WO2014062733A2 - Substituted benzene compounds - Google Patents

Substituted benzene compounds Download PDF

Info

Publication number
WO2014062733A2
WO2014062733A2 PCT/US2013/065127 US2013065127W WO2014062733A2 WO 2014062733 A2 WO2014062733 A2 WO 2014062733A2 US 2013065127 W US2013065127 W US 2013065127W WO 2014062733 A2 WO2014062733 A2 WO 2014062733A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound
substituted
methyl
piperidine
Prior art date
Application number
PCT/US2013/065127
Other languages
French (fr)
Other versions
WO2014062733A3 (en
Inventor
Kevin Wayne Kuntz
John Emmerson Campbell
Masashi Seki
Syuji SHIROTORI
Wataru ITANO
Wanjun Zheng
Original Assignee
Epizyme, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to MX2015004722A priority Critical patent/MX353929B/en
Priority to EP20161557.2A priority patent/EP3725314A1/en
Priority to JP2015537019A priority patent/JP6461803B2/en
Priority to US14/435,704 priority patent/US10092572B2/en
Priority to CA2888021A priority patent/CA2888021A1/en
Priority to EP13846696.6A priority patent/EP2906537B1/en
Priority to KR1020157012673A priority patent/KR102057366B1/en
Priority to AU2013331381A priority patent/AU2013331381B2/en
Priority to NZ706739A priority patent/NZ706739A/en
Priority to SG11201502803VA priority patent/SG11201502803VA/en
Priority to CN201380065683.2A priority patent/CN105102432B/en
Priority to RU2015118145A priority patent/RU2658919C2/en
Priority to BR112015008480A priority patent/BR112015008480A2/en
Priority to UAA201504699A priority patent/UA119136C2/en
Application filed by Epizyme, Inc. filed Critical Epizyme, Inc.
Publication of WO2014062733A2 publication Critical patent/WO2014062733A2/en
Publication of WO2014062733A3 publication Critical patent/WO2014062733A3/en
Priority to IL238197A priority patent/IL238197A0/en
Priority to PH12015500825A priority patent/PH12015500825A1/en
Priority to ZA2015/02560A priority patent/ZA201502560B/en
Priority to HK16101355.9A priority patent/HK1213264A1/en
Priority to US16/120,702 priority patent/US20190060322A1/en
Priority to IL265437A priority patent/IL265437A/en
Priority to US16/924,962 priority patent/US11642348B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • 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
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention features a substituted benzene compound of the
  • the invention relates to a compound according to Formula ⁇ :
  • R 801 is Ci alkyl, alkenyl, alkynyl, C3 cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, phenyl or 5- or 6-membered heteroaryl, each of which is substituted with O-Ci alkyl-R x or NH-Ci alkyl-R x , wherein R x is hydroxyl, O alkyl or NH alkyl, and R x is optionally further substituted with O alkyl or NH alkyl except when R x is hydroxyl; and R 801 is optionally further substituted;
  • each of R and R independently is H, halo, alkyl, Ci_g alkoxyl or Ce-Cio aryloxy, each optionally substituted with one or more halo;
  • each of R and R independently is alkyl; and is - , wherein is a bond or alkyl linker, is optionally substituted alkyl, optionally substituted C3-C8 cycioalkyl or optionally substituted 4- to 14-membered heterocycloalkyl.
  • Subsets of compounds of Formula III include those of Formula IVa or IVb and pharmaceutic
  • the invention relates to a compound according to Formula I:
  • R 701 is H, F, OR 707 , NHR 707 , -(C ⁇ C)-(CH -R 70S , phenyl, 5- or 6-membered heteroaryl, Cj.g cycioalkyl, or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the phenyl, S- or 6-membered heteroaryl, C3 cycioalkyl or 4-7 membered heterocycloalkyl each independently is optionally substituted with one or more groups selected from halo, alkyl, OH, 0-Ci alkyl, NH-Ci alkyl, and, alkyl substituted with C3 cycioalkyl or 4-7 membered heterocycloalkyl containing 1 -3 heteroatoms, wherein each of the O-Ci-e alkyl and NH alkyl is optionally substituted with hydroxyl, O alkyl or NH-C,.
  • each of and R independently is H, halo, CM alkyl, Q.6 alkoxyl or Ce-Qo aryloxy, each optionally substituted with one or more halo;
  • each of R 704 and R 705 independently is CM alkyl
  • R 706 is cyclohexyl substituted by N(C alkyl) 2 wherein one or both of the C alkyl is substituted with Q. ⁇ alkoxy; or R 706 is tetrahydropyranyl;
  • R 707 is Ci-4 alkyl optionally substituted with one or more groups selected from hydroxyl, C alkoxy, amino, mono- or di-C ⁇ alkylamino, C 3 . 8 cycloalkyl, and 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the . 8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is further optionally substituted with Ci_ 3 alkyl;
  • R 708 is Ci_4 alkyl optionally substituted with one or more groups selected from OH, halo, and CM alkoxy, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, or 0-C]_6 alkyl, wherein the 4-7 membered heterocycloalkyl can be optionally further substituted with OH or C,. 6 alkyl; and
  • n ? is 0, 1 or 2.
  • a subset of compounds of Formula I includes those of Formula II and pharmaceutically acceptable salts or solvates thereof:
  • the invention relates to compound according to formula V:
  • Wi N or CH
  • W 2 is N or CH
  • R 401 is hydrogen, C,-C 6 alkyl, C,-C 6 haloalkyl
  • R 402 is (a) OH, (b) (CH 2 )-0-(C,-C 6 alkyl), (c) 0(C,-C 6 alkyl), (d) (C3 ⁇ 4) r 3-8 membered saturated, unsaturated, or aromatic carbocycle, (e) CH 2 )t-3-8 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (f) 0-(C3 ⁇ 4) u -3-8 membered saturated, unsaturated, or aromatic carbocycle, or (g) 0-(CH 2 ) v -3-8 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, where (b)-(g) are optionally substituted with R 402 ,
  • R 02a is C r C 6 alkyl, C r C 6 haloalkyl, OH, or 0(C,-C 6 alkyl);
  • t is 1 , 2, or 3;
  • u 0, 1 , 2, or 3;
  • v 0, 1 ,2 , or 3;
  • j 0, 1 , 2, or 3;
  • k 0, 1 , 2, or 3; provided that when R 402 is piperazinyl, Wi and W 2 are N.
  • Wi is N and W 2 is CH.
  • R 401 is Ci-Ce alkyl.
  • R 401 is methyl or isopropyl.
  • R 401 is methyl.
  • R 402 is (CH 2 )k- -7 membered saturated heterocycle containing one or more nitrogen or oxygen atoms.
  • k is 0 or 1.
  • k is 0.
  • k is 1.
  • R 402 is azetidinyl, piperazinyl, or piperidinyl.
  • R 402 is (CH 2 )-azetidinyl, (CH 2 )-pyrrolidinyl, (CH 2 )-piperidinyl, (CH 2 )-morpholinyl, or (CH 2 )-diazepanyl.
  • R 02a is OH, methyl, or methoxy.
  • the invention relates to a compound according to Formula VI:
  • 3 ⁇ 4 is 0, 1, or 2;
  • R 501 is C(H) orN
  • R 502 , R 503 , R 504 and R 505 are, independently for each occurrence, C 1 alkyl
  • R is cyclohexyl substituted by ⁇ ( ⁇ alkyl) 2 or piperidine substituted by 1, 2, or 3 Cj. 4 alkyl groups;
  • R 501 is C(H)
  • R 507 is morpholine; piperidine; diazepane; pyrrolidine; azetidine; 0-Ci alkyl; or O-heterocycle, wherein the heterocycle is a 4-7 membered heterocycle containing an oxygen or nitrogen, or both, and wherein the nitrogen can optionally be substituted with Q alkyl; wherein the piperidine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH, alkyl, or ⁇ -(3 ⁇ 4 alkyl;
  • R 507 can be piperazine optionally further substituted with Q alkyl, provided that R 506 is piperidine substituted by 1, 2, or 3 C M alkyl groups;
  • R 507 is morpholine; piperidine; piperazine; diazepane; pyrrolidine; azetidine; O-Ci alkyl; or O-heterocycle, wherein the heterocycle is a 4-7 membered heterocycle containing an oxygen or nitrogen, or both, and wherein the nitrogen can optionally be substituted with alkyl; wherein the piperidine, piperazine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH, alkyl, or O-Cu alkyl.
  • the invention relates to a compound of Formula VII:
  • 3 ⁇ 4 is 1 or 2;
  • R 602 , R 603 , R 604 and R 605 are, independently for each occurrence, CM alkyl
  • R 606 is cyclohexyl substituted by N(CM alkyl) 2 or piperidine substituted by 1 , 2, or 3 CM alkyl groups;
  • R 607 is mo ⁇ holine, piperidine, piperazine, pyrrolidine, diazepane, azetidine or O-Ci-6 alkyl, wherein the piperidine, diazepane or azetidine groups can be optionally further substituted with OH or Ci-6 alkyl.
  • the present invention also provides pharmaceutical compositions comprising one or more pharmaceutically acceptable carriers and one or more compounds selected from those of any of the Formulae described herein.
  • Another aspect of this invention is a method of treating or preventing an EZH2-mediated disorder.
  • the method mcludes administering to a subject in need thereof a therapeutically effective amount of one or more compounds selected from those of any of the Formulae described herein.
  • the EZH2 -mediated disorder is a disease, disorder, or condition that is mediated at least in part by the activity of EZH2.
  • the EZH2-mediated disorder is related to an increased EZH2 activity.
  • the EZH2 -mediated disorder is a cancer.
  • the EZH2-mediated cancer may be lymphoma, leukemia or melanoma, for example, diffuse large B-cell lymphoma (DLBCL), non-Hodgkin's lymphoma (NHL), follicular lymphoma, chronic myelogenous leukemia (CML), acute myeloid leukemia, acute lymphocytic leukemia, mixed lineage leukemia, or myelodysplastic syndromes (DS).
  • the EZH2-mediated cancer may be a malignant rhabdoid tumor or INIl-defecient tumor.
  • malignant rhabdoid tumor The histologic diagnosis of malignant rhabdoid tumor depends on identification of characteristic rhabdoid cells (large cells with eccentrically located nuclei and abundant, eosinophilic cytoplasm) and immunohistochemistry with antibodies to vimentin, keratin and epithelial membrane antigen.
  • the SMARCB1/INI1 gene located in chromosome band 22ql 1.2, is inactivated by deletions and/or mutations.
  • the malignant rhabdoid tumors may be INIl-defecient tumor.
  • any description of a method of treatment includes uses of the compounds to provide such treatment or prophylaxis as is described in the specification, as well as uses of the compounds to prepare a medicament to treat or prevent such condition.
  • the treatment includes treatment of human or non-human animals including rodents and other disease models. Methods described herein may be used to identify suitable candidates for treating or preventing EZH2 -mediated disorders.
  • the invention also provides methods of identifying an inhibitor of a wild-type EZH2, a mutant EZH2 (e.g., a Y641 , A 6 77, and/or A687 mutant EZH2), or both.
  • the method comprises the step of administering to a subject having a cancer with aberrant H3-K27 methylation an effective amount of one or more compounds of Formulae described herein, wherein the compound(s) inhibits histone methyltransferase activity of EZH2, thereby treating the cancer.
  • aberrant H3-K27 methylation may include a global increase in and/or altered distribution of H3-K27 di or tri-methylation within the cancer cell chromatin.
  • the cancer is selected from the group consisting of cancers that overexpress EZH2 or other PRC2 subunits, contain loss-of-function mutations in H3-K27 demethylases such as UTX, or overexpress accessory proteins such as PHF19/PCL3 capable of increasing and or mislocalizing EZH2 activity (see references in Sneeringer et al. Proc Natl Acad Sci USA 107(49):20980-5, 2010).
  • the method comprises the step of administering to a subject having a cancer overexpressing EZH2 a therapeutically effective amount of one or more compounds of Formulae described herein, wherein the compound(s) inhibits histone methyltransferase activity of EZH2, thereby treating the cancer.
  • the method comprises the step of administering to a subject having a cancer with a loss-of-function mutation in the H3-K27 demethylase UTX a therapeutically effective amount of one or more compounds of Formulae described herein, wherein the compound(s) inhibits histone methyltransferase activity of EZH2, thereby treating the cancer
  • the method comprises the step of administering to a subject having a cancer overexpressing an accessory component(s) of the PRC2, such as PHF19/PCL3, a therapeutically effective amount of one or more compounds of Formulae described herein, wherein the compound(s) inhibits histone methyltransferase activity of EZH2, thereby treating the cancer
  • this invention relates to a method of modulating the activity of the wild-type EZH2, the catalytic subunit of the PRC2 complex which catalyzes the mono- through tri- methylation of lysine 27 on histone H3 (H3-K27).
  • the present invention relates to a method of inhibiting the activity of EZH2 in a cell. This method can be conducted either in vitro or in vivo.
  • this invention features to a method of inhibiting in a subject conversion of H3-K27 to trimethylated H3-K27.
  • the method comprises administering to a subject a therapeutically effective amount of one or more of the compounds of Formulae described herein to inhibit histone methyltransferase activity of EZH2, thereby inhibiting conversion of H3-K27 to trimethylated H3-K27 in the subject.
  • the method comprises the step of administering to a subject having a cancer expressing a mutant EZH2 a therapeutically effective amount of one or more compounds of Formulae described herein, wherein the compound(s) inhibits histone methyltransferase activity of EZH2, thereby treating the cancer.
  • the cancer is selected from the group consisting of follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) of germinal center B cell-like (GCB) subtype.
  • the cancer is lymphoma, leukemia or melanoma.
  • the lymphoma is non- Hodgkin's lymphoma (NHL), follicular lymphoma or diffuse large B-cell lymphoma.
  • the leukemia is chronic myelogenous leukemia (C L), acute myeloid leukemia, acute lymphocytic leukemia or mixed lineage leukemia.
  • the precancerous condition is myelodysplastic syndromes (MDS, formerly known as preleukemia).
  • MDS myelodysplastic syndromes
  • the cancer is a hematological cancer.
  • the cancer is selected from the group consisting of brain and central nervous system (CNS) cancer, head and neck cancer, kidney cancer, ovarian cancer, pancreatic cancer, leukemia, lung cancer, lymphoma, myeloma, sarcoma, breast cancer, and prostate cancer.
  • CNS central nervous system
  • a subject in need thereof is one who had, is having or is predisposed to developing brain and CNS cancer, kidney cancer, ovarian cancer, pancreatic cancer, leukemia, lymphoma, myeloma, and/or sarcoma.
  • exemplary brain and central CNS cancer includes medulloblastoma, oligodendroglioma, atypical teratoid/rhabdoid tumor, choroid plexus carcinoma, choroid plexus papilloma, ependymoma, glioblastoma, meningioma, neuroglial tumor, oligoastrocytoma, oligodendroglioma, and pineoblastoma.
  • Exemplary ovarian cancer includes ovarian clear cell adenocarcinoma, ovarian endomethrioid adenocarcinoma, and ovarian serous adenocarcinoma.
  • Exemplary pancreatic cancer includes pancreatic ductal adenocarcinoma and pancreatic endocrine tumor.
  • Exemplary sarcoma includes chondrosarcoma, clear cell sarcoma of soft tissue, ewing sarcoma, gastrointestinal stromal tumor, osteosarcoma, rhabdomyosarcoma, and not otherwise specified (NOS) sarcoma.
  • cancers to be treated by the compounds of the present invention are non NHL cancers.
  • the cancer is selected from the group consisting of medulloblastoma, oligodendroglioma, ovarian clear cell adenocarcinoma, ovarian endomethrioid adenocarcinoma, ovarian serous adenocarcinoma, pancreatic ductal adenocarcinoma, pancreatic endocrine tumor, malignant rhabdoid tumor, astrocytoma, atypical teratoid/rhabdoid tumor, choroid plexus carcinoma, choroid plexus papilloma, ependymoma, glioblastoma, meningioma, neuroglial tumor, oligoastrocytoma, oligodendroglioma, pineoblastoma, carcinosarcoma, chordoma, extragonadal germ cell tumor, extrarenal rhabdoid tumor, schwannoma, skin
  • the cancer is medulloblastoma, ovarian clear cell adenocarcinoma, ovarian endomethrioid adenocarcinoma, pancreatic ductal adenocarcinoma, malignant rhabdoid tumor, atypical teratoid/rhabdoid tumor, choroid plexus carcinoma, choroid plexus papilloma, glioblastoma, meningioma, pineoblastoma, carcinosarcoma, extrarenal rhabdoid tumor, schwannoma, skin squamous cell carcinoma, chondrosarcoma, ewing sarcoma, epitheloid sarcoma, renal medullo carcinoma, diffuse large B-cell lymphoma, follicular lymphoma and/or NOS sarcoma. More preferably, the cancer is malignant rhabdoid tumor, medulloblastoma and/or
  • the method comprises the step of administering to a subject having a cancer expressing a mutant EZH2 a therapeutically effective amount of one or more compounds of Formulae described herein, wherein the compound(s) inhibits activity (e.g., histone methyltransferase activity) of the mutant EZH2, the wild-type EZH2, or both, thereby treating the cancer.
  • activity e.g., histone methyltransferase activity
  • the method further comprises the steps of performing an assay to detect a mutant EZH2 in a sample comprising cancer cells from a subject in need thereof.
  • the invention features a method of selecting a therapy for a patient having a disease associated with EZH2 -mediated protein methylation.
  • the method includes the steps of determining the presence of gene mutation in the EZH2 gene of the subject; and selecting, based on the presence of a gene mutation in the EZH2 gene a therapy for treating the disease.
  • the therapy includes the administration of one or more of the compounds of the invention.
  • the method further includes administrating one or more of the compounds of the invention to the subject.
  • the disease is cancer and the mutation is a Y641 mutation.
  • a method of treatment for a patient in need thereof, the method comprising the steps of determining the presence of gene mutation in the EZH2 gene and treating the patient in need thereof, based on the presence of a gene mutation in the EZH2 gene, with a therapy that includes the adrninistration of the compounds of the invention.
  • the patient is a cancer patient and the mutation is a Y641 mutation.
  • this invention relates to a method of modulating the activity of the wild-type and mutant histone methyltransferase EZH2, the catalytic subunit of the P C2 complex which catalyzes the mono- through tri-methylation of lysine 27 on histone H3 (H3-K27).
  • the present invention relates to a method of inhibiting the activity of certain mutant forms of EZH2 in a cell.
  • the mutant forms of EZH2 include a substitution of another amino acid residue for tyrosine 6 41 (Y 6 41, also Tyr641) of wild-type EZH2.
  • the method includes contacting the cell with an effective amount of one or more of the compounds of any Formula described herein. This method can be conducted either in vitro or in vivo.
  • this invention features to a method of inhibiting in a subject conversion of H3-K27 to trimethylated H3-K27.
  • the method comprises administering to a subject expressing a mutant EZH2 a therapeutically effective amount of one or more of the compounds of any Formula described herein to inhibit histone methyltransferase activity of EZH2, thereby inhibiting conversion of H3-K27 to trimethylated H3-K27 in the subject.
  • the histone methyltransferase activity inhibited is that of the Y641 mutant of EZH2.
  • the compound of this invention selectively inhibits histone methyltransferase activity of the Y641 mutant of EZH2.
  • the Y641 mutant of EZH2 is selected from the group consisting of Y641C, Y641F, Y641H, Y641N, and Y641S.
  • the method of inhibiting in a subject conversion of H3-K27 to trimethylated H3-K27 may also comprise performing an assay to detect a mutant EZH2 in a sample from a subject before administering to the subject expressing a mutant EZH2 a therapeutically effective amount of one or more of the compounds of any Formula described herein.
  • performing the assay to detect the mutant EZH2 includes whole-genome resequencing or target region resequencing that detects a nucleic acid encoding the mutant EZH2.
  • performing the assay to detect the mutant EZH2 includes contacting the sample with an antibody that binds specifically to a polypeptide or fragment thereof characteristic of the mutant EZH2.
  • performing the assay to detect the mutant EZH2 includes contacting the sample under highly stringent conditions with a nucleic acid probe that hybridizes to a nucleic acid encoding a polypeptide or fragment thereof characteristic of the mutant EZH2.
  • the invention also relates to a method of identifying an inhibitor of a mutant EZH2, wild-type EZH2, or both.
  • the method comprises the steps of combining an isolated EZH2 with a histone substrate, a methyl group donor, and a test compound, wherein the histone substrate comprises a form of H3-K27 selected from the group consisting of unmethylated H3-K27, monomethylated H3-K27, dimethylated H3-K27, and any combination thereof; and performing an assay to detect methylation of H3-K27 (e.g., formation of trimethylated H3-K27) in the histone substrate, thereby identifying the test compound as an inhibitor of the EZH2 when methylation of H3- 27 (e.g., formation of trimethylated H3- 27) in the presence of the test compound is less than methylation of H3-K27 (e.g., formation of trimethylated H3-K27) in the absence of the test compound.
  • H3-K27
  • performing the assay to detect methylation of H3-K27 in the histone substrate comprises measuring incorporation of labeled methyl groups.
  • the labeled methyl groups are isotopically labeled methyl groups.
  • performing the assay to detect methylation of H3-K27 in the histone substrate comprises contacting the histone substrate with an antibody that binds specifically to trimethylated H3- 27.
  • a method of identifying a selective inhibitor of a mutant EZH2. comprises the steps of combining an isolated mutant EZH2 with a histone substrate, a methyl group donor, and a test compound, wherein the histone substrate comprises a form of H3-K27 selected from the group consisting of monomethylated H3- 27, dimethylated H3-K27, and a combination of monomethylated H3-K27 and dimethylated H3-K27, thereby forming a test mixture; combining an isolated wild-type EZH2 with a histone substrate, a methyl group donor, and a test compound, wherem the histone substrate comprises a form of H3- 27 selected from the group consisting of monomethylated H3-K27, dimethylated H3-K27, and a combination of monomethylated H3-K27 and dimethylated H3-K27, thereby forming a control mixture; performing an assay to detect trimethylation of the histone substrate in each
  • the present invention further provides a method of identifying a subject as a candidate for treatment with one or more compounds of the invention.
  • the method comprises the steps of performing an assay to detect a mutant EZH2 in a sample from a subject; and identifying a subject expressing a mutant EZH2 as a candidate for treatment with one or more compounds of the invention, wherein the compound(s) inhibits histone methyltransferase activity of EZH2.
  • Still another aspect of the invention is a method of inhibiting conversion of H3-K27 to trimethylated H3-K27.
  • the method comprises the step of contacting wild-type EZH2, a mutant EZH2, or both with a histone substrate comprising H3-K27 and an effective amount of a compound of the present invention, wherem the compound inhibits histone methyltransferase activity of EZH2, thereby inhibiting conversion of H3-K27 to trimethylated H3-K27.
  • the compounds or methods described herein can be used for research (e.g., studying epigenetic enzymes) and other non-therapeutic purposes.
  • the preferred compounds disclosed herein have improved pharmacological and/or pharmacokinetic properties, e.g., lower clearance rates, reduced risk of adverse drug-drug interactions in combination therapy through reduction of time-dependent and reversible inhibition of cytochrome P-450 enzymes.
  • the present invention provides novel substituted benzene compounds, synthetic methods for making the compounds, pharmaceutical compositions containing them and various uses of the compounds.
  • the invention relates to a compound according to Formula I:
  • R 701 is H, F, OR 707 , NHR 707 , -(C ⁇ C)-(CH 2 ) réelle7-R 708 , phenyl, 5- or 6-membered heteroaryl, C3-8 cycloalkyl, or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the phenyl, 5- or 6-membered heteroaryl, C 3 _8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is optionally substituted with one or more groups selected from halo, Q_3 alkyl, OH, O-Cj.6 alkyl, NH-Ci-6 alkyl, and, C1-3 alkyl substituted with C3 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein each of the O alkyl and NH-Ci_ 6 alkyl is optionally substituted with hydroxyl, O alkyl orNH-Ci alkyl
  • each of 702 and R 703 independently is H, halo, alkyl, Ci_ 6 alkoxyl orC 6 -Cio aryloxy, each optionally substituted with one or more halo;
  • each of R 704 and R 703 independently is C w alkyl
  • R 706 is cyclohexyl substituted by N(C
  • R 707 is alkyl optionally substituted with one or more groups selected from hydroxyl, alkoxy, amino, mono- or di- _ 4 alkylamino, C3_g cycloalkyl, and 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the C3 cycloalkyl or 4-7 membered heterocycloalkyl each independently is further optionally substituted with alkyl;
  • R 708 is alkyl optionally substituted with one or more groups selected from OH, halo, and alkoxy, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, or 0-C alkyl, wherein the 4-7 membered heterocycloalkyl can be optionally further substituted with OH or d- 6 alkyl; and
  • R 706 is cyclohexyl substituted by ( alky3 ⁇ 4 wherein one of the Q_ 4 alkyl is unsubstituted and the other is substituted with methoxy.
  • a subset of compounds of Formula I includes those of Formula II and pharmaceutically acceptable salts thereof:
  • the compounds of Formula I or II can include one or more of the following features:
  • 702 is methyl or isopropyl.
  • R 703 is methyl or methoxyl.
  • R 704 is methyl
  • R 701 is OR 707 .
  • R 707 is Q alkyl optionally substituted with OC3 ⁇ 4 or morpholine.
  • R 70 ' is H or F.
  • R 70 ' is tetrahydropyranyl optionally substituted with methyl, methoxy, ethyl substituted with morpholine, or -OCH 2 CH 2 OCH 3 .
  • R 701 is phenyl optionally substituted with methyl, methoxy, ethyl substituted with morpholine, or -OCH 2 CH 2 OCH 3 .
  • R 701 is 5- membered heteroaryl (e.g., pyrrolyl, furyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, or isoxazolyl) optionally substituted with methyl, methoxy, ethyl substituted with morpholine, or
  • R 701 is 6- membered heteroaryl (e.g., pyridyl, pyrazinyl, pyridazinyl, or pynmidyl) optionally substituted with methyl, methoxy, ethyl substituted with morpholine, or - OCH 2 CH 2 OCH 3 .
  • heteroaryl e.g., pyridyl, pyrazinyl, pyridazinyl, or pynmidyl
  • R 701 is pyridyl, pynmidyl, pyrazinyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with methyl, methoxy, ethyl substituted with morpholine, or -OCH 2 CH 2 OCH 3 .
  • R 708 is morpholine, piperidine, piperazine, pyrrolidine, diazepane, or azetidine, each of which is optionally substituted with OH or Ci_s alkyl.
  • R 708 is morpholine
  • R 708 is piperazine substituted with C . 6 alkyl.
  • R 708 is t-butyl or C(CH 3 ) 2 OH.
  • the compounds of Formula I or II do not comprise N-((4,6-dimethyl-2-oxo-l,2- dihydropyridm-3-yl)memyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)armno)-2-methyl-5-((l- methylpiperidin-4-yl)ethynyl)benzamide (i.e., Compound 105).
  • the compounds of Formula I or II do not comprise iV-((4,6-dimethyl-2-oxo-l,2- dihydropyridin-3-yl)methyl)-3-(ethyl(4-((2-methoxyethyl)(methyl)arrdno)cyclohexyl)amino)-2- methyl- 5 -(3-mo ⁇ holinoprop-l-yn-l-yl)benzamide or iV-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)-3-(ethyl((lr,4r)-4-((2-memoxyethyl)(methyl)amino)cyclohexyl)amino)-2-methyl-5-(3- morpholinoprop-l-yn-l-yl)benzamide (i.e., Compound 2).
  • the compounds of Formula I or II comprise iV-((4,6-dimethyl-2-oxo-l,2- dihydropyridin-3-yl)memyl)-3-(ethyl(te1rahydro-2H-pyran-4-yl)airuno)-2-methyl-5-((l- methylpiperidin-4-yl)ethynyl)benzamide (i.e., Compound
  • the invention relates to a compound according to Formula III:
  • R 801 is Ci alkyl, C alkenyl, C alkynyl, C 3 .s cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, phenyl or 5- or 6-membered heteroaryl, each of which is substituted with O-C ⁇ alkyl-R x or NH-Ci. 6 alkyl-R x , wherein R x is hydroxyl, O alkyl or NH alkyl, and R x is optionally further substituted with O alkyl or NH-Cu alkyl except when R x is hydroxyl; and R 801 is optionally further substituted;
  • each of R 802 and R 803 independently is H, halo, C M alkyl, Ci. 6 alkoxyl or C 6 -Cio aryloxy, each optionally substituted with one or more halo;
  • each of R 8U4 and R independently is alkyl; and R is -Q x -T x , wherein Q x is a bond or Ci alkyl linker, T x is H, optionally substituted C alkyl, optionally substituted C3-C8 cycloalkyl or optionally substituted 4- to 14-membered heterocycloalkyl.
  • the compounds of Formula III can include one or more of the following features:
  • Q x is a bond or methyl linker.
  • T x is tetrahydropyranyl.
  • T x is piperidinyl substituted by 1, 2, or 3 CM alkyl groups.
  • T x is cyclohexyl substituted by N(C]- t alkylh wherein one or both of the CM alkyl is optionally substimted with Q-s alkoxy.
  • R 801 is phenyl substituted with 0-C, grammar 6 alkyl-R x .
  • R 801 is 5- membered heteroaryl substituted (e.g., pyrrolyl, furyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl) with O-Ci. 6 alkyl-R*.
  • heteroaryl substituted e.g., pyrrolyl, furyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl
  • R 801 is 6-membered heteroaryl (e.g., pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl) substituted with 0-Q. 6 alkyl-R x .
  • 6-membered heteroaryl e.g., pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl
  • R 801 is pyridyl, pyrimidyl, pyrazinyl, imidazolyl, or pyrazolyl, each of which is substimted with O-Cue alkyl-R x .
  • subsets of compounds of Formula III include those of Formula IVa or IVb and pharmaceu
  • R 807 is -CH 2 CH 2 OH, -CH CH 2 OCH 3 , or -CH 2 CH 2 OCH 2 CH 2 OCH 3 .
  • R 80Z is methyl or isopropyl.
  • R 803 is methyl or methoxyl.
  • R 804 is methyl
  • the compounds of Formula III do not comprise JV-((4, 6 -dimethyl-2-oxo-l,2- dihydropyridin-3-yl)methyl)-5-((4-(dimemyla
  • the compounds of Formula III comprise V-((4,6-dimethyl-2-oxo-l,2- dihydropyridin-3-yl)memyl)- 5 -((4-(dimemylam ⁇
  • the compounds of Formula III comprise iV-((4, 6 -dimethyl-2-oxo-l,2- dihydropyridin-3-yl)methyl)-5-(((lr,4r)-4-(dimethylamino)cyclohexyl)(ethyl)amino)-4'-(2- methoxyethoxy)-4-methyl-[l,l'-biphenyl]-3-carboxamide (i.e., Compound 1).
  • R 21 is hydrogen or Ci- alkyl
  • R 22 is (a) 3-8 membered saturated, unsaturated, or aromatic carbocycle, or (b) 3-8 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, where (a)-(b) are optionally substituted with one or more R 2a ;
  • each of R 23 and R 24 independently is C
  • R la is (a) 3-8 membered saturated, unsaturated, or aromatic carbocycle, or (b) 3-8 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, where (a)-(b) are optionally substituted with one or more R 3a ; each R 2a independently is C t -C 6 alkyl, N3 ⁇ 4, NH(C,-C 6 alkyl), or N(d-C 6 alkyl) 2 ; each R 3a independently is (a) OH, (b) Ci-C 6 alkyl, or (c) 0(Ci-C 6 alkyl), where (b)- (c) are optionally substituted with one or more OH, and
  • n 0, 1, 2, or 3;
  • the compound is not N-((4,6-dimethyl-2-oxo-l ,2-dihydropyridin-3-yl)methyl)-3- ((4-(dimethylamino)cyclohexyl)(ethyl)amino)-2-methyl-5-(3-(4-methylpiperazin- l-yl)prop- 1 -yn- 1 -yl)benzamide or 5 -(cyclopropylethynyl)-N-((4,6-dimethyl-2-oxo- 1 ,2-dihydropyridin- 3-yl)methyl)-3-((4-(dimethylamino)cyclohexyl)(ethyl)amino)-2-methylbenzamide.
  • R 2 ' is Ci-Ce, alkyl.
  • R 1 is methyl or isopropyl.
  • R 22 is a 6-membered saturated carbocycle or a 6-membered saturated heterocycle.
  • R 22 is cyclohexyl or tetrahydropyranyl.
  • the cyclohexyl is substituted with N(Ci alkyl such as, e.g., N(CH 3 ) 2 .
  • R 22 is tetrahydropyranyl.
  • R l a is 4-7 membered saturated heterocycle.
  • R l a is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or diazepanyl.
  • R 23 is ethyl
  • R 24 is methyl
  • m is 0 or 1.
  • the invention relates to compound according to Formula Ilia:
  • R 101 is hydrogen, C C 6 alkyl, or C C 6 haloalkyl
  • R 102 is hydrogen or halogen
  • R' 03 is hydro gen or Ci-Q alkyl
  • R 104 is hydrogen or Ci-C 6 alkyl; provided that when R 10 ' is methyl, and when R 102 and R 103 are hydrogen, R 104 is not hydrogen.
  • R 101 is Ci-Q alkyl.
  • R 101 is methyl, n-propyl, or isopropyl.
  • R 101 is C 1 -C6 haloalkyl.
  • R 101 is CF 3 , CF 2 H, or CF3 ⁇ 4.
  • R 101 is CF 3 .
  • R 102 is halogen.
  • R 102 is fluoro.
  • the invention relates to compound according to Formula Illb:
  • Xi is N or CH
  • R 201 is hydrogen, C,-C 6 alkyl, C r C 6 haloalkyl
  • R 202 is hydrogen or Ci-C 6 alkyl
  • R 203 is (a) OH, (b) Cj-Q alkyl, (c) 0(C,-C 6 alkyl), (d) (CH 2 ) r 3-8 membered saturated, unsaturated, or aromatic carbocycle, (e) (C3 ⁇ 4) k -3-8 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (f) 0-(CH 2 ) u -3-8 membered saturated, unsaturated, or aromatic carbocycle, or (g) 0-(CI3 ⁇ 4)v-3-8 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, where (b)-(g) are optionally substituted with R 203A
  • R 203A is C,-C 6 alkyl, C C 6 haloalkyl, OH, or 0(C,-C 6 alkyl);
  • R 204 is C r C 6 alkyl
  • v 0, 1, 2 , or 3
  • z 0, 1, 2, or 3;
  • j is O, 1, 2, or 3;
  • k 0, 1, 2, or 3.
  • Xi is N and X 2 is CH.
  • R 201 is Ci-Ce alkyl.
  • R 201 is methyl.
  • R 202 is hydrogen.
  • R 202 is Ci -C1 ⁇ 4 alkyl.
  • R 202 is methyl.
  • R 203 is (CH 2 X-6 membered saturated heterocycle.
  • k is 1.
