sufficient to prevent or reduce the severity of one or more future symptoms of cancer when administered to an individual who is susceptible and/or who may develop cancer. For prophylactic use, beneficial or desired results include, e.g., results such as eliminating or reducing the risk, lessening the severity of future disease, or delaying the onset of the disease (e.g., delaying biochemical, histologic and/or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presenting during future development of the disease).
[0059] It is understood that an effective amount of a compound or pharmaceutically acceptable salt thereof, including a prophylactically effective amount, may be given to an individual in the adjuvant setting, which refers to a clinical setting in which an individual has had a history of cancer, and generally (but not necessarily) has been responsive to therapy, which includes, but is not limited to, surgery (e.g., surgical resection), radiotherapy, and chemotherapy. However, because of their history of the cancer, these individuals are considered at risk of developing cancer. Treatment or administration in the "adjuvant setting" refers to a subsequent mode of treatment.
[0060] As used herein, "unit dosage form" refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Unit dosage forms may contain a single or a combination therapy.
[0061] As used herein, the term "controlled release" refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate, i.e., with a "controlled release" formulation, administration does not result in immediate release of the drug into an absorption pool. The term encompasses depot formulations designed to gradually release the drug compound over an extended period of time. Controlled release formulations can include a wide variety of drug delivery systems, generally involving mixing the drug compound with carriers, polymers or other compounds having the desired release characteristics {e.g., pH- dependent or non-pH-dependent solubility, different degrees of water solubility, and the like) and formulating the mixture according to the desired route of delivery {e.g., coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, and the like).
[0062] As used herein, by "pharmaceutically acceptable" or "pharmacologically acceptable" is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
[0063] "Pharmaceutically acceptable salts" are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual. Such salts, for example, include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the invention in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.
[0064] The term "excipient" as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression/encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin,
carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.;
suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.
Compounds of the Invention
[0065] Compounds according to the invention are detailed herein, including in the appended claims. Compounds of the formula (I) or (II), or a salt thereof, are provided, as are compounds of Table 1.
[0066] In one aspect of the formula (I) or (II), X is O. In some embodiments, X is O and RSS H. In some embodiments, X is O and R1 is C(0)(Rz). In a particular embodiment, X is O and R1 is C(0)C(CH3)3. In some embodiments, X is CH2 and R1 is H. In some embodiments, X is O and R1 is alkenyl. In some embodiments, X is O and R1 is alkyl (e.g., methyl) substituted with phenyl or C3-C6 cycloalkyl (e.g., cyclopropyl). In some embodiments, X is O and R1 is heteroaryl (e.g., pyridyl).
[0067] In another aspect of the formula (I) or (II), X is NH. In some embodiments, X is NH and R1 is substituted or unsubstituted heteroaryl (e.g., pyridyl, quinolinyl, pyrazolyl). In some embodiments, X is NH and R1 is substituted or unsubstituted C6-C14 aryl (e.g., substituted or unsubstituted phenyl). In some embodiments, X is NH and R1 is alkyl (e.g., methyl) substituted with C3-C6 cycloalkyl (e.g., cyclopropyl). In some embodiments, X is NH and R1 is C(0)(Rz). In some embodiments, X is NR11, and R11 is alkyl (e.g., methyl).
[0068] In another aspect of the formula (I) or (II), X is CH2. In some embodiments, X is CHz and RSs H. In some embodiments, In some embodiments, X is CH2 and R is C(0)ORz, C(0)NHRz, or NHC(0)(Rz). In a particular embodiment, Rz is C1-C4 alkyl (e.g., CH3, CH2CH3, or C(CH3)3).
[0069] In one aspect of the formula (I) or (II), W is
Figure imgf000020_0001
or S02, and Y is a bond,
CH2 or NH. In some embodiments, W is
Figure imgf000020_0002
, and Y is a bond. In some
Figure imgf000020_0003
embodiments, W is , and Y is CH2. In some embodiments, W is , and Y is NH. In some embodiments, W is S02, and Y is a bond. In some embodiments, W is S02 and Y is NH.
[0070] In another aspect of the formula (I) or (II), W is NH and Y is C(O).
[0071] In one aspect of the formula (I) or (II), Z is O and Y is a bond. In some
embodiments, Z is O and R2 is H. In some embodiments, Z is O, R2 is H, and R5 is H. In some embodiments, Z is O, R2 is H, and R5 is Q-C6 alkyl (e.g., methyl). In some embodiments, Z is O, and R2 is C(0)(Rz). In a particular embodiment, R2 is C(0)C(CH3)3.
[0072] In another aspect of the formula (I) or (II), ZR2 and R5 are taken together to form an oxo, and Y is NH. In yet another aspect of the formula (I) or (II), Z is S02 and Y is a bond.
[0073] In one aspect of the formula (I) or (II), m and n are both 0. In another aspect, m and n are both 1. In another aspect, m is 1 and n is 0. In another aspect, m is 0 and n is 1. In some embodiments, Ra is halo (e.g., chloro). In some embodiments, Rb is halo (e.g., chloro). In some embodiments, Rb is alkoxy (e.g., methoxy). In some embodiments, n is 1, m is 0, and Rb is chloro or alkoxy. In some embodiments, n is 0, m is 1, and Ra is chloro.
[0074] In one aspect of the formula (I) or (II), R3 is Q-C6 alkyl or hydrogen. In some embodiments, R3 is hydrogen. In some embodiments, R3 is methyl.
[0075] In one aspect of the formula (I) or (II), R4 is R6C(0)-. In some embodiments, R is (R7)(R8)C=C(R9)-. In some embodiments, R6 is Q=C(CH2)o-i-. In some embodiments, R4 is CH2=CHC(0)-. In some embodiments, R4 is CH2=CHC(0)-, and R3 is alkyl (e.g., methyl). In some embodiments, R4 is CH2=C(CH3)C(0)-, and R3 is hydrogen. In some embodiments, R4 is N≡CCH2C(0)-. In some embodiments, R4 is N≡CCH2C(0)-, and R3 is alkyl (e.g., methyl). In some embodiments, R4 is CH2=C(C≡N)C(0)-. In some embodiments, R4 is CH2=C(C≡N)C(0)-, and R3 is alkyl (e.g., methyl).
[0076] In another aspect of the formula (I) or (II), R4 is R6S(0)2-. In some embodiments, R4 is CH2=CHS(0)2-. In some embodiments, R4 is CH2=CHS(0)2-, and R3 is alkyl (e.g., methyl).
[0077] In some embodiments of the formula (I) or (II), the -W-Y- moiety is selected from:
Figure imgf000021_0001
Figure imgf000022_0001
wherein the wavy lines represent the point of attachment in formula (I) or (II).
[0078] In some embodiments of the formula (I), (II), (A) or (B), the -XR1 moiety is selected from:
Figure imgf000022_0002
Figure imgf000023_0001
wherein the wavy lines represent the point of attachment in formula (I), (II), (A) or (B).
[0079] In some embodiments of the formula (I), (II), (A) or (B), the -N(R3)R4 moiety is selected from:
Figure imgf000023_0002
wherein the wavy lines represent the point of attachment in formula (I), (II), (A) or (B).
[0080] It is intended and understood that each and every variation of W, Y, R1, Rz, R2, R3, R4, R5, R7, R8, R9, R10, R11, Q, X, Z, Ra, Rb, Rc, Rd, Re, R12, R13, R14, m, and n described herein, where applicable, may be combined as if each and every combination is individually described. [0081] In one aspect of the formula (I), the compound is of the formula (I-A-1), (I-A-2), (I- A-3), or (I-A-4):
Figure imgf000024_0001
wherein each of the variables of the formulae (I-A-1), (I-A-2), (I-A-3), and (I-A-4) are as defined in the formula (I) or any variation thereof.
[0082] In one aspect of the formula (I), the compound is of the formula (I-B-1), (I-B-2), (I- B-3), (I-B-4), (I-B-5), (I-B-6), (I-B-7), or (I-B-8):
Figure imgf000024_0002
Figure imgf000025_0001
wherein each of the variables of the formulae (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-B-5), (I-B- 6), (I-B-7), and (I-B-8) are as defined in the formula (I) or any variation thereof.
[0083] In one aspect of the formula (I), the compound is of the formula (I-C-1), (I-C-2), (I- C-3), (I-C-4), (I-C-5), or (I-C-6):
Figure imgf000026_0001
wherein each of the variables of the formulae (I-C-1), (I-C-2), (I-C-3), (I-C-4), (I-C-5), and (I-C-6) are as defined in the formula (I) or any variation thereof.
[0084] Representative compounds of the invention are listed in Table 1.
Table 1
Figure imgf000027_0001
N-(3-hydroxy-5-
(hydroxy(phenyl)methyl)phenyl)-N- methylmethacrylamide
Figure imgf000028_0001
OH
N-(3-hydroxy-5-
(hydroxy(phenyl)methyl)phenyl)-N-
CH3 methylethenesulfonamide
N-(3-hydroxy-5-
(hydroxy(phenyl)me1hyl)phenyl)methacrylarnide
Figure imgf000028_0002
3 -(hydroxy(phenyl)methyl)-5-(N- methylacrylamido)phenyl pivalate
Figure imgf000028_0003
OH
A o 2-cyano-N-(3-hydroxy-5-
(hydroxy(phenyl)methyl)phenyl)-N-
Jk ^H3 methylacetamide
N-(4-chlorophenyl)-3-hydroxy-5-(N- methylvinylsulfonarnido)benzarnide
Figure imgf000029_0001
N-(3-(hydroxy(phenyl)methyl)phenyl)-N- methylacrylamide
Figure imgf000029_0002
N-(3 -benzoyl-5-hydroxyphenyl)-N- methylacrylamide
Figure imgf000029_0003
OH
N-(4-chlorophenyl)-3-hydroxy-5-(N- methylacrylamido)benzamide
N-(3 -hydroxy-5-( 1 -hydroxy- 1 - phenylethyl)phenyl)-N-methylacrylamide
Figure imgf000030_0001
N-(3-((4-chlorophenyl)(hydroxy)methyl)-5- hydroxyphenyl)-N-methylacrylamide
Figure imgf000030_0002
N-(3 -((3 -chlorophenyl)(hydroxy)methyl)-5 - hydroxyphenyl)-N-methylacrylamide
Figure imgf000030_0003
Figure imgf000031_0001
Figure imgf000032_0001
3 -(hydroxy(phenyl)methyl)-5-(N- methylacrylamido)phenyl 4-hydroxybenzoate
3 -(hydroxy(phenyl)methyl)-5-(N- methylacrylamido)phenyl
cyclopropanecarboxylate
N-(3-(hydroxy(phenyl)methyl)-5-(pyridin-4- ylamino)phenyl)-N-methylacrylamide
N-(3-(hydroxy(phenyl)methyl)-5-((4- hydroxyphenyl)amino)phenyl)-N- methylacrylamide
Figure imgf000033_0001
N-(3-(hydroxy(phenyl)methyl)-5-(quinolin-6- ylamino)phenyl)-N-methylacrylamide
jfl
N-(3 -(hydroxy(phenyl)methyl)-5 -((3 - hydroxyphenyl)amino)phenyl)-N- methylacrylamide
Figure imgf000034_0001
N-(3-((cyclopropylmethyl)amino)-5- (hydroxy(phenyl)methyl)phenyl)-N- methylacrylamide
N-(3 -((3 -cyclopropyl- 1 -methyl- 1
y(phenyl)me H-pyrazol-5 - yl)amino)-5-(hydrox thyl)phenyl)- N-methylacrylamide
Figure imgf000034_0002
4-hydroxy-N-(3-(hydroxy(phenyl)methyl)-5-(N- methylacrylarnido)phenyl)benzarnide
Figure imgf000035_0001
(3-hydroxy-5-(N- methylacrylamido)phenyl)(phenyl)methyl pivalate
Figure imgf000035_0002
N-(3-(hydroxy(phenyl)methyl)-5-(N- methylpivalarnido)phenyl)-N-methylacrylarnide
N-(3-(hydroxy(phenyl)methyl)-5- pivalarnidophenyl)-N-methylacrylarnide
Figure imgf000035_0003
N-(3-((tert-butylamino)methyl)-5-
(hydroxy(phenyl)methyl)phenyl)-N- methylacrylamide
N-(3-(hydroxy(phenyl)methyl)-5- (isobutyramidomethyl)phenyl)-N- methylacrylamide
tert-butyl 2-(3 -(hydroxy(phenyl)methyl)-5-(N- methylacrylamido)phenyl)acetate
Figure imgf000036_0001
^NH
N-(3-(2-(ethylamino)-2-oxoethyl)-5- (hydroxy(phenyl)methyl)phenyl)-N- ΗΟγΟ Ν- methylacrylamide
(3-(hydroxy(phenyl)methyl)-5-(N-
39 methylacrylamido)phenyl)(phenyl)methyl pivalate
(3-(benzyl(2-hydroxyethyl)arnino)-5-(N-
40 methylacrylamido)phenyl)(phenyl)methyl pivalate
Figure imgf000037_0001
0
3 -(2-cyano-N-methylacrylamido)-5 -
41
(hydroxy(phenyl)methyl)phenyl pivalate
3-((4-chlorophenyl)carbamoyl)-5-(2-cyano-N-
42
methylacrylamido)phenyl pivalate
Figure imgf000037_0002
Figure imgf000038_0001
N-(3-hydroxy-5-(phenylsulfonyl)phenyl)-N- methylacrylamide
Figure imgf000039_0001
3 -(N-methylacrylamido)-5 - (phenylsulfonyl)phenyl pivalate
Figure imgf000039_0002
2-cyano-N-(3-hydroxy-5-
(hydroxy(phenyl)methyl)phenyl)-N- methylacrylamide
Figure imgf000039_0003
N-(2-chloro-3 -hydroxy-5-
(hydroxy(phenyl)methyl)phenyl)-N- methylacrylamide
Figure imgf000039_0004
N-(3-((4-chlorophenyl)(hydroxy)methyl)-5-
51 (isobutyramidomethyl)phenyl)-N- methylacrylamide
N-(3-(hydroxy(phenyl)methyl)-5-
52 (propionamidomethyl)phenyl)-N- methylacrylamide
(3 -(N-methylacrylamido)-5-
53 (propionamidomethyl)phenyl)(phenyl)methyl pivalate
Figure imgf000040_0001
General Synthetic Methods
[0085] The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.
[0086] Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization, and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
[0087] Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
[0088] Solvates and/or polymorphs of a compound provided herein or a pharmaceutically acceptable salt thereof are also contemplated. Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are often formed during the process of
crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and/or solubility. Various factors such as the
recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
General Synthesis of Compounds of the formula (I)
[0089] Compounds of the formula (I) can be prepared according to the exemplary Scheme below.
Figure imgf000042_0001
[0090] It is understood that the scheme above may be modified to arrive at various compounds of the invention by selection of appropriate reagents and starting materials.
Further Embodiments of the Invention
[0091] In one embodiment, the invention relates to Compounds described in Table 1, and uses thereof.
[0092] The embodiments and variations described herein are suitable for compounds of any formulae detailed herein, where applicable.
[0093] Representative examples of compounds detailed herein, including intermediates and final compounds according to the invention are depicted in the tables herein. It is understood that in one aspect, any of the compounds may be used in the methods detailed herein, including, where applicable, intermediate compounds that may be isolated and administered to an individual.
[0094] Where tautomeric forms may be present for any of the compounds described herein, each and every tautomeric form is intended even though only one or some of the tautomeric forms may be explicitly depicted. The tautomeric forms specifically depicted may or may not be the predominant forms in solution or when used according to the methods described herein.
[0095] The invention also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms of the compounds described. The structure or name is intended to embrace all possible stereoisomers of a compound depicted, and each unique stereoisomer has a compound number bearing a suffix "a", "b", etc. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds. Compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof, or a composition comprising mixtures of compounds of the invention in any ratio, including two or more stereochemical forms, such as in a racemic or non-racemic mixture.
[0096] The invention also intends isotopically-labeled and/or isotopically-enriched forms of compounds described herein. The compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. In some embodiments, the compound is isotopically-labeled, such as an isotopically-labeled compound of the formula (I) or variations thereof described herein, where a fraction of one or more atoms are replaced by an isotope of the same element. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2H, 3H, nC, 13C, 14C 13N, 150, 170, 32P, 35S, 18F, and 36C1. Certain isotope-labeled compounds (e.g. 3H and 14C) are useful in compound or substrate tissue distribution study. Incorporation of heavier isotopes such as deuterium (2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements and, hence may be preferred in some instances.