  • R 203 is (CH 2 )-piperazinyl or
  • R 204 is methyl
  • Y 2 is N or CH
  • R 30 ' is hydrogen, C C 6 alkyl, C,-C 6 haloalkyl
  • R 302 is (a) Ci-C 6 alkyl (b) Ci-C haloalkyl, (c) 0(C,-C 6 alkyl), (d) (C3 ⁇ 4) r 3-8 membered saturated, unsaturated, or aromatic carbocycle, (e) (CH 2 )k-3-8 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (f) 0-(C3 ⁇ 4) u -3-8 membered saturated, unsaturated, or aromatic carbocycle, or (g) 0-(CH 2 ) v -3-8 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, where (a)-(g) are optionally substituted with R 02a
  • R 302a is Ci-C 6 alkyl, C,-C 6 haloalkyl, OH, or 0(Ci-C 6 alkyl);
  • t is 1, 2, or 3;
  • u is O, 1, 2, or 3;
  • v 0, 1,2 , or 3;
  • j 0, 1, 2, or 3;
  • k is 0, 1, 2, or 3; provided that (i) when R 302 is (CH 2 )-morpholinyl, R 301 is not methyl, isopropyl or n-propyl; or (ii) R 302 is not piperazinyl or (CH 2 )-piperazinyl.
  • Yi is N and Y2 is CH.
  • R 301 is Q-Ce alky.
  • R 301 is methyl or isopropyl.
  • R 301 is methyl.
  • R 301 is Ci-C ⁇ haloalkyl.
  • R 301 is CF3, CF 2 H, or CFH .
  • R 301 is CF3.
  • R 302 is 0(C C6 alkyl).
  • R 302 is methoxy or isopropoxy.
  • R 302 is 0-4-6 membered saturated heterocycle.
  • the heterocycle is azetidinyl or pipendinyl.
  • R 302 is (CH 2 )-4-7 membered saturated heterocycle.
  • the heterocycle is azetidinyl, pyrrolidinyl, pipendinyl, morpholinyl, or diazepanyl.
  • W is N or CH
  • W 2 is N or CH
  • R 40 ' is hydrogen, C,-C 6 alkyl, C,-C 6 haloalkyl
  • R m is (a) OH, (b) (CH 2 )-0-(C,-C 6 alkyl), (c) 0(C,-C 6 alkyl), (d) (CH 2 )j-3-8 membered saturated, unsaturated, or aromatic carbocycle, (e) C3 ⁇ 4)k-3-8 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (f) 0-(CH 2 ) u -3-8 membered saturated, unsaturated, or aromatic carbocycle, or (g) 0-(03 ⁇ 4) ⁇ -3-8 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, where (b)-(g) are optionally substituted with R 402 * ,
  • R 402a is C,-C 6 alkyl, C,-C 6 haloalkyl, OH, or 0(C,-C 6 alkyl);
  • t is 1 , 2, or 3;
  • u is O, 1, 2, or 3;
  • v is O, 1,2 , or 3;
  • j 0, 1, 2, or 3;
  • k 0, 1, 2, or 3; provided that when R 402 is piperazinyl, Wi and W 2 are N.
  • Wi is N and W 2 is CH.
  • R 401 is Ci-Ct alkyl.
  • R 401 is methyl or isopropyl.
  • R 401 is methyl.
  • R 402 is (C3 ⁇ 4) k -4-7 membered saturated heterocycle containing one or more nitrogen or oxygen atoms.
  • k is 0 or 1.
  • k is 0.
  • k is 1.
  • R 4M is azetidinyl, piperazinyl, or piperidinyl.
  • R 402 is (CFy-azetidinyl, (Cty-pyrrolidinyl, (C3 ⁇ 4)-piperidinyl, (CH 2 )-morpholinyl, or (C3 ⁇ 4)-diazepanyl.
  • t is 1.
  • R 402a is OH, methyl, or methoxy.
  • the invention relates to a compound of Formula VI:
  • n 5 is 0, l, or 2;
  • R 50 ' is C(H) or N
  • R 502 , R 503 , R 504 and R 505 are, independently for each occurrence, C M alkyl; R is cyclohexyl substituted by N(C alkylh or iperidine substituted by 1, 2, or 3 Ci-4 alkyl groups;
  • R S07 is morpholine; piperidine; diazepane; pyrrolidine; azetidine; O-Ci-6 alkyl; or O-heterocycle, wherein the heterocycle is a 4-7 membered heterocycle containing an oxygen or nitrogen, or both, and wherein the nitrogen can optionally be substituted with C1.3 alkyl; wherein the piperidine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH, Ci-6 alkyl, or O-C1.3 alkyl;
  • R 507 can be piperazine optionally further substituted with .6 alkyl, provided that R 506 is piperidine substituted by 1, 2, or 3 CM alkyl groups;
  • R 507 is morpholine; piperidine; piperazine; diazepane; pyrrolidine; azetidine; O-CM alkyl; or O-heterocycle, wherein the heterocycle is a 4-7 membered heterocycle containing an oxygen or nitrogen, or both, and wherein the nitrogen can optionally be substituted with C1.3 alkyl; wherein the piperidine, piperazine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH, Ci_6 alkyl, or O-C1.3 alkyl.
  • R 50 ' is C(H)
  • R 507 is piperidine; diazepane; pyrrolidine; azetidine; O-Ci-6 alkyl; or O-heterocycle, wherein the heterocycle is a 4-7 membered heterocycle containing an oxygen or nitrogen, or both, and wherein the nitrogen can optionally be substituted with .3 alkyl; wherein the piperidine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH, Ci-6 alkyl, or O-C1-3 alkyl.
  • R 501 is C(H) and R 507 is piperidine, diazepane, pyrrolidine, azetidine or O-CM alkyl, wherein the piperidine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH or Cj.6 alkyl.
  • R 501 is C(H)
  • R 507 is piperazine optionally further substituted with Ci-6 alkyl
  • R 506 is piperidine substituted by 1, 2, or 3 CM alkyl groups.
  • R 501 is N
  • R 507 is morpholine, piperidine, piperazine, diazepane, pyrrolidine, azetidine or O-Cj-6 alkyl, wherein the piperidine, piperazine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH or Ci_ 6 alkyl.
  • R 502 is methyl or isopropyl
  • R 503 is methyl
  • R S05 is ethyl
  • R 5m is C(H)
  • R 5U is piperidine or diazepane, which are substituted with OH or Ci- 6 alkyl
  • R 501 is N
  • R 507 is piperidine, piperazine, or diazepane, which are optionally further substituted with OH or Q alkyl.
  • R 507 when R 50 ' is C(H), R 507 is piperidine substituted with Cj alkyl, or when R 501 is N, R 507 is piperidine substituted with OH or piperazine substituted with C alkyl.
  • R 507 is unsubstituted piperazine.
  • ns is 0 or 1.
  • R 501 is C(H) orN
  • R 507 is 0-C,. 6 alkyl or O- heterocycle
  • n ? is 1.
  • R 507 is unsubstituted piperazine and
  • R 506 is piperidine substituted by 1 , 2, or 3 C alkyl groups.
  • the invention relates to a compound of Formula VII:
  • n 3 ⁇ 4 is 0, 1 or 2;
  • R 602 , R 603 , R 60 and R 605 are, independently for each occurrence, C M alkyl; or each of
  • R 602 and R 603 independently is C alkoxyl
  • K m is tetrahydropyran, cyclohexyl substituted by N(C alky3 ⁇ 4 or piperidine substituted by 1, 2, or 3 CM alkyl groups; and R is morpholine, piperidine, piperazine, pyrrolidine, diazepane, azetidine or O-Ci alkyl, wherein the piperidine, diazepane or azetidine groups can be optionally further substituted with OH; Q alkyl optionally substituted with one or more halo; cycloalkyl; C(0)Ci alkyl; or 4- to 7-membered heterocycloalkyl optionally substituted with Ci alkyl; provided that when R 606 is tetrahydropyran, r3 ⁇ 4 is 0 or 2.
  • R 602 is methyl or isopropyl and R 603 is methyl.
  • R 605 is ethyl
  • R 607 is piperidine or diazepane, each of which is substituted with OH or Ci. 6 alkyl.
  • R 607 is piperidine substituted with OH.
  • R 607 is piperidine substituted with Q alkyl optionally substituted with one or more halo; cycloalkyl; C(0)C alkyl; or 4- to 7-membered heterocycloalkyl.
  • R 607 is piperidine substituted with substituted with alkyl optionally substituted with one or more halo; cycloalkyl; C(0)Ci alkyl; or 4- to 7- membered heterocycloalkyl; and 3 ⁇ 4 is 0.
  • the invention relates to a compound of Formula Vila
  • R P2 is CH 3 or OCH 3 .
  • R P7 is C alkyl; C 3 .e cycloalkyl, or 4- to 7-membered heterocycloalkyl optionally substituted with CM alkyl.
  • R ⁇ is cyclopropyl or cyclobutyl.
  • R ⁇ is azetidinyl or piperidinyl, each optionally substituted with CH 3 .
  • the invention relates to a compound of Formula Vllb
  • R P2 is CH 3 or OCH 3 .
  • R P7 is C(0)CM alkyl or CM haloalkyl.
  • R P7 is C(0)CH 3 .
  • R P7 is C3 ⁇ 4CF 3 .
  • Xi is N or CRu;
  • X 2 is N or CR t3 ;
  • Z is NR 7 Rs, OR 7 , S(0) consentR 7 , or CR 7 RsRi4, in which n is 0, 1, or 2;
  • each of Rj, R 5 , R9, and Rio is H or C C6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOHj C(0)0-C
  • each of R 2 , R3, and R4, independently, is -Q1 -T1, in which Qi is a bond or C1 -C3 alkyl linker optionally substituted with halo, cyano, hydroxyl or Q-Ce alkoxy, and Ti is H, halo, hydroxyl, COOH, cyano, or R S] , in which Rsi is C1-C3 alkyl, C2-C6 alkenyl, C 2 -C3 ⁇ 4 alkynyl, C1-C6 alkoxyl, C(0)0-Ci -C 6 alkyl, C 3 -Cg cycloalkyl, Ci-Cio aryl, amino, mono-Ci-C6 alkylamino, di-G- 1 ⁇ 4 alkylamino, 4 to 12-membered heterocycloalkyl, or 5 - or 6-membered heteroaryl, and Rsi is optionally substituted with one or more substituents selected from the group consisting of halo
  • 6 is C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more -Q2-T2, wherein Q 2 is a bond or C1-C3 alkyl linker optionally substituted with halo, cyano, hydroxyl or C -Ce alkoxy, and T 2 is H, halo, cyano, -ORa, - NRaRb, -(NR a R b R c ) + A-,-C(0)R a , -C(0)OR a , -C(0)NR a R b , -NRbC(0)Rdin
  • each of Rs 2 and Rs3, independently is Ci-C alkyl, C3-CS cycloalkyl, Ci-Cio aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or 3 ⁇ 4 and 3 ⁇ 4 together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of Rs 2 , Rs 3 , and the 4 to 12-membered heterocycloalkyl ring formed by 3 ⁇ 4 and Rb, is optionally substituted with one or more one ormore -Q3-T3, wherein ⁇ 3 ⁇ 4 is a bond or -C3 alkyl linker each optionally substituted with halo, cyano, hydroxyl or Ci-Ci alkoxy, and T3 is selected from the group consisting of halo, cyano, C1-C6 alkyl, C
  • Rd and R independently being H or C1-C6 alkyl optionally substituted with OH, 0-C C 6 alkyl, or NH-Cj-Q alkyl, or
  • -Q 3 -T3 is oxo; or any two neighboring -Q2-T2, together with the atoms to which they are attached form a 5 - or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(0)0-Ci alkyl, cyano, Q alkoxyl, amino, mono-Ci alkylamino, di-Ci alkylamino, C 3 -Cg cycloalkyi, Ce-Qo aryl, 4 to 12- membered heterocycloalkyl, and 5- or 6-membered heteroaryl;
  • R7 is -Q4-T4, in which Q 4 is a bond, C1-C4 alkyl linker, or C2-C4 alkenyl linker, each linker optionally substituted with halo, cyano, hydroxyl or Ci-C3 ⁇ 4 alkoxy, and T4 is H, halo, cyano, NR f R g , -OR f , -C(0)R f , -C(0)OR f , -C(0)NR f R g , -C(0)NR f OR g ,
  • each of Rf and R g independently is H or Rss
  • each of s4 and ss independently is C1-C6 alkyl, C2-Q alkenyl, C 2 -C6 alkynyl, C 3 -Cs cycloalkyi, C -C10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl
  • each of Rs4 and Rss is optionally substituted with one or more -Q5-T5, wherein Qs is a bond, C(O), C(0)NR k , R k C(0), NR k , S(0) 2 , NR k S(0) 2 , or C1-C3 alkyl linker, R k being H or C,-C 6 alkyl, and T5 is H, halo, -Q alkyl, C2-C6 alkenyl, C 2 -C
  • 1, R12, and R13, independently, is H, halo, hydroxyl, COOH, cyano, Rse, ORs6, or COOR S6 , in which R S6 is Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyi, 4 to 12-membered heterocycloalkyl, amino, mono-Ci-C3 ⁇ 4 alkylamino, or di-Ci-C6 alkylamino, and Rs6 is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(0)0-Ci-C6 alkyl, cyano, -C6 alkoxyl, amino, mono-Ci-Cs alkylamino, and di- - alkylamino; or R7 and Rs, together with the N atom to which they are attached, form a 4 to 11-membered hetero
  • R M is absent, H, or C1 -C6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(0)0-Ci-Q alkyl, cyano, Q- C6 alkoxyl, amino, mono-Ci-C ⁇ alkylamino, di-Q-C6 alkylamino, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl.
  • substituents selected from the group consisting of halo, hydroxyl, COOH, C(0)0-Ci-Q alkyl, cyano, Q- C6 alkoxyl, amino, mono-Ci-C ⁇ alkylamino, di-Q-C6 alkylamino, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-
  • One subset of the compounds of Formula ( ⁇ ) includes those of Formula (la):
  • Another subset of the compounds of Formula ( ⁇ ) includes those of Formula (lb), (Ic), or (Id):
  • the compounds of Formula ( ⁇ ), (la), (lb), (Ic), and (Id) can include one or more of the following features when applicable:
  • X is CRn and X2 is CR13.
  • i is CR
  • X is N and X 2 is CRi
  • X is N and X 2 is N.
  • Z is NR 7 R 8 .
  • Z is CRyReRw- [0171]
  • Z is OR 7 .
  • Z is S(0 in which n is 0, 1 , or 2.
  • Z is SR 7.
  • 3 ⁇ 4 is unsubstituted C ⁇ -Cw aryl or unsubstituted 5- or 6-membered heteroaryl.
  • R 6 is C ⁇ -Cio aryl substituted with one or more or 5- or 6-membered heteroaryl substituted with one or more -Q 2 -T 2 .
  • R6 is unsubstituted phenyl.
  • 3 ⁇ 4 is phenyl substituted with one or more
  • R is 5 to 6-membered heteroaryl containing 1-3 additional heteroatoms selected from N, O, and S and optionally substituted with one or more
  • Rg is pyridinyl, pyrazolyl, pyrimidinyl, quinolinyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, or thienyl, each of which is optionally substituted with one or more
  • Q 2 is an unsubstituted alkyl linker.
  • T 2 is Ci-Ce alkyl or aryl, each optionally substituted with one or more -
  • Ci-Q or branched -Q alkyl including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl.
  • T 2 is phenyl
  • T 2 is halo (e.g., fluorine, chlorine, bromine, and iodine).
  • T 2 is 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyI, piperazinyl, tetrahydro-2H-pyranyl, 3,6- dihydro-2H-pyranyl, tetrahydro-2H-thiopyran, mo ⁇ holinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa- 5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-aza
  • T 2 is -OR a , -NR a R b , -(NR ) + A ⁇ -C(0)R a , -C(0)ORdepth
  • T 2 is or -C(0)NR in which each of R a and R b , independently is H or Ci-Ce alkyl, or R a and 3 ⁇ 4, together with the atom to which they are attached, form a 4 to 7- membered heterocycloalkyl ring having 0 or 1 additional heteroatom, the Cj-Q alkyl and the 4 to 7- membered heterocycloalkyl ring being optionally substituted with one or more
  • Q 2 is alkyl linker optionally substituted with halo or hydroxyl.
  • Q 2 is a bond or methyl linker and is H, halo
  • each of R a , R b , and independently is H or alkyl optionally substituted with one or more
  • heterocycloalkyl ring having 0 or 1 additional heteroatoms to the N atom (e.g., azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2, 5 -diazabicyclo[2.2.1]heptanyl, 2-oxa- 6 -azaspiro[3.3]heptanyl, 2,6- diazaspiro[3.3]heptanyl, and the like) and the ring
  • T 2 is 4 to 7-membered heterocycloalkyl or cycloalkyl and one or more - are oxo.
  • Qj is a bond or unsubstituted or substituted -C3 alkyl linker.
  • T 3 is H, halo, 4 to 7-membered heterocycloalkyl, alkyl, OR* COORa,- (0 or
  • one of 3 ⁇ 4 and R ⁇ is H.
  • R 6 is
  • R7 is not H.
  • R 7 is -C(0)R f .
  • R 7 is -C(0)R f , in which R f is C 3 -C 8 cycloalkyl.
  • R7 is phenyl optionally substituted with one or more [020 6 ]
  • heterocycloalkyl e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetoahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6- dihydro-2H-pyranyl, tetrahydro-2H-thiopyran, and morpholinyl, and the like) optionally substituted with one or more
  • R7 is isopropyl
  • pyrrolidinyl is pyrrolidinyl, piperidinyl, tetrahydropyran, cyclopentyl, cyclohexyl, or cycloheptyl, each optionally substituted with one
  • cyclopentyl or cyclohexyl are each optionally substituted with one
  • R7 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • one or more -Q5 are oxo.
  • Q5 is a bond and Ts is amino, mono-Ci-C6 alkylamino, or di-Ci-Q alkylammo.
  • Q s is NHC(O) and T 5 is Ci-C 6 alkyl or Ci-C 6 alkoxy.
  • -Q5-T5 is oxo.
  • T4 is 4 to 7-membered heterocycloalkyl or C3-C8 cycloalkyl and one or more -
  • T 5 is H, halo, C r C 6 alkyl, Q-C 6 alkoxyl, C 3 -C 8 cycloalkyl, Q-C 10 aryl, or 4 to 7-membered heterocycloalkyl.
  • (3 ⁇ 4 is a bond and is C ⁇ -Ce alkyl, C3-C8 cycloalkyl, or 4 to 7-membered heterocycloalkyl.
  • Q 5 is CO, S(0) 2 , or NHC(O); and T 5 is Ci-C 6 alkyl, Ci-C 6 alkoxyl, C 3 -C 8 cycloalkyl, or 4 to 7-membered heterocycloalkyl.
  • T5 is Ci-Ce alkyl or C ⁇ -C alkoxyl, each optionally substituted with halo, hydroxyl, cyano, C ⁇ -Ce alkoxyl, amino, mono-Cj-Ce alkylamino, di-Ci-Ce alkylamino, or C3-C3 ⁇ 4 cycloalkyl.
  • Q5 is C1 -C3 alkyl linker and T5 is H or C6-C10 aryl.
  • Q5 is Q -C 3 alkyl linker and T5 is C3-C 8 cycloalkyl, 4 to 7-membered heterocycloalkyl, or S(0) q R q .
  • Rn is H.
  • each of 2 and R4 is H or Q-Ce, alkyl optionally substituted with amino, mono-Ci-Q alkylamino, di-Ci-Ce alkylamino, or 1 ⁇ 4-Cio aryl.
  • each of R2 and R4 independently is C1 -C3 alkyl optionally substituted withQ- C6 alkoxyl.
  • each of R2 and R4 is methyl.
  • Ri is H.
  • Ri? is ethyl
  • Rg is H, methyl, ethyl, or ethenyl.
  • Rg is methyl
  • Rg is ethyl
  • Rg is 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, l,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6- dihydro-2H-pyranyl, tetrahydro-2H-thiopyran, morpholinyl, 1,4-diazepanyl, 1 ,4-oxazepanyl, 2-oxa- 5-azabicyclo[2.2.1]heptanyl, 2 > 5-diazabicyclo[2.2.1]heptanyl, 2-oxa
  • Rg is tetrahydropyran.
  • Rg is tetrahydropyran and R7 is -T4, in which is a bond or C1-C4 alkyl linker and T4 is H, Ci-C 6 alkyl, Cj-Cg cycloalkyl or 4 to 7-membered heterocycloalkyl.
  • Z is NR 7 8 or CR 7 RgRi 4 wherein R7 and R 8 , together with the atom to which they are attached, form a 4 to 11 -membered heterocycloalkyl ring having 1 to 3 heteroatoms (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1 ,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyran, and morpholinyl, 1,4- dioxa-8-azaspiro[4.S]de
  • the ring formed by R 7 and Rg is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, l ,4-dioxa-8-azaspiro[4.5]decanyl, and cyclohexenyl, each optionally substituted with one -Qe-T
  • T 6 is H, halo, C C 6 alkyl, Ci-C 6 alkoxyl, C 3 -C 3 cycloalkyl, C 6 -Ci 0 aryl, or 4 to 7-membered heterocycloalkyl.
  • Q 6 is a bond and T 6 is C ⁇ -C 6 alkyl, C 3 -C 3 cycloalkyl, or 4 to 7-membered heterocycloalkyl.
  • Q 6 is CO, S(0) 2 , or NHC(O); and T 6 is C,-Q, alkyl, C r C 6 alkoxyl, C 3 -C 8 cycloalkyl, or 4 to 7-membered heterocycloalkyl.
  • T 6 is Q-Ce alkyl or Ci-C ⁇ alkoxyl, each optionally substituted with halo, hydroxyl, cyano, Ci-Ce alkoxyl, amino, mono-G-Q alkylamino, di-Ci-Q alkylamino, or C 3 -Cs cycloalkyl.
  • (3 ⁇ 4 is C1-C3 alkyl linker and T 6 is H or C6-C10 aryl.
  • Qe is C1-C3 alkyl linker and T(, is C 3 -Cg cycloalkyl, 4 to 7-membered heterocyclo alkyl, or S(0) p R p .
  • each of R p and R is C ! -C 6 alkyl.
  • 3 is H or methyl.
  • R, 3 is H.
  • R 3 is H.
  • a " is Br " or CI " .
  • each of and Rio is H.
  • Still anoth ( ⁇ ) includes those of Formula (le), or (I).
  • R2, and R12 are each, independently alkyl.
  • Re is C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is optionally, independently substituted with one or more -Q2-T2, wherein Qj is a bond or Q-C3 alkyl linker, and T 2 is H, halo, cyano, -OR,, -NRA,, -(NR a R b Rc) + A " , -C(0)NR a R b ,
  • each of R a and R b independently is H or Rs , each of Rs2 and Rs3, independently, is Cj-C1 ⁇ 4 alkyl, or R a and R , together with the N atom to which they are attached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R S 2, Rs3, and the 4 to 7-membered heterocycloalkyl ring formed by Ra and R b , is optionally, independently substituted with one or more -Q3-T3, wherein Q 3 is a bond or C ⁇ -C 3 alkyl linker and T3 is selected from the group consisting of halo, C
  • T 2 is H, halo, -( ⁇ 3 ⁇ 43 ⁇ 43 ⁇ 4) + ⁇ ⁇ , or -S(0
  • T 2 is or ) + A ⁇ .
  • the compounds of Formula (IP) or (Ha) can include one or more of the following features when applicable:
  • each of 3 ⁇ 4 and independently is H or alkyl optionally substituted with one or more
  • heterocycloalkyl ring having 0 or 1 additional heteroatoms to the N atom (e.g., azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1 ,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, and the like) and the ring is optionally substituted with one or more -Q3-T3.
  • R dividend and 3 ⁇ 4 together with the N atom to which they are attached, form azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, or morpholinyl, and the ring is optionally substituted with one or more -Q3-T3.
  • one or more -Q3-T3 are oxo.
  • Q 3 is a bond or unsubstituted or substituted alkyl linker.
  • T 3 is H, halo, 4 to 7-membered heterocycloalkyl, C r C 3 alkyl, OR d , COOR d ,-
  • one of R d and 3 ⁇ 4 is H.
  • R7 is C3-C8 cycloalkyl or 4 to 7-membered heterocycloalkyl, each optionally substituted with one or more -Q5-T5.
  • R 7 is piperidinyl, tetrahydropyran, tetrahydro-2H-thiopyranyl, cyclopentyl, cyclohexyl, pyrrolidinyl, or cycloheptyl, each optionally substituted with one or more -Q5-T5.
  • R7 is cyclopentyl cyclohexyl or tetrahydro-2H-thiopyranyl, each optionally substituted with one or more -Q5-T5.
  • Q 5 is NHC(O) and T 5 is C C 6 alkyl or C,-C 6 alkoxy.
  • one or more -Q5-T5 are oxo.
  • R7 is l-oxide-tetrahydro-2H-thiopyranyl or 1 , 1 -dioxide-tetrahydro-2H- thiopyranyl.
  • Q5 is a bond and T 5 is amino, mono-C]-C6 alkylamino, di-Ci-C 6 alkylamino.
  • Q 5 is CO, S(0) 2 , or NHC(O); and T 5 is C,-C 6 alkyl, Ci-C 6 alkoxyl, C 3 -C 8 cycloalkyl, or 4 to 7-membered heterocycloalkyl.
  • Rg is H or -Q alkyl which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(0)0-C ! -C 6 alkyl, cyano, Ci-C3 ⁇ 4 alkoxyl, amino, mono-C alkylamino, and di-Ci alkylamino.
  • Re is H, methyl, or ethyl.
  • Still another subset of compounds of Formula ( ⁇ ) includes those of Formula ( ⁇ ):
  • R-3 is hydrogen, C 1 -C3 alkyl or halo
  • R 7 is C
  • Re is Ci -C 6 alkyl
  • Rh is -Q h -T h , wherein Q is a bond, a C1-C3 alkyl linker or N(RN); TJ, is OR i or
  • R i and Rh2 are independently hydrogen or C 1 -C6 alkyl, or one of Rhi and R h2 is methyl and the other is a 6-membered N-containing heterocycloalkyl optionally substituted with one or two methyl, or together with the N atom to which they are attached, R h i and Rh 2 form a 4 to 7- membered heterocycloalkyl ring having 0 or 1 additional heteroatoms selected from oxygen and nitrogen, wherein said heterocycloalkyl ring is optionally substituted with one or more 3 ⁇ 4;
  • Ri is Ci -C3 alkyl, -NRwiRra or a C3-C8 cycloalkyl or 5 or 6 membered heterocycle each of which cycloalkyl or heterocycle is independently optionally substituted with R j ;
  • RN is hydrogen, C ⁇ -C alkyl or C3-C8 cycloalkyl
  • R j is Ci-C 3 alkyl, -NR N1 R N2 , 0r -NC(O)R N ;
  • RNI and R N are each independently hydrogen, C ⁇ -Ce alkyl, C3-C8 cycloalkyl, 5 or 6 membered heterocycle, each of which cycloalkyl or heterocycle is independently optionally substituted with R j .
  • R3 is hydrogen
  • R 3 is halogen, such as, for example, fluoro or chloro.
  • R3 is fluoro.
  • methyl, ethyl, propyl, or isopropyl is methyl, ethyl, propyl, or isopropyl.
  • is methyl is isopropyl.
  • R 7 is 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropvriditiyl, pipetazinyl, tetrahydro-2H-pyranyl, 3,6- dihydro-2H-pyranyl, tetrahydro-2H-thiopyran, and morpholinyl, and the like).
  • 7 is a 5 or 6 membered cycloalkyl or heterocycloalkyl.
  • R7 is a 6 membered cycloalkyl or heterocycloalkyl.
  • R 7 is piperidinyl, tetrahydropyranyl, cyclopentyl, or cyclohexyl.
  • Rj is methyl. In some embodiments, Rj is N3 ⁇ 4.
  • Re is C], C2 or C3 alkyl.
  • Re is methyl.
  • R3 ⁇ 4 is ethyl.
  • Qh is a bond. In others, Q h is methylene.
  • T h is N(CH 3 ) 2 .
  • one of Rhi and Rh2 is methyl and the other is a 6-membered N- containing heterocycloalkyl optionally substituted with one or two methyl.
  • the 6- membered N-containing heterocycloalkyl does not contain further heteroatoms in the ring.
  • the 6-membered N-containing heterocycloalkyl is not further substituted besides the one or two methyl groups.
  • Rhi and Rh2 together with the N to which they are attached form a 6 membered ring.
  • Th is selected from piperidine, morpholine, piperazine, and N-methyl piperazine.
  • Th is morpholine.
  • R is methyl or (CH3)2.
  • Rj is C3-C8 cycloalkyl or 5 or 6 membered heterocycle.
  • R is a 6 membered cycloalkyl or heterocycle, substituted with zero or one Rj.
  • RN is H or methyl.
  • R3 is fluoro
  • R4 is isopropyl
  • Qh is a bond.
  • R3 is hydrogen
  • R4 is propyl or isopropyl
  • Qh is methylene
  • R3 is hydrogen
  • R4 is propyl or isopropyl
  • Qh is a bond
  • R3 is H or F
  • Compounds of the invention include those of Formula I", and pharmaceutically acceptable salts or solvates thereof:
  • Xi ' is N or CRi,';
  • X 2 ' is N or CRn'
  • Z 2 is NR 7 'R 8 ', OR 7 ', S(0) a -R 7 ⁇ or CRy'Rs'Ru', in which a' is 0, 1, or 2; each of Ri', R5', R9', and Rio', independently, is H or Cj-C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy!, COOH, C(0)0-C
  • each of R2', R3', and ⁇ is -Qi '- ⁇ , in which Qi ' is a bond or Q-C3 alkyl linker optionally substituted with halo, cyano, hydroxyl or C
  • R S2 ' in which Rs 2 ' is Ci-C 6 alkyl, C 2 -C 6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, or 4 to 12-membered heterocycloalkyl, b' is 0, 1, or 2, each of R a ' and Rb', independently is H or Rs 3 ', and Rs 3 ' is Cj-C6 alkyl, C z -Ce alkenyl, C 2 - C 6 alkynyl, C3-C8
  • R7' is -Q4 in which Q 4 ' is a bond, C r C4 alkyl linker, or C 2 -C 4 alkenyl linker, each linker optionally substituted with halo, cyano, hydroxyl or Ci-Ce alkoxy, and T4' is H, halo, cyano, NR g 'R h ', -OR g ', -C(0)R g ⁇ -C(0)OR g ', -C(0) R g 'R h ', -C(0)NR g 'OR h ', - NR g 'C(0)R h ', -S(0) 2 R g ', or se', in which each of R g ' and R h ', independently is H or Rs 7 ', each of s6' and Rs 7 ', independently is C] -C6 alkyl, C 2 -C6 alkenyl, C 2 -C6 al
  • Rn ' is H, halo, hydroxyl, COOH, cyano, Rss ⁇ ORss', or COOR S8 ', in which Rsg' is C,-C 6 alkyl, C -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 4 to 12-membered heterocycloalkyl, amino, mono-Ci-C6 alkylamino, or di-Ci-Cs alkylamino, and Rss* is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(0)0-C t -C 6 alkyl, cyano, Ci-Ce alkoxyl, amino, mono-Ci-Ci alkylamino, and di-Ci-C6 alkylamino; or and Rg', together with the N atom to which they are attached, form a 4 to 1 -membered heterocycl
  • Ci-Ci alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(0)0-Ci-C6 alkyl, cyano, Cj- Cs alkoxyl, amino, mono-Ci-C 6 alkylamino, di-Ci alkylamino, C 3 -Cg cycloalkyl, aryl, 4 to 12-membered heterocycloalkyl, and 5 - or 6-membered heteroaryl. provided that the compound is not
  • Another subset of the eompounds of Formula (I") includes those of Formula (I"b), (I"c), or (I"d):
  • n 0, 1, or 2;
  • U is O, S, N-Q j '-Ts', or CH- is CI, Br, or methyl; and Rg', Q 5 ', and are defined herein.
  • Still another subset of the compounds of Formula (I") includes those of Formula (IIB):
  • R3' is H or F
  • 4' is methyl, ethyl, n-propyl, isopropyl, or CF3, and R 6 ' is CF3, CI, or F, provided that when is methyl, (1) R ' is CF3, or (2) R3' is F, or (3) R6' is CF3 and R3' is F, or (4) IV is F or CI and is a 6-membered heterocycloalkyl having only one nitrogen and is substituted with two methyl groups.
  • the compounds of Formulae (I"), (Fa), (I"b), (I"c), (IIA) and (IIB) can include one or more of the following features when applicable:
  • X, ' is CRu' and 3 ⁇ 4' is CR
  • X, ' is CR, , ' and X 2 ' is N.
  • X, ' is N and X 2 ' is CR 1 3 ⁇
  • X, ' is N and X 2 ' is N.
  • X 3 is C.
  • Z 2 is Rv'Rs'-
  • Z 2 is CR 7 'R 8 'Ri4'.
  • Z 2 is OR 7 ' .
  • Z 2 is S(0) a .R 7 ⁇ in which a' is 0, 1, or 2
  • R 6 ' is H.
  • Re'is halo e.g., fluorine, chlorine, bromine, and iodine.
  • Re' is C r C 3 alkyl optionally substituted with one or more -Qj'-TY.
  • Re' is CF 3 .
  • R 6 ' is C 2 -C 6 alkenyl, C 2 -C6 alkynyl, or C 3 -C 6 cycloalkyl each optionally substituted with one or more -(3 ⁇ 4'-3 ⁇ 4'.
  • R 6 ' is ethenyl
  • R(,' is ethynyl.
  • C]-C 3 alkyl linker and T 2 ' is C r C6 alkyl, C 3 -C 6 cycloalkyl, or 4 to 7-membered heterocycloalkyl
  • 3 ⁇ 4' is cyano
  • 3 ⁇ 4' is azido.
  • 3 ⁇ 4' is C(0)H.
  • R 6 ' is ORa' or -C(0)R a '.
  • R a ' is C ⁇ -C6 alkyl or 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H- pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-£hiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa- 5-
  • 3 ⁇ 4' is 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6- dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, and morpholinyl, and the like
  • I is piperidinyl, 2,2,6,6-tetramethyl-piperidinyl, 1,2,3,6-tetrahydropyridinyl, 2,2,6,6-tetramethyl-l,2,3,6-tetrahydropyridinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, or pyrrolidinyl, each of which is optionally substituted with one or more - Q-'-TY.
  • Re' is 4 to 7-membered heterocycloalkyl optionally substituted with one or more -Q 2 '-T 2 ', and -Q 2 '-T 2 ' is oxo or Q 2 ' is a bond and ⁇ is -OR,;', -NRc'Rj', -C(0)R c ', - C(0)ORc', -S(0) 2 Rc', C ⁇ -Q alkyl, or 4 to 7-membered heterocycloalkyl, each of which is optionally substituted with one or mor when Rc' or Rd' is not H.
  • R 6 ' is -C(0)Ra', -C(0)ORa', -NR b 'C(0)Ra', -SR*', -
  • each of Ra' and R b ' independently is H, Ci-C 6 alkyl, or C3-C8 cycloalkyl optionally substituted with one or more -Q 2 '-T 2 '.