[0097] Isotopically-labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described in the accompanying Examples, substituting appropriate isotopically- labeled reagents in place of the corresponding non-labeled reagent.
[0098] The invention also includes any or all metabolites of any of the compounds described. The metabolites may include any chemical species generated by a
biotransformation of any of the compounds described, such as intermediates and products of metabolism of the compound.
[0099] Articles of manufacture comprising a compound of the invention, or a salt or solvate thereof, in a suitable container are provided. The container may be a vial, jar, ampoule, preloaded syringe, i.v. bag, and the like.
[0100] Preferably, the compounds detailed herein are orally bioavailable. However, the compounds may also be formulated for parenteral (e.g. , intravenous) administration.
[0101] One or several compounds described herein can be used in the preparation of a medicament by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier, which are known in the art. Depending on the therapeutic form of the medication, the carrier may be in various forms. In one variation, the manufacture of a medicament is for use in any of the methods disclosed herein, e.g., for the treatment of cancer.
Pharmaceutical Compositions and Formulations
[0102] Pharmaceutical compositions of any of the compounds detailed herein are embraced by this invention. Thus, the invention includes pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
[0103] A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as
compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form. In one variation, "substantially pure" intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof. Taking compound 1 as an example, a composition of substantially pure compound 1 intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than compound 1 or a salt thereof. In one variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25% impurity. In another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 20% impurity. In still another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 10% impurity. In a further variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 5% impurity. In another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3% impurity. In still another variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 1% impurity. In a further variation, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 0.5% impurity. In yet other variations, a composition of substantially pure compound means that the composition contains no more than 15% or preferably no more than 10% or more preferably no more than 5% or even more preferably no more than 3% and most preferably no more than 1% impurity, which impurity may be the compound in a different stereochemical form. For instance, a composition of substantially pure (S) compound means that the composition contains no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the (R) form of the compound.
[0104] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, the invention embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
[0105] The compound may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g.,
intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. A compound may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g. , aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.
[0106] One or several compounds described herein can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above. Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier may be in various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Formulations comprising the compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington 's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20th ed. (2000), which is incorporated herein by reference.
[0107] Compounds as described herein may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
[0108] Any of the compounds described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein or a pharmaceutically acceptable salt thereof can be formulated as a 10 mg tablet.
[0109] Compositions comprising a compound provided herein are also described. In one variation, the composition comprises a compound and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compound is provided. Methods of Use
[0110] Compounds and compositions of the invention, such as a pharmaceutical composition containing a compound of any formula provided herein or a salt thereof and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein. The compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality control assays.
[0111] In one aspect is provided a method of inhibiting a bromodomain protein comprising administering to an individual in need thereof a compound or composition as provided herein or a salt thereof. The compound may inhibit one or more of the bromodomains of BRD2, BRD3, BRD4, and BRDT.
[0112] Also provided are methods of treating a disease or indication in which
bromodomain is implicated, comprising administering to an individual in need thereof a compound or composition as provided herein, or a salt thereof. Also provided is a method of treating a cancer in which bromodomain is implicated, comprising administering to the individual a compound or composition as provided herein, or a salt thereof.
[0113] In some embodiments, the cancer that may be treated is a solid tumor such as sarcomas and carcinomas. In some embodiments, the cancer that may be treated is a liquid tumor such as leukemia. Examples of cancers that may be treated by methods of the invention include, but are not limited to, breast cancer, prostate cancer, ovarian cancer, lung cancer, colon cancer, brain tumors, gastric cancer, liver cancer, thyroid cancer, endometrial cancer, gallbladder cancer, kidney cancer, adrenocortical cancer, sarcoma, skin cancer, head and neck cancer, leukemia, bladder cancer, colorectal cancer, hematopoietic cancer and pancreatic cancer. In some embodiments, the breast cancer is breast carcinoma (ER negative or ER positive), primary breast ductal carcinoma, mammary adenocarcinoma, mammary ductal carcinoma (ER positive, ER negative or HER2 positive), HER2 positive breast cancer, luminal breast cancer or triple negative breast cancer (TNBC). In some embodiments, the breast cancer is unclassified. In some embodiments, the triple negative breast cancer is a basal-like TNBC, a mesenchymal TNBC (mesenchymal or mesenchymal stem-like), an immunomodulatory TNBC, or a luminal androgen receptor TNBC. In some embodiments, the prostate cancer is prostate adenocarcinoma. In some embodiments, the ovarian cancer is ovary adenocarcinoma. In some embodiments, the lung cancer is lung carcinoma, non-small lung carcinoma, adenocarcinoma, mucoepidermoid, anaplastic, large cell, or unclassified. In some embodiments, the colon cancer is colon adenocarcinoma, colon adenocarcinoma from a metastatic site lymph node, metastatic colorectal cancer, or colon carcinoma. In some embodiments, a brain tumor is glioblastoma, astrocytoma, meduloblastoma, meningioma or neuroblastoma. In some embodiments, gastric cancer is stomach cancer. In some embodiments, the liver cancer is hepatocellular carcinoma, hepatoblastoma or
cholangiocarcinoma. In some embodiments, the liver cancer is hepatitis B virus-derived. In some embodiments, the liver cancer is virus negative. In some embodiments, the thyroid cancer is papillary thyroid carcinoma, follicular thyroid cancer or medullary thyroid cancer. In some embodiments, the endometrial cancer is high grade endometroid cancer, uterine papillary serous carcinoma or uterine clear cell carcinoma. In some embodiments, the gallbladder cancer is gallbladder adenocarcinoma or squamous cell gallbladder carcinoma. In some embodiments, the kidney cancer is renal cell carcinoma or urothelial cell carcinoma. In some embodiments, the adrenocortical cancer is adrenal cortical carcinoma. In some embodiments, the sarcoma is synovial sarcoma, osteosarcoma, rhabdomyosarcoma, fibrosarcoma or Ewing's sarcoma. In some embodiments, the skin cancer is basal cell carcinoma, squamous carcinoma or melanoma. In some embodiments, the head and neck cancer is oropharyngeal cancer, nasopharyngeal cancer, laryngeal cancer and cancer of the trachea. In some embodiments, the leukemia is acute promyelocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, mantle cell lymphoma or multiple myeloma. In some embodiments, the leukemia is acute promyelocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, mantle cell lymphoma or multiple myeloma.
[0114] The invention additionally provides a method for treating a tumor comprising contacting the tumor with an effective amount of one or more compounds of the invention, or a salt thereof. In one aspect of the method, a compound or salt thereof is administered to an individual in need of tumor treatment. Exemplary tumors are derived from carcinomas of the breast, prostate, ovary, lung, or colon. In one aspect, the treatment results in a reduction of the tumor size. In another aspect, the treatment slows or prevents tumor growth and/or metastasis.
[0115] Any of the methods of treatment provided herein may be used to treat a primary tumor. Any of the methods of treatment provided herein may also be used to treat a metastatic cancer (that is, cancer that has metastasized from the primary tumor). Any of the methods of treatment provided herein may be used to treat cancer at an advanced stage. Any of the methods of treatment provided herein may be used to treat cancer at a locally advanced stage. Any of the methods of treatment provided herein may be used to treat early stage cancer. Any of the methods of treatment provided herein may be used to treat cancer in remission. In some of the embodiments of any of the methods of treatment provided herein, the cancer has reoccurred after remission. In some embodiments of any of the methods of treatment provided herein, the cancer is progressive cancer.
[0116] In one variation, a method of treating cancer in an individual is provided comprising administering to the individual an effective around of a compound described herein or a pharmaceutically acceptable salt thereof, wherein in the cancer is dependent on BRD2. In one variation, a method of treating cancer in an individual is provided comprising administering to the individual an effective around of a compound described herein or a pharmaceutically acceptable salt thereof, wherein in the cancer is dependent on BRD3. In one variation, a method of treating cancer in an individual is provided comprising administering to the individual an effective around of a compound described herein or a pharmaceutically acceptable salt thereof, wherein in the cancer is dependent on BRD4. In one variation, a method of treating cancer in an individual is provided comprising administering to the individual an effective around of a compound described herein or a pharmaceutically acceptable salt thereof, wherein in the cancer is dependent on BRDT.
[0117] Any of the methods of treatment provided herein may be used to treat an individual (e.g., human) who has been diagnosed with or is suspected of having cancer. In some embodiments, the individual may be a human who exhibits one or more symptoms associated with cancer. In some embodiments, the individual may have advanced disease or a lesser extent of disease, such as low tumor burden. In some embodiments, the individual is at an early stage of a cancer. In some embodiments, the individual is at an advanced stage of cancer. In some of the embodiments of any of the methods of treatment provided herein, the individual may be a human who is genetically or otherwise predisposed (e.g., has one or more so-called risk factors) to developing cancer who has or has not been diagnosed with cancer. In some embodiments, these risk factors include, but are not limited to, age, sex, race, diet, history of previous disease, presence of precursor disease, genetic (e.g., hereditary) considerations, and environmental exposure. In some embodiments, the individuals at risk for cancer include, e.g., those having relatives who have experienced this disease, and those whose risk is determined by analysis of genetic or biochemical markers.
[0118] Any of the methods of treatment provided herein may be practiced in an adjuvant setting. In some embodiments, any of the methods of treatment provided herein may be used to treat an individual who has previously been treated for cancer, e.g., with one or more other therapies such as radiation, surgery or chemotherapy. Any of the methods of treatment provided herein may be used to treat an individual who has not previously been treated for cancer. Any of the methods of treatment provided herein may be used to treat an individual at risk for developing cancer, but who has not been diagnosed with cancer. Any of the methods of treatment provided herein may be used as a first-line therapy. Any of the methods of treatment provided herein may be used as a second- or subsequent-line therapy.
[0119] In some embodiments, the amount of the compound or pharmaceutically acceptable salt thereof that is administered to an individual is an amount sufficient to decrease the size of a tumor, decrease the number of cancer cells, or decrease the growth rate of a tumor by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% compared to the corresponding tumor size, number of cancer cells, or tumor growth rate in the same subject prior to treatment or compared to the corresponding activity in other subjects not receiving the treatment. Standard methods can be used to measure the magnitude of this effect, such as in vitro assays with purified enzyme, cell-based assays, animal models, or human testing.
[0120] Any of the methods of treatment provided herein in one aspect reduce the severity of one or more symptoms associated with cancer by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% compared to the corresponding symptom in the same subject prior to treatment or compared to the corresponding symptom in other subjects not receiving a compound or composition of the invention.
[0121] In some embodiments, the compounds and compositions of the invention may be used to treat or prevent cancer in conjunction with a second therapy useful for cancer treatment. The second therapy includes, but is not limited to, surgery, radiation, and/or chemotherapy.
[0122] Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein or a salt thereof and a pharmaceutically acceptable excipient.
Dosing and Method of Administration
[0123] A compound or composition of the invention may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual's life. In one variation, the compound is administered on a daily or intermittent schedule. The compound can be administered to an individual continuously (for example, at least once daily) over a period of time. The dosing frequency can also be less than once daily, e.g., about a once weekly dosing. The dosing frequency can be more than once daily, e.g., twice or three times daily. The dosing frequency can also be intermittent, including a 'drug holiday' (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.
[0124] The compounds provided herein or a salt thereof may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral and transdermal. A compound provided herein can be administered frequently at low doses, known as 'metronomic therapy,' or as part of a maintenance therapy using compound alone or in combination with one or more additional drugs. Metronomic therapy or maintenance therapy can comprise administration of a compound provided herein in cycles. Metronomic therapy or maintenance therapy can comprise intra-tumoral administration of a compound provided herein.
[0125] In one aspect, the invention provides a method of treating cancer in an individual by parenterally administering to the individual (e.g., a human) an effective amount of a compound or salt thereof. In some embodiments, the route of administration is intravenous, intra-arterial, intramuscular, or subcutaneous. In some embodiments, the route of
administration is oral. In still other embodiments, the route of administration is transdermal.
[0126] The invention also provides compositions (including pharmaceutical compositions) as described herein for the use in treating, preventing, and/or delaying the onset and/or development of cancer and other methods described herein. In certain embodiments, the composition comprises a pharmaceutical formulation which is present in a unit dosage form.
[0127] Also provided are articles of manufacture comprising a compound of the invention or a salt thereof, composition, and unit dosages described herein in suitable packaging for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and/or sealed.
Kits
[0128] The invention further provides kits for carrying out the methods of the invention, which comprises one or more compounds described herein or a pharmacological composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein or a pharmaceutically acceptable salt thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for use in the treatment of cancer.
[0129] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit. One or more components of a kit may be sterile and/or may be contained within sterile packaging.
[0130] The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or a second pharmaceutically active compound useful for a disease detailed herein (e.g., cancer) to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g. , hospital pharmacies and compounding pharmacies).
[0131] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g. , magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present invention. The instructions included with the kit generally include information as to the components and their administration to an individual.
EXAMPLES
[0132] The following Examples are provided to illustrate but not to limit the invention.
[0133] The following abbreviations are used herein: thin layer chromatography (TLC); hour (h); minute (min); second (sec); ethanol (EtOH); dimethylsulfoxide (DMSO); N,N- dimethylformamide (DMF); trifluoroacetic acid (TFA); tetrahydroiuran (THF); Normal (N); aqueous (aq.); methanol (MeOH); dichloromethane (DCM); ethyl acetate (EtOAc); Retention factor (Rf); room temperature (RT). [0134] Compounds detailed herein may be prepared by those of skill in the art by referral to the General Methods. Particular examples of the General Methods are provided in the Examples below.
Example 1 : Preparation of Compound Nos. 1. la. and lb
Synthesis of N-{3-hydroxy-5-[hydroxy(phenyl)methyl]phenyl}-N-methylprop-2-enamide Step-1 : Synthesis of 3-bromo-5-hydroxybenzaldehyde:
[0135] To a solution of 3, 5-dibromophenol (2.5 g, 9.92 mmol) in THF (25 mL) at -78 °C was added a 2.5 M solution of n-BuLi (7.9 mL, 19.84 mmol) dropwise over a period of 15 min. The yellow solution was stirred at the same temperature for 20 min, followed by dropwise addition of dry DMF (15.29 mL, 198.4 mmol). The reaction mixture was stirred at - 78 °C for 30 min and then at RT for 1 h. The reaction was quenched with saturated ammonium chloride solution (200 mL) and extracted with EtOAc (3x250 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-6% EtOAc in hexane) to yield the desired compound, 3-bromo-5-hydroxybenzaldehyde (1.0 g, 50.12%) as a white solid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 10.5 (bs, 1H), 9.85 (s, 1H), 7.50 (s, 1H), 7.25 (d, 2H).
Step-2: Synthesis of 3-bromo-5-(hydroxy(phenyl)methyl)phenol:
[0136] To a solution of 3-bromo-5-hydroxybenzaldehyde (1.0 g, 4.97 mmol) in THF (10 mL) was added a 1.0 M solution of phenyl magnesium bromide (10.44 mL) dropwise at 0 °C. The reaction mixture was stirred at RT overnight. The reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (2x150 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-9% EtOAc in hexane) to yield the desired compound, 3-bromo-5-(hydroxy(phenyl)methyl)phenol (700 mg, 50.72%) as a white solid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 9.80 (s, 1H), 7.40-7.20 (m, 5H), 7.00 (s, 1H), 6.75 (s, 2H), 5.95 (d, 1H), 5.60 (d, 1H).
Step-3: Synthesis of l-bromo-3-(methoxymethoxy)-5-((methoxymethoxy)( phenyl)methyl)benzene :
[0137] To a solution of 3-bromo-5-(hydroxy(phenyl)methyl)phenol (700 mg, 2.50 mmol) in THF (15 mL) sodium hydride (398.4 mg, 10.0 mmol) was added portion-wise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Chloromethyl methyl ether (1.15 mL, 15.04 mmol) was added dropwise and the reaction mixture was stirred at RT overnight. The reaction was quenched with ice cold water (100 mL) and extracted with EtOAc (2x100 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-3% EtOAc in hexane) to yield the desired compound, l-bromo-3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl) benzene (600 mg, 65.15%) as a colorless liquid.
'HNMR (400 MHz, DMSO-d6): δ (ppm): 7.40-7.20 (m, 5H), 7.15 (s, IH), 7.10 (s, IH), 7.05 (s, IH), 5.70 (s, IH), 5.20 (s, 3H), 4.60 (s, 2H), 3.30 (s, 3H), 3.20 (s, 3H).
Step-4: Synthesis of 3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl)- N-methylaniline :
[0138] A mixture of l-bromo-3-(methoxymethoxy)-5-
((methoxymethoxy)(phenyl)methyl)benzene (400 mg, 1.08 mmol), 40% aqueous methyl amine (4.2 mL, 54.4 mmol) and copper powder (68 mg, 1.08 mmol) was heated in a microwave at 100 °C for 1.5 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2x100 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-25% EtOAc in hexane) to yield the desired compound, 3- (methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl)-N-methylaniline (120 mg, 34.71%) as a colorless liquid. LCMS: 367 (M+l). !HNMR (400 MHz, DMSO-d6): δ (ppm): 7.40-7.15 (m, 5H), 6.20 (s, 2H), 6.05 (s, IH), 5.70 (m, IH), 5.45 (s, IH), 5.05 (s, 2H), 4.55 (m, 2H), 3.30 (s, 3H), 3.20(s, 3H), 2.60 (d, 3H).
Step-5: Synthesis of N-(3-(methoxymethoxy)-5-((methoxymethoxy)
(phenyl)methyl)phenyl)-N-methylacrylamide:
[0139] To a solution of 3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl)-N- methylaniline (120 mg, 0.378 mmol) in DCM (5 mL) at 0 °C was added triethylamine (0.15 mL, 1.13 mmol) and acryloyl chloride (0.04 mL, 0.567 mmol). The reaction mixture was stirred at RT for 2h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2x20 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to yield the desired compound, N-(3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl) phenyl)-N-methylacrylamide (120 mg, 85.45%) as a light yellow solid, which was used for the next step without any further purification. LCMS: 284 (M+l).
Step-6: Synthesis of N-(3-hydroxy-5-(hydroxy(phenyl)methyl)phenyl)-N- methylacrylamide : [0140] To a solution of 3-bromo-5-(hydroxy(phenyl)methyl)phenol (120 mg, 0.323 mmol) in THF (5 mL) was added 6 N hydrochloric acid (5 mL). The reaction mixture was stirred at RT for 48 h. The reaction mixture was neutralized with saturated sodium bicarbonate solution (5 mL) and extracted with EtOAc (3x30 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-5% MeOH in DCM) to yield the desired compound, N-(3- hydroxy-5-(hydroxy(phenyl)methyl)phenyl)-N-methylacrylamide (70 mg, 76.53%) as a light green solid. 'HNMR (400 MHz, DMSO-d6): δ (ppm): 9.65 (s. 1H), 7.40-7.15 (m, 4H), 6.70 (d, 2H), 6.45 (s, 1H), 6.15-5.95 (m, 2H), 5.90 (d, 1H), 5.60 (d, 1H), 5.50 (dd, 1H), 3.20 (s, 3H). LCMS: 284 (M+l). Chiral separation of racemic Compound no. 1 provided enantiomers la and lb.
Example 2: Preparation of Compound No. 2
Synthesis of N-({3-hydroxy-5-[hydroxy(phenyl)methyl]phenyl}methyl)-N-methylprop-2- enamide
Step-1 : Synthesis of 3-bromo-5-hydroxybenzaldehyde:
[0141] To a solution of 3, 5-dibromophenol (2.5 g, 9.92 mmol) in THF (25 mL) at -78 °C was added a 2.5 M solution of n-BuLi (7.9 mL, 19.84 mmol) dropwise over a period of 15 min. The yellow solution was stirred at the same temperature for 20 min, followed by dropwise addition of dry DMF (15.29 mL, 198.4 mmol). The reaction mixture was stirred at - 78 °C for 30 min and then at RT for 1 h. The reaction was quenched with saturated ammonium chloride solution (200 mL) and extracted with EtOAc (3x250 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-6% EtOAc in hexane) to yield the desired compound, 3-bromo-5-hydroxybenzaldehyde (1.0 g, 50.12%) as a white solid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 10.5 (bs, 1H), 9.85 (s, 1H), 7.50 (s, 1H), 7.25 (d, 2H).
Step-2: Synthesis of 3-bromo-5-(hydroxy(phenyl)methyl)phenol:
[0142] To a solution of 3-bromo-5-hydroxybenzaldehyde (1.0 g, 4.97 mmol) in THF (10 mL) was added a 1.0 M solution of phenyl magnesium bromide (10.44 mL) dropwise at 0 °C. The reaction mixture was stirred at RT overnight. The reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (2x150 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-9% EtOAc in hexane) to yield the desired compound, 3-bromo-5-(hydroxy(phenyl)methyl)phenol (1.0 g, 72.04%) as a white solid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 9.80 (s, IH), 7.40-7.20 (m, 5H), 7.00 (s, IH), 6.75 (s, 2H), 5.95 (d, IH), 5.60 (d, IH).
Step-3: Synthesis of l-bromo-3-(methoxymethoxy)-5-((methoxymethoxy)
(phenyl)methyl) benzene:
[0143] To a solution of 3-bromo-5-(hydroxy(phenyl)methyl)phenol (700 mg, 2.50 mmol) in DMF (15 mL) sodium hydride (398.4 mg, 10.0 mmol) was added portion-wise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Chloromethyl methyl ether (1.15 mL, 15.04 mmol) was added dropwise and the reaction mixture was stirred at RT overnight. The reaction was quenched with ice cold water (100 mL) and extracted with EtOAc (2x100 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-3% EtOAc in hexane) to yield the desired compound, l-bromo-3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl) methyl) benzene (1.0 g, 76.33%) as a colorless liquid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 7.40-7.20 (m, 5H), 7.15 (s, IH), 7.10 (s, IH), 7.05 (s, IH), 5.70 (s, IH), 5.20 (s, 3H), 4.60 (s, 2H), 3.30 (s, 3H), 3.20 (s, 3H).
Step-4: Synthesis of 3-(methoxymethoxy)-5-((methoxymethoxy)
(pheny l)methyl)benzaldehyde :
[0144] To a solution of l-bromo-3-(methoxymethoxy)-5-
((methoxymethoxy)(phenyl)methyl) benzene (500 mg, 1.36 mmol) in THF (15 mL) at -78 °C was added a 2.5M solution of n-BuLi (1.08 mL, 2.72 mmol) dropwise over a period of 15 min. The yellow solution was stirred at the same temperature for 20 min, followed by dropwise addition of dry DMF (2.09 mL, 27.2 mmol). The reaction mixture was stirred at -78 °C for 30 min and then at RT for 1 h. The reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (3x100 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-6% EtOAc in hexane) to yield the desired compound, 3 -(methoxymethoxy)-5 -((methoxymethoxy)(phenyl)methyl)benzaldehyde (400 mg, 92.86%) as a colorless liquid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 9.95 (s, IH), 7.50 (s, IH), 7.45 (s, IH), 7.30-7.20 (m, 6H), 6.20 (s, 2H), 5.75 (s, IH), 5.20 (s, 2H), 4.65 (s, 2H), 3.45 (s, 3H), 3.55 (s, 3H).
Step-5: Synthesis of l-(3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl)phenyl)-N-methylmethanamine: [0145] To a solution of 3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl) benzaldehyde (184 mg, 0.581 mmol) in methanol (10 mL) was added lithium hydroxide monohydrate (49 mg, 1.162 mmol). The reaction mixture was stirred at RT for 20 min followed by addition of 40% aqueous methylamine solution (0.45 mL, 5.81 mmol). The reaction mixture was allowed to stir at RT for 1 h. Sodium borohydride (66 mg, 1.74 mmol) was added portion-wise. The reaction mixture was stirred at RT overnight. The reaction mixture solvents were removed under reduced pressure, diluted with water (10 mL) and extracted with EtOAc (2x50 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure to yield the desired compound, N-(3- (methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl)phenyl)-N-methylacrylamide (190 mg, 98.57%) as a colorless liquid, which was used for the next step without any further purification. LCMS: 332 (M+l). 'HNMR (400 MHz, DMSO-d6): δ (ppm): 7.40-7.20 (m, 5H), 6.95 (s, 2H), 6.90 (s, IH), 5.65 (s, IH), 5.10 (s, 2H), 4.65 (s, 2H), 3.45 (s, 3H), 3.40 (s, 3H), 2.40 (s, 3H).
Step-6: Synthesis of N-(3-(methoxymethoxy)-5- ((memoxymethoxy)(phenyl)methyl)benzyl)-N-me1hylacrylamide:
[0146] To a solution of l-(3-(methoxymethoxy)-5-
((methoxymethoxy)(phenyl)methyl)phenyl)-N-methylmethanamine (190 mg, 0.573 mmol) in DCM (5 mL) at 0 °C was added triemylamine (0.24 mL, 1.71 mmol) and acryloyl chloride (0.07 mL, 0.859 mmol). The reaction mixture was stirred at RT for 20 min. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2x20 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Combiflash, Elution: 0-4% MeOH in DCM) to yield the desired compound, N-(3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl)benzyl)-N- methylacrylamide (150 mg, 67.87%) as a light yellow semi-solid. LCMS: 386 (M+l).
!HNMR (400 MHz, DMSO-d6): δ (ppm): 7.40-7.20 (m, 5H), 7.00-6.25 (m, 5H), 5.75-5.60 (m, 2H), 5.10 (s, 2H), 4.65 (s, 2H), 4.60 (s, IH), 4.50 (s, IH), 3.45 (s, 3H), 3.40 (s, 3H), 3.00 (s, 3H).
Step-7: Synthesis of N-(3-hydroxy-5-(hydroxy(phenyl)methyl)benzyl)-N- methylacrylamide :
[0147] To a solution of N-(3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl) benzyl)-N-methylacrylamide (150 mg, 0.389 mmol) in THF (5 mL) was added 6 N hydrochloric acid (5 mL). The reaction mixture was stirred at RT for 24 h. The reaction mixture was neutralized with saturated sodium bicarbonate solution (5 mL) and extracted with EtOAc (3x30 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Combiflash, Elution: 0-5% MeOH in DCM) to yield the desired compound, N-(3-hydroxy-5-(hydroxy(phenyl)methyl)phenyl)- N-methylacrylamide (70 mg, 60.49%) as a white solid. 'HNMR (400 MHz, DMSO-d6): δ (ppm): 7.40-7.20 (m, 3H), 6.85-6.25 (m, 7H), 5.80-5.60 (m, 2H), 4.60 (s, 1H), 4.55 (s, 1H), 3.00 (s, 3H), 2.25 (d, 1H), 1.25 (s, 1H). LCMS: 298 (M+l).
Example 3 : Preparation of Compound No. 3
Synthesis ofN-{3-hydroxy-5-[hydroxy(phenyl)me1hyl]phenyl}-N,2-dime1hylprop-2-enamide
Step-1: Synthesis of 3-bromo-5-hydroxybenzaldehyde:
[0148] To a solution of 3, 5-dibromophenol (2.5 g, 9.92 mmol) in THF (25 mL) at -78 °C was added 2.5 M solution of n-BuLi (7.9 mL, 19.84 mmol) dropwise over a period of 15 min. The yellow solution was stirred at the same temperature for 20 min, followed by dropwise addition of dry DMF (15.29 mL, 198.4 mmol). The reaction mixture was stirred at -78 °C for 30 min and then at RT for 1 h. The reaction was quenched with saturated ammonium chloride solution (200 mL) and extracted with EtOAc (3x250 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-6% EtOAc in hexane) to yield the desired compound, 3- bromo-5-hydroxybenzaldehyde (1.0 g, 50.12%) as a white solid. !HNMR (400 MHz, DMSO- d6): δ (ppm): 10.5 (bs, 1H), 9.85 (s, 1H), 7.50 (s, 1H), 7.25 (d, 2H).
Step-2: Synthesis of 3-bromo-5-(hydroxy(phenyl)methyl)phenol:
[0149] To a solution of 3-bromo-5-hydroxybenzaldehyde (1.0 g, 4.97 mmol) in THF (10 mL) was added a 1.0 M solution of phenyl magnesium bromide (10.44 mL) dropwise at 0 °C. The reaction mixture was stirred at RT overnight. The reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (2x150 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-9% EtOAc in hexane) to yield the desired compound, 3 -bromo-5 -(hydroxy (phenyl)methyl)phenol (700 mg, 50.72%) as a white solid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 9.80 (s, 1H), 7.40-7.20 (m, 5H), 7.00 (s, 1H), 6.75 (s, 2H), 5.95 (d, 1H), 5.60 (d, 1H).
Step-3: Synthesis of l-bromo-3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl) benzene :