  • one of R a ' and Rb' is H.
  • -Q 2 '-T 2 ' is oxo.
  • Q 2 ' is a bond.
  • Q 2 ' is an unsubstituted C1 -C3 alkyl linker.
  • T 2 ' is C C alkyl or C 6 -Cio aryl, each optionally substituted with one or more -Q 3 '-T 3 '.
  • T ' is an unsubstituted substituted straight chain Q-Q or branched alkyl, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl.
  • halo e.g., fluorine, chlorine, bromine, and iodine.
  • T 2 ' is 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6- dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1 ,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, and morpholinyl, and
  • T 2 ' is (0 -0(0)0 ⁇ ', or (0
  • Ci-Q alkyl or 4 to 7-membered heterocycloalkyl e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H- pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1 ,4-oxazepanyl, 2-oxa- 5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, and morpholin
  • each of and independently is H or C ⁇ -C 6 alkyl optionally substituted with one or more - ⁇ 3 ⁇ 4'- ⁇ 3 '
  • a 4 to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatoms to the N atom e.g., azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2. l]heptanyl, 2,5-diazabicyclo[2.2. l]heptanyl, and morpholinyl, and the like) and the ring is optionally substituted with one or more -Q
  • Q 2 ' is a bond and T 2 ' is -C(0 -C(0 -S(0 C,- alkyl, or 4 to 7-membered heterocycloalkyl, each of which is optionally substituted with one or more when or is not H.
  • T2' is 4 to 7-membered heterocycloalkyl or C3-C8 cycloalkyl and one or more - '-Ts' are oxo.
  • Q 3 ' is a bond or unsubstituted or substituted Q-C3 alkyl linker.
  • T 3 ' is H, halo, 4 to 7-membered heterocycloalkyl, C1-C3 alkyl, OR*', COOR,.',-
  • one of Rd' and 3 ⁇ 4' is H.
  • (3 ⁇ 4' is a bond or C1-C3 alkyl linker and T3' is selected from the group consisting of C C 3 alkyl, halo, ⁇ 3 ⁇ 4', -NRe'Rf', and-C(0)NRe'Rf' .
  • Q 3 ' is a bond or C1-C3 alkyl linker and T3' is selected from the group consisting of C,-C 3 alkyl, O , -S(0) 2 R c ', or -NRe'Rf'.
  • Re' is H.
  • Rf' is H.
  • R 7 ' is -C(0)R g '.
  • R 7 ' is -C(0)R g ', in which R g ' is C 3 -C 3 cycloalkyl, 4 to 7-membered heterocycloalkyl, C3-C8 cycloalkyl.
  • R7' is C 6 -C
  • R 7 ' is phenyl optionally substituted with one or more -Qs'-Ts'.
  • R7' is C ⁇ -C 6 alkyl optionally substituted with one or more -Q 5 '-T 5 '.
  • R7' is C3-C8 cycloalkyl optionally substituted with one or more
  • heterocycloalkyl e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6- dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1 ,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2, -diazabicyclo[2.2.1]heptanyl, and morpholinyl, and the like) optional
  • pyrrolidinyl is pyrrolidinyl, piperidinyl, tetrahydropyran, cyclopentyl, or cyclohexyl, cycloheptyl, each optionally substituted with one -Qs'-Ts'.
  • R7' is cyclopentyl or cyclohexyl, each optionally substituted with one -Q 5 '- T 5 ' .
  • R7' is tetrahydropyran
  • Q 5 ' is NHC(O) and T 5 ' is C
  • -Q 5 '-T 5 ' is oxo.
  • R7' is l-oxide-tetrahydro-2H-thiopyranyl or 1 , 1 -dioxide-tetrahydro-2H- thiopyranyl.
  • R7' is cyclohexanonyl, e.g., cyclohexanon-4-yl.
  • T 5 ' is H, halo, C,-C 6 alkyl, C r C 6 alkoxyl, C 3 -C 8 cycloalkyl, Ce-Cio aryl, or 4 to 7-membered heterocycloalkyl.
  • (3 ⁇ 4' is a bond and is Ci-Ci alkyl, cycloalkyl, or 4 to 7-membered heterocycloalkyl.
  • Q 5 ' is a bond and T5' is 5- or 6-membered heteroaryl, amino, mono-Ci-C6 alkylamino, di- -Ce alkylamino, T5' being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy!, C
  • ⁇ 1 ⁇ 4' is CO, S(0) 2 , or NHC(O); and T s ' is C Q alkyl, C,-C 6 alkoxyl, C 3 -C 8 cycloalkyl, or 4 to 7-membered heterocycloalkyl.
  • Ts' is Ci-Ce alkyl or Ci-C 6 alkoxyl, each optionally substituted with halo, hydroxyl, cyano, C ⁇ -C alkoxyl, amino, mono-Ci-Ci alkylamino, di-C]-C6 alkylamino, or C3-C8 cycloalkyl.
  • Q 5 ' is C1-C3 alkyl linker and T 5 ' is H or C 6 -Cio aryl.
  • Qj' is C1-C3 alkyl linker and T5' is C3-C8 cycloalkyl, 4 to 7-membered heterocycloalkyl, or S(0) q' R q ⁇
  • IV is halo (e.g., fluorine, chlorine, bromine, and iodine) and Z 2 is in which a' is 0, 1, or 2 and R7' is Q-C6 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, butyl, or t-butyl), C 3 -Cs cycloalkyl (e.g., cyclopentyl, cyclohexyl, or cycloheptyl) or 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,
  • Ri' is halo (e.g., fluorine, chlorine, bromine, and iodine) and Z 2 is ORy'.in which R7' is 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyI, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H- pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1 ,4-oxazepanyl, 2-oxa- 5
  • R7' is 4
  • Ri 1 ' is H.
  • each of R2' and R4' is H or Ci-Ct alkyl optionally substituted with azido, halo, amino, mono-Q-Ca alkylamino, di-Ci-C1 ⁇ 4 alkylamino, or C -C o aryl.
  • each of R2' and R4' independently is C1-C3 alkyl optionally substituted with C1-C6 alkoxyl.
  • each of R2' and R4' is methyl.
  • Ri' is H.
  • Ri' is Q-Q alkyl optionally substituted with azido, halo, amino, mono-Cj-Cs alkylamino, di-Ci-Ci alkylamino, or Ce-Cio aryl.
  • R12' is H, methyl, ethyl, ethenyl, or halo.
  • R ⁇ ' is methyl
  • R ⁇ ' is ethyl
  • R12' is ethenyl or propenyl.
  • R12' is methoxyl
  • Rg' is H, methyl, ethyl, or ethenyl.
  • R 8 ' is methyl
  • Rg' is ethyl
  • R 8 ' is propyl
  • R is ethenyl or propenyl.
  • Rs' is Ci-C alkyl substituted with one or more substituents selected from the group consisting of halo (e.g., F, CI, or Br), hydroxyl, or Cj-Cs alkoxyl.
  • halo e.g., F, CI, or Br
  • Rs' is 4 to 7-membered optionally substituted heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyI, 1,4-diazepanyl, 1,4- oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, and morpholinyl,
  • Rg' is piperidinyl
  • Rs' is 4 to 7-membered optionally substituted heterocycloalkyl and R7' is - Q 4 ' -T4', in which Q 4 ' is a bond or C r C alkyl linker and T 4 ' is H, C,-C 3 alkyl, C 3 -C 8 cycloalkyl or 4 to 7-membered heterocycloalkyl.
  • 2 is NR 7 'Rs' or CRy'Rg' w' wherein R7' and Rs', together with the atom to which they are attached, form a 4 to 11-membered heterocycloalkyl ring having 1 to 3 heteroatoms (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1,4- oxazepany
  • the ring formed by R 7 ' and Rs' is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and cyclohexenyl, each optionally substituted with one -Qe'-TV .
  • -Qe'-TV is oxo.
  • T 6 ' is H, halo, C,-C 6 alkyl, d-Q, alkoxyl, C 3 -C 8 cycloalkyl, C 6 -Ci 0 aryl, or 4 to 7-membered heterocycloalkyl.
  • (3 ⁇ 4' is a bond and is C
  • Q 6 ' is CO, S(0) 2 , or NHC(O); and T 6 ' is Ci-C 6 alkyl, Ci-C 6 alkoxyl, C 3 -Cg cycloalkyl, or 4 to 7-membered heterocycloalkyl.
  • ⁇ ' is C] -C6 alkyl or C
  • Q 6 ' is C1-C3 alkyl linker and TV is H orC ⁇ -Cio aryl.
  • Qjs' is C1-C3 alkyl linker and Te' is C3-Q cycloalkyl, 4 to 7-membered heterocycloalkyl, or S(0) p' R p '.
  • each of R p ' and q' is C1 -C6 alkyl.
  • R ⁇ ' is -S(0) b .Ra' or azido, in which b' is 0, 1, or 2 and R a ' is C ⁇ -C alkyl or C 3 - Cs cycloalkyl; and Z 2 is ⁇ 3 ⁇ 43 ⁇ 4', in which R 7 ' is C 3 -Cg cycloalkyl (e.g., cyclopentyl, cyclohexyl, or cycloheptyl) or 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, terrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, pipe
  • R(,'is halo (e.g., fluorine, chlorine, bromine, and iodine) and 3 ⁇ 4 is N v'Rs' or CR7'Rg' i 4 ' wherein R7' and Rg', together with the atom to which they are attached, form a 4 to 1 1- membered heterocycloalkyl ring having 1 to 3 heteroatoms (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6- dihydro-2H-pyranyl, t
  • R13' is H or methyl.
  • Rn' is H.
  • R 3 ' is H.
  • 0 ' is H.
  • the compounds of Formula (IIA) can include one or more of the following features:
  • (3 ⁇ 4' is a bond and T 5 ' is H, Ci-Ce alkyl, C3-C8 cycloalkyl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, amino, mono-Ci-C6 alkylamino, or di-Ci-Ce alkylamino, T5' being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, C1-C6 alkoxyl, or C3-C8 cycloalkyl.
  • Q 5 ' is CO, S(0) 2 , or NHC(O); and T 5 ' is Ci-C 6 alkyl, d-C 6 alkoxyl, C 3 -C 8 cycloalkyl, or 4 to 12-membered heterocycloalkyl.
  • Q 5 ' is C1-C3 alkyl linker and T 5 ' is H or Q-C10 aryl.
  • Q 5 ' is C1-C3 alkyl linker and T5' is C3-C8 cycloalkyl, 4 to 12-membered heterocycloalkyl, or S(0) q R q .
  • Q 5 ' is NHC(O) and T 5 ' is C,-C 6 alkyl or C,-C 6 alkoxy.
  • one or more -Qj'-Ts' are oxo.
  • U is CH-Q 5 '-T 5 ' and n is 0
  • one or more - ⁇ '- ⁇ ⁇ ' are oxo.
  • (3 ⁇ 4' is a bond or C(O) and T 6 ' is alkyl or Q-C6 alkoxy.
  • Representative compounds of the present invention include compounds listed in Tables 1A and IB.
  • alkyl As used herein, "alkyl”, "Ci, C 2 , C 3 , C 4 , C 5 or C 6 alkyl” or “Ci-C 6 alkyl” is intended to include Cj, C 2 , C 3 , C4, C5 or C6 straight chain (linear) saturated aliphatic hydrocarbon groups and C 3 , C4, C 5 or C(, branched saturated aliphatic hydrocarbon groups.
  • C -C6 alkyl is intended to include Ci, C2, C3, C4, C5 and Cg alkyl groups.
  • alkyl examples include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl or n-hexyl.
  • a straight chain or branched alkyl has six or fewer carbon atoms (e.g., for straight chain, for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.
  • cycloalkyl refers to a saturated or unsaturated nonaromatic hydrocarbon mono-or multi-ring (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C 1 0).
  • cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantyl.
  • heterocycloalkyl refers to a saturated or unsaturated nonaromatic 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, or Se), unless specified otherwise.
  • heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, oxiranyl, azetidinyl, oxeranyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, 1 ,4-diazepanyl, 1 ,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5- diazabicyclo[2.2.1]heptanyl,
  • optionally substituted alkyl refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
  • arylalkyl or an “aralkyl” moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
  • alkylaryl moiety is an aryl substituted with an alkyl (e.g., methylphenyl).
  • alkyl linker is intended to include Cr, C2, C 3 , C 4 , C5 or C 6 straight chain (linear) saturated divalent aliphatic hydrocarbon groups and C 3 , C 4 , C5 or (, branched saturated aliphatic hydrocarbon groups.
  • C ⁇ -C(, alkyl linker is intended to include Ci, C2, C3, C4, C5 and C3 ⁇ 4 alkyl linker groups.
  • alkyl linker examples include, moieties having from one to six carbon atoms, such as, but not limited to, methyl (-CH2-), ethyl (-CH2CH2-), n-propyl (- CH 2 CH 2 CH 2 -), i-propyl (-CHCH3CH2-), n-butyl (-C3 ⁇ 4CH 2 CH 2 CH 2 -), s-butyl (-CHCH 3 CH 2 C3 ⁇ 4-), i-butyl (-C(CH 3 ) 2 CH2-), n-pentyl (-CH 2 CH 2 CH2CH 2 CH 2 -), s-pentyl (-CHCH 3 CH2CH 2 CH2-) or n- hexyl (-CH 2 CH2CH 2 CH 2 CH 2 CH 2 -).
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • alkenyl includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups.
  • a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C 2 - 3 ⁇ 4 for straight chain, C for branched chain).
  • C includes alkenyl groups containing two to six carbon atoms.
  • -C 6 includes alkenyl groups containing three to six carbon atoms.
  • alkenyl refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino,
  • alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • alkynyl includes straight chain alkynyl groups (e.g. , ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups.
  • a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g.
  • C2-C6 includes alkynyl groups containing two to six carbon atoms.
  • C ⁇ -C includes alkynyl groups containing three to six carbon atoms.
  • alkynyl refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonyla
  • optionally substituted moieties include both the unsubstituted moieties and the moieties having one or more of the designated substituents.
  • substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6- tetramethyl-l,2,3,6-tetrahydropyridinyl.
  • Aryl includes groups with aromaticity, including “conjugated,” or multicyclic systems with at least one aromatic ring and do not contain any heteroatom in the ring structure. Examples include phenyl, benzyl, 1,2,3,4-tetrahydronaphthalenyl, etc.
  • Heteroaryl groups are aryl groups, as defined above, except having from one to four heteroatoms in the ring structure, and may also be referred to as “aryl heterocycles" or
  • heteroaryl is intended to include a stable 5-, 6-, or 7- membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1- 6 heteroatoms, or e.g. , 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur.
  • the nitrogen atom may be substituted or unsubstituted (i.e. , N or NR wherein R is H or other substituents, as defined).
  • heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.
  • aryl and heteroaryl include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.
  • multicyclic aryl and heteroaryl groups e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran,
  • the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino
  • Carbocycle or “carbocyclic ring” is intended to include any stable monocyclic, bicyclic or tricyclic ring having the specified number of carbons, any of which may be saturated, unsaturated, or aromatic.
  • Carbocycle includes cycloalkyl and aryl.
  • a carbocycle is intended to include a monocyclic, bicyclic or tricyclic ring having 3, 4, 5 , 6, 7, 8, 9, 10, 1 1, 12, 13 or 14 carbon atoms.
  • carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl, indanyl, adamantyl and tetrahydronaphthyl.
  • Bridged rings are also included in the definition of caxbocycle, including, for example, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane and [2.2.2]bicyclooctane.
  • a bridged ring occurs when one or more carbon atoms link two non- adjacent carbon atoms.
  • bridge rings are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge. Fused (e.g., naphthyl, tetrahydronaphthyl) and spiro rings are also included.
  • heterocycle or “heterocyclic group” includes any ring structure (saturated, unsaturated, or aromatic) which contains at least one ring heteroatom (e.g., N, O or S).
  • Heterocycle includes heterocycloalkyl and heteroaryl. Examples of heterocycles include, but are not limited to, morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazine, oxetane, pyran, tetrahydropyran, azetidine, and tetrahydrofuran.
  • heterocyclic groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4ai/-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2/i,6ii-l,5,2-dithiazinyl, dihydrofuro[2,3-3 ⁇ 4]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, li
  • substituted means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogen atoms on the atom are replaced.
  • Keto substituents are not present on aromatic moieties.
  • “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • hydroxy or "hydroxyl” includes groups with an -OH or -O " .
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • halogenated generally refers to a moiety wherein all hydrogen atoms are replaced by halogen atoms.
  • haloalkyl or haloalkoxyl refers to an alkyl or alkoxyl substituted with one or more halogen atoms.
  • carbonyl includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom.
  • moieties containing a carbonyl include, but are not limited to, aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.
  • carboxyl refers to -COOH or its Ci-Q alkyl ester.
  • Acyl includes moieties that contain the acyl radical (R-C(O)-) or a carbonyl group.
  • substituted acyl includes acyl groups where one or more of the hydrogen atoms are replaced by, for example, alkyl groups, alkynyl groups, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylammo, dialkylammo, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, aryl
  • Alkoxyalkyl “alkylaminoalkyl,” and “thioalkoxyalkyl” include alkyl groups, as described above, wherein oxygen, nitrogen, or sulfur atoms replace one or more hydrocarbon backbone carbon atoms.
  • alkoxy or "alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom.
  • alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups.
  • substituted alkoxy groups include halogenated alkoxy groups.
  • the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, s
  • ether or "alkoxy” includes compounds or moieties which contain an oxygen bonded to two carbon atoms or heteroatoms.
  • alkoxyalkyl refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to an alkyl group.
  • esters includes compounds or moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group.
  • ester includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.
  • thioalkyl includes compounds or moieties which contain an alkyl group connected with a sulfur atom.
  • the thioalkyl groups can be substituted with groups such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfonine,
  • thiocarbonyl or "thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
  • thioether includes moieties which contain a sulfur atom bonded to two carbon atoms or heteroatoms.
  • examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls.
  • alkthioalkyls include moieties with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group.
  • alkthioalkenyls refers to moieties wherein an alkyl, alkenyl or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkenyl group
  • alkthioalkynyls refers to moieties wherein an alkyl, alkenyl or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.
  • amine or “amino” refers to unsubstituted or substituted -N3 ⁇ 4-
  • Alkylamino includes groups of compounds wherein nitrogen of -N3 ⁇ 4 is bound to at least one alkyl group. Examples of alkylamino groups include benzylamino, methylamino, ethylamino, phenethylamino, etc.
  • Dialkylamino includes groups wherein the nitrogen of -N3 ⁇ 4 is bound to at least two additional alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino and diethylamino.
  • Arylamino and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively.
  • Aminoaryl and “aminoaryloxy” refer to aryl and aryloxy substituted with amino.
  • Alkylarylamino alkylaminoaryl or “arylaminoalkyl” refers to an amino group which is bound to at least one alkyl group and at least one aryl group.
  • Alkaminoalkyl refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group.
  • acylamino includes groups wherein nitrogen is bound to an acyl group.
  • examples of acylamino include, but are not limited to, alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
  • amide or “aminocarboxy” includes compounds or moieties that contain a nitrogen atom that is bound to the carbon of a carbonyl or a thiocarbonyl group.
  • alkaminocarboxy groups that include alkyl, alkenyl or alkynyl groups bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group. It also includes
  • arylaminocarboxy groups that include aryl or heteroaryl moieties bound to an amino group that is bound to the carbon of a carbonyl or thiocarbonyl group.
  • alkylaminocarboxy alkenylaminocarboxy
  • alkynylaminocarboxy and arylaminocarboxy
  • Amides can be substituted with substituents such as straight chain alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl or heterocycle. Substituents on amide groups may be further substituted.
  • N-oxides can be converted to N-oxides by treatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid (mCPBA) and/or hydrogen peroxides) to afford other compounds of the present invention.
  • an oxidizing agent e.g., 3-chloroperoxybenzoic acid (mCPBA) and/or hydrogen peroxides
  • mCPBA 3-chloroperoxybenzoic acid
  • hydrogen peroxides hydrogen peroxides
  • all shown and claimed nitrogen-containing compounds are considered, when allowed by valency and structure, to include both the compound as shown and its N-oxide derivative (which can be designated as N-»0 or TNT-O " ).
  • the nitrogens in the compounds of the present invention can be converted to N-hydroxy or N-alkoxy compounds.
  • N-hydroxy compounds can be prepared by oxidation of the parent amine by an oxidizing agent such as ⁇ -CPBA.
  • nitrogen-containing compounds are also considered, when allowed by valency and structure, to cover both the compound as shown and its N-hydroxy (i.e., N-OH) and N-alkoxy (i.e., N-OR, wherein R is substituted or unsubstituted Ci-C 6 alkyl, Cj-Cs alkenyl, Ci-C6 alkynyl, 3-14-membered carbocycle or 3-14-membered heterocycle) derivatives.
  • N-OH N-hydroxy
  • N-alkoxy i.e., N-OR, wherein R is substituted or unsubstituted Ci-C 6 alkyl, Cj-Cs alkenyl, Ci-C6 alkynyl, 3-14-membered carbocycle or 3-14-membered heterocycle
  • the structural formula of the compound represents a certain isomer for convenience in some cases, but the present invention may include all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, enantiomers, rotamers, diastereomers, racemates and the like, it being understood that not all isomers may have the same level of activity.
  • a crystal polymorphism may be present for the compounds represented by the formula. It is noted that any crystal form, crystal form mixture, or anhydride or hydrate thereof is included in the scope of the present invention.
  • Racemic mixture means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non- superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture.”
  • Chiral isomer means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed "diastereomeric mixture.” When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.
  • Gaometric isomer means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cylcobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold- Prelog rules.
  • atropic isomers are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.
  • Tautomer is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism.
  • keto-enol equilibria is between pyridin-2( 1H)- ones and the corresponding pyridin-2-ols, as shown below.
  • crystal polymorphs means crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by crystallization under different conditions.
  • the compounds of this invention include the compounds themselves, such as any of the formulae disclosed herein.
  • the compounds of this invention may also include their salts, and their solvates, if applicable.
  • a salt for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted benzene compound.
  • Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).
  • pharmaceutically acceptable anion refers to an anion suitable for forming a pharmaceutically acceptable salt.
  • a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted benzene compound.
  • Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion.
  • the substituted benzene compounds also include those salts containing quaternary nitrogen atoms.
  • the compounds of the present invention can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
  • hydrates include monohydrates, dihydrates, etc.
  • solvates include ethanol solvates, acetone solvates, etc.
  • Solvate means solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as 3 ⁇ 40.
  • analog refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group).
  • an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.
  • derivative refers to compounds that have a common core structure, and are substituted with various groups as described herein.
  • all of the compounds represented by Formula (F) are substituted benzene compounds, and have a common core.
  • bioisostere refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms.
  • the objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound.
  • the bioisosteric replacement may be physicochemically or topologically based.
  • Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonimides, tetrazoles, sulfonates and phosphorates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.
  • the present invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium
  • isotopes of carbon include C-13 and C-14.
  • the present invention provides methods for the synthesis of the compounds of any Formula disclosed herein.
  • the present invention also provides detailed methods for the synthesis of various disclosed compounds of the present invention according to the following schemes as shown in the Examples.
  • compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
  • the synthetic processes of the invention can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used.
  • the processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • Preferred protecting groups include, but are not limited to:
  • aldehydes di-alkyl acetals such as dimethoxy acetal or diethyl acetyl.
  • LiHMDs Lithium hexamethyldisilazide
  • Scheme B depicts a route of synthesizmg various benzoic acid methyl ester intermediates:
  • Scheme C depicts a route of synthesizing various tetrahydropyran moieties:
  • Scheme D depicts a route of synthesizing various Dimethylaminocyclohexyl analogs:
  • Scheme 1 shows the synthesis of modified aryl analogs following a general route that utilizes well-established chemistry.
  • Scheme 1 shows the synthesis of modified aryl analogs following a general route that utilizes well-established chemistry.
  • Substituted nitrobenzoic acids many of which are commercially available or can be made by nitration of the appropriate substituted benzoic acids or other chemistry known to one skilled in the art, can be converted to their methyl esters by treatment with methyliodide in a polar solvent, such as DMF, in the presence of an appropriate base, such as sodium carbonate, at an appropriate temperature, such as 60 °C (Step 1).
  • the nitro group can be reduced to an amine using an appropriate reducing agent, such as iron, in the presence of an acid, such as ammonium chloride, in a protic solvent, such as ethanol, at an appropriate temperature, such as 80 °C (Step 2).
  • an appropriate reducing agent such as iron
  • an acid such as ammonium chloride
  • a protic solvent such as ethanol
  • an appropriate temperature such as 80 °C
  • Introduction of the Rg can be done using a reductive amination with an appropriate ketone or aldehyde in the presence of an appropriate reducing agent, such as sodium cyanoborohydride, and catalytic acid, such as acetic acid, in an appropriate solvent, such as methanol.
  • R 7 groups can be introduced by alkylation using R7-LG, where LG is a leaving group, such as iodine, in the presence of a mild base, such as cesium carbonate, in an appropriate polar solvent, such as acetonitrile, at an appropriate temperature, such as 80 °C (Step 4).
  • R7 groups can be introduced by reductive amination with R 7 -ketone or R 7 -aldehyde in the presence of an appropriate reducing agent, such as sodium cyanoborohydride, and catalytic acid, such as acetic acid, in an appropriate solvent, such as methanol.
  • the ester moiety can be converted to an amide using a standard two step protocol.
  • the ester can be hydrolyzed to the corresponding acid using a suitable base, such as sodium hydroxide, in a polar solvent, such as ethanol (Step 5).
  • a suitable base such as sodium hydroxide
  • a polar solvent such as ethanol
  • the acid would then be subjecting to a standard amide coupling reaction whereupon the appropriate amine would be added along with a suitable amide coupling reagent such as PYBOP in a suitable solvent such as DMSO to give the desired amide (Step 6).
  • R 6 is a bromide
  • alternative R substituents could then be introduced using standard transition metal-based protocols that rely upon a leaving group such as a bromide as a connection point.
  • the bromide would be combined with an appropriate boronic ester derivative, in the presence of a mild base and a palladium catalyst in a polar solvent such as dioxane/water, at elevated temperature to give the desired new R 6 substituent (i.e. Suzuki reaction).
  • a mild base and a palladium catalyst in a polar solvent such as dioxane/water
  • a polar solvent such as dioxane/water
  • R 7 substituent may be subjected to deprotection reaction (e.g. Boc group cleavage) to give free amino groups.
  • deprotection reaction e.g. Boc group cleavage
  • free amino groups maybe subjected to reductive amination reactions or alkylation reactions to give substituted amines.
  • Scheme 4 shows the general synthesis of 2,6-disubstituted isonicotinamide compounds.
  • Suzuki reaction in Step 1 of an aryl boronic acid compound with methyl 2,6-dichloroisonicoa ' nate starting material can be used to introduce an aryl group which may be substituted with a functional group X that is suitable for further transformation.
  • X groups include formyl or hydroxymethyl which can readily be transformed in Step 2 to various groups Y.
  • Ester hydrolysis a subsequent step gives an acid intermediate which can be coupled with appropriate 3-(aminomethyl)-pyridin-2(lH)-ones to give the penultimate 2-chloro-6-aryl-isonicotine amide intermediate.
  • Suzuki reaction or amination reaction then gives compounds substituted in the 2-position with a Z group.
  • Z can be monoalkylamino or dialkylamino.
  • Z can be aryl, dihydroaryl or tetrahydroaryl such as cyclohexenyl.
  • Scheme 5 shows the general synthesis of 6-aryl-3-methyl-picolinamides having monoalkylamino or dialkylamino groups in the 4-position.
  • the 4-chloro group can be selectively substituted with diverse mono and dialkyl amines which may also contain functional or protected functional groups that may be unmasked at a later stage.
  • a diketone can be condensed with 2-cyanoacetamide in the presence of an appropriate reagent such as piperidine acetate in a polar solvent such as ethanol to provide a cyanopyridone (Step 9).
  • an appropriately substituted alkynyl ketone can be condensed with 2-cyanoacetamide in the presence of an appropriate reagent such as piperidine acetate in a polar solvent such as ethanol to provide a cyanopyridone (Step 11).
  • the cyano group can be reduced under appropriate conditions such as hydrogenation in the presence of catalytic Raney nickel in a polar solvent such as ammonium in methanol to provide the amine (Step 10).
  • Scheme 4 depicts a variant of the general synthesis route of Scheme 1 based on 2-substituted (substituent is an R12 group) methyl 3-amino- 5 -bromo-benzoate starting materials.
  • These starting materials can in turn be prepared from 2-substituted 3-nitro-benzoic acids which are commercially available or can be prepared by nitration of 2-substituted benzoic acids.
  • a suitable reagent such as l,3-dibromo- 5 ,5-dimethyl-2,4- imidazolidinedione yields the appropriate 2-substituted 3-nitro- 5 -bromo-benzoic acids.
  • the R7 group can be introduced from 2-substituted methyl 3-amino- 5-bromo-benzoates in Step 1 using a reductive amination with an appropriate R7-ketone or R7- aldehyde in the presence of an appropriate reducing agent such as sodium cyanoborohydride and catalytic acid such as acetic acid in an appropriate solvent such as methanol.
  • an appropriate reducing agent such as sodium cyanoborohydride and catalytic acid
  • 3 ⁇ 4 groups can be introduced in Step 2 by reductive amination with Rs-ketone or Rg-aldehyde in the presence of an appropriate reducing agent such as sodium cyanoborohydride and catalytic acid such as acetic acid in an appropriate solvent such as methanol.
  • a variety of Rs groups can be introduced by alkylation using Rj-LG, where LG is a leaving group such as iodine, in the presence of a mild base such as cesium carbonate in an appropriate polar solvent such as acetonitrile at an appropriate temperature such as 80 °C.
  • aryl groups corresponding to 3 ⁇ 4 can be introduced by Suzuki reaction of the intermediate bromide with an appropriate aryl boronic acid or ester derivative, e,g, X-Ar-B(OH)2, in the presence of a mild base and a palladium catalyst in a polar solvent such as dioxane/ water, at elevated temperature.
  • the X group in X-Ar-B(OH)2 may be a fully elaborated substituent on the aryl ring or may be a functional group that can be converted into another group by functional group modification.
  • a representative sampling of such modifications could include hydrogenation, protecting group removal followed by additional amide coupling reactions, palladium catalyzed coupling reactions, reductive amination reactions or alkylation reactions.
  • the Suzuki reaction is conducted with a boronic acid derivative bearing a formyl group further modification by reductive amination reaction with primary and secondary amines (e.g. morpholine, dimethylamine) can be conducted to introduce amine groups.
  • the ester moiety can be hydrolyzed to the corresponding acid using a suitable base such as sodium hydroxide in a polar solvent such as ethanol.
  • the acid can be subjected to a standard amide coupling reaction whereupon the appropriate amine would be added along with a suitable amide coupling reagent such as PYBOP in a suitable solvent such as DMSO to give the desired amide.
  • a suitable amide coupling reagent such as PYBOP in a suitable solvent such as DMSO
  • further chemical modification subsequent to Step 5 of Scheme 4 could be employed to convert the R 7 substituent into an alternative R7 substituent.
  • a protected amino group contained within R7 may be subjected to deprotection reaction (e.g. Boc group cleavage) to give free amino groups.
  • deprotection reaction e.g. Boc group cleavage
  • free amino groups may be subjected to reductive animation reactions or alkylation reactions to give substituted amines.
  • Scheme 8 depicts the general synthesis of 2-monoalkylamino and 2-dialkylmino-3- substituted-6-aryl-isonicotinamides wherein the 3-substituent corresponds to and the 6-aryl group corresponds to R ⁇ , Formula ⁇
  • the 3-substituent may be introduced by the method described by Epsztain J. et al. Tetrahedron, 1991, v. 47, 1697-16708, by metallation of 2-chloro- isonicotinanilide with n-butyllithium followed by trapping with an an alkyliodide such as methyliodide or aldehyde or other electrophilic group.
  • Step 2 anilide amide hydrolysis under standard acidic conditions maybe conducted followed by methyl ester synthesis under standard conditions for example as shown with methyl iodide and base gives corresponding methyl 2-chloro-3-substituted isonicotinates.
  • Step 4 an alkylamino group can be introduced by Buchwald coupling reaction of an R 7 NH7 monoalkylamine with the methyl 2-chloro-3-substituted isonicotinates. This reaction is well precedented for diverse 2- chloropyridine systems in the chemical literature.
  • R.8 groups can be introduced by reductive amination with Rg-ketone or Rs-aldehyde in the presence of an appropriate reducing agent such as sodium cyanoborohydride and catalytic acid such as acetic acid in an appropriate solvent such as methanol.
  • an appropriate reducing agent such as sodium cyanoborohydride and catalytic acid such as acetic acid in an appropriate solvent such as methanol.
  • a variety of s groups can be introduced by alkylation using Rs-LG, where LG is a leaving group such as iodine, in the presence of a mild base such as cesium carbonate in an appropriate polar solvent such as acetonitrile at an appropriate temperature such as 80 °C.
  • Step 6 oxidation to the N-oxide followed by chlorination with phosphorus oxychloride gives methyl 6-chloro-2-mono or dialkylamino-3-substituted isonicotinates.
  • Step 7 the ester moiety can be hydrolyzed to the corresponding acid using a suitable base such as sodium hydroxide in a polar solvent such as ethanol.
  • Step 8 the acid can be subjected to a standard amide coupling reaction whereupon the appropriate amine or substituted 3- (aminomethyl)-pyridin-2(lH)-one would be added along with a suitable amide coupling reagent such as PYBOP in a suitable solvent such as DMSO to give the desired amide.
  • a suitable amide coupling reagent such as PYBOP in a suitable solvent such as DMSO
  • aryl groups corresponding to R3 ⁇ 4 can be introduced by Suzuki reaction of the intermediate bromide with an appropriate aryl boronic acid or ester derivative, e,g, X-Ar-B(OH) 2 , in the presence of a mild base and a palladium catalyst in a polar solvent such as dioxane/water, at elevated temperature.
  • the X group in X-Ar-B(OH) 2 may be a fully elaborated substituent on the aryl ring or may be a functional group that can be converted into another group by functional group modification.
  • a representative sampling of such modifications could include hydrogenation, protecting group removal followed by additional amide coupling reactions, palladium catalyzed coupling reactions, reductive amination reactions or alkylation reactions.
  • the Suzuki reaction is conducted with a boronic acid derivative bearing a formyl group further modification by reductive amination reaction with primary and secondary amines (e.g. morpholine, dimethylamine) can be conducted to introduce amine groups.
  • R 7 substituent Depending upon the nature of the R 7 substituent, further chemical modification steps may be employed to convert the R 7 substituent into an alternative R 7 substituent.
  • a protected amino group contained within R 7 may be subjected to deprotection reaction (e.g. Boc group cleavage) to give free amino groups.