[0150] To a solution of 3-bromo-5-(hydroxy(phenyl)methyl)phenol (700 mg, 2.50 mmol) in DMF (15 mL) sodium hydride (398.4 mg, 10.0 mmol) was added portion-wise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Chloromethyl methyl ether (1.15 mL, 15.04 mmol) was added dropwise and the reaction mixture was stirred at RT overnight. The reaction was quenched with ice cold water (100 mL) and extracted with EtOAc (2x100 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-3% EtOAc in hexane) to yield the desired compound, l-bromo-3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl) benzene (600 mg, 65.15%) as a colorless liquid. 'HNMR (400 MHz, DMSO-d6): δ (ppm): 7.40-7.20 (m, 5H), 7.15 (s, IH), 7.10 (s, IH), 7.05 (s, IH), 5.70 (s, IH), 5.20 (s, 3H), 4.60 (s, 2H), 3.30 (s, 3H), 3.20 (s, 3H).
Step-4: Synthesis of 3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl)- N-methylaniline :
[0151] A mixture of l-bromo-3-(methoxymethoxy)-5-
((methoxymethoxy)(phenyl)methyl)benzene (400 mg, 1.08 mmol), 40% aqueous methyl amine (4.2 mL, 54.4 mmol) and copper powder (68 mg, 1.08 mmol) was heated in a microwave at 100 °C for 1.5 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2x100 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-25% EtOAc in hexane) to yield the desired compound, 3- (methoxymethoxy)-5-((methoxymethoxy) (phenyl)methyl)-N-methylaniline (120 mg, 34.71%) as a colorless liquid. LCMS: 317 (M+l). !HNMR (400 MHz, DMSO-d6): δ (ppm): 7.40-7.15 (m, 5H), 6.20 (s, 2H), 6.05 (s, IH), 5.70 (m, IH), 5.45 (s, IH), 5.05 (s, 2H), 4.55 (m, 2H), 3.30 (s, 3H), 3.20(s, 3H), 2.60 (d, 3H).
Step-5: Synthesis of N-(3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl)phenyl)-N-methyl methacrylamide :
[0152] To a solution of 3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl)-N- methylaniline (120 mg, 0.378 mmol) in DCM (5 mL) at 0 °C was added triethylamine (0.16 mL, 1.13 mmol) and methacryloyl chloride (59 mg, 0.567 mmol). The reaction mixture was stirred at RT for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2x20 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure to yield the desired compound N-(3-(methoxymethoxy)-5- ((methoxymethoxy) (phenyl)methyl) phenyl)-N-methylmethacrylamide (110 mg, 75.47%) as a light yellow solid, which was used for the next step without any further purification.
LCMS: 386 (M+l). Step-6: Synthesis of N-(3-hydroxy-5-(hydroxy(phenyl)methyl)phenyl)-N- methylmethacrylamide :
[0153] To a solution of N-(3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl) phenyl)-N-methylmethacrylamide (110 mg, 0.285 mmol) in THF (5 mL) was added 6 N hydrochloric acid (5 mL). The reaction mixture was stirred at RT for 4 h. The reaction mixture was neutralized with saturated sodium bicarbonate solution (5 mL) and extracted with EtOAc (3x30 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-5% MeOH in DCM) to yield the desired compound, N-(3-hydroxy-5- (hydroxy(phenyl)methyl)phenyl)-N-me1hylmethacrylamide (21 mg, 24.74%) as an off white solid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 9.50 (s. 1H), 7.35-7.15 (m, 5H), 6.70 (s, 1H), 6.65 (s, 1H), 6.45 (s, 1H), 5.85 (d, 1H), 5.60 (d, 1H), 4.96 (s, 1H), 4.80 (s, 1H), 3.20 (s, 3H), 1.60 (s, 1H) LCMS: 298 (M+l).
Example 4: Preparation of Compound No. 4
Synthesis of N- {3 -hydroxy-5-[hydroxy(phenyl)methyl]phenyl} -N-methylethene- 1 - sulfonamide
Step-1: Synthesis of 3-bromo-5-hydroxybenzaldehyde:
[0154] To a solution of 3, 5-dibromophenol (2.5 g, 9.92 mmol) in THF (25 mL) at -78 °C was added 2.5 M solution of n-BuLi (7.9 mL, 19.84 mmol) dropwise over a period of 15 min. The yellow solution was stirred at the same temperature for 20 min, followed by dropwise addition of dry DMF (15.29 mL, 198.4 mmol). The reaction mixture was stirred at -78 °C for 30 min and then at RT for 1 h. The reaction was quenched with saturated ammonium chloride solution (200 mL) and extracted with EtOAc (3x250 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-6% EtOAc in hexane) to yield the desired compound, 3- bromo-5-hydroxybenzaldehyde (1.0 g, 50.12%) as a white solid. 'HNMR (400 MHz, DMSO- d6): δ (ppm): 10.5 (bs, 1H), 9.85 (s, 1H), 7.50 (s, 1H), 7.25 (d, 2H).
Step-2: Synthesis of 3-bromo-5-(hydroxy(phenyl)methyl)phenol:
[0155] To a solution of 3-bromo-5-hydroxybenzaldehyde (1.0 g, 4.97 mmol) in THF (10 mL) was added a 1.0 M solution of phenyl magnesium bromide (10.44 mL) dropwise at 0 °C. The reaction mixture was stirred at RT overnight. The reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (2x150 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-9% EtOAc in hexane) to yield the desired compound, 3-bromo-5-(hydroxy(phenyl)methyl)phenol (700 mg, 50.72%) as a white solid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 9.80 (s, IH), 7.40-7.20 (m, 5H), 7.00 (s, IH), 6.75 (s, 2H), 5.95 (d, IH), 5.60 (d, IH).
Step-3: Synthesis of l-bromo-3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl) benzene :
[0156] To a solution of 3-bromo-5-(hydroxy(phenyl)methyl)phenol (700 mg, 2.50 mmol) in DMF (15 mL) sodium hydride (398.4 mg, 10.0 mmol) was added portion-wise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Chloromethyl methyl ether (1.15 mL, 15.04 mmol) was added dropwise and the reaction mixture was stirred at RT overnight. The reaction was quenched with ice cold water (100 mL) and extracted with EtOAc (2x100 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-3% EtOAc in hexane) to yield the desired compound, l-bromo-3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl) methyl)benzene (600 mg, 65.15%) as a colorless liquid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 7.40-7.20 (m, 5H), 7.15 (s, IH), 7.10 (s, IH), 7.05 (s, IH), 5.70 (s, IH), 5.20 (s, 3H), 4.60 (s, 2H), 3.30 (s, 3H), 3.20 (s, 3H).
Step-4: Synthesis of 3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl)- N-methylaniline :
[0157] A mixture of l-bromo-3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl) benzene (400 mg, 1.08 mmol), 40% aqueous methyl amine (4.2 mL, 54.4 mmol) and copper powder (68 mg, 1.08 mmol) was heated in a microwave at 100 °C for 1.5 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2x100 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-25% EtOAc in hexane) to yield the desired compound, 3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl)-N- methylaniline (120 mg, 34.71%) as a colorless liquid. LCMS: 317 (M+l). !HNMR (400 MHz, DMSO-d6): δ (ppm): 7.40-7.15 (m, 5H), 6.20 (s, 2H), 6.05 (s, IH), 5.70 (m, IH), 5.45 (s, IH), 5.05 (s, 2H), 4.55 (m, 2H), 3.30 (s, 3H), 3.20(s, 3H), 2.60 (d, 3H).
Step-5: Synthesis of N-(3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl)phenyl)-N-methylethenesulfonamide:
[0158] To a solution of 3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl)-N- methylaniline (120 mg, 0.378 mmol) in DCM (5 mL) at 0 °C was added triethylamine (0.16 mL, 1.13 mmol) and ethenesulfonyl chloride (72 mg, 0.567 mmol). The reaction mixture was stirred at RT for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2x20 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Combiflash, Elution: 0-25% EtOAc in hexane) to yield the desired compound, N-(3-(methoxymethoxy)-5- ((methoxymethoxy) (phenyl)methyl)phenyl)-N-methylethenesulfonamide (80 mg, 51.97%) as a colorless liquid. 'HNMR ( 400 MHz, CDC13): δ (ppm): 7.40-7.20 (m, 5H), 6.95 (d, 2H), 6.90 (d, IH), 6.40 (m, IH), 6.10 (d, IH), 5.90 (d, IH), 5.60 (s, IH), 5.10 (s, 2H), 4.65 (s, 2H), 3.45 (s, 3H), 3.40 (s, 3H), 3.20 (s, 3H).
Step-6: Synthesis of N-(3-hydroxy-5-(hydroxy(phenyl)methyl)phenyl)-N- methylethene sulfonamide:
[0159] To a solution of N-(3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl) phenyl)-N-methylmethacrylamide (110 mg, 0.285 mmol) in THF (5 mL) was added 6 N hydrochloric acid (5 mL). The reaction mixture was stirred at RT for 4 h. The reaction mixture was neutralized with saturated sodium bicarbonate solution (5 mL) and extracted with EtOAc (3x30 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-5% MeOH in DCM) to yield the desired compound, N-(3-hydroxy-5-(hydroxy
(phenyl)methyl)phenyl)-N-methyl ethenesulfonamide (21 mg, 24.74%) as an off white solid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 7.40-7.20 (m, 5H), 6.95 (s, IH), 6.80-6.70 (d, 2H), 6.40 (m, IH), 6.20 (d, IH), 6.00 (d, IH), 5.75 (s, IH), 5.00 (bs, IH), 3.20 (s, 3H), 2.25 (bs, IH). LCMS: 298 (M+l).
Example 5: Preparation of Compound No. 5
Synthesis of N-{3-hydroxy-5-[hydroxy(phenyl)methyl]phenyl}-2-methylprop-2-enamide Step-1 : Synthesis of 3-bromo-5-hydroxybenzaldehyde:
[0160] To a solution of 3, 5-dibromophenol (2.5 g, 9.92 mmol) in THF (25 mL) at -78 °C was added 2.5 M solution of n-BuLi (7.9 mL, 19.84 mmol) dropwise over a period of 15 min. The yellow solution was stirred at the same temperature for 20 min, followed by dropwise addition of dry DMF (15.29 mL, 198.4 mmol). The reaction mixture was stirred at -78 °C for 30 min and then at RT for 1 h. The reaction was quenched with saturated ammonium chloride solution (200 mL) and extracted with EtOAc (3x250 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-6% EtOAc in hexane) to yield the desired compound, 3- bromo-5-hydroxybenzaldehyde (1.0 g, 50.12%) as a white solid. !HNMR (400 MHz, DMSO- d6): δ (ppm): 10.5 (bs, 1H), 9.85 (s, 1H), 7.50 (s, 1H), 7.25 (d, 2H).
Step-2: Synthesis of 3-bromo-5-(hydroxy(phenyl)methyl)phenol:
[0161] To a solution of 3-bromo-5-hydroxybenzaldehyde (1.0 g, 4.97 mmol) in THF (10 mL) was added a 1.0 M solution of phenyl magnesium bromide (10.44 mL) dropwise at 0 °C. The reaction mixture was stirred at RT for overnight. The reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (2x150 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-9% EtOAc in hexane) to yield the desired compound, 3-bromo-5-(hydroxy(phenyl)methyl)phenol (700 mg, 50.72%) as a white solid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 9.80 (s, 1H), 7.40-7.20 (m, 5H), 7.00 (s, 1H), 6.75 (s, 2H), 5.95 (d, 1H), 5.60 (d, 1H).
Step-3: Synthesis of l-bromo-3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl) benzene :
[0162] To a solution of 3-bromo-5-(hydroxy(phenyl)methyl)phenol (3.0 g, 10.74 mmol) in DMF (50 mL) sodium hydride (1.71 g, 42.96 mmol) was added portion-wise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Chloromethyl methyl ether (2.47 mL, 32.24 mmol) was added dropwise and the reaction mixture was stirred at RT for 2 h. The reaction was quenched with ice cold water (200 mL) and extracted with EtOAc (200 mL X 2). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-3% EtOAc in hexane) to yield the desired compound, l-bromo-3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl) methyl)benzene (2.8 g, 71.06%) as a colorless liquid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 7.40-7.20 (m, 5H), 7.15 (s, 1H), 7.10 (s, 1H), 7.05 (s, 1H), 5.70 (s, 1H), 5.20 (s, 3H), 4.60 (s, 2H), 3.30 (s, 3H), 3.20 (s, 3H).
Step-4: Synthesis of 3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl)aniline:
[0163] A mixture of l-bromo-3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl) benzene (500 mg, 1.36 mmol), ammonia solution (10 mL) and copper powder (260 mg, 4.08 mmol) was heated in a microwave at 100 °C for 1.5 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2x100 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-25% EtOAc in hexane) to yield the desired compound, 3-(methoxyme1hoxy)-5-((methoxymethoxy)(phenyl)methyl)aniline (150 mg, 36.31%) as a colorless liquid. LCMS: 304 (M+l).
Step-5: Synthesis of N-(3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl)phenyl)-methacryl amide:
[0164] To a solution of 3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl)aniline (150 mg, 0.494 mmol) in DCM (10 mL) at 0 °C was added triethylamine (0.20 mL, 1.48 mmol) and methacryloyl chloride (78 mg, 0.741 mmol). The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2x20 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-45% EtOAc in hexane) to yield the desired compound, N-(3-(methoxymethoxy)-5-((methoxy methoxy)(phenyl)methyl)phenyl)methacrylamide (70 mg, 38.11%) as a light brown solid. LCMS: 372 (M+l).
Step-6: Synthesis of N-(3-hydroxy-5- (hydroxy(phenyl)methyl)phenyl)methacrylamide:
[0165] To a solution of N-(3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl) phenyl) methacrylamide (70 mg, 0.188 mmol) in THF (2 mL) was added 6 N hydrochloric acid (2 mL). The reaction mixture was stirred at RT for 4 h. The reaction mixture was neutralized with saturated sodium bicarbonate solution (5 mL) and extracted with EtOAc (3x30 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-3% MeOH in DCM) to yield the desired compound, N-(3-hydroxy-5- (hydroxy(phenyl)methyl)phenyl)methacrylamide (12 mg, 22.47%) as an off white solid. !HNMR ( 400 MHz, DMSO-d6): δ (ppm): 9.60 (s. 1H), 9.25 (s, 1H), 7.35-7.15 (m, 5H), 7.10 (s, 1H), 7.05 (s, 1H), 6.50 (s, 1H), 5.75 (d, 1H), 5.70 (s, 1H), 5.50 (d, 1H), 5.45 (s, 1H), 1.90 (s, 3H). LCMS: 282 (M-l).
Example 6: Preparation of Compound No. 6
Synthesis of 3-[hydroxy(phenyl)methyl]-5-(N-methylprop-2-enamido)phenyl-2,2-dimethyl propanoate:
Step-1: Synthesis of 3-bromo-5-hydroxybenzaldehyde:
[0166] To a solution of 3, 5-dibromophenol (2.5 g, 9.92 mmol) in 25 mL of THF at -78 °C was added a 2.5M solution of n-BuLi (7.9 mL, 19.84 mmol) dropwise over a period of 15 min. The yellow solution was stirred at the same temperature for 20 min, followed by dropwise addition of dry DMF (15.29 mL, 198.4 mmol). The reaction mixture was stirred at - 78 °C for 30 min and then at RT for 1 h. The reaction was quenched with saturated ammonium chloride solution (200 mL) and extracted with EtOAc (3x250 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-6% EtOAc in hexane) to yield the desired compound, 3-bromo-5-hydroxybenzaldehyde (1.0 g, 50.12%) as a white solid. 'HNMR (400 MHz, DMSO-d6): δ (ppm): 10.5 (bs, 1H), 9.85 (s, 1H), 7.50 (s, 1H), 7.25 (d, 2H).
Step-2: Synthesis of 3-bromo-5-(hydroxy(phenyl)methyl)phenol:
[0167] To a solution of 3-bromo-5-hydroxybenzaldehyde (1.0 g, 4.97 mmol) in THF (10 mL) was added a 1.0 M solution of phenyl magnesium bromide (10.44 mL) dropwise at 0 °C. The reaction mixture was stirred at r. t. overnight. The reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (2x150 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-9% EtOAc in hexane) to yield the desired compound, 3-bromo-5-(hydroxy(phenyl)methyl)phenol (700 mg, 50.72%) as a white solid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 9.80 (s, 1H), 7.40-7.20 (m, 5H), 7.00 (s, 1H), 6.75 (s, 2H), 5.95 (d, 1H), 5.60 (d, 1H).
Step-3: Synthesis of l-bromo-3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl) benzene :
[0168] To a solution of 3-bromo-5-(hydroxy(phenyl)methyl)phenol (700 mg, 2.50 mmol) in THF (15 mL) sodium hydride (398.4 mg, 10.0 mmol) was added portion-wise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Chloromethyl methyl ether (1.15 mL, 15.04 mmol) was added dropwise and the reaction mixture was stirred at RT overnight. The reaction was quenched with ice cold water (100 mL) and extracted with EtOAc (2x100 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-3% EtOAc in hexane) to yield the desired compound, l-bromo-3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl)benzene (600 mg, 65.15%) as a colorless liquid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 7.40-7.20 (m, 5H), 7.15 (s, 1H), 7.10 (s, 1H), 7.05 (s, 1H), 5.70 (s, 1H), 5.20 (s, 3H), 4.60 (s, 2H), 3.30 (s, 3H), 3.20 (s, 3H). Step-4: Synthesis of 3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl)- N-methylaniline :