  • deprotection reaction e.g. Boc group cleavage
  • free amino groups may be subjected to reductive amination reactions or alkylation reactions to give substituted amines.
  • Scheme 9 depicts a synthesis of modified aryl analogs following a general route that utilizes well-established chemistry.
  • a substituted benzoic acid such as 5 -chloro-2- methylbenzoic acid
  • nitration using standard conditions such as treatment with cone. H2SO 4 and cone.
  • HNO 3 can provide the nitro analog.
  • Esterification of the acid can be achieved using an alkylating agent such as methyl iodide in the presence of a base such as sodium carbonate in a polar solvent such as DMF.
  • the nitro group can be reduced using conditions such iron and ammonium chloride in a protic solvent such as ethanol with heating to a temperature such as 80 °C.
  • the resulting aniline can be converted to a bromide using a Sandmeyer reaction such treatment with CuB3 ⁇ 4 and t-butyl nitrite in a solvent such as acetonitrile.
  • a palladium catalyzed coupling of a thiol with the bromide can be achieved using a palladium source such as Pd(OAc) 2 with a ligand such as Xanthphos in the presence of a base such as ⁇ , ⁇ -diisopropyl ethylamine in a solvent such as 1,4- dioxane optionally heating to a temperature such as 100 °C.
  • the ester can be hydrolyzed with an aqueous base such as NaOH in water.
  • the resulting acid can be coupled to the 3-(amino methyl)- 4 , 6-dimethylpyridin-2(lH)-one using standard amino acid coupling conditions such as PYBOP in DMSO.
  • the resulting thioether may be oxidized to the corresponding sulfoxide or sulfone by using the appropriate equivalents of an oxidant such as m-CPBA in a solvent such as DCM.
  • Aryl substituents can be incorporated by using palladium couplings such as a Suzuki reaction as described above.
  • Scheme 10 depicts a synthesis of modified aryl analogs following a general route that utilizes well-established chemistry.
  • a substituted aniline such as methyl 3-amino-S- chloro-2-methylbenzoate
  • the aniline can be converted to a phenol using a Sandmeyer reaction such as treatment with aqueous Na 0 2 solution in a aqueous acid such as 5 0% H 2 SO 4 .
  • the phenol can be alkylated using an alkylating agent such as tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate in the presence of an appropriate base such as cesium carbonate in as polar solvent such as DMF optionally heating to a temperature such as 80 °C.
  • the ester can be hydrolyzed with an aqueous base such as NaOH in water.
  • the resulting acid can be coupled to the 3-(amino methyl)-4, 6- dimethylpyridin-2(lH)-one using standard amino acid coupling conditions such as PYBOP in DMSO.
  • Aryl substituents can be incorporated by using palladium couplings such as a Suzuki reaction as described above.
  • Substituted nitrobenzoic acids many of which are commercially available or can be prepared by nitrations of the appropriate substituted benzoic acids or other chemistry known to one skilled in the art, can be converted to their methyl esters by treatment with methyliodide in a polar solvent such as DMF in the presence of an appropriate base such as sodium carbonate at an appropriate temperature such as 60 °C (Step 1).
  • the nitro group can be reduced to an amine using an appropriate reducing agent such as iron in the presence of an acid such as ammonium chloride in a pro tic solvent such as ethanol at an appropriate temperature such as 80 °C (Step 2).
  • Introduction of the R 7 can be done using a reductive amination with an appropriate -ketone or Ryaldehyde in the presence of an appropriate reducing agent such as sodium cyanoborohydride and catalytic acid such as acetic acid in an appropriate solvent such as methanol.
  • Rg groups can be introduced by alkylation using Rj-LG, where LG is a leaving group such as iodine, in the presence of a mild base such as cesium carbonate in an appropriate polar solvent such as acetonitrile at an appropriate temperature such as 80 °C (Step 4).
  • Rs groups can be introduced by reductive amination with Rg-ketone or Rg-aldehyde in the presence of an appropriate reducing agent such as sodium cyanoborohydride and catalytic acid such as acetic acid in an appropriate solvent such as methanol.
  • the ester moiety can be converted to an amide using a standard two step protocol.
  • the ester can be hydrolyzed to the corresponding acid using a suitable base such as sodium hydroxide in a polar solvent such as ethanol (Step 5 ).
  • a suitable base such as sodium hydroxide in a polar solvent such as ethanol
  • the acid would then be subjecting to a standard amide coupling reaction whereupon the appropriate amine would be added along with a suitable amide coupling reagent such as PYBOP in a suitable solvent such as D SO to give the desired amide (Step 6).
  • an appropriate unsaturated non-aromatic boronic ester derivative e.g. an olefinic boronic ester derivative such as vinyl 4 , 4 , 5 , 5 -tetramethyl-2-vinyl-l,3,2-dioxaborolane
  • the resulting compound wherein the 3 ⁇ 4 substituent is an alkynyl group may be subject to subsequent suitable modifications to give an alternative 3 ⁇ 4 substituent.
  • a representative sampling of such modifications could include hydrogenation, protecting group removal followed by additional amide coupling reactions, reductive amination reactions or alkylation reactions.
  • substitution reactions include coupling reactions with zinc reagents such as cyanation and Negishi reactions.
  • the cyano group in such compounds may be subject to further modification to give other 3 ⁇ 4 groups.
  • Such cyano modifications include i.
  • R 3 ⁇ 4 Br using palladium or nickel catalysts.
  • the introduced 3 ⁇ 4 group may be converted to an alternative group by further modifications of the 3 ⁇ 4 group in subsequent steps such as deprotection, amide formation or alkylation.
  • the coupling product sulfides may be subject to subsequent suitable modifications to give an alternative R $ substituent.
  • Such modifications include sulfur oxidation reactions to give sulfoxides and sulfones, protecting group removal, amide coupling reactions, reductive amination reactions or alkylation reactions.
  • Scheme 5' shows the general synthesis of picolinamide compounds.
  • the 4-chloro group can be selectively substituted with diverse mono and dialkyl amines which may also contain functional or protected functional groups that may be unmasked at a later stage.
  • the 3-bromo group may be retained or may be optionally converted into an alternative R12 group by suitable substitution reaction and further functional group modifications.
  • Such reactions include coupling reactions mediated with palladium catalysts.
  • the chloro group may optionaUy be converted to alternative R6 groups by suitable substitution reactions either in a final step or alternatively prior to ester hydrolysis Step 6. Examples of such substitution reactions include cyanation and animation reactions either directly or mediated with palladium catalysts.
  • Analogous compounds wherein R is chloro may be prepared in analogous fashion from methyl 3,4, 6-trichloropyridine-2-carboxylate.
  • an appropriately substituted alkynyl ketone when R 3 is H, can be condensed with 2-cyanoacetamide in the presence of an appropriate reagent such as piperidine acetate in a polar solvent such as ethanol to provide a cyanopyridone (Step 11).
  • the cyano group can be reduced under appropriate conditions such as hydrogenation in the presence of catalytic Raney nickel in a polar solvent such as ammonium in methanol to provide the amine (Step 10).
  • R 2, or R4 group further chemical modification can be employed to convert each of them independently into an alternative substituent.
  • a representative sampling of such modifications can include hydrogenation, protecting group removal followed by additional amide coupling reactions, palladium catalyzed coupling reactions, reductive amination reactions, and alkylation reactions.
  • Scheme T depicts a variant of the general synthesis route of Scheme 1 ' based on 2- substituted (substituent is an 12 group) methyl 3-amino-5-bromo-benzoate starting materials.
  • These starting materials can in turn be prepared from 2-substituted 3-nitro-benzoic acids which are commercially available or can be prepared by nitration of 2-substituted benzoic acids.
  • a suitable reagent such as l,3-dibromo- 5 , 5 - dimethyl-2,4-imidazolidinedione yields the appropriate 2-substituted 3-nitro-S-bromo-benzoic acids.
  • the R 7 group can be introduced from 2-substituted methyl 3- amino-5-bromo-benzoates in Step 1 using a reductive amination with an appropriate Ry-ketone or R 7 -aldehyde in the presence of an appropriate reducing agent such as sodium cyanoborohydride and catalytic acid such as acetic acid in an appropriate solvent such as methanol.
  • Rg groups can be introduced in Step 2 by reductive amination with Rg-ketone or Rs-aldehyde in the presence of an appropriate reducing agent such as sodium cyanoborohydride and catalytic acid such as acetic acid in an appropriate solvent such as methanol.
  • Rg groups can be introduced by alkylation using Rg-LG, where LG is a leaving group such as iodine, in the presence of a mild base such as cesium carbonate in an appropriate polar solvent such as acetonitrile at an appropriate temperature such as 80 °C.
  • R3 ⁇ 4 groups other than bromine can be introduced via palladium catalyzed coupling reactions. Examples of such groups and methods have been described above. For example amines may be introduced by Buchwald reactions and unsaturated groups may be introduced by Suzuki or Sonogashiri reactions.
  • the R $ substituent may be subject to subsequent suitable modifications to give an alternative R 3 ⁇ 4 substituent.
  • a representative sampling of such modifications could include hydrogenation (e.g.
  • the ester moiety can be hydrolyzed to the corresponding acid using a suitable base such as sodium hydroxide in a polar solvent such as ethanol.
  • a suitable base such as sodium hydroxide in a polar solvent such as ethanol.
  • the acid can be subjected to a standard amide coupling reaction whereupon the appropriate 3-(aminomethyl)-pyridin- 2-one would be added along with a suitable amide coupling reagent such as PYBOP in a suitable solvent such as DMSO to give the desired amide.
  • a suitable amide coupling reagent such as PYBOP
  • DMSO suitable solvent
  • further chemical modification subsequent to Step 5 of Scheme 4' could be employed to convert the R ?
  • a protected amino group contained within may be subjected to deprotection reaction (e.g. Boc group cleavage) to give free amino groups.
  • deprotection reaction e.g. Boc group cleavage
  • free amino groups may be subjected to reductive amination reactions or alkylation reactions to give substituted amines.
  • Scheme 8' depicts the general synthesis of 2-monoalkylamino and 2-dialkylamino- 3,6-disubstituted-isonicotinamides wherein the 3-substituent corresponds to and the 6-substituent corresponds to R$.
  • the 3-substituent may be introduced by the method described by Epsztain J. et al. Tetrahedron, 1991, v. 47, 1697-16708, by metalation of 2-chloro-isonicotinanilide with n-butyllithium followed by trapping with an alkyliodide such as methyliodide or aldehyde or other electrophilic group.
  • Step 2 anilide amide hydrolysis under standard acidic conditions may be conducted followed by methyl ester synthesis under standard conditions for example as shown with methyl iodide and base gives corresponding methyl 2-chloro-3-substituted isonicotinates.
  • Step 4 an alkylamino group can be introduced by Buchwald coupling reaction of an R7NH2 monoalkylamine with the methyl 2-chloro-3-substituted isonicotinates. This reaction is well precedented for diverse 2- chloropyridine systems in the chemical literature.
  • Rg groups can be introduced by reductive amination with Rs-ketone or Rs-aldehyde in the presence of an appropriate reducing agent such as sodium cyanoborohydride and catalytic acid such as acetic acid in an appropriate solvent such as methanol.
  • an appropriate reducing agent such as sodium cyanoborohydride and catalytic acid such as acetic acid in an appropriate solvent such as methanol.
  • a variety of Rs groups can be introduced by alkylation using Rj-LG, where LG is a leaving group such as iodine, in the presence of a mild base such as cesium carbonate in an appropriate polar solvent such as acetonitrile at an appropriate temperature such as 80 °C.
  • Step 6 oxidation to the N-oxide followed by chlorination with phosphorus oxychloride gives methyl 6-chloro-2-mono or dialkylamino-3-substituted isonicotinates.
  • the ester moiety can be hydrolyzed to the corresponding acid using a suitable base such as sodium hydroxide in a polar solvent such as ethanol.
  • the acid can be subjected to a standard amide coupling reaction whereupon the appropriate substituted 3- (aminomethyl)-pyridm-2-one would be added along with a suitable amide coupling reagent such as PYBOP in a suitable solvent such as DMSO to give the desired amide.
  • the chloro group may optionally be converted to alternative 3 ⁇ 4 groups by suitable substitution reactions either in a final step or alternatively prior to ester hydrolysis Step 6.
  • suitable substitution reactions include cyanation and amination reactions either directly or mediated with palladium catalysts.
  • the Ri substituent may be subject to subsequent suitable modifications to give an alternative Re substituent.
  • a representative sampling of such modifications could include hydrogenation (e.g. to saturate unsaturated groups), protecting group removal followed by additional amide coupling reactions, reductive amination reactions or alkylation reactions.
  • further chemical modification steps may be employed to convert the R7 substituent into an alternative R7 substituent.
  • a protected amino group contained within R7 may be subjected to deprotection reaction (e.g. Boc group cleavage) to give free amino groups.
  • deprotection reaction e.g. Boc group cleavage
  • free amino groups may be subjected to reductive amination reactions or alkylation reactions to give substituted amines.
  • Scheme 9' depicts a synthesis of benzene analogs wherein Z is a sulfide, sulfoxide or sulfone group following a general route that utilizes well-established chemistry.
  • a substituted benzoic acid such as 5-chloro-2-methylbenzoic acid
  • nitration using standard conditions such as treatment with cone. H 2 SO 4 and cone.
  • HNO3 can provide the nitro analog.
  • Esterification of the acid can be achieved using an alkylating agent such as methyl iodide in the presence of a base such as sodium carbonate in a polar solvent such as DMF.
  • the nitro group can be reduced using conditions such iron and ammonium chloride in a protic solvent such as ethanol with heating to a temperature such as 80 °C.
  • the resulting aniline can be converted to a bromide using a Sandmeyer reaction such treatment with ⁇ 3 ⁇ 4 and t-butyl nitrite in a solvent such as acetonitrile.
  • a palladium catalyzed coupling of a thiol with the bromide can be achieved using a palladium source such as Pd(OAc) 2 with a ligand such as Xanthphos in the presence of a base such as ⁇ , ⁇ -diisopropyl ethylamine in a solvent such as 1,4-dioxane optionally heating to a temperature such as 100 °C.
  • the ester can be hydrolyzed with an aqueous base such as NaOH in water.
  • the resulting acid can be coupled to the appropriate substituted 3-(aminomethyl)-pyridin-2-one (e.g.
  • the aniline can be converted to a phenol using a Sandmeyer reaction such as treatment with aqueous NaN0 2 solution in a aqueous acid such as 5 0% H 2 SO 4 .
  • the phenol can be alkylated using an alkylating agent such as tetrahydro-2H-pyran-4-yl 4- methylbenzenesulfonate in the presence of an appropriate base such as cesium carbonate in as polar solvent such as DMF optionally heating to a temperature such as 80 °C.
  • the ester can be hydrolyzed with an aqueous base such as NaOH in water.
  • the resulting acid can be coupled to the appropriate substituted 3-(aminomethyl)-pyridin-2-one using standard amino acid coupling conditions such as PYBOP in DMSO.
  • the R 6 chloro group may be replaced with an alternative R ⁇ group in an additional after Step 5 or prior to amide coupling.
  • alternative Regroups include substituents that can be incorporated by using palladium couplings such as a Buchwald reaction to give amine groups (e.g. morpholino).
  • the R 6 substituent may be subject to subsequent suitable modifications to give an alternative 3 ⁇ 4 substituent.
  • a representative sampling of such modifications includes protecting group removal followed by additional amide coupling reactions, reductive amination reactions or alkylation.
  • Compounds of the present invention inhibit the histone methyltransferase activity of EZH2 or a mutant thereof and, accordingly, in one aspect of the invention, certain compounds disclosed herein are candidates for treating, or preventing certain conditions and diseases.
  • the present invention provides methods for treating conditions and diseases the course of which can be influenced by modulating the methylation status of histones or other proteins, wherein said methylation status is mediated at least in part by the activity of EZH2. Modulation of the methylation status of histones can in turn influence the level of expression of target genes activated by methylation, and/or target genes suppressed by methylation.
  • the method includes administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, polymorph, solvate, or stereoisomeror thereof.
  • any description of a method of treatment includes uses of the compounds to provide such treatment or prophylaxis as is described in the specification, as well as uses of the compounds to prepare a medicament to treat or prevent such condition.
  • the treatment includes treatment of human or non-human animals including rodents and other disease models.
  • this invention relates to a method of modulating the activity of the EZH2, the catalytic subunit of the PRC2 complex which catalyzes the mono- through tri-methylation of lysine 27 on histone H3 (H3-K27) in a subject in need thereof.
  • the method comprises the step of administering to a subject having a cancer expressing a mutant EZH2 a therapeutically effective amount of a compound described herein, wherein the compound(s) inhibits histone methyltransferase activity of EZH2, thereby treating the cancer.
  • the cancer is selected from the group consisting of follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) of germinal center B cell-like (GCB) subtype.
  • the cancer is lymphoma, leukemia or melanoma.
  • the lymphoma is non- Hodgkin's lymphoma (NHL), follicular lymphoma or diffuse large B-cell lymphoma.
  • the leukemia is chronic myelogenous leukemia (CML), acute myeloid leukemia, acute lymphocytic leukemia or mixed lineage leukemia.
  • the precancerous condition is myelodysplastic syndromes (MDS, formerly known as preleukemia).
  • MDS myelodysplastic syndromes
  • the cancer is a hematological cancer.
  • the compound(s) of the present invention inhibit the histone methyltransferase activity of EZH2 or a mutant thereof and, accordingly, the present invention also provides methods for treating conditions and diseases the course of which can be influenced by modulating the methylation status of histones or other proteins, wherein said methylation status is mediated at least in part by the activity of EZH2.
  • certain compounds disclosed herein are candidates for treating, or preventing certain conditions and diseases. Modulation of the methylation status of histones can in turn influence the level of expression of target genes activated by methylation, and/or target genes suppressed by methylation.
  • the method includes administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the present invention.
  • a "subject” is interchangeable with a "subject in need thereof, both of which refer to a subject having a disorder in which EZH2-mediatEd protein methylation plays a part, or a subject having an increased risk of developing such disorder relative to the population at large.
  • a "subject” includes a mammal.
  • the mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig.
  • the subject can also be a bird or fowl.
  • the mammal is a human.
  • a subject in need thereof can be one who has been previously diagnosed or identified as having cancer or a precancerous condition.
  • a subject in need thereof can also be one who has (e.g., is suffering from) cancer or a precancerous condition.
  • a subject in need thereof can be one who has an increased risk of developing such disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large).
  • a subject in need thereof can have a precancerous condition.
  • a subject in need thereof can have refractory or resistant cancer (i.e., cancer that doesn't respond or hasn't yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment.
  • the subject in need thereof has cancer recurrence following remission on most recent therapy.
  • the subject in need thereof received and failed all known effective therapies for cancer treatment.
  • the subject in need thereof received at least one prior therapy.
  • the subject has cancer or a cancerous condition.
  • the cancer is lymphoma, leukemia, melanoma, or rhabdomyosarcoma.
  • the lymphoma is non-Hodgkin's lymphoma, follicular lymphoma or diffuse large B-cell lymphoma.
  • the leukemia is chronic myelogenous leukemia (CML).
  • CML chronic myelogenous leukemia
  • the precancerous condition is myelodysplastic syndromes (MDS, formerly known as preleukemia).
  • treating describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder.
  • the term "treaf ' can also include treatment of a cell in vitro or an animal model.
  • a compound of the present invention can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes.
  • preventing describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

Abstract

The present invention relates to substituted benzene compounds. The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating cancer by administering these compounds and pharmaceutical compositions to subjects in need thereof. The present invention also relates to the use of such compounds for research or other non-therapeutic purposes.

Description

SUBSTITUTED BENZENE COMPOUNDS
[001] This application claims priority to, and the benefit of, provisional application Nos. 61/714,140, filed October 15, 2012, 61/714,145, filed October 15, 2012, 61/780,703, filed March 13, 2013, and 61/786,277, filed March 14, 2013. The entire contents of each of these provisional applications are incorporated herein by reference in their entireties.
[002] There is an ongoing need for new agents as inhibitors of EZH2 activity, which can be used for treating EZH2-mediated disorder (e.g., cancer).
[003] In one aspect, the present invention features a substituted benzene compound of the
Formulae below or a pharmaceutically acceptable salt thereof.
[004] In one aspect, the invention relates to a compound according to Formula ΠΙ:
Figure imgf000002_0001
or a pharmaceutically acceptable salt, or solvate thereof, wherein
R801 is Ci alkyl, alkenyl, alkynyl, C3 cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, phenyl or 5- or 6-membered heteroaryl, each of which is substituted with O-Ci alkyl-Rx or NH-Ci alkyl-Rx, wherein Rx is hydroxyl, O alkyl or NH alkyl, and Rx is optionally further substituted with O alkyl or NH alkyl except when Rx is hydroxyl; and R801 is optionally further substituted;
each of R and R , independently is H, halo,
Figure imgf000002_0002
alkyl, Ci_g alkoxyl or Ce-Cio aryloxy, each optionally substituted with one or more halo;
each of R and R , independently is alkyl; and is - , wherein is a bond or alkyl linker, is optionally substituted alkyl, optionally substituted C3-C8 cycioalkyl or optionally substituted 4- to 14-membered heterocycloalkyl.
[005] Subsets of compounds of Formula III include those of Formula IVa or IVb and pharmaceutic
wherein V is
Figure imgf000003_0001
[006] In another aspect, the invention relates to a compound according to Formula I:
Figure imgf000003_0002
(I)
or a pharmaceutically acceptable salt or solvate thereof; wherein
R701 is H, F, OR707, NHR707, -(C≡C)-(CH -R70S, phenyl, 5- or 6-membered heteroaryl, Cj.g cycioalkyl, or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the phenyl, S- or 6-membered heteroaryl, C3 cycioalkyl or 4-7 membered heterocycloalkyl each independently is optionally substituted with one or more groups selected from halo, alkyl, OH, 0-Ci alkyl, NH-Ci alkyl, and, alkyl substituted with C3 cycioalkyl or 4-7 membered heterocycloalkyl containing 1 -3 heteroatoms, wherein each of the O-Ci-e alkyl and NH alkyl is optionally substituted with hydroxyl, O alkyl or NH-C,.3 alkyl, each of the O-C^ alkyl and ΝΗ-(¾ alkyl being optionally further substituted with O alkyl or NH alkyl; each of and R , independently is H, halo, CM alkyl, Q.6 alkoxyl or Ce-Qo aryloxy, each optionally substituted with one or more halo;
each of R704 and R705, independently is CM alkyl;
R706 is cyclohexyl substituted by N(C alkyl)2 wherein one or both of the C alkyl is substituted with Q.^ alkoxy; or R706 is tetrahydropyranyl;
R707 is Ci-4 alkyl optionally substituted with one or more groups selected from hydroxyl, C alkoxy, amino, mono- or di-C^ alkylamino, C3.8 cycloalkyl, and 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the .8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is further optionally substituted with Ci_3 alkyl;
R708 is Ci_4 alkyl optionally substituted with one or more groups selected from OH, halo, and CM alkoxy, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, or 0-C]_6 alkyl, wherein the 4-7 membered heterocycloalkyl can be optionally further substituted with OH or C,.6 alkyl; and
n? is 0, 1 or 2.
[007] A subset of compounds of Formula I includes those of Formula II and pharmaceutically acceptable salts or solvates thereof:
Figure imgf000004_0001
In another aspect, the invention relates to compound according to formula V:
Figure imgf000005_0001
Wi is N or CH;
W2 is N or CH;
R401 is hydrogen, C,-C6 alkyl, C,-C6 haloalkyl;
R402 is (a) OH, (b) (CH2)-0-(C,-C6 alkyl), (c) 0(C,-C6 alkyl), (d) (C¾)r3-8 membered saturated, unsaturated, or aromatic carbocycle, (e) CH2)t-3-8 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (f) 0-(C¾)u-3-8 membered saturated, unsaturated, or aromatic carbocycle, or (g) 0-(CH2)v-3-8 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, where (b)-(g) are optionally substituted with R402 ,
R 02a is CrC6 alkyl, CrC6 haloalkyl, OH, or 0(C,-C6 alkyl);
t is 1 , 2, or 3;
u is 0, 1 , 2, or 3;
v is 0, 1 ,2 , or 3;
j is 0, 1 , 2, or 3; and
k is 0, 1 , 2, or 3; provided that when R402 is piperazinyl, Wi and W2 are N.
[009] In certain compounds of Formula V, Wi is N and W2 is CH.
[010] In certain compounds of Formula V, R401 is Ci-Ce alkyl. For example, R401 is methyl or isopropyl. For example, R401 is methyl.
[01 1] In certain compounds of Formula V, R402 is (CH2)k- -7 membered saturated heterocycle containing one or more nitrogen or oxygen atoms.
[012] In certain compounds of Formula V, k is 0 or 1. For example, k is 0. For example, k is 1.
[013] In certain compounds of Formula V, R402 is azetidinyl, piperazinyl, or piperidinyl.
[014] In certain compounds, R402 is (CH2)-azetidinyl, (CH2)-pyrrolidinyl, (CH2)-piperidinyl, (CH2)-morpholinyl, or (CH2)-diazepanyl.
[015] In certain compounds of Formula V, t is 1.
[016] In certain compounds of Formula V, R 02a is OH, methyl, or methoxy. [017] In yet another aspect, the invention relates to a compound according to Formula VI:
Figure imgf000006_0001
(VI)
or a pharmaceutically acceptable salt or solvate thereof, wherein
¾ is 0, 1, or 2;
R501 is C(H) orN;
R502, R503, R504 and R505 are, independently for each occurrence, C1 alkyl;
R is cyclohexyl substituted by Ν(ϋμ alkyl)2 or piperidine substituted by 1, 2, or 3 Cj.4 alkyl groups;
when R501 is C(H), R507 is morpholine; piperidine; diazepane; pyrrolidine; azetidine; 0-Ci alkyl; or O-heterocycle, wherein the heterocycle is a 4-7 membered heterocycle containing an oxygen or nitrogen, or both, and wherein the nitrogen can optionally be substituted with Q alkyl; wherein the piperidine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH, alkyl, or θ-(¾ alkyl;
or when 501 is C(H), R507 can be piperazine optionally further substituted with Q alkyl, provided that R506 is piperidine substituted by 1, 2, or 3 CM alkyl groups;
when R50' is N, R507 is morpholine; piperidine; piperazine; diazepane; pyrrolidine; azetidine; O-Ci alkyl; or O-heterocycle, wherein the heterocycle is a 4-7 membered heterocycle containing an oxygen or nitrogen, or both, and wherein the nitrogen can optionally be substituted with alkyl; wherein the piperidine, piperazine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH, alkyl, or O-Cu alkyl.
[018] In still another aspect, the invention relates to a compound of Formula VII:
Figure imgf000006_0002
(VII)
or a pharmaceutically acceptable salt or solvate thereof, wherein
¾ is 1 or 2;
R602, R603, R604 and R605 are, independently for each occurrence, CM alkyl;
R606 is cyclohexyl substituted by N(CM alkyl)2 or piperidine substituted by 1 , 2, or 3 CM alkyl groups; and
R607 is moφholine, piperidine, piperazine, pyrrolidine, diazepane, azetidine or O-Ci-6 alkyl, wherein the piperidine, diazepane or azetidine groups can be optionally further substituted with OH or Ci-6 alkyl.
[01 ] The present invention also provides pharmaceutical compositions comprising one or more pharmaceutically acceptable carriers and one or more compounds selected from those of any of the Formulae described herein.
[020] Another aspect of this invention is a method of treating or preventing an EZH2-mediated disorder. The method mcludes administering to a subject in need thereof a therapeutically effective amount of one or more compounds selected from those of any of the Formulae described herein. The EZH2 -mediated disorder is a disease, disorder, or condition that is mediated at least in part by the activity of EZH2. In one embodiment, the EZH2-mediated disorder is related to an increased EZH2 activity. In one embodiment, the EZH2 -mediated disorder is a cancer. The EZH2-mediated cancer may be lymphoma, leukemia or melanoma, for example, diffuse large B-cell lymphoma (DLBCL), non-Hodgkin's lymphoma (NHL), follicular lymphoma, chronic myelogenous leukemia (CML), acute myeloid leukemia, acute lymphocytic leukemia, mixed lineage leukemia, or myelodysplastic syndromes ( DS). In one embodiment the EZH2-mediated cancer may be a malignant rhabdoid tumor or INIl-defecient tumor. The histologic diagnosis of malignant rhabdoid tumor depends on identification of characteristic rhabdoid cells (large cells with eccentrically located nuclei and abundant, eosinophilic cytoplasm) and immunohistochemistry with antibodies to vimentin, keratin and epithelial membrane antigen. In most malignant rhabdoid tumors, the SMARCB1/INI1 gene, located in chromosome band 22ql 1.2, is inactivated by deletions and/or mutations. In one embodiment, the malignant rhabdoid tumors may be INIl-defecient tumor.
[021] Unless otherwise stated, any description of a method of treatment includes uses of the compounds to provide such treatment or prophylaxis as is described in the specification, as well as uses of the compounds to prepare a medicament to treat or prevent such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models. Methods described herein may be used to identify suitable candidates for treating or preventing EZH2 -mediated disorders. For example, the invention also provides methods of identifying an inhibitor of a wild-type EZH2, a mutant EZH2 (e.g., a Y641 , A677, and/or A687 mutant EZH2), or both.
[022] For example, the method comprises the step of administering to a subject having a cancer with aberrant H3-K27 methylation an effective amount of one or more compounds of Formulae described herein, wherein the compound(s) inhibits histone methyltransferase activity of EZH2, thereby treating the cancer. Examples of aberrant H3-K27 methylation may include a global increase in and/or altered distribution of H3-K27 di or tri-methylation within the cancer cell chromatin.
[023] For example, the cancer is selected from the group consisting of cancers that overexpress EZH2 or other PRC2 subunits, contain loss-of-function mutations in H3-K27 demethylases such as UTX, or overexpress accessory proteins such as PHF19/PCL3 capable of increasing and or mislocalizing EZH2 activity (see references in Sneeringer et al. Proc Natl Acad Sci USA 107(49):20980-5, 2010).
[024] For example, the method comprises the step of administering to a subject having a cancer overexpressing EZH2 a therapeutically effective amount of one or more compounds of Formulae described herein, wherein the compound(s) inhibits histone methyltransferase activity of EZH2, thereby treating the cancer.
[02S] For example, the method comprises the step of administering to a subject having a cancer with a loss-of-function mutation in the H3-K27 demethylase UTX a therapeutically effective amount of one or more compounds of Formulae described herein, wherein the compound(s) inhibits histone methyltransferase activity of EZH2, thereby treating the cancer
[026] For example, the method comprises the step of administering to a subject having a cancer overexpressing an accessory component(s) of the PRC2, such as PHF19/PCL3, a therapeutically effective amount of one or more compounds of Formulae described herein, wherein the compound(s) inhibits histone methyltransferase activity of EZH2, thereby treating the cancer
[027] In still another aspect, this invention relates to a method of modulating the activity of the wild-type EZH2, the catalytic subunit of the PRC2 complex which catalyzes the mono- through tri- methylation of lysine 27 on histone H3 (H3-K27). For example, the present invention relates to a method of inhibiting the activity of EZH2 in a cell. This method can be conducted either in vitro or in vivo.
[028] In yet another aspect, this invention features to a method of inhibiting in a subject conversion of H3-K27 to trimethylated H3-K27. The method comprises administering to a subject a therapeutically effective amount of one or more of the compounds of Formulae described herein to inhibit histone methyltransferase activity of EZH2, thereby inhibiting conversion of H3-K27 to trimethylated H3-K27 in the subject. [029] For example, the method comprises the step of administering to a subject having a cancer expressing a mutant EZH2 a therapeutically effective amount of one or more compounds of Formulae described herein, wherein the compound(s) inhibits histone methyltransferase activity of EZH2, thereby treating the cancer.
[030] For example, the cancer is selected from the group consisting of follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) of germinal center B cell-like (GCB) subtype. For example, the cancer is lymphoma, leukemia or melanoma. Preferably, the lymphoma is non- Hodgkin's lymphoma (NHL), follicular lymphoma or diffuse large B-cell lymphoma. Alternatively, the leukemia is chronic myelogenous leukemia (C L), acute myeloid leukemia, acute lymphocytic leukemia or mixed lineage leukemia.
[031] For example, the precancerous condition is myelodysplastic syndromes (MDS, formerly known as preleukemia).
[032] For example, the cancer is a hematological cancer.
[033] For example, the cancer is selected from the group consisting of brain and central nervous system (CNS) cancer, head and neck cancer, kidney cancer, ovarian cancer, pancreatic cancer, leukemia, lung cancer, lymphoma, myeloma, sarcoma, breast cancer, and prostate cancer.
Preferably, a subject in need thereof is one who had, is having or is predisposed to developing brain and CNS cancer, kidney cancer, ovarian cancer, pancreatic cancer, leukemia, lymphoma, myeloma, and/or sarcoma. Exemplary brain and central CNS cancer includes medulloblastoma, oligodendroglioma, atypical teratoid/rhabdoid tumor, choroid plexus carcinoma, choroid plexus papilloma, ependymoma, glioblastoma, meningioma, neuroglial tumor, oligoastrocytoma, oligodendroglioma, and pineoblastoma. Exemplary ovarian cancer includes ovarian clear cell adenocarcinoma, ovarian endomethrioid adenocarcinoma, and ovarian serous adenocarcinoma. Exemplary pancreatic cancer includes pancreatic ductal adenocarcinoma and pancreatic endocrine tumor. Exemplary sarcoma includes chondrosarcoma, clear cell sarcoma of soft tissue, ewing sarcoma, gastrointestinal stromal tumor, osteosarcoma, rhabdomyosarcoma, and not otherwise specified (NOS) sarcoma. Alternatively, cancers to be treated by the compounds of the present invention are non NHL cancers.
[034] For example, the cancer is selected from the group consisting of medulloblastoma, oligodendroglioma, ovarian clear cell adenocarcinoma, ovarian endomethrioid adenocarcinoma, ovarian serous adenocarcinoma, pancreatic ductal adenocarcinoma, pancreatic endocrine tumor, malignant rhabdoid tumor, astrocytoma, atypical teratoid/rhabdoid tumor, choroid plexus carcinoma, choroid plexus papilloma, ependymoma, glioblastoma, meningioma, neuroglial tumor, oligoastrocytoma, oligodendroglioma, pineoblastoma, carcinosarcoma, chordoma, extragonadal germ cell tumor, extrarenal rhabdoid tumor, schwannoma, skin squamous cell carcinoma, chondrosarcoma, clear cell sarcoma of soft tissue, ewing sarcoma, gastrointestinal stromal tumor, osteosarcoma, rhabdomyosarcoma, and not otherwise specified (NOS) sarcoma. Prefereably, the cancer is medulloblastoma, ovarian clear cell adenocarcinoma, ovarian endomethrioid adenocarcinoma, pancreatic ductal adenocarcinoma, malignant rhabdoid tumor, atypical teratoid/rhabdoid tumor, choroid plexus carcinoma, choroid plexus papilloma, glioblastoma, meningioma, pineoblastoma, carcinosarcoma, extrarenal rhabdoid tumor, schwannoma, skin squamous cell carcinoma, chondrosarcoma, ewing sarcoma, epitheloid sarcoma, renal medullo carcinoma, diffuse large B-cell lymphoma, follicular lymphoma and/or NOS sarcoma. More preferably, the cancer is malignant rhabdoid tumor, medulloblastoma and/or atypical teratoid/rhabdoid tumor.
[035] For example, the method comprises the step of administering to a subject having a cancer expressing a mutant EZH2 a therapeutically effective amount of one or more compounds of Formulae described herein, wherein the compound(s) inhibits activity (e.g., histone methyltransferase activity) of the mutant EZH2, the wild-type EZH2, or both, thereby treating the cancer.
[036] For example, the method further comprises the steps of performing an assay to detect a mutant EZH2 in a sample comprising cancer cells from a subject in need thereof.
[037] In another aspect, the invention features a method of selecting a therapy for a patient having a disease associated with EZH2 -mediated protein methylation. The method includes the steps of determining the presence of gene mutation in the EZH2 gene of the subject; and selecting, based on the presence of a gene mutation in the EZH2 gene a therapy for treating the disease. In one embodiment, the therapy includes the administration of one or more of the compounds of the invention. In one embodiment, the method further includes administrating one or more of the compounds of the invention to the subject. In one embodiment, the disease is cancer and the mutation is a Y641 mutation.
[038] In yet another aspect, a method of treatment is provided for a patient in need thereof, the method comprising the steps of determining the presence of gene mutation in the EZH2 gene and treating the patient in need thereof, based on the presence of a gene mutation in the EZH2 gene, with a therapy that includes the adrninistration of the compounds of the invention. In one embodiment, the patient is a cancer patient and the mutation is a Y641 mutation.
[039] In still another aspect, this invention relates to a method of modulating the activity of the wild-type and mutant histone methyltransferase EZH2, the catalytic subunit of the P C2 complex which catalyzes the mono- through tri-methylation of lysine 27 on histone H3 (H3-K27). For example, the present invention relates to a method of inhibiting the activity of certain mutant forms of EZH2 in a cell. The mutant forms of EZH2 include a substitution of another amino acid residue for tyrosine 641 (Y641, also Tyr641) of wild-type EZH2. The method includes contacting the cell with an effective amount of one or more of the compounds of any Formula described herein. This method can be conducted either in vitro or in vivo.
[040] In yet another aspect, this invention features to a method of inhibiting in a subject conversion of H3-K27 to trimethylated H3-K27. The method comprises administering to a subject expressing a mutant EZH2 a therapeutically effective amount of one or more of the compounds of any Formula described herein to inhibit histone methyltransferase activity of EZH2, thereby inhibiting conversion of H3-K27 to trimethylated H3-K27 in the subject. For example, the histone methyltransferase activity inhibited is that of the Y641 mutant of EZH2. For example, the compound of this invention selectively inhibits histone methyltransferase activity of the Y641 mutant of EZH2. For example, the Y641 mutant of EZH2 is selected from the group consisting of Y641C, Y641F, Y641H, Y641N, and Y641S.
[041] The method of inhibiting in a subject conversion of H3-K27 to trimethylated H3-K27 may also comprise performing an assay to detect a mutant EZH2 in a sample from a subject before administering to the subject expressing a mutant EZH2 a therapeutically effective amount of one or more of the compounds of any Formula described herein. For example, performing the assay to detect the mutant EZH2 includes whole-genome resequencing or target region resequencing that detects a nucleic acid encoding the mutant EZH2. For example, performing the assay to detect the mutant EZH2 includes contacting the sample with an antibody that binds specifically to a polypeptide or fragment thereof characteristic of the mutant EZH2. For example, performing the assay to detect the mutant EZH2 includes contacting the sample under highly stringent conditions with a nucleic acid probe that hybridizes to a nucleic acid encoding a polypeptide or fragment thereof characteristic of the mutant EZH2.
[042] Further, the invention also relates to a method of identifying an inhibitor of a mutant EZH2, wild-type EZH2, or both. The method comprises the steps of combining an isolated EZH2 with a histone substrate, a methyl group donor, and a test compound, wherein the histone substrate comprises a form of H3-K27 selected from the group consisting of unmethylated H3-K27, monomethylated H3-K27, dimethylated H3-K27, and any combination thereof; and performing an assay to detect methylation of H3-K27 (e.g., formation of trimethylated H3-K27) in the histone substrate, thereby identifying the test compound as an inhibitor of the EZH2 when methylation of H3- 27 (e.g., formation of trimethylated H3- 27) in the presence of the test compound is less than methylation of H3-K27 (e.g., formation of trimethylated H3-K27) in the absence of the test compound.
[043] In one embodiment, performing the assay to detect methylation of H3-K27 in the histone substrate comprises measuring incorporation of labeled methyl groups. [044] In one embodiment, the labeled methyl groups are isotopically labeled methyl groups.
[045] In one embodiment, performing the assay to detect methylation of H3-K27 in the histone substrate comprises contacting the histone substrate with an antibody that binds specifically to trimethylated H3- 27.
[046] Also within the scope of the invention is a method of identifying a selective inhibitor of a mutant EZH2. The method comprises the steps of combining an isolated mutant EZH2 with a histone substrate, a methyl group donor, and a test compound, wherein the histone substrate comprises a form of H3-K27 selected from the group consisting of monomethylated H3- 27, dimethylated H3-K27, and a combination of monomethylated H3-K27 and dimethylated H3-K27, thereby forming a test mixture; combining an isolated wild-type EZH2 with a histone substrate, a methyl group donor, and a test compound, wherem the histone substrate comprises a form of H3- 27 selected from the group consisting of monomethylated H3-K27, dimethylated H3-K27, and a combination of monomethylated H3-K27 and dimethylated H3-K27, thereby forming a control mixture; performing an assay to detect trimethylation of the histone substrate in each of the test mixture and the control mixture; calculating the ratio of (a) trimethylation with the mutant EZH2 and the test compound (M+) to (b) trimethylation with the mutant EZH2 without the test compound (M-); calculating the ratio of (c) trimethylation with wild-type EZH2 and the test compound (WT+) to (d) trimethylation with wild-type EZH2 without the test compound (WT-); comparing the ratio (a)/(b) with the ratio (c)/(d); and identifying the test compound as a selective inhibitor of the mutant EZH2 when the ratio (a)/(b) is less than the ratio (c)/(d).
[047] The present invention further provides a method of identifying a subject as a candidate for treatment with one or more compounds of the invention. The method comprises the steps of performing an assay to detect a mutant EZH2 in a sample from a subject; and identifying a subject expressing a mutant EZH2 as a candidate for treatment with one or more compounds of the invention, wherein the compound(s) inhibits histone methyltransferase activity of EZH2.
[048] Still another aspect of the invention is a method of inhibiting conversion of H3-K27 to trimethylated H3-K27. The method comprises the step of contacting wild-type EZH2, a mutant EZH2, or both with a histone substrate comprising H3-K27 and an effective amount of a compound of the present invention, wherem the compound inhibits histone methyltransferase activity of EZH2, thereby inhibiting conversion of H3-K27 to trimethylated H3-K27.
[049] Further, the compounds or methods described herein can be used for research (e.g., studying epigenetic enzymes) and other non-therapeutic purposes.
[050] In certain embodiments, the preferred compounds disclosed herein have improved pharmacological and/or pharmacokinetic properties, e.g., lower clearance rates, reduced risk of adverse drug-drug interactions in combination therapy through reduction of time-dependent and reversible inhibition of cytochrome P-450 enzymes.
[051] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting.
[052] Other features and advantages of the invention will be apparent from the following detailed description and claims.
DETAILED DESCRIPTION OF THE INVENTION
[053] The present invention provides novel substituted benzene compounds, synthetic methods for making the compounds, pharmaceutical compositions containing them and various uses of the compounds.
[054] In one aspect, the invention relates to a compound according to Formula I:
Figure imgf000013_0001
or a pharmaceutically acceptable salt thereof; wherein
R701 is H, F, OR707, NHR707, -(C≡C)-(CH2)„7-R708, phenyl, 5- or 6-membered heteroaryl, C3-8 cycloalkyl, or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the phenyl, 5- or 6-membered heteroaryl, C3_8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is optionally substituted with one or more groups selected from halo, Q_3 alkyl, OH, O-Cj.6 alkyl, NH-Ci-6 alkyl, and, C1-3 alkyl substituted with C3 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein each of the O alkyl and NH-Ci_6 alkyl is optionally substituted with hydroxyl, O alkyl orNH-Ci alkyl, each of the O alkyl andNH-Ci alkyl being optionally further substituted with 0-C,. alkyl orNH-Ci alkyl;
each of 702 and R703, independently is H, halo, alkyl, Ci_6 alkoxyl orC6-Cio aryloxy, each optionally substituted with one or more halo;
each of R704 and R703, independently is Cw alkyl;
R706 is cyclohexyl substituted by N(C|_4 alkyl wherein one or both of the alkyl is substituted with alkoxy; or R706 is tetrahydropyranyl;
R707 is alkyl optionally substituted with one or more groups selected from hydroxyl, alkoxy, amino, mono- or di- _4 alkylamino, C3_g cycloalkyl, and 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the C3 cycloalkyl or 4-7 membered heterocycloalkyl each independently is further optionally substituted with alkyl;
R708 is alkyl optionally substituted with one or more groups selected from OH, halo, and alkoxy, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, or 0-C alkyl, wherein the 4-7 membered heterocycloalkyl can be optionally further substituted with OH or d-6 alkyl; and
is 0, 1 or 2.
[055] For example, R706 is cyclohexyl substituted by ( alky¾ wherein one of the Q_4 alkyl is unsubstituted and the other is substituted with methoxy.
[056] For example, wherein R is
Figure imgf000014_0001
[057] A subset of compounds of Formula I includes those of Formula II and pharmaceutically acceptable salts thereof:
Figure imgf000015_0001
[058] The compounds of Formula I or II can include one or more of the following features:
[059] For example, 702 is methyl or isopropyl.
[060] For example, R703 is methyl or methoxyl.
[061 ] For example, R704 is methyl.
[062] For example, R701 is OR707.
[063] For example, R707 is Q alkyl optionally substituted with OC¾ or morpholine.
[064] For example, R70' is H or F.
[065] For example, R70' is tetrahydropyranyl optionally substituted with methyl, methoxy, ethyl substituted with morpholine, or -OCH2CH2OCH3.
[066] For example, R701 is phenyl optionally substituted with methyl, methoxy, ethyl substituted with morpholine, or -OCH2CH2OCH3.
[067] For example, R701 is 5- membered heteroaryl (e.g., pyrrolyl, furyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, or isoxazolyl) optionally substituted with methyl, methoxy, ethyl substituted with morpholine, or
-OCH2CH2OCH3.
[068] For example, R701 is 6- membered heteroaryl (e.g., pyridyl, pyrazinyl, pyridazinyl, or pynmidyl) optionally substituted with methyl, methoxy, ethyl substituted with morpholine, or - OCH2CH2OCH3.
[069] For example, R701 is pyridyl, pynmidyl, pyrazinyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with methyl, methoxy, ethyl substituted with morpholine, or -OCH2CH2OCH3.
[070] For example, R708 is morpholine, piperidine, piperazine, pyrrolidine, diazepane, or azetidine, each of which is optionally substituted with OH or Ci_s alkyl.
[071] For example, R708 is morpholine
[072] For example, R708 is piperazine substituted with C .6 alkyl.
[073] For example, R708 is t-butyl or C(CH3)2OH. [074] For example, the compounds of Formula I or II do not comprise N-((4,6-dimethyl-2-oxo-l,2- dihydropyridm-3-yl)memyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)armno)-2-methyl-5-((l- methylpiperidin-4-yl)ethynyl)benzamide (i.e., Compound 105).
[075] For example, the compounds of Formula I or II do not comprise iV-((4,6-dimethyl-2-oxo-l,2- dihydropyridin-3-yl)methyl)-3-(ethyl(4-((2-methoxyethyl)(methyl)arrdno)cyclohexyl)amino)-2- methyl-5-(3-moφholinoprop-l-yn-l-yl)benzamide or iV-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)-3-(ethyl((lr,4r)-4-((2-memoxyethyl)(methyl)amino)cyclohexyl)amino)-2-methyl-5-(3- morpholinoprop-l-yn-l-yl)benzamide (i.e., Compound 2).
[076] For example, the compounds of Formula I or II comprise iV-((4,6-dimethyl-2-oxo-l,2- dihydropyridin-3-yl)memyl)-3-(ethyl(te1rahydro-2H-pyran-4-yl)airuno)-2-methyl-5-((l- methylpiperidin-4-yl)ethynyl)benzamide (i.e., Compound
Figure imgf000016_0001
dihydropyridin-S- tymethyty-S-iethyl^-iP-me
methyl-5-(3-mo holinoprop-l- n-l-yl)berlzamide, e.g., iV-((4,6-dimethyl-2-oxo-l,2-dihydropyridin- 3-yl)methyl)-3-(ethyl((lr,4r)-4-((2-methoxyeftyl)(memyl)amino)cyclohexyl)amino)-2-methyl-5-(3- morpholinoprop-l-yn-l-yl)benzamide (i.e., Compound 2).
[077] In another aspect, the invention relates to a compound according to Formula III:
Figure imgf000016_0002
(III)
or a pharmaceutically acceptable salt thereof; wherein
R801 is Ci alkyl, C alkenyl, C alkynyl, C3.s cycloalkyl, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, phenyl or 5- or 6-membered heteroaryl, each of which is substituted with O-C^ alkyl-Rx or NH-Ci.6 alkyl-Rx, wherein Rx is hydroxyl, O alkyl or NH alkyl, and Rx is optionally further substituted with O alkyl or NH-Cu alkyl except when Rx is hydroxyl; and R801 is optionally further substituted;
each of R802 and R803, independently is H, halo, CM alkyl, Ci.6 alkoxyl or C6-Cio aryloxy, each optionally substituted with one or more halo;
each of R8U4 and R , independently is alkyl; and R is -Qx-Tx, wherein Qx is a bond or Ci alkyl linker, Tx is H, optionally substituted C alkyl, optionally substituted C3-C8 cycloalkyl or optionally substituted 4- to 14-membered heterocycloalkyl.
[078] The compounds of Formula III can include one or more of the following features:
[079] For example, Qx is a bond or methyl linker.
[080] For example, Tx is tetrahydropyranyl.
[081] For example, Tx is piperidinyl substituted by 1, 2, or 3 CM alkyl groups.
[082] For example, Tx is cyclohexyl substituted by N(C]-t alkylh wherein one or both of the CM alkyl is optionally substimted with Q-s alkoxy. 1
[083] For example, R
Figure imgf000017_0001
[084] For example, R801 is phenyl substituted with 0-C,„6 alkyl-Rx.
[085] For example, R801 is 5- membered heteroaryl substituted (e.g., pyrrolyl, furyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl) with O-Ci.6 alkyl-R*.
[086] For example, R801 is 6-membered heteroaryl (e.g., pyridyl, pyrazinyl, pyridazinyl, or pyrimidinyl) substituted with 0-Q.6 alkyl-Rx.
[087] For example, R801 is pyridyl, pyrimidyl, pyrazinyl, imidazolyl, or pyrazolyl, each of which is substimted with O-Cue alkyl-Rx.
[088] For example, subsets of compounds of Formula III include those of Formula IVa or IVb and pharmaceu
Figure imgf000017_0002
(IVa) or (IVb), wherein Z' is CH or N, and R is C2.3 alkyl-Rx.
[089] For example, R807 is -CH2CH2OH, -CH CH2OCH3, or -CH2CH2OCH2CH2OCH3.
[090] For example, R80Z is methyl or isopropyl.
[091] For example, R803 is methyl or methoxyl.
[092] For example, R804 is methyl.
[093] For example, the compounds of Formula III do not comprise JV-((4,6-dimethyl-2-oxo-l,2- dihydropyridin-3-yl)methyl)-5-((4-(dimemyla
4-methyl-[l,l'-biphenyl]-3-carboxamide or ^-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)-5-(((lr,4r)-4-(dimethylammo)cyclohexyl)(ethyI)amino)-4'-(2-methoxyethoxy)-4-methyl- [l,l'-biphenyl]-3-carboxamide (i.e., Compound 1).
[094] For example, the compounds of Formula III comprise V-((4,6-dimethyl-2-oxo-l,2- dihydropyridin-3-yl)memyl)-5-((4-(dimemylam^
4-methyl-[ 1 , 1 '-biphenyl]-3-carboxamide.
[095] For example, the compounds of Formula III comprise iV-((4,6-dimethyl-2-oxo-l,2- dihydropyridin-3-yl)methyl)-5-(((lr,4r)-4-(dimethylamino)cyclohexyl)(ethyl)amino)-4'-(2- methoxyethoxy)-4-methyl-[l,l'-biphenyl]-3-carboxamide (i.e., Compound 1).
the invention relates to a compound according to Formula IA:
Figure imgf000018_0001
(IA), or a pharmaceutically acceptable salt or solvate thereof, wherein
R21 is hydrogen or Ci- alkyl,
R22 is (a) 3-8 membered saturated, unsaturated, or aromatic carbocycle, or (b) 3-8 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, where (a)-(b) are optionally substituted with one or more R2a;
each of R23 and R24 independently is C|-C6 alkyl,
Rla is (a) 3-8 membered saturated, unsaturated, or aromatic carbocycle, or (b) 3-8 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, where (a)-(b) are optionally substituted with one or more R3a; each R2a independently is Ct-C6 alkyl, N¾, NH(C,-C6 alkyl), or N(d-C6 alkyl)2; each R3a independently is (a) OH, (b) Ci-C6 alkyl, or (c) 0(Ci-C6 alkyl), where (b)- (c) are optionally substituted with one or more OH, and
m is 0, 1, 2, or 3;
provided that
(i) when R22 is tetrahydropyranyl, Rla is not morpholinyl; or
(ii) when Rl a is piperazinyl or cyclopropyl, R21 is not methyl or
(iii) the compound is not N-((4,6-dimethyl-2-oxo-l ,2-dihydropyridin-3-yl)methyl)-3- ((4-(dimethylamino)cyclohexyl)(ethyl)amino)-2-methyl-5-(3-(4-methylpiperazin- l-yl)prop- 1 -yn- 1 -yl)benzamide or 5-(cyclopropylethynyl)-N-((4,6-dimethyl-2-oxo- 1 ,2-dihydropyridin- 3-yl)methyl)-3-((4-(dimethylamino)cyclohexyl)(ethyl)amino)-2-methylbenzamide.
[097] For example, in certain compounds of Formula IA, R2' is Ci-Ce, alkyl. Such as, for example, R1 is methyl or isopropyl.
[098] For example, in certain compounds of Formula IA, R22 is a 6-membered saturated carbocycle or a 6-membered saturated heterocycle. Such as, for example, R22 is cyclohexyl or tetrahydropyranyl. In some compounds, the cyclohexyl is substituted with N(Ci alkyl such as, e.g., N(CH3)2.
[099] For example, in certain compounds of Formula IA, R22 is tetrahydropyranyl.
[0100] For example, in certain compounds of Formula IA, Rl a is 4-7 membered saturated heterocycle. For example, Rl a is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or diazepanyl.
[0101 ] For example, R23 is ethyl.
[0102] For example, R24 is methyl.
[0103] For example, m is 0 or 1.
[0104] In another aspect, the invention relates to compound according to Formula Ilia:
Figure imgf000019_0001
solvate thereof, wherein R101 is hydrogen, C C6 alkyl, or C C6 haloalkyl;
R102 is hydrogen or halogen;
R'03 is hydro gen or Ci-Q alkyl; and
R104 is hydrogen or Ci-C6 alkyl; provided that when R10' is methyl, and when R102 and R103 are hydrogen, R104 is not hydrogen.
[0105] For example, in certain compounds of Formula Ilia, R101 is Ci-Q alkyl. Such as, for example, R101 is methyl, n-propyl, or isopropyl.
[0106] In certain compounds of Formula Ilia, R101 is C1-C6 haloalkyl. For example, R101 is CF3, CF2H, or CF¾. In certain compounds of Formula Ilia, R101 is CF3.
[0107] For example, in certain compounds of Formula Ilia, R102 is halogen. For example, R102 is fluoro.
[0108] In another aspect, the invention relates to compound according to Formula Illb:
Figure imgf000020_0001
solvate thereof, wherein
Xi is N or CH;
R201 is hydrogen, C,-C6 alkyl, CrC6 haloalkyl;
R202 is hydrogen or Ci-C6 alkyl;
R203 is (a) OH, (b) Cj-Q alkyl, (c) 0(C,-C6 alkyl), (d) (CH2)r3-8 membered saturated, unsaturated, or aromatic carbocycle, (e) (C¾)k-3-8 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (f) 0-(CH2)u-3-8 membered saturated, unsaturated, or aromatic carbocycle, or (g) 0-(CI¾)v-3-8 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, where (b)-(g) are optionally substituted with R203A
R203A is C,-C6 alkyl, C C6 haloalkyl, OH, or 0(C,-C6 alkyl);
R204 is CrC6 alkyl;
t is 1, 2, or 3; u is 0, 1, 2, or 3;
v is 0, 1, 2 , or 3
z is 0, 1, 2, or 3;
j is O, 1, 2, or 3;
k is 0, 1, 2, or 3.
[0109] For example, in certain compounds of Formula Illb, Xi is N and X2 is CH. For example, in certain compounds of Formula III, R201 is Ci-Ce alkyl. For example, R201 is methyl.
[0110] For example, in certain compounds of Formula Illb, R202 is hydrogen. In certain other compounds of Formula III, R202 is Ci -C¼ alkyl. For example, R202 is methyl.
[01 11] For example, in certain compounds of Formula Illb, R203 is (CH2X-6 membered saturated heterocycle. For example, k is 1.
[0112] For example, in certain other compounds of Formula Illb, R203 is (CH2)-piperazinyl or
(Cty-morpholfnyl. For example, t is 1.
[0113] In certain compounds of Formula Illb, R204 is methyl.
[0114] In certain compounds of Formula Illb, z is 2.
to Formula IV:
Figure imgf000021_0001
wherein
Yi is N or CH;
Y2 is N or CH;
R30' is hydrogen, C C6 alkyl, C,-C6 haloalkyl;
R302 is (a) Ci-C6 alkyl (b) Ci-C haloalkyl, (c) 0(C,-C6 alkyl), (d) (C¾)r3-8 membered saturated, unsaturated, or aromatic carbocycle, (e) (CH2)k-3-8 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (f) 0-(C¾)u-3-8 membered saturated, unsaturated, or aromatic carbocycle, or (g) 0-(CH2)v-3-8 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, where (a)-(g) are optionally substituted with R 02a
R302a is Ci-C6 alkyl, C,-C6 haloalkyl, OH, or 0(Ci-C6 alkyl);
t is 1, 2, or 3;
u is O, 1, 2, or 3;
v is 0, 1,2 , or 3;
j is 0, 1, 2, or 3; and
k is 0, 1, 2, or 3; provided that (i) when R302 is (CH2)-morpholinyl, R301 is not methyl, isopropyl or n-propyl; or (ii) R302 is not piperazinyl or (CH2)-piperazinyl.
[01 16] For example, in certain compounds of Formula IV, Yi is N and Y2 is CH.
[0117] For example, in certain compounds of Formula IV, R301 is Q-Ce alky. For example, R301 is methyl or isopropyl. In certain compounds, R301 is methyl. In other compounds R301 is Ci-C^ haloalkyl. For example, R301 is CF3, CF2H, or CFH . In some compounds, R301 is CF3.
[0118] For example, in certain compounds of Formula IV, R302 is 0(C C6 alkyl). For example, R302 is methoxy or isopropoxy. In certain other compounds, R302 is 0-4-6 membered saturated heterocycle. For example, the heterocycle is azetidinyl or pipendinyl. In certain compounds, of Formula IV, R302 is (CH2)-4-7 membered saturated heterocycle. For example, the heterocycle is azetidinyl, pyrrolidinyl, pipendinyl, morpholinyl, or diazepanyl.
to compound according to formula V:
Figure imgf000022_0001
salt or solvate thereof, wherein
W, is N or CH;
W2 is N or CH;
R40' is hydrogen, C,-C6 alkyl, C,-C6 haloalkyl;
Rm is (a) OH, (b) (CH2)-0-(C,-C6 alkyl), (c) 0(C,-C6 alkyl), (d) (CH2)j-3-8 membered saturated, unsaturated, or aromatic carbocycle, (e) C¾)k-3-8 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (f) 0-(CH2)u-3-8 membered saturated, unsaturated, or aromatic carbocycle, or (g) 0-(0¾)ν-3-8 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, where (b)-(g) are optionally substituted with R402* ,
R402a is C,-C6 alkyl, C,-C6 haloalkyl, OH, or 0(C,-C6 alkyl);
t is 1 , 2, or 3;
u is O, 1, 2, or 3;
v is O, 1,2 , or 3;
j is 0, 1, 2, or 3; and
k is 0, 1, 2, or 3; provided that when R402 is piperazinyl, Wi and W2 are N.
[0120] In certain compounds of Formula V, Wi is N and W2 is CH.
[0121 ] In certain compounds of Formula V, R401 is Ci-Ct alkyl. For example, R401 is methyl or isopropyl. For example, R401 is methyl.
[0122] In certain compounds of Formula V, R402 is (C¾)k-4-7 membered saturated heterocycle containing one or more nitrogen or oxygen atoms.
[0123] In certain compounds of Formula V, k is 0 or 1. For example, k is 0. For example, k is 1.
[0124] In certain compounds of Formula V, R4M is azetidinyl, piperazinyl, or piperidinyl.
[0125] In certain compounds, R402 is (CFy-azetidinyl, (Cty-pyrrolidinyl, (C¾)-piperidinyl, (CH2)-morpholinyl, or (C¾)-diazepanyl.
[0126] In certain compounds of Formula V, t is 1.
[0127] In certain compounds of Formula V, R402a is OH, methyl, or methoxy.
[0128] In another aspect, the invention relates to a compound of Formula VI:
Figure imgf000023_0001
(VI)
or a pharmaceutically acceptable salt or solvate thereof, wherein
n5 is 0, l, or 2;
R50' is C(H) or N;
R502, R503, R504 and R505 are, independently for each occurrence, CM alkyl; R is cyclohexyl substituted by N(C alkylh or iperidine substituted by 1, 2, or 3 Ci-4 alkyl groups;
when R50' is C(H), RS07 is morpholine; piperidine; diazepane; pyrrolidine; azetidine; O-Ci-6 alkyl; or O-heterocycle, wherein the heterocycle is a 4-7 membered heterocycle containing an oxygen or nitrogen, or both, and wherein the nitrogen can optionally be substituted with C1.3 alkyl; wherein the piperidine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH, Ci-6 alkyl, or O-C1.3 alkyl;
or when RS01 is C(H), R507 can be piperazine optionally further substituted with .6 alkyl, provided that R506 is piperidine substituted by 1, 2, or 3 CM alkyl groups;
when R501 is N, R507 is morpholine; piperidine; piperazine; diazepane; pyrrolidine; azetidine; O-CM alkyl; or O-heterocycle, wherein the heterocycle is a 4-7 membered heterocycle containing an oxygen or nitrogen, or both, and wherein the nitrogen can optionally be substituted with C1.3 alkyl; wherein the piperidine, piperazine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH, Ci_6 alkyl, or O-C1.3 alkyl.
[0129] In certain compounds of Formula VI, R50' is C(H), and R507 is piperidine; diazepane; pyrrolidine; azetidine; O-Ci-6 alkyl; or O-heterocycle, wherein the heterocycle is a 4-7 membered heterocycle containing an oxygen or nitrogen, or both, and wherein the nitrogen can optionally be substituted with .3 alkyl; wherein the piperidine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH, Ci-6 alkyl, or O-C1-3 alkyl.
[0130] In certain compounds of Formula VI, R501 is C(H) and R507 is piperidine, diazepane, pyrrolidine, azetidine or O-CM alkyl, wherein the piperidine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH or Cj.6 alkyl.
[0131] In certain compounds of Formula VI, R501 is C(H), R507 is piperazine optionally further substituted with Ci-6 alkyl, and R506 is piperidine substituted by 1, 2, or 3 CM alkyl groups.
[0132] In certain compounds of Formula VI, R501 is N, and R507 is morpholine, piperidine, piperazine, diazepane, pyrrolidine, azetidine or O-Cj-6 alkyl, wherein the piperidine, piperazine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH or Ci_6 alkyl.
[0133] In certain compounds of Formula VI, R502 is methyl or isopropyl, and R503 is methyl.
[0134] In certain compounds of Formula VI, wherein R504 is methyl.
[0135] In certain compounds of Formula VI, RS05 is ethyl.
[0136] In certain compounds
[0137] In certain compounds
Figure imgf000025_0001
[0138] In certain compounds of Formula VI, when R5m is C(H), R5U is piperidine or diazepane, which are substituted with OH or Ci-6 alkyl, or when R501 is N, R507 is piperidine, piperazine, or diazepane, which are optionally further substituted with OH or Q alkyl.
[0139] In certain compounds of Formula VI, when R50' is C(H), R507 is piperidine substituted with Cj alkyl, or when R501 is N, R507 is piperidine substituted with OH or piperazine substituted with C alkyl.
[0140] In certain compounds of Formula VI, when R501 is N, R507 is unsubstituted piperazine.
[0141] In certain compounds of Formula VI, ns is 0 or 1.
[0142] In certain compounds of Formula VI, when R501 is C(H) orN, R507 is 0-C,.6 alkyl or O- heterocycle, and n? is 1.
[0143] In certain compounds of Formula VI, when R501 is C(H), R507 is unsubstituted piperazine and
R506 is piperidine substituted by 1 , 2, or 3 C alkyl groups.
[0144] In yet another aspect, the invention relates to a compound of Formula VII:
Figure imgf000025_0002
(VII)
or a pharmaceutically acceptable salt or solvate thereof; wherein
n¾ is 0, 1 or 2;
R602, R603, R60 and R605 are, independently for each occurrence, CM alkyl; or each of
R602and R603, independently is C alkoxyl;
Km is tetrahydropyran, cyclohexyl substituted by N(C alky¾ or piperidine substituted by 1, 2, or 3 CM alkyl groups; and R is morpholine, piperidine, piperazine, pyrrolidine, diazepane, azetidine or O-Ci alkyl, wherein the piperidine, diazepane or azetidine groups can be optionally further substituted with OH; Q alkyl optionally substituted with one or more halo; cycloalkyl; C(0)Ci alkyl; or 4- to 7-membered heterocycloalkyl optionally substituted with Ci alkyl; provided that when R606 is tetrahydropyran, r¾ is 0 or 2.
[0145] In certain compounds of Formula VII, R602 is methyl or isopropyl and R603 is methyl.
and R605 is ethyl.
Figure imgf000026_0001
[0149] In certain compounds of Formula VII, R607 is piperidine or diazepane, each of which is substituted with OH or Ci.6 alkyl.
[0150] In certain compounds of Formula VII, R607 is piperidine substituted with OH.
[0151] In certain compounds of Formula VII, R607 is piperidine substituted with Q alkyl optionally substituted with one or more halo; cycloalkyl; C(0)C alkyl; or 4- to 7-membered heterocycloalkyl.
[0152] In certain compounds of Formula VII, R607 is piperidine substituted with substituted with alkyl optionally substituted with one or more halo; cycloalkyl; C(0)Ci alkyl; or 4- to 7- membered heterocycloalkyl; and ¾ is 0.
[0153] In certain compounds of Formula VII, ¾ is 2.
[0154] In yet another aspect, the invention relates to a compound of Formula Vila
Figure imgf000026_0002
or a pharmaceutically acceptable salt or solvate thereof; wherein
RP2 is CH3 or OCH3, and
RP7 is C alkyl; C3.e cycloalkyl, or 4- to 7-membered heterocycloalkyl optionally substituted with CM alkyl.
[0155] In certain compounds of Formula Vila, R^ is cyclopropyl or cyclobutyl.
[0156] In certain compounds of Formula Vila, R^ is azetidinyl or piperidinyl, each optionally substituted with CH3.
[0157] In certain compounds of Formula Vila, is oxetanyl.
[0158] In yet another aspect, the invention relates to a compound of Formula Vllb
Figure imgf000027_0001
(Vllb)
or a pharmaceutically acceptable salt or solvate thereof; wherein
RP2 is CH3 or OCH3, and
RP7 is C(0)CM alkyl or CM haloalkyl.
[0159] In certain compounds of Formula Vllb, RP7 is C(0)CH3.
[0160] In certain compounds of Formula Vllb, RP7 is C¾CF3.