[0169] A mixture of l-bromo-3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl) methyl)benzene (400 mg, 1.08 mmol), 40% aqueous methyl amine (4.2 mL, 54.4 mmol) and copper powder (68 mg, 1.08 mmol) was heated in a microwave at 100 °C for 1.5 h. The reaction mixture was diluted with 100 mL water and extracted with EtOAc (2x100 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-25% EtOAc in hexane) to yield the desired compound, 3-(methoxymethoxy)-5-
((methoxymethoxy)(phenyl)methyl)-N-methylaniline (120 mg, 34.71%) as a colorless liquid. LCMS: 318 (M+l). 'HNMR (400 MHz, DMSO-d6): δ (ppm): 7.40-7.15 (m, 5H), 6.20 (s, 2H), 6.05 (s, 1H), 5.70 (m, 1H), 5.45 (s, 1H), 5.05 (s, 2H), 4.55 (m, 2H), 3.30 (s, 3H), 3.20(s, 3H), 2.60 (d, 3H).
Step-5: Synthesis of N-(3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl)phenyl)-N-methyl acrylamide :
[0170] To a solution of 3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl)-N- methylaniline (120 mg, 0.378 mmol) in DCM (5 mL) at 0 °C was added triethylamine (0.15 mL, 1.13 mmol) and acryloyl chloride (0.04 mL, 0.567 mmol). The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with 10 mL water and extracted with DCM (2x20 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure to yield the desired compound, N-(3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl) methyl)phenyl)-N-methylacrylamide (120 mg, 85.45%) as a light yellow solid, which was used for the next step without any further purification. LCMS: 372 (M+l).
Step-6: Synthesis of N-(3-hydroxy-5-(hydroxy(phenyl)methyl)phenyl)-N- methylacrylamide :
[0171] To a solution of 3-bromo-5-(hydroxy(phenyl)methyl)phenol (120 mg, 0.323 mmol) in THF (5 mL) was added 5 mL of 6 N hydrochloric acid. The reaction mixture was stirred at RT for 48 h. The reaction mixture was neutralized with saturated sodium bicarbonate solution (5 mL) and extracted with EtOAc (3x30 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-5% MeOH in DCM) to yield the desired compound, N-(3- hydroxy-5-(hydroxy(phenyl)methyl)phenyl)-N-methylacrylamide (70 mg, 76.53%) as a light green solid. LCMS: 284 (M+l). !HNMR (400 MHz, DMSO-d6): δ (ppm): 9.65 (s. 1H), 7.40- 7.15 (m, 4H), 6.70 (d, 2H), 6.45 (s, 1H), 6.15-5.95 (m, 2H), 5.90 (d, 1H), 5.60 (d, 1H), 5.50 (dd, 1H), 3.20 (s, 3H).
Step-7: Synthesis of 3-[hydroxy(phenyl)methyl]-5-(N-methylprop-2- enamido)phenyl 2,2 -dimethylpropanoate :
[0172] To a solution of N-(3-hydroxy-5-(hydroxy(phenyl)methyl)phenyl)-N- methylacrylamide (50 mg, 0.176 mmol) in 10 mL of DCM at 0 °C was added triethylamine (0.05 mL, 0.352 mmol) and pivaloyl chloride (32 mL, 0.264 mmol). The reaction mixture was stirred at RT for lh. The reaction mixture was diluted with 10 mL of water and extracted with DCM (2x20 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica-gel: 100-200 mesh, elution: 0-3% MeOH in DCM) to yield the desired compound, (3-hydroxy-5-(N- methylacrylamido)phenyl)(phenyl)methyl pivalate (21 mg, 32.36%) as a light yellow solid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 7.40-7.20 (m, 5H), 7.15 (s, 1H), 7.10 (s, 1H), 6.95 (s, 1H), 6.15 (d, 1H), 6.05 (d, 2H), 5.65 (d, 1H), 5.55 (d, 1H), 3.20 (s, 3H), 1.25 (s, 9H). LCMS: 368 (M+l).
Example 7: Preparation of Compound No. 7
Synthesis of 2-cyano-N-{3-hydroxy-5-[hydroxy(phenyl)methyl]phenyl}-N-methylacetamide
Step-1 : Synthesis of 3-bromo-5-hydroxybenzaldehyde:
[0173] To a solution of 3, 5-dibromophenol (2.5 g, 9.92 mmol) in THF (25 mL) at -78 °C was added a 2.5 M solution of n-BuLi (7.9 mL, 19.84 mmol) dropwise over a period of 15 min. The yellow solution was stirred at the same temperature for 20 min, followed by dropwise addition of dry DMF (15.29 mL, 198.4 mmol). The reaction mixture was stirred at - 78 °C for 30 min and then at RT for 1 h. The reaction was quenched with saturated ammonium chloride solution (200 mL) and extracted with EtOAc (3x250 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-6% EtOAc in hexane) to yield the desired compound, 3-bromo-5-hydroxybenzaldehyde (1.0 g, 50.12%) as a white solid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 10.5 (bs, 1H), 9.85 (s, 1H), 7.50 (s, 1H), 7.25 (d, 2H).
Step-2: Synthesis of 3-bromo-5-(hydroxy(phenyl)methyl)phenol:
[0174] To a solution of 3-bromo-5-hydroxybenzaldehyde (1.0 g, 4.97 mmol) in THF (10 mL) was added a 1.0 M solution of phenyl magnesium bromide (10.44 mL) dropwise at 0 °C. The reaction mixture was stirred at RT overnight. The reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (2x150 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-9% EtOAc in hexane) to yield the desired compound 3-bromo-5-(hydroxy(phenyl)methyl)phenol (700 mg, 50.72%) as a white solid.
Step-3: Synthesis of 3-(hydroxy(phenyl)methyl)-5-(methylamino)phenol:
[0175] A mixture of 3-bromo-5-(hydroxy(phenyl)methyl)phenol (800 mg, 2.8 mmol), 40% aqueous methyl amine (10.0 mL, 288.0 mmol) and copper powder (910 mg, 14.0 mmol) was heated in a microwave at 100 °C for 1.0 h. The reaction mixture was diluted with 100 mL of water and extracted with EtOAc (2x100 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-50% EtOAc in hexane) to yield the desired compound, 3- (hydroxy(phenyl) methyl)-5-(methylamino)phenol (400 mg, 60.6%) as a light yellow oil. LCMS: 230.1 (M+l). !HNMR (400 MHz, DMSO-d6): δ (ppm): 8.58 (s, 1H), 7.60 -7.59 (m, 2H), 7.38-7.20 (m, 2H), 7.19-7.05 (m, 1H), 6.18 (d, 2H), 5.89 (s, 1H), 5.18 (d, 1H), 4.40 (m, 1H), 2.76 (d, 3H).
Step-4: Synthesis of 2-cyano-N-(3-hydroxy-5-(hydroxy(phenyl)methyl)phenyl)-N- methylacetamide :
[0176] To a solution of compound 3 -(hydroxy (phenyl)methyl)-5-(methylamino)phenol (100 mg, 0.436 mmol), was added acrylic acid (55.0 mg, 0.065 mmol) followed by addition of HATU (330.0 mg, 0.087 mmol), and DIPEA (224 mg, 1.74 mmol). The reaction mixture was stirred under nitrogen atmosphere for 10 min at RT. The reaction mixture was diluted with 50 mL of water and extracted with EtOAc (2x100 mL), washed with brine (2x100 mL). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated and purified by prep purification to yield the desired compound, 2-cyano-N-(3-hydroxy-5- (hydroxy(phenyl)methyl)phenyl)-N-methylacetamide (15 mg, 12.91%) as a white solid. 'HNMR (400 MHz, DMSO-d6): δ (ppm): 9.72 (s, 1H), 7.40-7.34 (m, 2H), 7.33 -7.30 (m, 2H), 7.24-7.19 (m, 1H), 6.81 (s, 1H), 6.78 (s, 1H), 6.59 (s, 1H), 5.91 (d, 1H), 5.60 (d, 1H), 3.60 (s, 2H), 3.18 (s, 3H). LCMS: 297.1 (M+l). UPLC: 99.60 %.
Example 8: Preparation of Compound No. 8
Synthesis of N-(4-chlorophenyl)-3-hydroxy-5-( NT-me1hylethenesulfonamido)benzamide: Step-1: Synthesis of 3-bromo-N-(4-chlorophenyl)-5-hydroxybenzamide:
[0177] To a solution of compound p-chloroaniline (292 mg, 2.6 mmol), in DMF was added 3-bromo-5-hydroxybenzoic acid (500.0 mg, 2.3 mmol) followed by addition of HATU (1.74 g, 4.6 mmol) and DIPEA (1.2 g, 9.2 mmol). The reaction mixture was stirred under nitrogen atmosphere for 1 h at 100 °C. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2x100 mL), washed with brine (2x100 mL). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-20% EtOAc in hexane) to yield the desired compound 3-bromo-N-(4-chlorophenyl)-5-hydroxybenzamide (600 mg, 80.1%) as a brown solid . LCMS: 326.0 (M+l). 'HNMR (400 MHz, DMSO-d6): δ (ppm): 10.38 (s, 1H), 10.22 (s, 1H), 7.80 (d, 2H), 7.59 (s, 1H), 7.40 (d, 2H), 7.38 (s, 1H), 7.19 (s, 1H).
Step-2 : Synthesis of N-(4-chlorophenyl)-3 -hydroxy-5 -(methylamino)benzamide :
[0178] A mixture of 3-bromo-N-(4-chlorophenyl)-5-hydroxybenzamide (600 mg, 1.84 mmol), 40% aqueous methyl amine (6.0 mL, 184.0 mmol) and copper powder (584 mg, 9.2 mmol) was heated in a microwave at 100 °C for 1.0 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2x100 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-50% EtOAc in hexane) to yield the desired compound N-(4-chlorophenyl)-3-hydroxy-5-(memylamino)benzamide (400 mg, 80%) as a light yellow oil. LCMS: 277.1 (M+l). !HNMR (400 MHz, DMSO-d6): δ (ppm): 10.19 (s, 1H), 9.22 (s, 1H), 7.78 (d, 2H), 7.38 (d, 2H), 6.50 (m, 2H), 6.18 (m, 1H), 5.79 (m, 1H), 2.70 (d, 3H).
Step-3: Synthesis ofN-(4-chlorophenyl)-3-hydroxy-5-(N- me1hylvinylsulfonamido)benzamide :
[0179] To a solution of N-(4-chlorophenyl)-3-hydroxy-5-(methylamino)benzamide (200 mg, 0.72 mmol) in 10 mL of dichloroethane at 0 °C was added pyridine (0.85 mg, 1.08 mmol) and vinyl sulphone (90 mg, 0.72 mmol). The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with 10 mL of water and extracted with ethylacetate (2x20 mL). The organic layer washed with 1 N HC1 (3x15 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by prep HPLC to yield the desired compound, N-(4-chlorophenyl)-3-hydroxy-5-(N- methylvinylsulfonamido)benzamide (40 mg, 15.09%) as a white solid. !HNMR (400 MHz, CD3OD): δ (ppm): 7.68 (d, 2H), 7.38 (d, 2H), 7.24 (s, 1H), 7.00 (s, 1H), 6.67 (dd, 1H), 6.20 (s, 1H), 6.18-6.16 (m, 2H). LCMS: 367 (M+l). UPLC: 98.57% Example 9: Preparation of Compound No. 9
Synthesis ofN-{3-[hydroxy(phenyl)methyl]phenyl}-N-methylprop-2-enamide:
Step-1 : Synthesis of 3-bromobenzaldehyde:
[0180] To a solution of 1,3-dibromobenzene (1.0 g, 4.27 mmol) in THF (10 mL) at -78 °C was added a 2.5 M solution of n-BuLi (2.05 mL, 5.13 mmol) dropwise over a period of 15 min. The yellow solution was stirred at the same temperature for 20 min, followed by dropwise addition of dry DMF (6.6 mL, 85.4 mmol). The reaction mixture was stirred at -78 °C for 30 min and then at RT for 1 h. The reaction was quenched with saturated ammonium chloride solution (200 mL) and extracted with EtOAc (3x250 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-6% EtOAc in hexane) to yield the desired compound, 3-bromobenzaldehyde (500 mg, 63.21%) as a colorless liquid. LCMS: 185 (M+l).
Step-2: Synthesis of (3-bromophenyl)(phenyl)methanol:
[0181] To a solution of 3-bromobenzaldehyde (400 mg, 2.16 mmol) in THF (10 mL) was added 1.0M solution of phenyl magnesium bromide (4.32 mL, 4.32 mmol) dropwise at 0 °C. The reaction mixture was stirred at RT overnight. The reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (2x150 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-9% EtOAc in hexane) to yield the desired compound, (3-bromophenyl)(phenyl)methanol (700 mg, 96.15%) as a white solid. 'HNMR (400 MHz, DMSO-d6): δ (ppm): 7.55 (s, 1H), 7.40-7.20 (m, 8H), 6.00 (d, 1H), 5.65 (d, 1H).
Step-3: Synthesis of (3-(methylamino)phenyl)(phenyl)methanol:
[0182] A mixture of (3-bromophenyl)(phenyl)methanol (547 mg, 2.07 mmol), 40% aqueous methyl amine (16 mL, 207.88 mmol) and copper powder (263 mg, 6.21 mmol) was heated in a microwave at 100 °C for 1.5 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2x100 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-25% EtOAc in hexane) to yield the desired compound, (3- (methylamino)phenyl)(phenyl)methanol (200 mg, 45.10%) as a colorless liquid. LCMS: 214 (M+l). Step-4 : Synthesis of N-(3 -(hydroxy(phenyl)methyl)phenyl)-N-methylacrylamide :
[0183] To a solution of compound (3-(methylamino)phenyl)(phenyl)methanol (100 mg, 0.458 mmol) in DMF (10 mL) was added acrylic acid (33.78 mg, 0.468 mmol) followed by addition of EDC.HC1 (134.8 mg, 0703 mmol), HOBt (95 mg, 0.703 mmol) and DIPEA (0.2 mL, 1.17 mmol). The reaction mixture was stirred under nitrogen atmosphere for 30 min. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2x100 mL), washed with brine (2x100 mL). The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated and purified by prep HPLC to yield the desired compound, N- (3-(hydroxy(phenyl) methyl)phenyl)-N-methylacrylamide (30 mg, 23.91%) as a brown viscous solid. 'HNMR (400 MHz, DMSO): δ (ppm): 7.40-7.00 (m, 9H), 6.10 (d, 1H), 5.95 (m, 2H), 5.70 (d, 1H), 5.55 (d, 1H), 3.20 (s, 3H). LCMS: 268 (M+l)
Example 10: Preparation of Compound No. 10
Synthesis of N-(3-benzoyl-5-hydroxyphenyl)-N-methylprop-2-enamide: Step-1 : Synthesis of 3-bromo-5-hydroxybenzaldehyde:
[0184] To a solution of 3, 5-dibromophenol (2.5 g, 9.92 mmol) in 25 mL of THF at -78 °C was added a 2.5 M solution of n-BuLi (7.9 mL, 19.84 mmol) dropwise over a period of 15 min. The yellow solution was stirred at the same temperature for 20 min, followed by dropwise addition of dry DMF (15.29 mL, 198.4 mmol). The reaction mixture was stirred at - 78 °C for 30 min and then at RT for 1 h. The reaction was quenched with saturated ammonium chloride solution (200 mL) and extracted with EtOAc (3x250 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-6% EtOAc in hexane) to yield the desired compound, 3-bromo-5-hydroxybenzaldehyde (1.0 g, 50.12%) as a white solid. !HNMR (400 MHz, DMSO-d6) δ (ppm): 10.5 (bs, 1H), 9.85 (s, 1H), 7.50 (s, 1H), 7.25 (d, 2H).
Step-2: Synthesis of 3-bromo-5-(hydroxy(phenyl)methyl)phenol:
[0185] To a solution of 3-bromo-5-hydroxybenzaldehyde (1.0 g, 4.97 mmol) in THF (10 mL) was added a 1.0 M solution of phenyl magnesium bromide (10.44 mL) dropwise at 0 °C. The reaction mixture was stirred at RT overnight. The reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (2x150 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-9% EtOAc in hexane) to yield the desired compound, 3-bromo-5-(hydroxy(phenyl)methyl)phenol (700 mg, 50.72%) as a white solid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 9.80 (s, IH), 7.40-7.20 (m, 5H), 7.00 (s, IH), 6.75 (s, 2H), 5.95 (d, IH), 5.60 (d, IH).
Step-3: Synthesis of l-bromo-3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl) benzene :
[0186] To a solution of 3-bromo-5-(hydroxy(phenyl)methyl)phenol (700 mg, 2.50 mmol) in THF (15 mL) sodium hydride (398.4 mg, 10.0 mmol) was added portion-wise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Chloromethyl methyl ether (1.15 mL, 15.04 mmol) was added dropwise and the reaction mixture was stirred at RT overnight. The reaction was quenched with ice cold water (100 mL) and extracted with EtOAc (2x100 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-3% EtOAc in hexane) to yield the desired compound, l-bromo-3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl) methyl)benzene (600 mg, 65.15%) as a colorless liquid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 7.40-7.20 (m, 5H), 7.15 (s, IH), 7.10 (s, IH), 7.05 (s, IH), 5.70 (s, IH), 5.20 (s, 3H), 4.60 (s, 2H), 3.30 (s, 3H), 3.20 (s, 3H).
Step-4: Synthesis of 3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl)- N-methylaniline :
[0187] A mixture of l-bromo-3-(methoxymethoxy)-5-((methoxymethoxy) (phenyl)methyl) benzene (400 mg, 1.08 mmol), 40% aqueous methyl amine (4.2 mL, 54.4 mmol) and copper powder (68 mg, 1.08 mmol) was heated in a microwave at 100 °C for 1.5 h. The reaction mixture was diluted with 100 mL water and extracted with EtOAc (2x100 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-25% EtOAc in hexane) to yield the desired compound, 3-(methoxymethoxy)-5-((methoxymethoxy)(phenyl)methyl)-N- methylaniline (120 mg, 34.71%) as a colorless liquid. LCMS: 318 (M+l). !HNMR (400 MHz, DMSO-d6): δ (ppm): 7.40-7.15 (m, 5H), 6.20 (s, 2H), 6.05 (s, IH), 5.70 (m, IH), 5.45 (s, IH), 5.05 (s, 2H), 4.55 (m, 2H), 3.30 (s, 3H), 3.20(s, 3H), 2.60 (d, 3H).
Step-5: Synthesis of N-(3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl)phenyl)-N-methyl acrylamide :
[0188] To a solution of 3-(methoxymethoxy)-5-((methoxymethoxy) (phenyl)methyl)-N- methylaniline (120 mg, 0.378 mmol) in DCM (5 mL) at 0 °C was added triethylamine (0.15 mL, 1.13 mmol) and acryloyl chloride (0.04 mL, 0.567 mmol). The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2x20 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure to yield the desired compound, N-(3-(methoxymethoxy)-5- ((methoxymethoxy)(phenyl)methyl) phenyl)-N-methylacrylamide (120 mg, 85.45%) as a light yellow solid which was used for the next step without any further purification. LCMS: 372 (M+l).
Step-6: Synthesis of N-(3-hydroxy-5-(hydroxy(phenyl)methyl)phenyl)-N- methylacrylamide :