[0161] The present invention provides the compounds of Formula (Γ):
Figure imgf000027_0002
(I'), or a pharmaceutically acceptable salt thereof. In this formula,
Xi is N or CRu; X2 is N or CRt3;
Z is NR7Rs, OR7, S(0)„R7, or CR7RsRi4, in which n is 0, 1, or 2;
each of Rj, R5, R9, and Rio, independently, is H or C C6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOHj C(0)0-C|-C6 alkyl, cyano, C|-C6 alkoxyl, amino, mono-Ci-C6 alkylamino, di-Ci-C6 alkylamino, C3-Cs cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6- membered heteroaryl;
each of R2, R3, and R4, independently, is -Q1 -T1, in which Qi is a bond or C1 -C3 alkyl linker optionally substituted with halo, cyano, hydroxyl or Q-Ce alkoxy, and Ti is H, halo, hydroxyl, COOH, cyano, or RS], in which Rsi is C1-C3 alkyl, C2-C6 alkenyl, C2-C¾ alkynyl, C1-C6 alkoxyl, C(0)0-Ci -C6 alkyl, C3-Cg cycloalkyl, Ci-Cio aryl, amino, mono-Ci-C6 alkylamino, di-G- ¼ alkylamino, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and Rsi is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, COOH, C(0)0-C]-C6 alkyl, cyano, G-C6 alkoxyl, amino, mono-Ci-Q alkylamino, di-Ci-Ce alkylamino, C -C8 cycloalkyl, Ce-Cio aryl, 4 to 12- membered heterocycloalkyl, and 5- or 6-membered heteroaryl;
6 is C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more -Q2-T2, wherein Q2 is a bond or C1-C3 alkyl linker optionally substituted with halo, cyano, hydroxyl or C -Ce alkoxy, and T2 is H, halo, cyano, -ORa, - NRaRb, -(NRaRbRc)+A-,-C(0)Ra, -C(0)ORa, -C(0)NRaRb, -NRbC(0)R„
-NR C(0)ORa, -S(0¾Ra, -S(0)2NRaRb, or Rs2, in which each of R,, b, and Re,
independently is H or Rs3, A" is a pharmaceutically acceptable anion, each of Rs2 and Rs3, independently, is Ci-C alkyl, C3-CS cycloalkyl, Ci-Cio aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or ¾ and ¾ together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of Rs2, Rs3, and the 4 to 12-membered heterocycloalkyl ring formed by ¾ and Rb, is optionally substituted with one or more one ormore -Q3-T3, wherein <¾ is a bond or -C3 alkyl linker each optionally substituted with halo, cyano, hydroxyl or Ci-Ci alkoxy, and T3 is selected from the group consisting of halo, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, ORd, COORd, -S(0)2Rd,
-NRdRe, and -C(0)NR<jRe, each of Rd and R,, independently being H or C1-C6 alkyl optionally substituted with OH, 0-C C6 alkyl, or NH-Cj-Q alkyl, or
-Q3-T3 is oxo; or any two neighboring -Q2-T2, together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(0)0-Ci alkyl, cyano, Q alkoxyl, amino, mono-Ci alkylamino, di-Ci alkylamino, C3-Cg cycloalkyi, Ce-Qo aryl, 4 to 12- membered heterocycloalkyl, and 5- or 6-membered heteroaryl;
R7 is -Q4-T4, in which Q4 is a bond, C1-C4 alkyl linker, or C2-C4 alkenyl linker, each linker optionally substituted with halo, cyano, hydroxyl or Ci-C¾ alkoxy, and T4 is H, halo, cyano, NRfRg, -ORf, -C(0)Rf, -C(0)ORf, -C(0)NRfRg, -C(0)NRfORg,
-NRfC(0)Rg, -S(0) Rf, or Rs4, in which each of Rf and Rg, independently is H or Rss, each of s4 and ss, independently is C1-C6 alkyl, C2-Q alkenyl, C2-C6 alkynyl, C3-Cs cycloalkyi, C -C10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and each of Rs4 and Rss is optionally substituted with one or more -Q5-T5, wherein Qs is a bond, C(O), C(0)NRk, RkC(0), NRk, S(0)2, NRkS(0)2, or C1-C3 alkyl linker, Rk being H or C,-C6 alkyl, and T5 is H, halo, -Q alkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxyl, cyano, Ci-C6 alkoxyl, amino, mono-CrC6 alkylamino, di- -Ci alkylamino, C3- cycloalkyi, C6-C|0 aryl, 4 to 12- membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(0)qRq in which q is 0, 1, or 2 and R, is Ci-C6 alkyl, C2-C6 alkenyl, C2- alkynyl, C3-C8 cycloalkyi, C6-Ci0 aryl, 4 to 12- membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T5 is optionally substituted with one or more substituents selected from the group consisting of halo, Q-Ce alkyl, hydroxyl, cyano, Ci-Ci alkoxyl, amino, mono-C[-C6 alkylamino, di-Ci -C alkylamino, C3-Cs cycloalkyi, Ce-Cio aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T5 is H, halo, hydroxyl, or cyano; or-Qs-Ts is oxo;
each of Re, R| 1, R12, and R13, independently, is H, halo, hydroxyl, COOH, cyano, Rse, ORs6, or COORS6, in which RS6 is Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyi, 4 to 12-membered heterocycloalkyl, amino, mono-Ci-C¾ alkylamino, or di-Ci-C6 alkylamino, and Rs6 is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(0)0-Ci-C6 alkyl, cyano, -C6 alkoxyl, amino, mono-Ci-Cs alkylamino, and di- - alkylamino; or R7 and Rs, together with the N atom to which they are attached, form a 4 to 11-membered heterocycloalkyl ring having 0 to 2 additional heteroatoms, or R? and Rs, together with the C atom to which they are attached, form C3-C8 cycloalkyi or a 4 to 11-membered heterocycloalkyl ring having 1 to 3 heteroatoms, and each of the 4 to 1 1-membered heterocycloalkyl rings or C3-C8 cycloalkyi formed by R7 and Rs is optionally substituted with one or more -Qe-Te, wherein Qe is a bond, C(O), C(0)NRm, NRraC(0), S(0)2, or CrC3 alkyl linker, Rm being H or Ci-C6 alkyl, and T6 is H, halo, C| -C6 alkyl, hydroxyl, cyano, C|-C¾ alkoxyl, amino, mono-C| -C6 alkylamino, di- - Q alkylamino, C3-C8 cycloalkyi, C6-Q0 aryl, 4 to 12-membered heterocycloalkyl, 5- or 6- membered heteroaryl, or S(0)pRp in which p is 0, 1, or 2 and p is C\-C(, alkyl, CTQ, alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C C10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6- membered heteroaryl, and T¾ is optionally substituted with one or more substituents selected from the group consisting of halo, - alkyl, hydroxyl, cyano, C1-C6 alkoxyl, amino, mono-C|-C6 alkylamino, di-Ci-C6 alkylamino, C3-Cs cycloalkyl, C6-C10 aryl, 4 to 12- membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when Ί is H, halo, hydroxyl, or cyano; or -Q6- 6 is oxo; and
RM is absent, H, or C1 -C6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(0)0-Ci-Q alkyl, cyano, Q- C6 alkoxyl, amino, mono-Ci-C^ alkylamino, di-Q-C6 alkylamino, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl.
[0162] One subset of the compounds of Formula (Γ) includes those of Formula (la):
Figure imgf000030_0001
[0163] Another subset of the compounds of Formula (Γ) includes those of Formula (lb), (Ic), or (Id):
Figure imgf000030_0002
(Ib) (Ic) (Id)
[0164] The compounds of Formula (Γ), (la), (lb), (Ic), and (Id) can include one or more of the following features when applicable:
[0165] For example, X] is CRn and X2 is CR13. [0166] For example, i is CR| i and is N.
[0167] For example, X, is N and X2 is CRi
[0168] For example, X, is N and X2 is N.
[0169] For example, Z is NR7R8.
[0170] For example, Z is CRyReRw- [0171] For example, Z is OR7.
[0172] For example, Z is S(0 in which n is 0, 1 , or 2.
[0173] For example, Z is SR7.
[0174] For example, ¾ is unsubstituted C^-Cw aryl or unsubstituted 5- or 6-membered heteroaryl.
[0175] For example, R6 is C^-Cio aryl substituted with one or more or 5- or 6-membered heteroaryl substituted with one or more -Q2-T2.
[0176] For example, R6 is unsubstituted phenyl.
[0177] For example, ¾ is phenyl substituted with one or more
[0178] For example, R is 5 to 6-membered heteroaryl containing 1-3 additional heteroatoms selected from N, O, and S and optionally substituted with one or more
[0179] For example, Rg is pyridinyl, pyrazolyl, pyrimidinyl, quinolinyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, or thienyl, each of which is optionally substituted with one or more
[0180] For example, is a bond.
[0181] For example, Q2 is an unsubstituted alkyl linker.
[0182] For example, T2 is Ci-Ce alkyl or aryl, each optionally substituted with one or more -
[0183] For example, is an unsubstituted substituted straight chain Ci-Q or branched -Q alkyl, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl.
[0184] For example, T2 is phenyl.
[0185] For example, T2 is halo (e.g., fluorine, chlorine, bromine, and iodine).
[0186] For example, T2 is 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyI, piperazinyl, tetrahydro-2H-pyranyl, 3,6- dihydro-2H-pyranyl, tetrahydro-2H-thiopyran, moφholinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa- 5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6- diazaspiro[3.3]heptanyl, and the like) optionally substituted with one or more
[0187] For example, T2 is -ORa, -NRaRb, -(NR )+A~ -C(0)Ra, -C(0)OR„
(0 -NRbC(0)Ra, -NRbC(0)ORa, -S(0)2Ra, or (0 [0188] For example, T2 is or -C(0)NR in which each of Ra and Rb, independently is H or Ci-Ce alkyl, or Ra and ¾, together with the atom to which they are attached, form a 4 to 7- membered heterocycloalkyl ring having 0 or 1 additional heteroatom, the Cj-Q alkyl and the 4 to 7- membered heterocycloalkyl ring being optionally substituted with one or more
[0189] For example, Q2 is alkyl linker optionally substituted with halo or hydroxyl.
[0190] For example, Q2 is a bond or methyl linker and is H, halo,
or -S(0)2NRaRb.
[0191] For example, each of Ra, Rb, and independently is H or alkyl optionally substituted with one or more
[01 2] For example, one of Ra> and is
[0193] For example, and together with the N atom to which they are attached, form a 4 to 7- membered heterocycloalkyl ring having 0 or 1 additional heteroatoms to the N atom (e.g., azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6- diazaspiro[3.3]heptanyl, and the like) and the ring is optionally substituted with one or more
[0194] For example, is oxo.
[0195] For example, T2 is 4 to 7-membered heterocycloalkyl or cycloalkyl and one or more - are oxo.
[0196] For example, Qj is a bond or unsubstituted or substituted -C3 alkyl linker.
[0197] For example, T3 is H, halo, 4 to 7-membered heterocycloalkyl, alkyl, OR* COORa,- (0 or
[0198] For example, one of ¾ and R^ is H.
[0199] For example, is phenyl or 5- or 6-membered heteroaryl substituted with alkyl or alkyl, each of which is optionally substituted with hydroxyl, alkyl or NH-Ci alkyl, each of the alkyl and H alkyl being optionally further substituted with alkyl or -C alkyl.
[0200] For example, R6 is
Figure imgf000032_0001
[0201] For example, R7 is not H.
[0202] For example, R7 is -C(0)Rf.
[0203] For example, R7 is -C(0)Rf, in which Rf is C3-C8 cycloalkyl.
[0204] For example, is aryl substituted with one or more
[0205] For example, R7 is phenyl optionally substituted with one or more [0206] For example, is alkyl optionally substituted with one or more
[0207] For example, is -Cg cycloalkyl optionally substituted with one or more
-Qs-T5.
[0208] For example, is 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetoahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6- dihydro-2H-pyranyl, tetrahydro-2H-thiopyran, and morpholinyl, and the like) optionally substituted with one or more
[0209] For example, is 5 to 6-membered heterocycloalkyl optionally substituted with one or more
[0210] For example, R7 is isopropyl.
[0211 ] For example, is pyrrolidinyl, piperidinyl, tetrahydropyran, cyclopentyl, cyclohexyl, or cycloheptyl, each optionally substituted with one
[0212] For example, is cyclopentyl or cyclohexyl, each optionally substituted with one [0213] For example, is pyrrolidinyl, piperidinyl, tetrahydropyran, tetrahydro-2H-thiopyranyl, cyclopentyl, cyclohexyl, or cycloheptyl, each optionally substituted with one or more
[0214] For example, is cyclopentyl, cyclohexyl or tetrahydro-2H-thiopyranyl, each optionally substituted with one or more
[0215] For example, is tetrahydropyran
Figure imgf000033_0001
[0216] For example, R7 is
[0217] For example, is
[0218] For example, is
Figure imgf000033_0002
[0219] For example, or I
[0220] For example,
Figure imgf000034_0001
[0221 ] For example, one or more -Q5 are oxo.
[0222] For example, is l-oxide-tetrahydro-2H-thiopyranyl or 1, l-dioxide-tetrahydro-2H- thiopyranyl.
[0223] For example, Q5 is a bond and Ts is amino, mono-Ci-C6 alkylamino, or di-Ci-Q alkylammo.
[0224] For example, Qs is NHC(O) and T5 is Ci-C6 alkyl or Ci-C6 alkoxy.
[0225] For example, -Q5-T5 is oxo.
[0226] For example, T4 is 4 to 7-membered heterocycloalkyl or C3-C8 cycloalkyl and one or more -
[0227] For example, T5 is H, halo, CrC6 alkyl, Q-C6 alkoxyl, C3-C8 cycloalkyl, Q-C10 aryl, or 4 to 7-membered heterocycloalkyl.
[0228] For example, (¾ is a bond and is C\-Ce alkyl, C3-C8 cycloalkyl, or 4 to 7-membered heterocycloalkyl.
[0229] For example, Q5 is CO, S(0)2, or NHC(O); and T5 is Ci-C6 alkyl, Ci-C6 alkoxyl, C3-C8 cycloalkyl, or 4 to 7-membered heterocycloalkyl.
[0230] For example, T5 is Ci-Ce alkyl or C\-C alkoxyl, each optionally substituted with halo, hydroxyl, cyano, C\-Ce alkoxyl, amino, mono-Cj-Ce alkylamino, di-Ci-Ce alkylamino, or C3-C¾ cycloalkyl.
[023Ϊ] For example, Q5 is C1 -C3 alkyl linker and T5 is H or C6-C10 aryl.
[0232] For example, Q5 is Q -C3 alkyl linker and T5 is C3-C8 cycloalkyl, 4 to 7-membered heterocycloalkyl, or S(0)qRq.
[0233] For example, Rn is H.
[0234] For example, each of 2 and R4, independently, is H or Q-Ce, alkyl optionally substituted with amino, mono-Ci-Q alkylamino, di-Ci-Ce alkylamino, or ¼-Cio aryl.
[0235] For example, each of R2 and R4, independently is C1 -C3 alkyl optionally substituted withQ- C6 alkoxyl.
[0236] For example, each of R2 and R4 is methyl. [0237] For example, Ri is H.
[0238] For example, is H, methyl, ethyl, ethenyl, or halo.
[0239] For example, is methyl.
[0240] For example, Ri? is ethyl.
[0241] For example, is ethenyl.
[0242] For example, Rg is H, methyl, ethyl, or ethenyl.
[0243] For example, Rg is methyl.
[0244] For example, Rg is ethyl.
[0245] For example, Rg is 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, l,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6- dihydro-2H-pyranyl, tetrahydro-2H-thiopyran, morpholinyl, 1,4-diazepanyl, 1 ,4-oxazepanyl, 2-oxa- 5-azabicyclo[2.2.1]heptanyl, 2>5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6- diazaspiro[3.3]heptanyl, and the like).
[0246] For example, Rg is tetrahydropyran.
[0247] For example, Rg is tetrahydropyran and R7 is -T4, in which is a bond or C1-C4 alkyl linker and T4 is H, Ci-C6 alkyl, Cj-Cg cycloalkyl or 4 to 7-membered heterocycloalkyl.
[0248] For example, neither R7 nor Rg is tetrahydropyran.
[0249] For example, Z is NR7 8 or CR7RgRi4 wherein R7 and R8, together with the atom to which they are attached, form a 4 to 11 -membered heterocycloalkyl ring having 1 to 3 heteroatoms (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1 ,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyran, and morpholinyl, 1,4- dioxa-8-azaspiro[4.S]decanyl, and the like) or C3-Cg cycloalkyl, each optionally substituted with one
[0250] For example, the ring formed by R7 and Rg is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, l ,4-dioxa-8-azaspiro[4.5]decanyl, and cyclohexenyl, each optionally substituted with one -Qe-T
[0251] For example, is oxo.
[0252] For example, T6 is H, halo, C C6 alkyl, Ci-C6 alkoxyl, C3-C3 cycloalkyl, C6-Ci0 aryl, or 4 to 7-membered heterocycloalkyl.
[0253] For example, Q6 is a bond and T6 is C\-C6 alkyl, C3-C3 cycloalkyl, or 4 to 7-membered heterocycloalkyl.
[0254] For example, Q6 is CO, S(0)2, or NHC(O); and T6 is C,-Q, alkyl, CrC6 alkoxyl, C3-C8 cycloalkyl, or 4 to 7-membered heterocycloalkyl. [0255] For example, T6 is Q-Ce alkyl or Ci-C^ alkoxyl, each optionally substituted with halo, hydroxyl, cyano, Ci-Ce alkoxyl, amino, mono-G-Q alkylamino, di-Ci-Q alkylamino, or C3-Cs cycloalkyl.
[0256] For example, (¾ is C1-C3 alkyl linker and T6 is H or C6-C10 aryl.
[0257] For example, Qe is C1-C3 alkyl linker and T(, is C3-Cg cycloalkyl, 4 to 7-membered heterocyclo alkyl, or S(0)pRp.
[0258] For example, each of Rp and R,, independently, is C!-C6 alkyl.
[0259] For example, R| 3 is H or methyl.
[0260] For example, R,3 is H.
[0261] For example, R3 is H.
[0262] For example, A" is Br" or CI".
[0263] For example, each of and Rio is H.
[0264] Still anoth (Γ) includes those of Formula (le), or (I
Figure imgf000036_0001
or a pharmaceutically acceptable salts thereof, wherein Z, X2, R2, R3, Re, and 12 are defined herein.
[0265] For example, R2, and R12 are each, independently alkyl.
[0266] For example, Re is C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is optionally, independently substituted with one or more -Q2-T2, wherein Qj is a bond or Q-C3 alkyl linker, and T2 is H, halo, cyano, -OR,, -NRA,, -(NRaRbRc)+A", -C(0)NRaRb,
-NRbC(0)Ra, -S(0)2Ra, or RS2, in which each of Ra and Rb, independently is H or Rs , each of Rs2 and Rs3, independently, is Cj-C¼ alkyl, or Ra and R , together with the N atom to which they are attached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of RS2, Rs3, and the 4 to 7-membered heterocycloalkyl ring formed by Ra and Rb, is optionally, independently substituted with one or more -Q3-T3, wherein Q3 is a bond or C\ -C3 alkyl linker and T3 is selected from the group consisting of halo, C| -C6 alkyl, 4 to 7-membered heterocycloalkyl, ORd, -S(0)2Rd, and -NRJRe, each of Rd and Re independently being H or Ci-Ce alkyl, or -Q3-T3 is oxo; or any two neighboring -Q2-T2, together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S. [0267] Another subset of the compounds of Formula (P) includes those of Formula (IT):
Figure imgf000037_0001
or pharmaceutically acceptable salts thereof,
wherein
is a bond or methyl linker;
T2 is H, halo, -(Ν¾¾¾)+Α~, or -S(0
is piperidinyl, tetrahydropyran, cyclopentyl, or cyclohexyl, each optionally substituted with one
is ethyl and
and are defined herein.
[0268] For example, (¾ is a bond
[0269] For example, is a methyl linker
[0270] For example, T2 is or )+A~.
[0271] Yet another subset of those of Formula (Ha):
Figure imgf000037_0002
or pharmaceutically acceptable salts thereof, wherein and are defined herein.
[0272] The compounds of Formula (IP) or (Ha) can include one or more of the following features when applicable:
[0273] For example, each of ¾ and independently is H or alkyl optionally substituted with one or more
[0274] For example, one of and is H.
For example, and together with the N atom to which they are attached, form a 4 to 7- membered heterocycloalkyl ring having 0 or 1 additional heteroatoms to the N atom (e.g., azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1 ,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, and the like) and the ring is optionally substituted with one or more -Q3-T3.
[0276] For example, R„ and ¾, together with the N atom to which they are attached, form azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, or morpholinyl, and the ring is optionally substituted with one or more -Q3-T3.
[0277] For example, one or more -Q3-T3 are oxo.
[0278] For example, Q3 is a bond or unsubstituted or substituted alkyl linker.
[0279] For example, T3 is H, halo, 4 to 7-membered heterocycloalkyl, CrC3 alkyl, ORd, COORd,-
S(0)2Rd, or-NRdRe-
[0280] For example, one of Rd and ¾ is H.
[0281 ] For example, R7 is C3-C8 cycloalkyl or 4 to 7-membered heterocycloalkyl, each optionally substituted with one or more -Q5-T5.
[0282] For example, R7 is piperidinyl, tetrahydropyran, tetrahydro-2H-thiopyranyl, cyclopentyl, cyclohexyl, pyrrolidinyl, or cycloheptyl, each optionally substituted with one or more -Q5-T5.
[0283] For example, R7 is cyclopentyl cyclohexyl or tetrahydro-2H-thiopyranyl, each optionally substituted with one or more -Q5-T5.
[0284] For example, Q5 is NHC(O) and T5 is C C6 alkyl or C,-C6 alkoxy.
[0285] For example, one or more -Q5-T5 are oxo.
[0286] For example, R7 is l-oxide-tetrahydro-2H-thiopyranyl or 1 , 1 -dioxide-tetrahydro-2H- thiopyranyl.
[0287] For example, Q5 is a bond and T5 is amino, mono-C]-C6 alkylamino, di-Ci-C6 alkylamino.
[0288] For example, Q5 is CO, S(0)2, or NHC(O); and T5 is C,-C6 alkyl, Ci-C6 alkoxyl, C3-C8 cycloalkyl, or 4 to 7-membered heterocycloalkyl.
[0289] For example, Rg is H or -Q alkyl which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(0)0-C!-C6 alkyl, cyano, Ci-C¾ alkoxyl, amino, mono-C alkylamino, and di-Ci alkylamino.
[0290] For example, Re is H, methyl, or ethyl.
[0291] Still another subset of compounds of Formula (Γ) includes those of Formula (ΠΓ):
Figure imgf000039_0001
fill'), or pharmaceutically acceptable salts thereof, wherein
R-3 is hydrogen, C1-C3 alkyl or halo;
is C1 -C3 alkyl,
R7 is C| -C6 alkyl, C3-C8 cycloalkyl or 4 to 7-membered heterocycloalkyl, optionally substituted with one or more Rsj
Re is Ci -C6 alkyl;
Rh is -Qh-Th, wherein Q is a bond, a C1-C3 alkyl linker or N(RN); TJ, is OR i or
-NRhiRh2, in which R i and Rh2 are independently hydrogen or C1-C6 alkyl, or one of Rhi and Rh2 is methyl and the other is a 6-membered N-containing heterocycloalkyl optionally substituted with one or two methyl, or together with the N atom to which they are attached, Rhi and Rh2 form a 4 to 7- membered heterocycloalkyl ring having 0 or 1 additional heteroatoms selected from oxygen and nitrogen, wherein said heterocycloalkyl ring is optionally substituted with one or more ¾;
Ri is Ci -C3 alkyl, -NRwiRra or a C3-C8 cycloalkyl or 5 or 6 membered heterocycle each of which cycloalkyl or heterocycle is independently optionally substituted with Rj;
RN is hydrogen, C\-C alkyl or C3-C8 cycloalkyl;
Rj is Ci-C3 alkyl, -NRN1RN2, 0r -NC(O)RN;
RNI and RN are each independently hydrogen, C\-Ce alkyl, C3-C8 cycloalkyl, 5 or 6 membered heterocycle, each of which cycloalkyl or heterocycle is independently optionally substituted with Rj.
[0292] For example, R3 is hydrogen.
[0293] For example, R3 is halogen, such as, for example, fluoro or chloro. For example, R3 is fluoro.
[0294] For example is methyl, ethyl, propyl, or isopropyl. For example, is methyl. For example, is isopropyl.
[0295] For example, R7 is 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropvriditiyl, pipetazinyl, tetrahydro-2H-pyranyl, 3,6- dihydro-2H-pyranyl, tetrahydro-2H-thiopyran, and morpholinyl, and the like). [0296] For example, 7 is a 5 or 6 membered cycloalkyl or heterocycloalkyl.
[0297] For example, R7 is a 6 membered cycloalkyl or heterocycloalkyl.
[0298] In some embodiments, R7 is piperidinyl, tetrahydropyranyl, cyclopentyl, or cyclohexyl.
[0299] In some embodiments, Rj is methyl. In some embodiments, Rj is N¾.
[0300] For example, Re is C], C2 or C3 alkyl. For example, Re is methyl. For example, R¾ is ethyl.
[0301] Γη some embodiments, Qh is a bond. In others, Qh is methylene.
[0302] In some embodiments, Th is N(CH3)2.
[0303] In some embodiments, one of Rhi and Rh2 is methyl and the other is a 6-membered N- containing heterocycloalkyl optionally substituted with one or two methyl. For example, the 6- membered N-containing heterocycloalkyl does not contain further heteroatoms in the ring. For example, the 6-membered N-containing heterocycloalkyl is not further substituted besides the one or two methyl groups.
[0304] In some embodiments, Rhi and Rh2, together with the N to which they are attached form a 6 membered ring. For example, Th is selected from piperidine, morpholine, piperazine, and N-methyl piperazine.
[0305] For example, Th is morpholine.
[0306] In some embodiments, R; is methyl or (CH3)2. In some embodiments, Rj is C3-C8 cycloalkyl or 5 or 6 membered heterocycle. For example, R, is a 6 membered cycloalkyl or heterocycle, substituted with zero or one Rj.
[0307] In some embodiments, RN is H or methyl.
[0308] In certain compounds of Formula ΙΙΓ, 3 is hydrogen, R4 is C¾ and Qh is methylene.
[0309] In certain compounds of formula III', R3 is fluoro, R4 is isopropyl and Qh is a bond.
[0310] In certain compounds of formula III', R3 is hydrogen, R4 is propyl or isopropyl and Qh is methylene.
[0311] In certain compounds of formula ΙΙΓ, R3 is hydrogen, R4 is propyl or isopropyl and Qh is a bond.
[0312] In certain compounds of formula ΙΙΓ, compounds are of Formula (Hie),
Figure imgf000040_0001
wherein R3 is H or F
methyl,
Figure imgf000041_0001
or .
[0313] Compounds of the invention include those of Formula I", and pharmaceutically acceptable salts or solvates thereof:
Figure imgf000041_0002
In this formula,
Xi ' is N or CRi,';
X2' is N or CRn';
is N or C, and when is N, ¾' is absent;
Z2 is NR7'R8', OR7', S(0)a-R7\ or CRy'Rs'Ru', in which a' is 0, 1, or 2; each of Ri', R5', R9', and Rio', independently, is H or Cj-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy!, COOH, C(0)0-C|-C6 alkyl, cyano, Cj-C6 alkoxyl, amino, mono-Ci-C6 alkylamino, di-Ci-C6 alkylamino, C3-C8 cycloalkyl, C6-Cio aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl;
each of R2', R3', and ^, independently, is -Qi '-ΊΥ, in which Qi ' is a bond or Q-C3 alkyl linker optionally substituted with halo, cyano, hydroxyl or C|-C6 alkoxy, and TV is H, halo, hydroxyl, COOH, cyano, azido, or Rsi ', in which Rsi' is C1 -C3 alkyl, C2-C6 alkenyl, C2- C6 alkynyl, C C6 alkoxyl, C(0)0-CrC6 alkyl, C3-C8 cycloalkyl, C6-Cio aryl, amino, mono- Ci-Ce alkylamino, di-Ci-Ce alkylamino, 4 to 12-membered heterocycloalkyl, or 5- or 6- membered heteroaryl, and Rsi' is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, COOH, C(0)0-Ci-Ce alkyl, cyano, C1-C6 alkoxyl, amino, mono-Q-Q alkylamino, di-Ci-Cj alkylamino, C3-C8 cycloalkyl, Q- C10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl;
IV is H, halo, cyano, azido, OR,', -NRa'Rb', -C(0)Ra', -C(0)ORa', -C(0)NRa'Rb', - NRb'C(0)Ra', -S(0)b-Ra', -S(0)b.NRa'Rb', or RS2', in which Rs2' is Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, or 4 to 12-membered heterocycloalkyl, b' is 0, 1, or 2, each of Ra' and Rb', independently is H or Rs3', and Rs3' is Cj-C6 alkyl, Cz-Ce alkenyl, C2- C6 alkynyl, C3-C8 cycloalkyl, C6- 0 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6- membered heteroaryl; or Ra' and Rb', together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom; and each
Figure imgf000042_0001
and the 4 to 12-membered heterocycloalkyl ring formed by Ra' and Rb', is optionally substituted with one or more -Q2'-T2\ wherein Q2' is a bond or C1-C3 alkyl linker each optionally substituted with halo, cyano, hydroxyl or Ci-Q alkoxy, and T2' is H, halo, cyano, -OR-', -NRc'Rd', -C(0)Rc', -C(0)ORc\ -C(0)NRc'Rd\ -NRd'C(0)Rc', - NRd'C^OR-', -S(0)2Ro', -S(0)2NRc'Rd', orRS4', in which each of Rc' and d', independently is H or Rs5', each of R^' and RS5', independently, is Q-Ce alkyl, C3-C8 cycloalkyl, C6-C]0 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or Rc' and Rd', together with the N atom to which they are attached, form a 4 to 12- membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each
Figure imgf000042_0002
Rss', and the 4 to 12-membered heterocycloalkyl ring formed by Rc' and Rd', is optionally substituted with one or more -Q3'-T3', wherein Q3' is a bond or C1-C3 alkyl linker each optionally substituted with halo, cyano, hydroxyl or C]-Cs alkoxy, and T3' is selected from the group consisting of halo, cyano, Q-Ce alkyl, C -C8 cycloalkyl, Ce-Qo aryl, 4 to 12- membered heterocycloalkyl, 5- or 6-membered heteroaryl, ORe', COORe', -S(0)2Re', - NRe'Rr', and -C(0)NRe'Rf', each of Re' and Rf' independently being H or Q -C6 alkyl, or - Q3'-T3' is oxo; or-Q2'-T ' is oxo; provided that -Q2'-T2' is not H;
R7' is -Q4 in which Q4' is a bond, CrC4 alkyl linker, or C2-C4 alkenyl linker, each linker optionally substituted with halo, cyano, hydroxyl or Ci-Ce alkoxy, and T4' is H, halo, cyano, NRg'Rh', -ORg', -C(0)Rg\ -C(0)ORg', -C(0) Rg'Rh', -C(0)NRg'ORh', - NRg'C(0)Rh', -S(0)2Rg', or se', in which each of Rg' and Rh', independently is H or Rs7', each of s6' and Rs7', independently is C] -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C¾-C|o aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and each of Rse' andRS7' is optionally substituted with one or more -Q5'-T5', wherein Q5' is a bond, C(O), C(0)NRk', NRk'C(0), NRk', S(0)2, NRk'S(0)2, or C1-C3 alkyl linker, Rk' being H or Ci-C6 alkyl, and T5' is H, halo, Cj-Q alkyl, C2-C6 alkenyl, C2-(¾ alkynyl, hydroxyl, cyano, Ci-Ce alkoxyl, amino, mono-Ci-Ce alkylamino, di-Ci-Ci alkylamino, C3-C8 cycloalkyl, Ce-Cio aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(0),'Rq' in which q' is 0, 1, or 2 and R,* is Q-Q alkyl, C2-C<s alkenyl, C2-C6 alkynyl, C3-Cg cycloalkyl, C aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T5' is optionally substituted with one or more substituents selected from the group consisting of halo, -C alkyl, hydroxyl, cyano, Ci- s alkoxyl, amino, mono-Ci-Ci alkylammo, di-Ci-C6 alkylamino, C3-Cg cycloalkyl, Ci-Cio aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T5 is H, halo, hydroxyl, or cyano; or-Qs'-Ts' is oxo; provided that is not H;
Figure imgf000043_0001
Rn ', and independently, is H, halo, hydroxyl, COOH, cyano, Rss\ ORss', or COORS8', in which Rsg' is C,-C6 alkyl, C -C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4 to 12-membered heterocycloalkyl, amino, mono-Ci-C6 alkylamino, or di-Ci-Cs alkylamino, and Rss* is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(0)0-Ct-C6 alkyl, cyano, Ci-Ce alkoxyl, amino, mono-Ci-Ci alkylamino, and di-Ci-C6 alkylamino; or and Rg', together with the N atom to which they are attached, form a 4 to 1 -membered heterocycloalkyl ring having 0 to 2 additional heteroatoms, or and Rs', together with the C atom to which they are attached, form C3-C8 cycloalkyl or a 4 to 12-membered heterocycloalkyl ring having 1 to 3 heteroatoms, and each of the 4 to 12-membered heterocycloalkyl rings or C3-C3 cycloalkyl formed by R7' and is optionally substituted with one or more -Qe'-Tf,', wherein Qe' is a bond, C(O), C(0)NRm\ NRm'C(0), S(0)2, or Cj-Cj alkyl linker, being H or C,-C6 alkyl, and Te is H, halo, Cj-Q alkyl, hydroxyl, cyano, CpC^ alkoxyl, amino, mono-Ci-Q alkylamino, di-Q-Q alkylamino, C3-C8 cycloalkyl, Q-Cio aryl, 4 to 12-membered heterocyclo lkyl, 5- or 6-membered heteroaryl, or S(0)p'Rp' in which p' is 0, 1, or 2 and is d-Qs alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-Ci0 aryl, 4 to 12- membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and TV is optionally substituted with one or more substituents selected from the group consisting of halo, Ci-Ce alkyl, hydroxyl, cyano, Ci-(¾ alkoxyl, amino, mono-C|-C6 alkylamino, di- -Cs alkylamino, C3-C8 cycloalkyl, Ce-Cio aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when Tt is H, halo,
Figure imgf000043_0002
is oxo; and
' is absent, H, or Ci-Ci alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(0)0-Ci-C6 alkyl, cyano, Cj- Cs alkoxyl, amino, mono-Ci-C6 alkylamino, di-Ci alkylamino, C3-Cg cycloalkyl, aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl. provided that the compound is not
N-(5-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-2- methylphenyl)furan-2-carboxamide,
N,N'-(5-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-l,3- phenylene)diacetamide,
N-((4,6-dimethyl-2-oxo-l,2-dmydropyridin-3-yl)methyl)-3-pivalamidobenzamide, 3-(3,4-dihydro-2H-benzo[b][l,4]dioxepine-7-sulfonamido)-N-((4,6-dimethyl-2-oxo- l,2-dihydropyridin-3-yl)methyl)benzamide,
N-((4,6-dimemyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3,5-dimethoxybenzamide, N-((4,6-dimemyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3,4,5-trimethoxybenz amide,
3- allyl-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-4,5- dimethoxybenzamide,
4- (2-ammo-2-oxoethoxy)-3-chloro-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)-5-methoxybenzamide,
3-chloro-N-((4,6-dimemyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-4-hydroxy-5- methoxybenzamide, or
3-bromo-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-5-methoxy-4- propoxybenzamide.
[0314] One subset of the compounds of Formula (I") includes those of Formula (I"a):
Figure imgf000044_0001
[0315] Another subset of the eompounds of Formula (I") includes those of Formula (I"b), (I"c), or (I"d):
Figure imgf000045_0001
(Tb) (I"c) (I"d)
[0316] Yet another subset of the compounds of Formula (1") includes those of Formula (IIA):
Figure imgf000045_0002
or pharmaceutically acceptable salts thereof, wherein n is 0, 1, or 2; U is O, S, N-Qj'-Ts', or CH- is CI, Br, or methyl; and Rg', Q5', and are defined herein.
[0317] Still another subset of the compounds of Formula (I") includes those of Formula (IIB):
Figure imgf000045_0003
or pharmaceutically acceptable salts thereof, wherein is a 4 or 6-membered heterocycloalkyl having one nitrogen atom in the ring and is substituted with one or two methyl groups or one i-propyl group; R3' is H or F; 4' is methyl, ethyl, n-propyl, isopropyl, or CF3, and R6' is CF3, CI, or F, provided that when is methyl, (1) R ' is CF3, or (2) R3' is F, or (3) R6' is CF3 and R3' is F, or (4) IV is F or CI and is a 6-membered heterocycloalkyl having only one nitrogen and is substituted with two methyl groups.
[0318] The compounds of Formulae (I"), (Fa), (I"b), (I"c), (IIA) and (IIB) can include one or more of the following features when applicable:
[0319] For example, X, ' is CRu' and ¾' is CR|3'.
[0320] For example, X, ' is CR, , ' and X2' is N.
[0321] For example, X, ' is N and X2' is CR1 3\
[0322] For example, X, ' is N and X2' is N.
[0323] For example, X3 is C.
[0324] For example, is N and ¾' is absent.