[0189] To a solution of 3-bromo-5-(hydroxy(phenyl)methyl)phenol (120 mg, 0.323 mmol) in THF (5 mL) was added 5 mL of 6N hydrochloric acid. The reaction mixture was stirred at RT for 48 h. The reaction mixture was neutralized with saturated sodium bicarbonate solution (5 mL) and extracted with EtOAc (3x30 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-5% MeOH in DCM) to yield the desired compound, N-(3- hydroxy-5-(hydroxy(phenyl)methyl)phenyl)-N-methylacrylamide (70 mg, 76.53%) as a light green solid. LCMS: 284 (M+l). !HNMR (400 MHz, DMSO-d6): δ (ppm): 9.65 (s. IH), 7.40- 7.15 (m, 4H), 6.70 (d, 2H), 6.45 (s, IH), 6.15-5.95 (m, 2H), 5.90 (d, IH), 5.60 (d, IH), 5.50 (dd, IH), 3.20 (s, 3H).
Step-7 : N-(3 -benzoyl-5 -hydroxyphenyl)-N-methylacrylamide :
[0190] To a solution of N-(3-hydroxy-5-(hydroxy(phenyl)methyl)phenyl)-N- methylacrylamide (50 mg, 0.176 mmol) in THF (5 mL) was added Dess-Martin periodinone (90 mg, 0.211 mmol) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2x20 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica-gel: 100-200 mesh, elution: 0-2% MeOH in DCM) to yield the desired compound, N-(3 -benzoyl-5 -hydroxyphenyl)-N-methylacrylamide (21 mg, 32.36%) a dark brown solid. !HNMR (400 MHz, CDC13): δ (ppm): 7.80 (d, 2H), 7.60 (s, IH), 7.50 (m, 2H), 7.15 (s, IH), 6.90 (s, IH), 6.70 (s, IH), 6.40 (d, IH), 6.25-6.15 (m, IH), 5.60 (d, IH), 3.35 (s, 3H). LCMS: 282 (M+l).
Example 11 : Preparation of Compound No. 11
Synthesis ofN-(4-chlorophenyl)-3-hydroxy-5-( NT-methylprop-2-enamido)benzamide
[0191] To a solution of N-(4-chlorophenyl)-3-hydroxy-5-(memylamino)benzamide (100 mg, 0.36 mmol) in 5 mL of dichloromethane at 0 °C was added acryloyl chloride (32 mg, 0.36 mmol). The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with 10 mL of water and extracted with ethylacetate (2x20 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure. The off white solid obtained was washed with pentane to yield the desired compound, N-(4-chlorophenyl)-3- hydroxy-5-( ^methylacrylarmdo)benzamide (100 mg, 83.33%) as off white solid. 'HNMR (400 MHz, DMSO-d6): δ (ppm): 10.38 (s, IH), 10.19 (s, IH), 7.80 (d, 2H), 7.38 (d, 2H), 7.36 (d, 2H), 6.84-6.79 (m, IH), 6.18-6.16 (m, 2H), 5.61-5.56 (m, IH), 3.28 (s, 3H). LCMS: 330.8 (M+1) UPLC: 91.41%.
Example 12: Preparation of Compound No. 12
Synthesis of N-[3 -hydroxy-5-( 1 -hydroxy- 1 -phenylethyl)phenyl] -N-methylprop-2-enamide
[0192] To a stirred solution of N-(3-benzoyl-5-hydroxyphenyl)-N-methylacrylamide (100 mg, 0.355 mmol) in 5 mL of THF was added MeLi (0.35 mL, 1.066 mmol) dropwise under nitrogen atmosphere at -78 °C. The reaction mixture was further stirred for 1 h at the same temperature. The reaction mixture was then quenched with saturated ammonium chloride solution (10 mL) and extracted with EtOAc (3x10 mL). The organic layer dried over sodium sulfate and concentrated in vacuo. The crude product was further purified using preparative HPLC to yield the desired compound, N-(3-hydroxy-5-(l-hydroxy-l-phenylethyl)phenyl)-N- methylacrylamide (2 mg, 1.9%) as a white solid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 9.60 (brs, IH), 7.51-7.38 (m, 2H), 7.36-7.21 (m, 2H), 7.20-7.16 (m, IH), 6.82 (s, IH), 6.73 (s, IH), 6.42 (s, IH), 6.18-6.05 (m, 2H), 5.72 (s, IH), 5.56-5.50 (m, IH), 3.18 (6.73 (s, IH), 1.76 (s, 3H). LCMS: 298.2 (M+1) UPLC: 99.27%.
Example 13: Preparation of Compound No. 13
Synthesis ofN-{3-[(4-chlorophenyl)(hydroxy)methyl]-5-hydroxyphenyl}-N-methylprop-2- enamide
Step-1 : Synthesis of 3-bromo-5-((4-chlorophenyl)(hydroxy)methyl)phenol:
[0193] To a solution of 3-bromo-5-hydroxybenzaldehyde (0.5 g, 2.48 mmol) in THF (10 mL) was added a 1.0 M solution of 4-chlorophenyl magnesium bromide (5.2 mL, 5.2 mmol) dropwise at 0 °C. The reaction mixture was stirred at the same temperature for 1 h. The reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (2x150 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-9% EtOAc in hexane) to yield the desired compound, 3-bromo-5-((4- chlorophenyl)(hydroxy) methyl)phenol (500 mg, 65.7%) as a white solid. HI NMR (400 MHz, DMSO-d6): δ (ppm): 9.80 (s, IH), 7.38-7.36 (m, 5H), 6.93 (s, IH), 6.79-6.76 (m, 2H), 6.00 (d, IH), 5.58 (d, IH).
Step-2: Synthesis of 3-((4-chlorophenyl)(hydroxy)memyl)-5-(memylamino)phenol:
[0194] A mixture of 3-bromo-5-((4-chlorophenyl)(hydroxy)methyl)phenol (200 mg, 0.637 mmol), 40% aqueous methyl amine (5.5 mL, 63.78 mmol) and copper powder (117.5 mg, 1.849 mmol) was heated in a microwave at 100 °C for 1.0 h. The reaction mixture was diluted with 100 mL water and extracted with EtOAc (2x100 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-25% EtOAc in hexane) to yield the desired compound, 3-((4-chlorophenyl)(hydroxy)methyl)-5-(methylamino)phenol (80 mg, 47.6%) as a colorless liquid. LCMS: 264.1 (M+l).
Step-3 : Synthesis of N-(3-((4-chlorophenyl)(hydroxy)methyl)-5-hydroxyphenyl)-N- methylacrylamide :
[0195] To a solution of 3-((4-chlorophenyl)(hydroxy)methyl)-5-(methylamino)phenol (80 mg, 0.303 mmol) in DCM (5 mL) at 0 °C was added acryloyl chloride (27.0 mg, 0.303 mmol). The reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was diluted with 10 mL water and extracted with DCM (2x20 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-25% EtOAc in hexane) to yield the desired compound, N-(3 -((4-chlorophenyl)(hydroxy)methyl)-5-hydroxyphenyl)-N- methylacrylamide (5 mg, 5.2%) as an off white solid. !H NMR (400 MHz, DMSO-d6): δ (ppm): 9.67 (s, IH), 7.39-7.35 (m, 4H), 6.79-6.72 (m, 2H), 6.43 (s, IH), 6.18-6.02 (m, 2H), 5.98 (d, IH), 5.61 (d, IH), 5.56 (d, IH), 3.18 (s, 3H). LCMS: 318.1 (M+1) UPLC: At Max Plot: 94.20%, At 220 nm: 86.05%.
Example 14: Preparation of Compound No. 14
Synthesis ofN-{3-[(3 -chlorophenyl)(hydroxy)methyl] -5 -hydroxyphenyl} -N-methylprop-2- enamide
Step-1 : Synthesis of 3-bromo-5-((3-chlorophenyl)(hydroxy)methyl)phenol:
[0196] To a solution of 3-bromo-5-hydroxybenzaldehyde (0.5 g, 2.48 mmol) in THF (10 mL) was added 0.5 M solution of 3-chlorophenyl magnesium bromide (10.4 mL, 5.22 mmol) dropwise at 0 °C. The reaction mixture was stirred at the same temperature for 1 h. The reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (2x150 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-9% EtOAc in hexane) to yield the desired compound, 3-bromo-5-((3- chlorophenyl)(hydroxy) methyl)phenol (400 mg, 51.3%) as a white solid. 'HNMR (400 MHz, DMSO-d6): δ (ppm): 9.80 (s, 1H), 7.40 (s, 1H), 7.39-7.26 (m, 3H), 7.00 (s, 1H), 6.81- 6.79 (m, 2H), 6.15 (d, 1H), 5.61 (d, 1H).
Step-2: Synthesis of 3-((3-chlorophenyl)(hydroxy)memyl)-5-(memylamino)phenol:
[0197] A mixture of 3-bromo-5-((4-chlorophenyl)(hydroxy)methyl)phenol (400 mg, 1.275 mmol), 40% aqueous methyl amine (12.6 mL, 127.56 mmol) and copper powder (235.0 mg, 3.69 mmol) was heated in a microwave at 100 °C for 1.0 h. The reaction mixture was diluted with 100 mL water and extracted with EtOAc (2x100 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-25% EtOAc in hexane) to yield the desired compound, 3-((3-chlorophenyl)(hydroxy)methyl)-5-(methylamino)phenol (132 mg, 47.6%) as a colorless liquid. LCMS: 264.1 (M+l).
Step-3 : Synthesis of N-(3-((3-chlorophenyl)(hydroxy)methyl)-5-hydroxyphenyl)-N- methylacrylamide :
[0198] To a solution of 3-((3-chlorophenyl)(hydroxy)methyl)-5-(methylamino)phenol (132 mg, 0.500 mmol) in DCM (5 mL) at 0 °C was added acryloyl chloride (45.3 mg, 0.500 mmol). The reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was diluted with 10 mL water and extracted with DCM (2x20 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-25% EtOAc in hexane) to yield the desired compound, N-(3 -((4-chlorophenyl)(hydroxy)methyl)-5-hydroxyphenyl)-N- methylacrylamide (10 mg, 5.2%) as an off-white solid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 9.70 (s, 1H), 7.40 (s, 1H), 7.38-7.25 (m, 3H), 6.70 (d, 2H), 6.50 (s, 1H), 6.18-5.59 (m, 3H), 5.66 (d, 1H), 5.57 (d, 1H), 3.20 (s, 3H). LCMS: 318.1 (M+l) UPLC: At Max Plot: 95.95%, At 220 nm: 86.01%.
Example 15: Preparation of Compound No. 15
Synthesis of 3-[hydroxy(2-methoxyphenyl)methyl]-5-( NT-methylprop-2-enamido)phenyl-2,2- dimethylpropanoate
Step-1 : Synthesis of 3-bromo-5-(hydroxy(2-methoxyphenyl)methyl)phenol:
[0199] To a solution of 3-bromo-5-hydroxybenzaldehyde (1.0 g, 4.97 mmol) in THF (25 mL) was added a 1.0 M solution of 2-methoxyphenyl magnesium bromide (10.4 mL, 10.44 mmol) dropwise at 0 °C. The reaction mixture was stirred at the same temperature for 1 h. The reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (2x150 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-9% EtOAc in hexane) to yield the desired compound, 3-bromo-5- (hydroxy(2-methoxyphenyl) methyl)phenol (1.1 g, 71.4%) as a white solid. 'HNMR (400 MHz, DMSO-d6): δ (ppm): 9.71 (s, 1H), 7.40 (d, 1H), 7.20 (s, 1H), 6.99-6.90 (m, 3H), 6.71 (d, 2H), 5.89 (d, 1H), 5.75 (d, 1H), 3.79 (s, 3H).
Step-2: Synthesis of 3-(hydroxy(2-methoxyphenyl)methyl)-5-(methylamino)phenol:
[0200] A mixture of 3-bromo-5-(hydroxy(2-methoxyphenyl)methyl)phenol (1.1 g, 3.55 mmol), 40% aqueous methyl amine (34.4 mL, 355.8 mmol) and copper powder (654.0 mg, 10.29 mmol) was heated in a microwave at 100 °C for 1.0 h. The reaction mixture was diluted with 100 mL water and extracted with EtOAc (2x100 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Silica gel: 100-200 mesh, Elution: 0-25% EtOAc in hexane) to yield the desired compound, 3-(hydroxy(2-memoxyphenyl)methyl)-5-(memylamino)phenol (500 mg, 59.6%) as a brown solid. !HNMR (400 MHz, DMSO-d6): δ (ppm): 8.70 (s, 1H), 7.40 (d, 1H), 7.20 (t, 1H), 6.97-6.90 (m, 2H), 6.10 (d, 1H), 5.59 (d, 1H), 5.80 (d, 1H), 5.75 (d, 1H), 5.71 (d, 1H), 5.46-5.42 (m, 2H), 3.79 (s, 3H), 2.60 (d, 3H).
Step-3 : Synthesis of N-(3-hydroxy-5-(hydroxy(2-methoxyphenyl)methyl)phenyl)- N-methy lacrylamide :
[0201] To a solution of 3-(hydroxy(2-methoxyphenyl)methyl)-5-(methylamino)phenol (500 mg, 1.928 mmol) in DCM (10 mL) at 0 °C was added acryloyl chloride (174.0 mg, 1.928 mmol). The reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was diluted with 10 mL water and extracted with DCM (2x20 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure to yield the desired compound, N-(3-hydroxy-5-(hydroxy(2-memoxyphenyl)memyl)phenyl)-N-methylacrylamide (200 mg, 33.3%) as an off-white solid. LCMS: 314.1 (M+l). !HNMR (400 MHz, DMSO- d6): δ (ppm): 9.60 (s, 1H), 7.41 (d, 1H), 7.20 (t, 1H), 6.99-6.92 (m, 2H), 6.70 (s, 1H), 6.61 (s, 1H), 6.41 (s, 1H), 6.18-6.05 (m, 2H), 5.90 (d, 1H), 5.70 (d, 1H), 5.50 (d, 1H), 3.78 (s, 3H), 3.17 (s, 3H). Step-4: Synthesis of 3-(hydroxy(2-methoxyphenyl)methyl)-5-(N- methylacrylamido)phenyl pivalate:
[0202] To a solution of N-(3-hydroxy-5-(hydroxy(2-methoxyphenyl)methyl)phenyl)-N- methylacrylamide (150 mg, 0.479 mmol) in DCM (10 mL) and triethylamine (0.1 niL, 0.957 mmol), at 0 °C was added pivaloyl chloride (87.0 mg, 0.718 mmol). The reaction mixture was stirred at the RT for 1 h. The reaction mixture was diluted with 10 mL water and extracted with DCM (2x20 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure to yield the desired compound, 3-(hydroxy(2- methoxyphenyl)methyl)-5-(N-methylacrylamido)phenyl pivalate (20 mg, 10.6%) as an off- white solid. 'HNMR (400 MHz, DMSO-d6): δ (ppm): 7.41 (d, IH), 7.22 (t, IH), 7.05 (dd, 2H), 6.96-6.90 (m, 3H), 6.19-6.16 (m, IH), 6.15-6.10 (m, IH), 5.99-5.96 (m, IH), 5.90 (d, IH), 5.58 (dd, IH), 3.78 (s, 3H), 3.20 (s, 3H), 1.21 (s, 9H). LCMS: 398.1 (M+1) UPLC: At Max Plot: 98.81%, At 220 nm: 95.03%.
Example 16: Preparation of Compound No. 16
Synthesis of 3-[(S)-hydroxy(phenyl)methyl]-5-( NT-methylprop-2-enamido)phenyl 2,2- dimethylpropanoate :
[0203] The racemic form of 3-[hydroxy(phenyl)methyl]-5-(N-methylprop-2- enamido)phenyl 2,2-dimethylpropanoate was separated using chiral HPLC to give 3-[(S)- hydroxy(phenyl) methyl]-5-(N-methylprop-2-enamido)phenyl 2,2-dimethylpropanoate. !HNMR (400 MHz, DMSO-d6): δ (ppm): 7.40-7.20 (m, 5H), 7.15 (s, IH), 7.10 (s, IH), 6.95 (s, IH), 6.15 (d, IH), 6.05 (d, 2H), 5.65 (d, IH), 5.55 (d, IH), 3.20 (s, 3H), 1.25 (s, 9H). LCMS: 368 (M+1).
Example 17: Preparation of Compound No. 17
Synthesis of 3-[(R)-hydroxy(phenyl)methyl]-5-(TsT-methylprop-2-enamido)phenyl 2,2- dimethylpropanoate
[0204] The racemic form of 3-[hydroxy(phenyl)methyl]-5-(N-methylprop-2- enamido)phenyl 2,2-dimethylpropanoate was separated using chiral HPLC to give 3-[(R)- hydroxy(phenyl) methyl]-5-(N-methylprop-2-enamido)phenyl 2,2-dimethylpropanoate. !HNMR (400 MHz, DMSO-d6): δ (ppm): 7.40-7.20 (m, 5H), 7.15 (s, IH), 7.10 (s, IH), 6.95 (s, IH), 6.15 (d, IH), 6.05 (d, 2H), 5.65 (d, IH), 5.55 (d, IH), 3.20 (s, 3H), 1.25 (s, 9H). LCMS: 368 (M+1). Example 18: Preparation of Compound Nos. 18 to 53
[0205] Compound nos. 18 to 53 can be prepared using experimental procedures in a similar fashion to those presented in the General Methods and the Examples provided herein.
Examples B1-B4
[0206] Compounds of the present invention may be assessed for bromodomain activity according to standard methods. Examples B1-B4 describe inhibition assessments for certain compounds.
[0207] The protocols used for Examples B1-B4 employed the reader assay, which is a binding assay using AlphaScreen technology FRET assay. The biotinylated peptide binding to the reader domain of His-tagged protein is monitored by the singlet oxygen transfer from the Streptavidin-coated donor beads to the AlphaScreen Ni-chelate acceptor beads.
[0208] Examples B1-B4 employed the following reagents: reaction buffer: 50 mM Hepes, pH7.5, 100 mM NaCl, 0.05% CHAPS, 0.1 % BSA, and 1% DMSO; histone H4 peptide (1- 21) K5/8/12/16Ac-Biotin.
[0209] The assays were performed by delivering 4X BRD in the wells of a reaction plate except for the control wells in which buffer was added instead. Test compounds were delivered in 100% DMSO into the BRD mixture by Acoustic technology (Echo550; nanoliter range), followed by spin down and pre-incubation for 30 min. 4X ligand (Histone H4 peptide (1-21) K5/8/12/16Ac-Biotin) was delivered, followed by spin and shake. The samples were allowed to incubate for 30 min at RT with gentle shaking. 4X donor beads (Streptavidin Donor beads) were delivered, followed by spin and shake. 4X acceptor beads (AlphaScreen Ni acceptor beads) were delivered, followed by spin and shake. The samples were gently shaken in the dark for 60 min. Detection was assessed via alpha measurement
(Ex/Em=680/520-620 nm) in Enspire.
[0210] The 4 Ac peptide ligand has C-terminus biotin, and BRD domains have His-Tag. When BRD binds peptide, energy transfer occurs and high signals are detected. If compounds interrupt the binding of BRD and peptide, the signals will be decreased. Thus IC50 values mean 50% inhibition of the binding of BRD and peptide. Example Bl: Inhibition of BRD2
[0211] Certain compounds of the invention were assessed for BRD2 inhibition. The results are summarized in Table Bl. BRD2-1 refers to the BDl domain of BRD2, and BRD2-2 refers to the BD2 domain of BRD2.
Table Bl. BRD2 Inhibition
Figure imgf000080_0001
Example B2: Inhibition of BRD3
[0212] Certain compounds of the invention were assessed for BRD3 inhibition. The results are summarized in Table B2. BRD3-1 refers to the BDl domain of BRD3, and BRD3-2 refers to the BD2 domain of BRD3.
Table B2. BRD3 Inhibition
Figure imgf000080_0002
Example B3 : Inhibition of BRD4
[0213] Certain compounds of the invention were assessed for BRD4 inhibition. The results are summarized in Table B3. BRD4-1 refers to the BDl domain of BREW, and BRD4-2 refers to the BD2 domain of BRD4.
Table B3. BRD4 Inhibition
Figure imgf000081_0001
Example B4: Inhibition of BRDT
[0214] Certain compounds of the invention were assessed for BRDT inhibition. The results are summarized in Table B4. BRDT-1 refers to the BDl domain of BRDT.
Table B4. BRDT Inhibition
Figure imgf000082_0001
[0215] All references throughout, such as publications, patents, patent applications and published patent applications, are incorporated herein by reference in their entireties.
[0216] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

A compound of the formula (I) or (II):
Figure imgf000083_0001
or a salt thereof, wherein:
Figure imgf000083_0002
Wis 0rS02,andYisabond,CH2orNH;orWisNH,andYisC(0);
R1 is hydrogen, -C6 alkyl, C2-C6 alkenyl, C6-C14 aryl, heteroaryl, C(0)(Rz), C(0)ORz, C(0)NHRz, C(0)NRnRz, NHC(0)(Rz), N(Rn)C(0)(Rz) or S(0)2Rz, wherein the C1-C6 alkyl, C2-C6 alkenyl, C6-C14 aryl, or heteroaryl of R1 are independently optionally substituted with 1-3 Rc groups which may be the same or different;
each Rz is independently Q-C6 alkyl, C3-C6 cycloalkyl, C6-Q4 aryl or heteroaryl, each of which is optionally substituted with 1-3 Rc groups which may be the same or different;
R2, when present, is hydrogen, -C6 alkyl, C3-C6 cycloalkyl, C(0)(Rz), aryl or heteroaryl, wherein the Q-C6 alkyl or C3-C6 cycloalkyl of R2 is optionally substituted with 1- 3 Rc groups which may be the same or different, and wherein the aryl or heteroaryl of R2 is optionally substituted with 1-3 Re groups which may be the same or different, or ZR2 is taken together with R5 to form an oxo group;
R3 is hydrogen, d-d alkyl or C3-C6 cycloalkyl, wherein the d-d alkyl or C3-C6 cycloalkyl of R3 is optionally substituted with 1-3 Rc groups which may be the same or different;
R4 is R6C(0)- or R6S(0)2-, where each R6 is independently (R7)(R8)C=C(R9)- or
Figure imgf000084_0001
R5, when present, is hydrogen, d-d alkyl or C3-C6 cycloalkyl, wherein the d-d alkyl or C3-C6 cycloalkyl of R5 is optionally substituted with 1-3 Rc groups which may be the same or different, or R5 is taken together with ZR2 to form an oxo group;
R7is hydrogen or d-d alkyl, wherein the d-d alkyl of R7 is optionally substituted with 1-3 Rc groups which may be the same or different;
R8 is hydrogen or d-d alkyl, wherein the d-d alkyl of R8 is optionally substituted with 1-3 Rc groups which may be the same or different;
R9 is hydrogen, cyano ord-d alkyl, wherein the d-d alkyl of R9 is optionally substituted with 1-3 Rc groups which may be the same or different;
R10 is hydrogen ord-d alkyl, wherein the d-d alkyl of R10 is optionally substituted with 1-3 Rc groups which may be the same or different;
R11 is d-d alkyl, wherein the d-d alkyl of R11 is optionally substituted with 1-3 Rc groups which may be the same or different;
Q is N or CR10;
X is a bond, CH2, CHOR12, NH, NR11 or O;
Z, when present, is NH, NR2, O, S, S(O) or S02, or ZR2 and R5 are taken together to form an oxo;
each Ra and Rb is independently halo, OR12, NR13R14, CN, CONR13R14, S02CH3, S02NR13R14, d-d alkyl or d-d cycloalkyl, wherein each d-d alkyl of Ra and Rb and each d-d cycloalkyl of Ra and Rb is optionally substituted with 1-3 Rd groups which may be the same or different;
each Rc is independently halo, phenyl, heteroaryl, d-d alkyl, d-d cycloalkyl, OR12 or NR13R14, wherein the phenyl or heteroaryl of Rc is optionally substituted with 1-3 Re groups which may be the same or different;
each Rd is independently halo, OR12 or NR13R14;
each Re is independently halo, trifluoromethyl, d-d alkyl, OR12 or NR13R14; each R is independently hydrogen, trifluoromethyl, C1-C4 alkyl or C3-C6 cycloalkyl; each R 13 is independently hydrogen, trifluoromethyl, C1-C4 alkyl or C3-C6 cycloalkyl; each R14 is independently hydrogen, trifluoromethyl, C1-C4 alkyl or C3-C6 cycloalkyl; m is an integer from 0-3; and
n is an integer from 0-5.
2. The compound of claim 1, or a salt thereof, wherein the compound is of the formula
(I) ·
3. The compound of claim 1, or a salt thereof, wherein the compound is of the formula
(II) .
4. The compound of any one of claims 1 to 3, or a salt thereof, wherein W is S02.
5. The compound of any one of claims 1 to 3, or a salt thereof, wherein W is
Figure imgf000085_0001
6. The compound of claim 1, or a salt thereof, wherein the compound is of the formula (A):
Figure imgf000085_0002
wherein X, Y, Z, R1, R2, R3, R4, R5, Ra, Rb, m, and n are as defined in claim 1.
The compound of claim 5 or 6, or a salt thereof, wherein Z is O; R is hydrogen C(0)(Rz); and R5 is hydrogen or Ci-C6 alkyl.
The compound of claim 5 or 6, or a salt thereof, wherein ZR2 and R5 are taken together to form an oxo.
9. The compound of claim 8, or a salt thereof, wherein Y is NH.
10. The compound of any one of claims 1 to 8, or a salt thereof, wherein Y is a bond.
11. The compound of any one of claims 1 to 10, or a salt thereof, wherein n is 0 or 1 ; and Rb is halo or OR12.
12. The compound of any one of claims 1 to 11, or a salt thereof, wherein m is 0 or 1; and Ra is halo.
13. The compound of any one of claims 1 to 12, or a salt thereof, wherein X is a bond and R1 is hydrogen or d-Ce alkyl optionally substituted with 1-3 Rc groups which may be the same or different.
14. The compound of any one of claims 1 to 12, or a salt thereof, wherein X is O.
15. The compound of any one of claims 1 to 12, or a salt thereof, wherein X is NH or NR11.
16. The compound of claim 14 or 15, or a salt thereof, wherein R1 is hydrogen, Q-C6 alkyl, C2-C6 alkenyl, C6-C14 aryl, heteroaryl, or C(0)(Rz), wherein the Q-C6 alkyl, C2-C6 alkenyl, C6-C14 aryl, or heteroaryl of R1 are independently optionally substituted with 1-3 Rc groups which may be the same or different.
17. The compound of any one of claims 1 to 12, or a salt thereof, wherein X is CH2 or CHOR12; and R1 is C(0)ORz, C(0)NHRz or NHC(0)(Rz).
18. The compound of any one of claims 1 to 17, or a salt thereof, wherein R3 is hydrogen or Ci-C6 alkyl.
19. The compound of any one of claims 1 to 18, or a salt thereof, wherein R4 is
H2C=C(R9)-C(0)- or H2C=C(R9)-S(0)2-, where each R9 is independently hydrogen, cyano or Q-C6 alkyl.
20. The compound of claim 1, or a salt thereof, wherein the compound is selected from the group consisting of Compound Nos. 1, la, lb and 2-53 in Table 1.
21. A pharmaceutical composition comprising a compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
22. A method of treating cancer in an individual in need thereof, comprising
administering to the individual a therapeutically effective amount of a compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.
23. Use of a compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, in the manufacturing of a medicament for the treatment of cancer.
24. A kit comprising a compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.
PCT/US2015/033407 2014-05-30 2015-05-29 Aromatic compounds, compositions and uses thereof WO2015184405A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1433DE2014 2014-05-30
IN1433/DEL/2014 2014-05-30