[0325] For example, Z2 is Rv'Rs'-
[0326] For example, Z2 is CR7'R8'Ri4'.
[0327] For example, Z2 is OR7' .
[0328] For example, Z2 is S(0)a.R7\ in which a' is 0, 1, or 2
[0329] For example, R6' is H.
[0330] For example, Re'is halo (e.g., fluorine, chlorine, bromine, and iodine).
[0331] For example, Rs'is not fluorine.
[0332] For example, Re' is CrC3 alkyl optionally substituted with one or more -Qj'-TY.
[0333] For example, Re' is CF3.
[0334] For example, R6' is C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl each optionally substituted with one or more -(¾'-¾'.
[0335] For example, R6' is ethenyl.
[0336] For example, R(,' is ethynyl.
[0337] For example, is ethynyl substituted with one or more -Q2'-T2', in which (¾' is a bond or
C]-C3 alkyl linker and T2' is CrC6 alkyl, C3-C6 cycloalkyl, or 4 to 7-membered heterocycloalkyl
(e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazoiidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyiidinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1 ,4-diazepanyl, 1 ,4- oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, and morpholinyl, and the like) optionally substituted with one or more -Q3'-T3'.
[0338] For example, ¾' is cyano.
[0339] For example, ¾' is azido.
[0340] For example, ¾' is C(0)H.
[0341] For example, R6' is ORa' or -C(0)Ra'. [0342] For example, Ra' is C\ -C6 alkyl or 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H- pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-£hiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa- 5-azabicyclo[2.2. l]heptanyl, 2,5-diazabicyclo[2.2. l]heptanyl, and morpholinyl, and the like), which is optionally substituted with one or more -Q2'-T2'.
[0343] For example, ¾' is 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6- dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, and morpholinyl, and the like) optionally substituted with one or more -Q2'-T2'.
[0344] For example, I is piperidinyl, 2,2,6,6-tetramethyl-piperidinyl, 1,2,3,6-tetrahydropyridinyl, 2,2,6,6-tetramethyl-l,2,3,6-tetrahydropyridinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, or pyrrolidinyl, each of which is optionally substituted with one or more - Q-'-TY.
[0345] For example, Re' is 4 to 7-membered heterocycloalkyl optionally substituted with one or more -Q2'-T2', and -Q2'-T2' is oxo or Q2' is a bond and ΊΥ is -OR,;', -NRc'Rj', -C(0)Rc', - C(0)ORc', -S(0)2Rc', C†-Q alkyl, or 4 to 7-membered heterocycloalkyl, each of which is optionally substituted with one or mor when Rc' or Rd' is not H.
[0346] For example, R6' is
Figure imgf000047_0001
-C(0)Ra', -C(0)ORa', -NRb'C(0)Ra', -SR*', -
Figure imgf000047_0002
[0347] For example, each of Ra' and Rb', independently is H, Ci-C6 alkyl, or C3-C8 cycloalkyl optionally substituted with one or more -Q2'-T2'.
[0348] For example, one of Ra' and Rb' is H.
[0349] For example, Ra' and Rb\ together with the N atom to which they are attached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatoms to the N atom (e.g., azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicycIo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, and morpholinyl, and the like) and the ring is optionally substituted with one or more -Q2'-T2'.
[0350] For example, -Q2'-T2' is oxo.
[0351] For example, Q2' is a bond.
[0352] For example, Q2' is an unsubstituted C1 -C3 alkyl linker. [0353] For example, T2' is C C alkyl or C6-Cio aryl, each optionally substituted with one or more -Q3'-T3'.
[0354] For example, T ' is an unsubstituted substituted straight chain Q-Q or branched alkyl, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl and n-hexyl.
[0355] For example, is phenyl.
[0356] For example, is halo (e.g., fluorine, chlorine, bromine, and iodine).
[0357] For example, T2' is 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6- dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1 ,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, and morpholinyl, and the like) optionally substituted with one or more
[0358] For example, T2' is (0 -0(0)0^', or (0
[0359] For example, is Ci-Q alkyl or 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H- pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1 ,4-oxazepanyl, 2-oxa- 5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, and morpholinyl, and the like), which is optionally substituted with one or more
[0360] For example, each of and independently is H or C\-C6 alkyl optionally substituted with one or more -<¾'-Τ3'
[0361] For example, is H.
[0362] For example, is H.
[0363] For example, and together with the N atom to which they are attached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatoms to the N atom (e.g., azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2. l]heptanyl, 2,5-diazabicyclo[2.2. l]heptanyl, and morpholinyl, and the like) and the ring is optionally substituted with one or more -Q
[0364] For example, Q2' is a bond and T2' is -C(0 -C(0 -S(0 C,- alkyl, or 4 to 7-membered heterocycloalkyl, each of which is optionally substituted with one or more when or is not H.
[0365] For example,-Q3'-T3' is oxo. [0366] For example, T2' is 4 to 7-membered heterocycloalkyl or C3-C8 cycloalkyl and one or more - '-Ts' are oxo.
[0367] For example, Q3' is a bond or unsubstituted or substituted Q-C3 alkyl linker.
[0368] For example, T3' is H, halo, 4 to 7-membered heterocycloalkyl, C1-C3 alkyl, OR*', COOR,.',-
8(θ)2¾',-Ν¾¾', or -C(0)NRc'Rf'.
[0369] For example, one of Rd' and ¾' is H.
[0370] For example, (¾' is a bond or C1-C3 alkyl linker and T3' is selected from the group consisting of C C3 alkyl, halo, θ¾',
Figure imgf000049_0001
-NRe'Rf', and-C(0)NRe'Rf' .
[0371] For example, Q3' is a bond or C1-C3 alkyl linker and T3' is selected from the group consisting of C,-C3 alkyl, O , -S(0)2Rc', or -NRe'Rf'.
[0372] For example, Re' is H.
[0373] For example, Rf' is H.
[0374] For example, R7' is -C(0)Rg'.
[037 ] For example, R7' is -C(0)Rg', in which Rg' is C3-C3 cycloalkyl, 4 to 7-membered heterocycloalkyl, C3-C8 cycloalkyl.
[0376] For example, R7' is C6-C|o aryl substituted with one or more -Qi'-Ts'.
[0377] For example, R7' is phenyl optionally substituted with one or more -Qs'-Ts'.
[0378] For example, R7' is C^-C6 alkyl optionally substituted with one or more -Q5'-T5'.
[0379] For example, R7' is C3-C8 cycloalkyl optionally substituted with one or more
-Qs'-iy.
[0380] For example, is 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6- dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1 ,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2, -diazabicyclo[2.2.1]heptanyl, and morpholinyl, and the like) optionally substituted with one or more -Qs'-Ts'.
[0381] For example, is 5 to 6-membered heterocycloalkyl optionally substituted with one or more -Qs'-Ts'.
[0382] For example, is isopropyl.
[0383] For example, is pyrrolidinyl, piperidinyl, tetrahydropyran, cyclopentyl, or cyclohexyl, cycloheptyl, each optionally substituted with one -Qs'-Ts'.
[0384] For example, R7' is cyclopentyl or cyclohexyl, each optionally substituted with one -Q5'- T5' .
[0385] For example, R7' is tetrahydropyran
Figure imgf000050_0001
[0386] For example, R7'
[0387] For example, R7'
[0388] For example, R7'
[0389] For example, R7'
[0390] For example, R7'
Figure imgf000050_0002
is
[0391] For example, Q5' is NHC(O) and T5' is C|-C6 alkyl or C,-C6 alkoxy.
[0392] For example, -Q5'-T5' is oxo.
[0393] For example, is 4 to 7-membered heterocycloalkyl, C3-C8 cycloalkyl, or Ce-Cio aryl, and one or more -Qs'-Ts' are oxo.
[0394] For example, R7' is l-oxide-tetrahydro-2H-thiopyranyl or 1 , 1 -dioxide-tetrahydro-2H- thiopyranyl.
[0395] For example, R7' is cyclohexanonyl, e.g., cyclohexanon-4-yl.
[0396] For example, T5' is H, halo, C,-C6 alkyl, CrC6 alkoxyl, C3-C8 cycloalkyl, Ce-Cio aryl, or 4 to 7-membered heterocycloalkyl. [0397] For example, (¾' is a bond and is Ci-Ci alkyl, cycloalkyl, or 4 to 7-membered heterocycloalkyl.
[0398] For example, Q5' is a bond and T5' is 5- or 6-membered heteroaryl, amino, mono-Ci-C6 alkylamino, di- -Ce alkylamino, T5' being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy!, C|-Ce alkoxyl, or C3-C8 cycloalkyl.
[0399] For example, <¼' is CO, S(0)2, or NHC(O); and Ts' is C Q alkyl, C,-C6 alkoxyl, C3-C8 cycloalkyl, or 4 to 7-membered heterocycloalkyl.
[0400] For example, Ts' is Ci-Ce alkyl or Ci-C6 alkoxyl, each optionally substituted with halo, hydroxyl, cyano, C\-C alkoxyl, amino, mono-Ci-Ci alkylamino, di-C]-C6 alkylamino, or C3-C8 cycloalkyl.
[0401] For example, Q5' is C1-C3 alkyl linker and T5' is H or C6-Cio aryl.
[0402] For example, Qj' is C1-C3 alkyl linker and T5' is C3-C8 cycloalkyl, 4 to 7-membered heterocycloalkyl, or S(0)q'Rq\
[0403] For example, IVis halo (e.g., fluorine, chlorine, bromine, and iodine) and Z2 is
Figure imgf000051_0001
in which a' is 0, 1, or 2 and R7' is Q-C6 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, butyl, or t-butyl), C3-Cs cycloalkyl (e.g., cyclopentyl, cyclohexyl, or cycloheptyl) or 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyI, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1,4- oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, and morpholmyl, and the like) and is optionally substituted with one or more -Qs'-Ts'.
[0404] For example, Ri'is halo (e.g., fluorine, chlorine, bromine, and iodine) and Z2 is ORy'.in which R7' is 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyI, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H- pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1 ,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, and morpholmyl, and the like) and R?' is optionally substituted with one or more -Qs'-Ts'.
[0405] For example, Ri 1 ' is H.
[0406] For example, each of R2' and R4', independently, is H or Ci-Ct alkyl optionally substituted with azido, halo, amino, mono-Q-Ca alkylamino, di-Ci-C¼ alkylamino, or C -C o aryl.
[0407] For example, each of R2' and R4', independently is C1-C3 alkyl optionally substituted with C1-C6 alkoxyl.
[0408] For example, each of R2' and R4' is methyl.
[0409] For example, Ri' is H.
so [0410] For example, Ri' is Q-Q alkyl optionally substituted with azido, halo, amino, mono-Cj-Cs alkylamino, di-Ci-Ci alkylamino, or Ce-Cio aryl.
[041 1] For example, R12' is H, methyl, ethyl, ethenyl, or halo.
[0412] For example, R^' is methyl.
[0413] For example, R^' is ethyl.
[0414] For example, R12' is ethenyl or propenyl.
[0415] For example, R12' is methoxyl.
[0416] For example, Rg' is H, methyl, ethyl, or ethenyl.
[0417] For example, R8 ' is methyl.
[0418] For example, Rg' is ethyl.
[0419] For example, R8' is propyl.
[0420] For example, R is ethenyl or propenyl.
[0421] For example, Rs' is Ci-C alkyl substituted with one or more substituents selected from the group consisting of halo (e.g., F, CI, or Br), hydroxyl, or Cj-Cs alkoxyl.
[0422] For example, Rs' is 4 to 7-membered optionally substituted heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyI, 1,4-diazepanyl, 1,4- oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, and morpholinyl, and the like).
[0423] For example, Rg' is piperidinyl.
[0424] For example, Rs' is 4 to 7-membered optionally substituted heterocycloalkyl and R7' is - Q4' -T4', in which Q4' is a bond or CrC alkyl linker and T4' is H, C,-C3 alkyl, C3-C8 cycloalkyl or 4 to 7-membered heterocycloalkyl.
[0425] For example, neither R7' nor Rs' is tetrahydropyran.
[0426] For example, 2 is NR7'Rs' or CRy'Rg' w' wherein R7' and Rs', together with the atom to which they are attached, form a 4 to 11-membered heterocycloalkyl ring having 1 to 3 heteroatoms (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 1,4- oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, morpholinyl, and the like) or C3-C8 cycloalkyl, each optionally substituted with one or more -Qe'-TV.
[0427] For example, the ring formed by R7' and Rs' is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and cyclohexenyl, each optionally substituted with one -Qe'-TV . [0428] For example, -Qe'-TV is oxo.
[0429] For example, T6' is H, halo, C,-C6 alkyl, d-Q, alkoxyl, C3-C8 cycloalkyl, C6-Ci0 aryl, or 4 to 7-membered heterocycloalkyl.
[0430] For example, (¾' is a bond and is C|-C6 alkyl, cycloalkyl, or 4 to 7-membered heterocycloalkyl.
[0431] For example, Q6' is CO, S(0)2, or NHC(O); and T6' is Ci-C6 alkyl, Ci-C6 alkoxyl, C3-Cg cycloalkyl, or 4 to 7-membered heterocycloalkyl.
[0432] For example, Ύ ' is C] -C6 alkyl or C|-C6 alkoxyl, each optionally substituted with halo, hydroxyl, cyano, Ci-C^ alkoxyl, amino, mono-Ci-Cg alkylamino, di-Q-Q alkylamino, or C3-C8 cycloalkyl.
[0433] For example, Q6' is C1-C3 alkyl linker and TV is H orC^-Cio aryl.
[0434] For example, Qjs' is C1-C3 alkyl linker and Te' is C3-Q cycloalkyl, 4 to 7-membered heterocycloalkyl, or S(0)p'Rp'.
[0435] For example, each of Rp' and q', independently, is C1 -C6 alkyl.
[0436] For example, R^'is -S(0)b.Ra' or azido, in which b' is 0, 1, or 2 and Ra' is C\-C alkyl or C3- Cs cycloalkyl; and Z2 is Μ¾¾', in which R7' is C3-Cg cycloalkyl (e.g., cyclopentyl, cyclohexyl, or cycloheptyl) or 4 to 7-membered heterocycloalkyl (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, terrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H- pyranyl, tetrahydro-2H-thiopyranyl, 1 ,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, and morpholinyl, and the like), each optionally substituted with one or more -Qs'-Ts' and R¾' is H or C^-C alkyl (e.g., methyl, ethyl, n- propyl, i-propyl, butyl, or t-butyl).
[0437] For example, R(,'is halo (e.g., fluorine, chlorine, bromine, and iodine) and ¾ is N v'Rs' or CR7'Rg' i4' wherein R7' and Rg', together with the atom to which they are attached, form a 4 to 1 1- membered heterocycloalkyl ring having 1 to 3 heteroatoms (e.g., azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, tetrahydro-2H-pyranyl, 3,6- dihydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1 ,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1 ]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, moφholinyl, and the like) or C3-C8 cycloalkyl, each optionally substituted with one or more -Qe'-Te'.
[0438] For example, R13' is H or methyl.
[0439] For example, Rn' is H.
[0440] For example, R3' is H.
[0441] For example, each of R5', R9', and R|0' is H. [0442] In addition to the above-described features of the compounds of this invention where applicable, the compounds of Formula (IIA) can include one or more of the following features:
[0443] For example, (¾' is a bond and T5' is H, Ci-Ce alkyl, C3-C8 cycloalkyl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, amino, mono-Ci-C6 alkylamino, or di-Ci-Ce alkylamino, T5' being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, C1-C6 alkoxyl, or C3-C8 cycloalkyl.
[0444] For example, Q5' is CO, S(0)2, or NHC(O); and T5' is Ci-C6 alkyl, d-C6 alkoxyl, C3-C8 cycloalkyl, or 4 to 12-membered heterocycloalkyl.
[0445] For example, Q5' is C1-C3 alkyl linker and T5' is H or Q-C10 aryl.
[0446] For example, Q5' is C1-C3 alkyl linker and T5' is C3-C8 cycloalkyl, 4 to 12-membered heterocycloalkyl, or S(0)qRq.
[0447] For example, Q5' is NHC(O) and T5' is C,-C6 alkyl or C,-C6 alkoxy.
[0448] For example, one or more -Qj'-Ts' are oxo.
[0449] For example, U is CH-Q5'-T5' and n is 0
[0450] For example, one or more -Ο^'-Τό' are oxo.
[0451] For example, (¾' is a bond or C(O) and T6' is
Figure imgf000054_0001
alkyl or Q-C6 alkoxy.
[0452] Representative compounds of the present invention include compounds listed in Tables 1A and IB.
Figure imgf000054_0002
Figure imgf000055_0001
S4
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001

Figure imgf000060_0001
Figure imgf000061_0001
60
Figure imgf000062_0001
Figure imgf000063_0001
62
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
65
Figure imgf000067_0001
66
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
[0453] As used herein, "alkyl", "Ci, C2, C3, C4, C5 or C6 alkyl" or "Ci-C 6 alkyl" is intended to include Cj, C2, C3, C4, C5 or C6 straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5 or C(, branched saturated aliphatic hydrocarbon groups. For example, C -C6 alkyl is intended to include Ci, C2, C3, C4, C5 and Cg alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl or n-hexyl.
[0454] In certain embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., for straight chain, for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.
[0455] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated nonaromatic hydrocarbon mono-or multi-ring (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C10). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantyl. The term "heterocycloalkyl" refers to a saturated or unsaturated nonaromatic 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, or Se), unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahyrofuranyl, oxiranyl, azetidinyl, oxeranyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, 1 ,4-diazepanyl, 1 ,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5- diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1 ,4-dioxa- 8-azaspiro[4.5]decanyl and the like.
[0456] The term "optionally substituted alkyl" refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
[0457] An "arylalkyl" or an "aralkyl" moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)). An "alkylaryl" moiety is an aryl substituted with an alkyl (e.g., methylphenyl).
[0458] As used herein, "alkyl linker" is intended to include Cr, C2, C3, C4, C5 or C6 straight chain (linear) saturated divalent aliphatic hydrocarbon groups and C3, C4, C5 or (, branched saturated aliphatic hydrocarbon groups. For example, C\-C(, alkyl linker is intended to include Ci, C2, C3, C4, C5 and C¾ alkyl linker groups. Examples of alkyl linker include, moieties having from one to six carbon atoms, such as, but not limited to, methyl (-CH2-), ethyl (-CH2CH2-), n-propyl (- CH2CH2CH2-), i-propyl (-CHCH3CH2-), n-butyl (-C¾CH2CH2CH2-), s-butyl (-CHCH3CH2C¾-), i-butyl (-C(CH3) 2CH2-), n-pentyl (-CH2CH2CH2CH2CH2-), s-pentyl (-CHCH3CH2CH2CH2-) or n- hexyl (-CH2CH2CH2CH2CH2CH2-).
[0459] "Alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term "alkenyl" includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2- ¾ for straight chain, C for branched chain). The term "C includes alkenyl groups containing two to six carbon atoms. The term -C6" includes alkenyl groups containing three to six carbon atoms.
[0460] The term "optionally substituted alkenyl" refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
[0461] "Alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, "alkynyl" includes straight chain alkynyl groups (e.g. , ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g. , C2-(¼ for straight chain, C^-C^ for branched chain). The term "C2-C6" includes alkynyl groups containing two to six carbon atoms. The term "C^-C " includes alkynyl groups containing three to six carbon atoms.
[0462] The term "optionally substituted alkynyl" refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
[0463] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6- tetramethyl-l,2,3,6-tetrahydropyridinyl.
[0464] "Aryl" includes groups with aromaticity, including "conjugated," or multicyclic systems with at least one aromatic ring and do not contain any heteroatom in the ring structure. Examples include phenyl, benzyl, 1,2,3,4-tetrahydronaphthalenyl, etc.
[0465] "Heteroaryl" groups are aryl groups, as defined above, except having from one to four heteroatoms in the ring structure, and may also be referred to as "aryl heterocycles" or
"heteroaromatics." As used herein, the term "heteroaryl" is intended to include a stable 5-, 6-, or 7- membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1- 6 heteroatoms, or e.g. , 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e. , N or NR wherein R is H or other substituents, as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e. , N→0 and S(0)p, where p = 1 or 2). It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.
[0466] Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.
[0467] Furthermore, the terms "aryl" and "heteroaryl" include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.
[0468] In the case of multicyclic aromatic rings, only one of the rings needs to be aromatic (e.g., 2,3-dihydroindole), although all of the rings may be aromatic (e.g., quinoline). The second ring can also be fused or bridged.
[0469] The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl).
[0470] As used herein, "carbocycle" or "carbocyclic ring" is intended to include any stable monocyclic, bicyclic or tricyclic ring having the specified number of carbons, any of which may be saturated, unsaturated, or aromatic. Carbocycle includes cycloalkyl and aryl. For example, a carbocycle is intended to include a monocyclic, bicyclic or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13 or 14 carbon atoms. Examples of carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl, indanyl, adamantyl and tetrahydronaphthyl. Bridged rings are also included in the definition of caxbocycle, including, for example, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane and [2.2.2]bicyclooctane. A bridged ring occurs when one or more carbon atoms link two non- adjacent carbon atoms. In one embodiment, bridge rings are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge. Fused (e.g., naphthyl, tetrahydronaphthyl) and spiro rings are also included.
[0471] As used herein, "heterocycle" or "heterocyclic group" includes any ring structure (saturated, unsaturated, or aromatic) which contains at least one ring heteroatom (e.g., N, O or S). Heterocycle includes heterocycloalkyl and heteroaryl. Examples of heterocycles include, but are not limited to, morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazine, oxetane, pyran, tetrahydropyran, azetidine, and tetrahydrofuran.
[0472] Examples of heterocyclic groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4ai/-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2/i,6ii-l,5,2-dithiazinyl, dihydrofuro[2,3-¾]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, li -indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridmyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, l,2,5-oxadiazolyl, 1,3,4- oxadiazolyl, l,2,4-oxadiazol5(4H)-one, oxazolidinyl, oxazolyi, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4fl"-quinolizinyl, quinoxalinyl, quinuclidinyl, terrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6ii-l,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4- triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl.
[0473] The term "substituted," as used herein, means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =0), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
[0474] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and or variables are permissible, but only if such combinations result in stable compounds.
[0475] When any variable (e.g., Ri) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence.
Thus, for example, if a group is shown to be substituted with 0-2 R] moieties, then the group may optionally be substituted with up to two | moieties and i at each occurrence is selected independently from the definition of Ri . Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.
[0476] The term "hydroxy" or "hydroxyl" includes groups with an -OH or -O".
[0477] As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo and iodo. The term
"perhalogenated" generally refers to a moiety wherein all hydrogen atoms are replaced by halogen atoms. The term "haloalkyl" or "haloalkoxyl" refers to an alkyl or alkoxyl substituted with one or more halogen atoms.
[0478] The term "carbonyl" includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom. Examples of moieties containing a carbonyl include, but are not limited to, aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.
[0479] The term "carboxyl" refers to -COOH or its Ci-Q alkyl ester.
[0480] "Acyl" includes moieties that contain the acyl radical (R-C(O)-) or a carbonyl group. "Substituted acyl" includes acyl groups where one or more of the hydrogen atoms are replaced by, for example, alkyl groups, alkynyl groups, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylammo, dialkylammo, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. [0481 ] "Aroyl" includes moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc.
[0482] "Alkoxyalkyl," "alkylaminoalkyl," and "thioalkoxyalkyl" include alkyl groups, as described above, wherein oxygen, nitrogen, or sulfur atoms replace one or more hydrocarbon backbone carbon atoms.
[0483] The term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.
[0484] The term "ether" or "alkoxy" includes compounds or moieties which contain an oxygen bonded to two carbon atoms or heteroatoms. For example, the term includes "alkoxyalkyl," which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to an alkyl group.
[0485] The term "ester" includes compounds or moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group. The term "ester" includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.
[0486] The term "thioalkyl" includes compounds or moieties which contain an alkyl group connected with a sulfur atom. The thioalkyl groups can be substituted with groups such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxyacid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties.
[0487] The term "thiocarbonyl" or "thiocarboxy" includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
[0488] The term "thioether" includes moieties which contain a sulfur atom bonded to two carbon atoms or heteroatoms. Examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls. The term "alkthioalkyls" include moieties with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group. Similarly, the term "alkthioalkenyls" refers to moieties wherein an alkyl, alkenyl or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkenyl group; and alkthioalkynyls" refers to moieties wherein an alkyl, alkenyl or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.
[0489] As used herein, "amine" or "amino" refers to unsubstituted or substituted -N¾- "Alkylamino" includes groups of compounds wherein nitrogen of -N¾ is bound to at least one alkyl group. Examples of alkylamino groups include benzylamino, methylamino, ethylamino, phenethylamino, etc. "Dialkylamino" includes groups wherein the nitrogen of -N¾ is bound to at least two additional alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino and diethylamino. "Arylamino" and "diarylamino" include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively. "Aminoaryl" and "aminoaryloxy" refer to aryl and aryloxy substituted with amino. "Alkylarylamino," "alkylaminoaryl" or "arylaminoalkyl" refers to an amino group which is bound to at least one alkyl group and at least one aryl group. "Alkaminoalkyl" refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group. "Acylamino" includes groups wherein nitrogen is bound to an acyl group. Examples of acylamino include, but are not limited to, alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
[0490] The term "amide" or "aminocarboxy" includes compounds or moieties that contain a nitrogen atom that is bound to the carbon of a carbonyl or a thiocarbonyl group. The term includes "alkaminocarboxy" groups that include alkyl, alkenyl or alkynyl groups bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group. It also includes
"arylaminocarboxy" groups that include aryl or heteroaryl moieties bound to an amino group that is bound to the carbon of a carbonyl or thiocarbonyl group. The terms "alkylaminocarboxy", "alkenylaminocarboxy", "alkynylaminocarboxy" and "arylaminocarboxy" include moieties wherein alkyl, alkenyl, alkynyl and aryl moieties, respectively, are bound to a nitrogen atom which is in turn bound to the carbon of a carbonyl group. Amides can be substituted with substituents such as straight chain alkyl, branched alkyl, cycloalkyl, aryl, heteroaryl or heterocycle. Substituents on amide groups may be further substituted.
[0491] Compounds of the present invention that contain nitrogens can be converted to N-oxides by treatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid (mCPBA) and/or hydrogen peroxides) to afford other compounds of the present invention. Thus, all shown and claimed nitrogen-containing compounds are considered, when allowed by valency and structure, to include both the compound as shown and its N-oxide derivative (which can be designated as N-»0 or TNT-O" ). Furthermore, in other instances, the nitrogens in the compounds of the present invention can be converted to N-hydroxy or N-alkoxy compounds. For example, N-hydroxy compounds can be prepared by oxidation of the parent amine by an oxidizing agent such as ίκ-CPBA. All shown and claimed nitrogen-containing compounds are also considered, when allowed by valency and structure, to cover both the compound as shown and its N-hydroxy (i.e., N-OH) and N-alkoxy (i.e., N-OR, wherein R is substituted or unsubstituted Ci-C 6 alkyl, Cj-Cs alkenyl, Ci-C6 alkynyl, 3-14-membered carbocycle or 3-14-membered heterocycle) derivatives.
[0492] In the present specification, the structural formula of the compound represents a certain isomer for convenience in some cases, but the present invention may include all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, enantiomers, rotamers, diastereomers, racemates and the like, it being understood that not all isomers may have the same level of activity. In addition, a crystal polymorphism may be present for the compounds represented by the formula. It is noted that any crystal form, crystal form mixture, or anhydride or hydrate thereof is included in the scope of the present invention.
[0493] "Isomerism" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereoisomers," and stereoisomers that are non- superimposable mirror images of each other are termed "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture."
[0494] A carbon atom bonded to four nonidentical substituents is termed a "chiral center."
[0495] "Chiral isomer" means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed "diastereomeric mixture." When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1 66, 5, 385; errata 51 1; Cahn et al. , Angew. Chem. 1966, 78, 13 ; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al, Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).
[0496] "Geometric isomer" means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cylcobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold- Prelog rules.
[0497] It is to be understood that the compounds of the present invention may be depicted as different chiral isomers or geometric isomers. It should also be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present invention, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity.
[0498] Furthermore, the structures and other compounds discussed in this invention include all atropic isomers thereof, it being understood that not all atropic isomers may have the same level of activity. "Atropic isomers" are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.
[0499] "Tautomer" is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism.
[0500] Of the various types of tautomerism that are possible, two are commonly observed. In keto- enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.
Figure imgf000088_0001
[0502] Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-Iactim, amide-imidic acid tautomerism in heterocyclic rings {e.g., in nucleobases such as guanine, thymine and cytosine), imine-enamine and enamine-enamine. An example of keto-enol equilibria is between pyridin-2( 1H)- ones and the corresponding pyridin-2-ols, as shown below.
Figure imgf000089_0001
pyridin-2(1H)-one pyridin-2-ol
[0503] It is to be understood that the compounds of the present invention may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present invention, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.
[0504] The term "crystal polymorphs", "polymorphs" or "crystal forms" means crystal structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of the compounds can be prepared by crystallization under different conditions.
[0505] The compounds of this invention include the compounds themselves, such as any of the formulae disclosed herein. The compounds of this invention may also include their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted benzene compound. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate). The term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt.
Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted benzene compound. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. The substituted benzene compounds also include those salts containing quaternary nitrogen atoms.
[0506] Additionally, the compounds of the present invention, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.
[0507] "Solvate" means solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as ¾0.
[0508] As used herein, the term "analog" refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.
[0509] As defined herein, the term "derivative" refers to compounds that have a common core structure, and are substituted with various groups as described herein. For example, all of the compounds represented by Formula (F) are substituted benzene compounds, and have a common core.
[0510] The term "bioisostere" refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonimides, tetrazoles, sulfonates and phosphorates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.
[0511] The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include C-13 and C-14.
[0512] The present invention provides methods for the synthesis of the compounds of any Formula disclosed herein. The present invention also provides detailed methods for the synthesis of various disclosed compounds of the present invention according to the following schemes as shown in the Examples.
[0513] Throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
[0514] The synthetic processes of the invention can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt, ester, or prodrug thereof.
[0515] Compounds of the present invention can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March 's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser 's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present invention.
[0516] One of ordinary skill in the art will recognize that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999.
[0517] Preferred protecting groups include, but are not limited to:
[0518] For a hydroxyl moiety: TBS, benzyl, THP, Ac
[051 ] For carboxylic acids: benzyl ester, methyl ester, ethyl ester, allyl ester
[0520] For amines: Cbz, BOC, DMB [0521] For diols: Ac (x2) TBS (x2), or when taken together acetonides
[0522] For thiols: Ac
[0523] For benzimidazoles: SEM, benzyl, PMB, DMB
[0524] For aldehydes: di-alkyl acetals such as dimethoxy acetal or diethyl acetyl.
[0525] In the reaction schemes described herein, multiple stereoisomers may be produced. When no particular stereoisomer is indicated, it is understood to mean all possible stereoisomers that could be produced from the reaction. A person of ordinary skill in the art will recognize that the reactions can be optimized to give one isomer preferentially, or new schemes may be devised to produce a single isomer. If mixtures are produced, techniques such as preparative thin layer chromatography, preparative HPLC, preparative chiral HPLC, or preparative SFC may be used to separate the isomers.
The following abbreviations are used throughout the specification and are defined below: AA ammonium acetate
ACN acetonitrile
Ac acetyl
AcOH acetic acid
arm atmosphere
aq. aqueous
BID or b.i.d. bis in die (twice a day)
tBuO potassium t-butoxide
Bn benzyl
BOC tert-butoxy carbonyl
BOP (benzotriazol- 1 -yloxy)tris(dimethylamino)- phosphoniumhexafluorophosphate
Cbz benzyloxy carbonyl
CDC¾ deuterated chloroform
CH2 ¾ dichloromethane
CO U ( 1 -Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethyl- amino-morpholino-carbenium hexafluorophosphate
d days
DBU 1 , 8-diazabicyclo [5.4.0]undec-7-ene
DCE 1,2 dichloroethane
DC dichloromethane
DEAD Diethyl azodicarboxylate
DIAD Diisopropyl azodicarboxylate [0548] DiBAL-H diisobutyl aluminium hydride
[0549] DIPEA Ν,Ν-diisopropylethylamine (Hunig's base)
[0550] DMA Dimethylacetamide
[0551] DMAP N, N dimethyl-4-aminopyridine
[0552] DMB 2,4 dimethoxy benzyl
[0553] DMF N,N-Dimethylformamide
[0554] DMSO Dimethyl sulfoxide
[0555] DPPA Diphenylphosphonic azide
[0556] EA or EtOAc Ethyl acetate
[0557] EDC or EDCI N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide
[0558] Et20 diethyl ether
[0559] ELS Evaporative Light Scattering
[0560] ESI- Electrospray negative mode
[0561] ESI+ Electrospray positive mode
[0562] Et3N or TEA triethylamine
[0563] EtOH ethanol
[0564] FA formic acid
[0565] FC orFCC Flash chromatogrpahy
[0566] h hours
[0567] ¾0 water
[0568] HATU 0-(7-Azabenzotriazol- 1 -yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate
[0569] HOAT 1 -Hydroxy-7-azabenzotriazole
[0570] HOBt 1 -Hydroxybenzotriazole
[0571] HO-Su N-Hydroxysuccinimide
[0572] HC1 hydrogen chloride or hydrochloric acid
[0573] HPLC High performance liquid chromatography
[0574] K2C03 potassium carbonate
[0575] KHMDs Potassium hexamethyldisilazide
[0576] LC/MS or LC-MS Liquid chromatography mass spectrum
[0577] LDA Lithium diisopropylamide
[0578] LiHMDs Lithium hexamethyldisilazide
[0579] LG leaving group
[0580] M Molar
[0581] m/z mass/charge ratio [0582] m-CPBA meta-chloroperbenzoic acid
[0583] MeCN Acetonitrile
[0584] MeOD d4-methanol
[0585] Mel Methyl iodide
[0586] MS3A 3A molecular sieves
[0587] MgS04 Magnesium Sulfate
[0588] min minutes
[0589] Ms Mesyl
[0590] MsCl Mesyl chloride
[0591] MsO Mesylate
[0592] MS Mass Spectrum
[0593] MWI microwave irradiation
[0594] Na2C03 sodium carbonate
[0595] Na2S04 sodium sulfate
[0596] NaHC03 sodium bicarbonate
[0597] NaHMDs Sodium hexamethyldisilazide
[0598] NaOH sodium hydroxide
[0599] NaHCOj sodium bicarbonate
[0600] Na2S04 sodium sulfate
[0601] NIS N-iodosuccinimide
[0602] NMR Nuclear Magnetic Resonance
[0603] o/n or O N overnight
[0604] PoVC Palladium on carbon
[0605] Pd(dppf)Cl2.DCM [1,1 '-Bis(diphenylphosphino)ferrocene]
dichloropalladium(Il),complex with dichloromethane
[0606] PPAA 1-Propanephosphonic acid cyclic anhydride
[0607] Pd(OH)2 Palladium dihydroxide
[0608] PE Petroleum Ether
[0609] PG protecting group
[0610] PMB para methoxybenzyl
[0611] p.o. per os (oral adinsitration)
[0612] ppm parts per million
[0613] prep HPLC preparative High Performance Liquid Chromatography
[0614] prep TLC preparative thin layer chromatography
[0615] p-TsOH para-toluenesulfonic acid [0616] PYBOP (Benzotriazol-l-yloxy)tripyrrolidinophosplionium
hexafluorophosphate
[0617] QD or q.d. quaque die (once a day)
[0618] RBF round bottom flask
[0619] RP-HPLC Reverse phase High Perfomance liquid chromatography
[0620] Rt or RT Room temperature
[0621] SEM (Trimethylsilyl)ethoxymethyl
[0622] SEMC1 (Trimethylsilyl)ethoxymethyl chloride
[0623] SFC Super critical chromatography
[0624] SGC silica gel chromatography
[0625] STAB Sodium triacetoxy borohydride
[0626] TBAF tetra-n-butylammonium fluoride
[0627] TBME iert-Butyl methyl ether
[0628] TEA Triethylamine
[0629] TFA trifluoroacetic acid
[0630] TfO triflate
[0631] THF tetrahydrofuran
[0632] THP tetrahydropyran
[0633] TID or ti.d ter in die (three times a day)
[0634] TLC thin layer chromatography
[0635] TMSC1 Trimethylsilyl chloride
[0636] Ts tosyl
[0637] TsOH to sic acid
[0638] uv ultraviolet
[0639] Compounds of the present invention can be conveniently prepared by a variety of methods familiar to those skilled in the art. The compounds of this invention with any Formula disclosed herein may be prepared according to the procedures illustrated in the Schemes below, from commercially available starting materials or starting materials which can be prepared using literature procedures. The Z and R groups (such as R, R2, Rj, R4, R6, R7, Rs, and R12) in the Schemes are as defined as the viriables in the corresponding positions in any of Formulae disclosed herein, unless otherwise specified.