Publications (1)

Publication Number Publication Date
WO2015184405A1 true WO2015184405A1 (en) 2015-12-03

Family

ID=54699937

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2015/033407 WO2015184405A1 (en) 2014-05-30 2015-05-29 Aromatic compounds, compositions and uses thereof

Country Status (1)

Country Link
WO (1) WO2015184405A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010031874A1 (en) * 1997-12-23 2001-10-18 Connor David Thomas Thiourea and benzamide compounds, compositions and methods of treating or preventing inflammatory diseases and atherosclerosis

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010031874A1 (en) * 1997-12-23 2001-10-18 Connor David Thomas Thiourea and benzamide compounds, compositions and methods of treating or preventing inflammatory diseases and atherosclerosis

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM [O] 19 November 2009 (2009-11-19), XP055239121, Database accession no. 44406688 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385130B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US11535670B2 (en) 2016-05-11 2022-12-27 Huyabio International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors

Similar Documents

Publication Publication Date Title
EP3761980B1 (en) Amino acid compounds and methods of use
CN111285850B (en) Isoindoline compounds, preparation method thereof, pharmaceutical composition and application thereof
EP3937943A1 (en) Novel small molecule inhibitors of tead transcription factors
JP6313416B2 (en) IDO inhibitor
JP7495395B2 (en) Antibacterial Compounds
EP3848367A1 (en) Tricyclic compounds acting on crbn proteins
TW202136275A (en) Pyridazinyl-thiazolecarboxamide compound
EP4146264A1 (en) Treatment of respiratory diseases with amino acid compounds
AU2010303822A1 (en) Novel TRPA1 antagonists
KR19990028325A (en) Substituted 4-phenylaminothiazoles, their preparation and pharmaceutical compositions containing them
JP2007520440A (en) Indan derivatives as muscarinic receptor agonists
EA034514B1 (en) Isoindole compounds
JP2022548250A (en) Thyroid hormone receptor beta agonist compounds
JP2013530130A (en) Heteroaryl (alkyl) dithiocarbamate compounds, their preparation and use
WO2015184405A1 (en) Aromatic compounds, compositions and uses thereof
JP2023532298A (en) Compounds, compositions and methods
WO2018028491A1 (en) Indoleamine2,3-dioxygenase inhibitors and uses thereof in pharmacy
AU2020214275A1 (en) Dezocine derivative and medical use thereof
JP2020519697A (en) Indolizine derivative and its medical application
TWI652265B (en) Azaindole derivatives
RU2686675C1 (en) Taxane compounds and also the production method and use thereof
CN111527069B (en) Quinoline derivatives
WO2022236257A1 (en) Heterocyclic compounds as kinase inhibitors
WO2019154380A1 (en) Kynurenine pathway inhibitor
WO2023201044A2 (en) Jak inhibitor analogs, formulations, and uses thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15800268

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15800268

Country of ref document: EP

Kind code of ref document: A1