[0640] One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. [0641 ] Scheme A depicts a route of synthesizing various pyridone moieties:
Scheme A
Figure imgf000097_0001
[0642] Scheme B depicts a route of synthesizmg various benzoic acid methyl ester intermediates:
Scheme B
Figure imgf000097_0002
[0643] Scheme C depicts a route of synthesizing various tetrahydropyran moieties:
Scheme C
Figure imgf000098_0001
97
Figure imgf000099_0001
ref.) WO200974812A1
Figure imgf000099_0002
Figure imgf000099_0003
Figure imgf000100_0001
then 4-hydroxypiperidine
[0644] Scheme D depicts a route of synthesizing various Dimethylaminocyclohexyl analogs:
Figure imgf000100_0002
[0645] Scheme 1 shows the synthesis of modified aryl analogs following a general route that utilizes well-established chemistry.
Figure imgf000100_0003
[0646] Scheme 1 shows the synthesis of modified aryl analogs following a general route that utilizes well-established chemistry. Substituted nitrobenzoic acids, many of which are commercially available or can be made by nitration of the appropriate substituted benzoic acids or other chemistry known to one skilled in the art, can be converted to their methyl esters by treatment with methyliodide in a polar solvent, such as DMF, in the presence of an appropriate base, such as sodium carbonate, at an appropriate temperature, such as 60 °C (Step 1). The nitro group can be reduced to an amine using an appropriate reducing agent, such as iron, in the presence of an acid, such as ammonium chloride, in a protic solvent, such as ethanol, at an appropriate temperature, such as 80 °C (Step 2). Introduction of the Rg can be done using a reductive amination with an appropriate ketone or aldehyde in the presence of an appropriate reducing agent, such as sodium cyanoborohydride, and catalytic acid, such as acetic acid, in an appropriate solvent, such as methanol. A variety of R7 groups can be introduced by alkylation using R7-LG, where LG is a leaving group, such as iodine, in the presence of a mild base, such as cesium carbonate, in an appropriate polar solvent, such as acetonitrile, at an appropriate temperature, such as 80 °C (Step 4). Alternatively, R7 groups can be introduced by reductive amination with R7-ketone or R7-aldehyde in the presence of an appropriate reducing agent, such as sodium cyanoborohydride, and catalytic acid, such as acetic acid, in an appropriate solvent, such as methanol. The ester moiety can be converted to an amide using a standard two step protocol. The ester can be hydrolyzed to the corresponding acid using a suitable base, such as sodium hydroxide, in a polar solvent, such as ethanol (Step 5). The acid would then be subjecting to a standard amide coupling reaction whereupon the appropriate amine would be added along with a suitable amide coupling reagent such as PYBOP in a suitable solvent such as DMSO to give the desired amide (Step 6).
Scheme 2
Figure imgf000101_0001
[0647] Depending upon the nature of the R6 substituent, further chemical modification could be employed to convert the R substituent into an alternative R¾ substituent. A representative sampling of such modifications could include hydrogenation, protecting group removal followed by additional amide coupling reactions, palladium catalyzed coupling reactions, reductive amination reactions or alkylation reactions. For example, as depicted in Scheme 2, if R6 is a bromide, alternative R substituents could then be introduced using standard transition metal-based protocols that rely upon a leaving group such as a bromide as a connection point. The bromide would be combined with an appropriate boronic ester derivative, in the presence of a mild base and a palladium catalyst in a polar solvent such as dioxane/water, at elevated temperature to give the desired new R6 substituent (i.e. Suzuki reaction). For example, as depicted in Scheme 3, if the Suzuki reaction is conducted with a boronic ester derivative bearing a formyl group further modification by reductive amination reaction with primary and secondary amines (e.g. morpholine, dimethylamine) can be conducted to introduce amine groups.
Scheme 3
Figure imgf000102_0001
[0648] Depending upon the nature of the R substituent, further chemical modification subsequent to Step 6 of Scheme 1 could be employed to convert the R7 substituent into an alternative R7 substituent. For example a protected amino group contained within R7 may be subjected to deprotection reaction (e.g. Boc group cleavage) to give free amino groups. Such free amino groups maybe subjected to reductive amination reactions or alkylation reactions to give substituted amines.
[0649] Scheme 4 shows the general synthesis of 2,6-disubstituted isonicotinamide compounds. Suzuki reaction in Step 1 of an aryl boronic acid compound with methyl 2,6-dichloroisonicoa'nate starting material can be used to introduce an aryl group which may be substituted with a functional group X that is suitable for further transformation. Such X groups include formyl or hydroxymethyl which can readily be transformed in Step 2 to various groups Y. Such Y groups include aminomethyl, monoalkylaminomethyl and dialkylaminomethyl groups. The latter can be prepared by reductive amination in the case where X is formyl or by converting X = hydroxymethyl to bromomethyl followed by alkylation with an amine. Ester hydrolysis a subsequent step gives an acid intermediate which can be coupled with appropriate 3-(aminomethyl)-pyridin-2(lH)-ones to give the penultimate 2-chloro-6-aryl-isonicotine amide intermediate. Suzuki reaction or amination reaction then gives compounds substituted in the 2-position with a Z group. In the case of an amination reaction examples of Z can be monoalkylamino or dialkylamino. In the case of a Suzuki reaction Z can be aryl, dihydroaryl or tetrahydroaryl such as cyclohexenyl.
Scheme 4
Figure imgf000103_0001
[0650] Scheme 5 shows the general synthesis of 6-aryl-3-methyl-picolinamides having monoalkylamino or dialkylamino groups in the 4-position. Starting from methyl 3-bromo-6- chloropicolinate oxidation to the N-oxide followed by chlorination with phosphorus oxychloride gives methyl 3-bromo-4,6-dichloropicolinate. The 4-chloro group can be selectively substituted with diverse mono and dialkyl amines which may also contain functional or protected functional groups that may be unmasked at a later stage. Palladium catalyzed methylation with tetramethyltin followed by ester hydrolysis and amide coupling with appropriate 3-(aminomethyl)-pyridin-2(lH)-ones yields penultimate 2-chloro pyridine intermediates. Suzuki coupling reaction group of these intermediates with aryl boronic acids results in replacement of the 2-chloro group with an aryl group. Thus, this yields 6-aryl-3-methyl-picolinamides having monoalkylamino or dialkylamino groups in the 4- position. The aryl group which may be substituted with a functional group X that remains in the final product oris converted to an another group by deprotection or functional group conversion reaction e.g. reductive amination.
Scheme 5
Figure imgf000103_0002
[0651] General syntheses of 3-(aminomethyl)-pyridin-2(lH)-ones intermediates for the amide coupling reaction from Scheme 1 are depicted in Scheme 6 below. In one method, a diketone can be condensed with 2-cyanoacetamide in the presence of an appropriate reagent such as piperidine acetate in a polar solvent such as ethanol to provide a cyanopyridone (Step 9). In another method, when R3 is H, an appropriately substituted alkynyl ketone can be condensed with 2-cyanoacetamide in the presence of an appropriate reagent such as piperidine acetate in a polar solvent such as ethanol to provide a cyanopyridone (Step 11). The cyano group can be reduced under appropriate conditions such as hydrogenation in the presence of catalytic Raney nickel in a polar solvent such as ammonium in methanol to provide the amine (Step 10).
Figure imgf000104_0001
[0652] Additionally, depending upon the nature of the R¾ R3, or group, further chemical modification can be employed to convert each of them independently into an alternative substituent. A representative sampling of such modifications can include hydrogenation, protecting group removal followed by additional amide coupling reactions, palladium catalyzed coupling reactions, reductive animation reactions, and alkylation reactions.
Scheme 4 depicts a variant of the general synthesis route of Scheme 1 based on 2-substituted (substituent is an R12 group) methyl 3-amino-5-bromo-benzoate starting materials. These starting materials can in turn be prepared from 2-substituted 3-nitro-benzoic acids which are commercially available or can be prepared by nitration of 2-substituted benzoic acids. Thus, bromination of 2- substituted 3-nitro-benzoic acids with a suitable reagent such as l,3-dibromo-5,5-dimethyl-2,4- imidazolidinedione yields the appropriate 2-substituted 3-nitro-5-bromo-benzoic acids. A variety of esterification and then nitro group reduction methods can then be sequentially implemented to prepare the 2-substituted methyl 3-amino-5-bromo-benzoate starting materials from the 2-substituted 3-nitro-5-bromo-benzoic acids. Scheme 7
Figure imgf000105_0001
[0653] As depicted in Scheme 7 the R7 group can be introduced from 2-substituted methyl 3-amino- 5-bromo-benzoates in Step 1 using a reductive amination with an appropriate R7-ketone or R7- aldehyde in the presence of an appropriate reducing agent such as sodium cyanoborohydride and catalytic acid such as acetic acid in an appropriate solvent such as methanol. Similarly, ¾ groups can be introduced in Step 2 by reductive amination with Rs-ketone or Rg-aldehyde in the presence of an appropriate reducing agent such as sodium cyanoborohydride and catalytic acid such as acetic acid in an appropriate solvent such as methanol. Alternatively, a variety of Rs groups can be introduced by alkylation using Rj-LG, where LG is a leaving group such as iodine, in the presence of a mild base such as cesium carbonate in an appropriate polar solvent such as acetonitrile at an appropriate temperature such as 80 °C. In Step 3, aryl groups corresponding to ¾ can be introduced by Suzuki reaction of the intermediate bromide with an appropriate aryl boronic acid or ester derivative, e,g, X-Ar-B(OH)2, in the presence of a mild base and a palladium catalyst in a polar solvent such as dioxane/ water, at elevated temperature. The X group in X-Ar-B(OH)2 may be a fully elaborated substituent on the aryl ring or may be a functional group that can be converted into another group by functional group modification. A representative sampling of such modifications could include hydrogenation, protecting group removal followed by additional amide coupling reactions, palladium catalyzed coupling reactions, reductive amination reactions or alkylation reactions. For example if the Suzuki reaction is conducted with a boronic acid derivative bearing a formyl group further modification by reductive amination reaction with primary and secondary amines (e.g. morpholine, dimethylamine) can be conducted to introduce amine groups. In Step 4 the ester moiety can be hydrolyzed to the corresponding acid using a suitable base such as sodium hydroxide in a polar solvent such as ethanol. In Step 5, the acid can be subjected to a standard amide coupling reaction whereupon the appropriate amine would be added along with a suitable amide coupling reagent such as PYBOP in a suitable solvent such as DMSO to give the desired amide. Depending upon the nature of the R7 substituent, further chemical modification subsequent to Step 5 of Scheme 4 could be employed to convert the R7 substituent into an alternative R7 substituent. For example a protected amino group contained within R7 may be subjected to deprotection reaction (e.g. Boc group cleavage) to give free amino groups. Such free amino groups may be subjected to reductive animation reactions or alkylation reactions to give substituted amines.
[0654] Scheme 8 below depicts the general synthesis of 2-monoalkylamino and 2-dialkylmino-3- substituted-6-aryl-isonicotinamides wherein the 3-substituent corresponds to and the 6-aryl group corresponds to R^, Formula Γ In Step 1 the 3-substituent may be introduced by the method described by Epsztain J. et al. Tetrahedron, 1991, v. 47, 1697-16708, by metallation of 2-chloro- isonicotinanilide with n-butyllithium followed by trapping with an an alkyliodide such as methyliodide or aldehyde or other electrophilic group.
s
Figure imgf000106_0001
Step-8
[0655] In cases where the trapping reagent yields a substituent with a functional group this group may be masked or converted into another functional group compatible with the subsequent chemical steps. In Step 2 anilide amide hydrolysis under standard acidic conditions maybe conducted followed by methyl ester synthesis under standard conditions for example as shown with methyl iodide and base gives corresponding methyl 2-chloro-3-substituted isonicotinates. In Step 4 an alkylamino group can be introduced by Buchwald coupling reaction of an R7NH7 monoalkylamine with the methyl 2-chloro-3-substituted isonicotinates. This reaction is well precedented for diverse 2- chloropyridine systems in the chemical literature. In an optional Step 5 for dialkylamino compounds R.8 groups can be introduced by reductive amination with Rg-ketone or Rs-aldehyde in the presence of an appropriate reducing agent such as sodium cyanoborohydride and catalytic acid such as acetic acid in an appropriate solvent such as methanol. Alternatively, a variety of s groups can be introduced by alkylation using Rs-LG, where LG is a leaving group such as iodine, in the presence of a mild base such as cesium carbonate in an appropriate polar solvent such as acetonitrile at an appropriate temperature such as 80 °C. In Step 6, oxidation to the N-oxide followed by chlorination with phosphorus oxychloride gives methyl 6-chloro-2-mono or dialkylamino-3-substituted isonicotinates. In Step 7 the ester moiety can be hydrolyzed to the corresponding acid using a suitable base such as sodium hydroxide in a polar solvent such as ethanol. In Step 8, the acid can be subjected to a standard amide coupling reaction whereupon the appropriate amine or substituted 3- (aminomethyl)-pyridin-2(lH)-one would be added along with a suitable amide coupling reagent such as PYBOP in a suitable solvent such as DMSO to give the desired amide.In Step 9, aryl groups corresponding to R¾ can be introduced by Suzuki reaction of the intermediate bromide with an appropriate aryl boronic acid or ester derivative, e,g, X-Ar-B(OH)2, in the presence of a mild base and a palladium catalyst in a polar solvent such as dioxane/water, at elevated temperature. The X group in X-Ar-B(OH)2 may be a fully elaborated substituent on the aryl ring or may be a functional group that can be converted into another group by functional group modification. A representative sampling of such modifications could include hydrogenation, protecting group removal followed by additional amide coupling reactions, palladium catalyzed coupling reactions, reductive amination reactions or alkylation reactions. For example if the Suzuki reaction is conducted with a boronic acid derivative bearing a formyl group further modification by reductive amination reaction with primary and secondary amines (e.g. morpholine, dimethylamine) can be conducted to introduce amine groups. Depending upon the nature of the R7 substituent, further chemical modification steps may be employed to convert the R7 substituent into an alternative R7 substituent. For example a protected amino group contained within R7 may be subjected to deprotection reaction (e.g. Boc group cleavage) to give free amino groups. Such free amino groups may be subjected to reductive amination reactions or alkylation reactions to give substituted amines.
Figure imgf000108_0001
[0656] Scheme 9 depicts a synthesis of modified aryl analogs following a general route that utilizes well-established chemistry. Starting with a substituted benzoic acid such as 5-chloro-2- methylbenzoic acid, nitration using standard conditions such as treatment with cone. H2SO4 and cone. HNO3 can provide the nitro analog. Esterification of the acid can be achieved using an alkylating agent such as methyl iodide in the presence of a base such as sodium carbonate in a polar solvent such as DMF. The nitro group can be reduced using conditions such iron and ammonium chloride in a protic solvent such as ethanol with heating to a temperature such as 80 °C. The resulting aniline can be converted to a bromide using a Sandmeyer reaction such treatment with CuB¾ and t-butyl nitrite in a solvent such as acetonitrile. A palladium catalyzed coupling of a thiol with the bromide can be achieved using a palladium source such as Pd(OAc)2 with a ligand such as Xanthphos in the presence of a base such as Ν,Ν-diisopropyl ethylamine in a solvent such as 1,4- dioxane optionally heating to a temperature such as 100 °C. The ester can be hydrolyzed with an aqueous base such as NaOH in water. The resulting acid can be coupled to the 3-(amino methyl)-4, 6-dimethylpyridin-2(lH)-one using standard amino acid coupling conditions such as PYBOP in DMSO. The resulting thioether may be oxidized to the corresponding sulfoxide or sulfone by using the appropriate equivalents of an oxidant such as m-CPBA in a solvent such as DCM. Aryl substituents can be incorporated by using palladium couplings such as a Suzuki reaction as described above.
Scheme 10
Figure imgf000109_0001
[0657] Scheme 10 depicts a synthesis of modified aryl analogs following a general route that utilizes well-established chemistry. Starting with a substituted aniline such as methyl 3-amino-S- chloro-2-methylbenzoate, the aniline can be converted to a phenol using a Sandmeyer reaction such as treatment with aqueous Na 02 solution in a aqueous acid such as 50% H2SO4. The phenol can be alkylated using an alkylating agent such as tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate in the presence of an appropriate base such as cesium carbonate in as polar solvent such as DMF optionally heating to a temperature such as 80 °C. The ester can be hydrolyzed with an aqueous base such as NaOH in water. The resulting acid can be coupled to the 3-(amino methyl)-4, 6- dimethylpyridin-2(lH)-one using standard amino acid coupling conditions such as PYBOP in DMSO. Aryl substituents can be incorporated by using palladium couplings such as a Suzuki reaction as described above.
Scheme 1'
Figure imgf000109_0002
Figure imgf000110_0001
[0658] Scheme 1 ' shows the synthesis of benzene analogs wherein Z = -N )(Rg) following a general route that utilizes well-established chemistry. Substituted nitrobenzoic acids, many of which are commercially available or can be prepared by nitrations of the appropriate substituted benzoic acids or other chemistry known to one skilled in the art, can be converted to their methyl esters by treatment with methyliodide in a polar solvent such as DMF in the presence of an appropriate base such as sodium carbonate at an appropriate temperature such as 60 °C (Step 1). The nitro group can be reduced to an amine using an appropriate reducing agent such as iron in the presence of an acid such as ammonium chloride in a pro tic solvent such as ethanol at an appropriate temperature such as 80 °C (Step 2). Introduction of the R7 can be done using a reductive amination with an appropriate -ketone or Ryaldehyde in the presence of an appropriate reducing agent such as sodium cyanoborohydride and catalytic acid such as acetic acid in an appropriate solvent such as methanol. A variety of Rg groups can be introduced by alkylation using Rj-LG, where LG is a leaving group such as iodine, in the presence of a mild base such as cesium carbonate in an appropriate polar solvent such as acetonitrile at an appropriate temperature such as 80 °C (Step 4). Alternatively, Rs groups can be introduced by reductive amination with Rg-ketone or Rg-aldehyde in the presence of an appropriate reducing agent such as sodium cyanoborohydride and catalytic acid such as acetic acid in an appropriate solvent such as methanol. The ester moiety can be converted to an amide using a standard two step protocol. The ester can be hydrolyzed to the corresponding acid using a suitable base such as sodium hydroxide in a polar solvent such as ethanol (Step 5). The acid would then be subjecting to a standard amide coupling reaction whereupon the appropriate amine would be added along with a suitable amide coupling reagent such as PYBOP in a suitable solvent such as D SO to give the desired amide (Step 6).
Scheme 2'
Figure imgf000111_0001
[0659] Depending upon the nature of the ¾¾ substituent, further chemical modification could be employed to convert the ¾ substituent into an alternative R$ substituent. A representative sampling of such modifications could include hydrogenation, protecting group removal followed by additional amide coupling reactions, palladium catalyzed coupling reactions, reductive amination reactions or alkylation reactions. For example, if ¾ is a bromide, alternative ¾ substituents could then be introduced using standard transition metal-based protocols that rely upon a leaving group such as a bromide as a connection point.
[0660] In one such protocol as depicted in Scheme 2' non-aromatic ¾ substituents attached via a carbon-carbon bond may be introduced by Suzuki reaction of a compound where ¾ = Br with an appropriate unsaturated non-aromatic boronic ester derivative (e.g. an olefinic boronic ester derivative such as vinyl 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane) in the presence of a mild base and a palladium catalyst in a polar solvent such as dioxane/water, at elevated temperature to give the desired new ¾ substituent. Depending upon the nature of the ¾ substituent, further chemical modification could be employed to convert the unsaturated ¾ substituent into an alternative ¾ substituent. A representative sampling of such modifications could include hydrogenation, protecting group removal followed by additional amide coupling reactions, palladium catalyzed coupling reactions, reductive amination reactions or alkylation reactions._For example, in cases where an unsaturated non-aromatic 1¾ group is introduced, further modification by hydrogenation can give the corresponding saturated ¾ group (e.g. conversion of a vinyl group to an ethyl group). In cases of where ¾ groups introduced have protected amine functionality further modifications include deprotection to give amines which may in subsequent steps be further modified for example by amide formation or reductive amination reactions.
[0661] In another protocol as depicted in Scheme 3', non-aromatic ¾ substituents attached via a carbon-carbon bond may be introduced by Sonogashira reaction of a compound where ¾ = Br optionally followed by further modification of the introduced alkynyl group. In the Sonogashira reaction, a compound where ¾ = Br is coupled with a terminal alkyne derivative in the presence of a mild base, a copper catalyst and a palladium catalyst in an organic solvent such as toluene at elevated temperature. This results in the replacement of the Br group with an alkynyl group. The resulting compound wherein the ¾ substituent is an alkynyl group may be subject to subsequent suitable modifications to give an alternative ¾ substituent. A representative sampling of such modifications could include hydrogenation, protecting group removal followed by additional amide coupling reactions, reductive amination reactions or alkylation reactions.
Scheme 3'
Figure imgf000112_0001
[0662] In another protocol non-aromatic ¾ substituents attached via a carbon-carbon bond may be prepared by other substitution reactions of the bromine atom compounds where ¾= Br, optionally followed by further modification of the introduced ¾ group. Examples of such substitution reactions include coupling reactions with zinc reagents such as cyanation and Negishi reactions. In the case of cyanation reaction, compounds where ¾ = Br may be reacted with zinc cyanide under standard palladium catalyst mediated reaction conditions to give compounds where ¾ = CN. The cyano group in such compounds may be subject to further modification to give other ¾ groups. Such cyano modifications include i. reduction to an amine which may be subsequently converted to an amide by acylation or alkylation, ii. reduction to an aldehyde which may be subjected to reductive amination reaction to give corresponding derivatives. In Negishi reactions alkylzinc reagents which may be prepared from alkyl iodides (e.g. iV-Boc-3-iodoazetidine) are coupled to compounds where R¾ = Br using palladium or nickel catalysts. In the resulting products the introduced ¾ group may be converted to an alternative group by further modifications of the ¾ group in subsequent steps such as deprotection, amide formation or alkylation.
[0663] Compounds with R¾ substituents which are amines attached via a nitrogen-carbon bond may be introduced by Buchwald coupling reaction of compounds where Re = Br followed by optional modification of the ¾ group as depicted in Scheme 4\ In the Buchwald reaction compounds where Ri = Br are treated with a primary or secondary amine (e.g. tert-butyl piperazine-l-carboxylate) in the presence of a palladium catalyst (e.g. Pd(dba)2/BINAP) and abase (e.g. cesium carbonate) in an organic solvent (e.g. toluene) at elevated temperature. The Buchwald coupling product may be subjected to subsequent suitable modifications to give an alternative R<s substituent. Such modifications are exemplified by protecting group removal, amide coupling reactions, reductive amination reactions or alkylation reactions.
Scheme 4'
Figure imgf000113_0001
[0664] Compounds with ¾ substituents which are alkylthio groups attached via a sulfur-carbon bond may be prepared by coupling reaction of compounds where ¾ = Br with thiols in the presence of a palladium catalyst and a weak base (e.g.DIPEA) in an organic solvent at elevated temperature. The coupling product sulfides may be subject to subsequent suitable modifications to give an alternative R$ substituent. Such modifications include sulfur oxidation reactions to give sulfoxides and sulfones, protecting group removal, amide coupling reactions, reductive amination reactions or alkylation reactions.
[0665] In a modification of the general synthesis in Scheme 1 ', depending upon the nature of the R7 substituent, further chemical modification subsequent to Step 6 of Scheme 1 ' could be employed to convert the R7 substituent into an alternative substituent. For example a protected amino group contained within may be subjected to deprotection reaction (e.g. Boc group cleavage) to give free amino groups. Such free amino groups may be subjected to reductive amination reactions or alkylation reactions to give substituted amines.
[0666] Scheme 5' shows the general synthesis of picolinamide compounds. Starting from methyl 3- bromo-6-chloropicolinate oxidation to the N-oxide followed by chlorination with phosphorus oxychloride gives methyl 3-bromo-4,6-dichloropicolinate. The 4-chloro group can be selectively substituted with diverse mono and dialkyl amines which may also contain functional or protected functional groups that may be unmasked at a later stage. The 3-bromo group may be retained or may be optionally converted into an alternative R12 group by suitable substitution reaction and further functional group modifications. Such reactions include coupling reactions mediated with palladium catalysts. For example the 3-bromo group may be converted to an R12 = methyl group by Stifle reaction with tetramethyltin. Ester hydrolysis followed by amide coupling with appropriate 3- (aminomethyl)-pyridin-2-ones yields picolinamide compounds wherein R^is a chloro group. The chloro group may optionaUy be converted to alternative R6 groups by suitable substitution reactions either in a final step or alternatively prior to ester hydrolysis Step 6. Examples of such substitution reactions include cyanation and animation reactions either directly or mediated with palladium catalysts. Analogous compounds wherein R is chloro may be prepared in analogous fashion from methyl 3,4, 6-trichloropyridine-2-carboxylate.
Figure imgf000114_0001
[0667] General syntheses of 3-(aminomethyl)-pyridin-2(lH)-ones intermediates for the amide coupling reaction from Scheme 1 ' are depicted in Scheme 6'. In one method, a diketone can be condensed with 2-cyanoacetamide in the presence of an appropriate reagent such as piperidine acetate in a polar solvent such as ethanol to provide a cyanopyridone (Step 9). In another method, when R3 is H, an appropriately substituted alkynyl ketone can be condensed with 2-cyanoacetamide in the presence of an appropriate reagent such as piperidine acetate in a polar solvent such as ethanol to provide a cyanopyridone (Step 11). The cyano group can be reduced under appropriate conditions such as hydrogenation in the presence of catalytic Raney nickel in a polar solvent such as ammonium in methanol to provide the amine (Step 10).
Scheme 6'
Figure imgf000114_0002
[0668] Additionally, depending upon the nature of the R2, or R4 group, further chemical modification can be employed to convert each of them independently into an alternative substituent. A representative sampling of such modifications can include hydrogenation, protecting group removal followed by additional amide coupling reactions, palladium catalyzed coupling reactions, reductive amination reactions, and alkylation reactions.
[0669] Scheme T depicts a variant of the general synthesis route of Scheme 1 ' based on 2- substituted (substituent is an 12 group) methyl 3-amino-5-bromo-benzoate starting materials. These starting materials can in turn be prepared from 2-substituted 3-nitro-benzoic acids which are commercially available or can be prepared by nitration of 2-substituted benzoic acids. Thus, bromination of 2-substituted 3-nitro-benzoic acids with a suitable reagent such as l,3-dibromo-5,5- dimethyl-2,4-imidazolidinedione yields the appropriate 2-substituted 3-nitro-S-bromo-benzoic acids. A variety of esterification and then nitro group reduction methods can then be sequentially implemented to prepare the 2-substituted methyl 3-amino-5-bromo-benzoate starting materials from the 2-substituted 3-nitro-5-bromo-benzoic acids.
Scheme 7'
Figure imgf000115_0001
[0670] As depicted in Scheme 7' the R7 group can be introduced from 2-substituted methyl 3- amino-5-bromo-benzoates in Step 1 using a reductive amination with an appropriate Ry-ketone or R7-aldehyde in the presence of an appropriate reducing agent such as sodium cyanoborohydride and catalytic acid such as acetic acid in an appropriate solvent such as methanol. Similarly, Rg groups can be introduced in Step 2 by reductive amination with Rg-ketone or Rs-aldehyde in the presence of an appropriate reducing agent such as sodium cyanoborohydride and catalytic acid such as acetic acid in an appropriate solvent such as methanol. Alternatively, a variety of Rg groups can be introduced by alkylation using Rg-LG, where LG is a leaving group such as iodine, in the presence of a mild base such as cesium carbonate in an appropriate polar solvent such as acetonitrile at an appropriate temperature such as 80 °C. In Step 3, R¾ groups other than bromine can be introduced via palladium catalyzed coupling reactions. Examples of such groups and methods have been described above. For example amines may be introduced by Buchwald reactions and unsaturated groups may be introduced by Suzuki or Sonogashiri reactions. The R$ substituent may be subject to subsequent suitable modifications to give an alternative R¾ substituent. A representative sampling of such modifications could include hydrogenation (e.g. to saturate unsaturated groups), protecting group removal followed by additional amide coupling reactions, reductive amination reactions or alkylation reactions.Jfa Step 4 the ester moiety can be hydrolyzed to the corresponding acid using a suitable base such as sodium hydroxide in a polar solvent such as ethanol. In Step 5, the acid can be subjected to a standard amide coupling reaction whereupon the appropriate 3-(aminomethyl)-pyridin- 2-one would be added along with a suitable amide coupling reagent such as PYBOP in a suitable solvent such as DMSO to give the desired amide. Depending upon the nature of the R7 substituent, further chemical modification subsequent to Step 5 of Scheme 4' could be employed to convert the R? substituent into an alternative substituent. For example a protected amino group contained within may be subjected to deprotection reaction (e.g. Boc group cleavage) to give free amino groups. Such free amino groups may be subjected to reductive amination reactions or alkylation reactions to give substituted amines.
[0671] Scheme 8' below depicts the general synthesis of 2-monoalkylamino and 2-dialkylamino- 3,6-disubstituted-isonicotinamides wherein the 3-substituent corresponds to and the 6-substituent corresponds to R$. In Step 1 the 3-substituent may be introduced by the method described by Epsztain J. et al. Tetrahedron, 1991, v. 47, 1697-16708, by metalation of 2-chloro-isonicotinanilide with n-butyllithium followed by trapping with an alkyliodide such as methyliodide or aldehyde or other electrophilic group.
Figure imgf000116_0001
Step-8
Figure imgf000117_0001
[0672] In cases where the trapping reagent yields a substituent with a functional group this group may be masked or converted into another functional group compatible with the subsequent chemical steps. In Step 2 anilide amide hydrolysis under standard acidic conditions may be conducted followed by methyl ester synthesis under standard conditions for example as shown with methyl iodide and base gives corresponding methyl 2-chloro-3-substituted isonicotinates. In Step 4 an alkylamino group can be introduced by Buchwald coupling reaction of an R7NH2 monoalkylamine with the methyl 2-chloro-3-substituted isonicotinates. This reaction is well precedented for diverse 2- chloropyridine systems in the chemical literature. In an optional Step 5 for dialkylamino compounds Rg groups can be introduced by reductive amination with Rs-ketone or Rs-aldehyde in the presence of an appropriate reducing agent such as sodium cyanoborohydride and catalytic acid such as acetic acid in an appropriate solvent such as methanol. Alternatively, a variety of Rs groups can be introduced by alkylation using Rj-LG, where LG is a leaving group such as iodine, in the presence of a mild base such as cesium carbonate in an appropriate polar solvent such as acetonitrile at an appropriate temperature such as 80 °C. In Step 6, oxidation to the N-oxide followed by chlorination with phosphorus oxychloride gives methyl 6-chloro-2-mono or dialkylamino-3-substituted isonicotinates. In Step 7 the ester moiety can be hydrolyzed to the corresponding acid using a suitable base such as sodium hydroxide in a polar solvent such as ethanol. In Step 8, the acid can be subjected to a standard amide coupling reaction whereupon the appropriate substituted 3- (aminomethyl)-pyridm-2-one would be added along with a suitable amide coupling reagent such as PYBOP in a suitable solvent such as DMSO to give the desired amide. In Step 9, the chloro group may optionally be converted to alternative ¾ groups by suitable substitution reactions either in a final step or alternatively prior to ester hydrolysis Step 6. Examples of such substitution reactions include cyanation and amination reactions either directly or mediated with palladium catalysts. The Ri substituent may be subject to subsequent suitable modifications to give an alternative Re substituent. A representative sampling of such modifications could include hydrogenation (e.g. to saturate unsaturated groups), protecting group removal followed by additional amide coupling reactions, reductive amination reactions or alkylation reactions. Depending upon the nature of the R7 substituent, further chemical modification steps may be employed to convert the R7 substituent into an alternative R7 substituent. For example a protected amino group contained within R7 may be subjected to deprotection reaction (e.g. Boc group cleavage) to give free amino groups. Such free amino groups may be subjected to reductive amination reactions or alkylation reactions to give substituted amines.
Figure imgf000118_0001
[0673] Scheme 9' depicts a synthesis of benzene analogs wherein Z is a sulfide, sulfoxide or sulfone group following a general route that utilizes well-established chemistry. Starting with a substituted benzoic acid such as 5-chloro-2-methylbenzoic acid, nitration using standard conditions such as treatment with cone. H2SO4 and cone. HNO3 can provide the nitro analog. Esterification of the acid can be achieved using an alkylating agent such as methyl iodide in the presence of a base such as sodium carbonate in a polar solvent such as DMF. The nitro group can be reduced using conditions such iron and ammonium chloride in a protic solvent such as ethanol with heating to a temperature such as 80 °C. The resulting aniline can be converted to a bromide using a Sandmeyer reaction such treatment with ΟιΒ¾ and t-butyl nitrite in a solvent such as acetonitrile. A palladium catalyzed coupling of a thiol with the bromide can be achieved using a palladium source such as Pd(OAc)2 with a ligand such as Xanthphos in the presence of a base such as Ν,Ν-diisopropyl ethylamine in a solvent such as 1,4-dioxane optionally heating to a temperature such as 100 °C. The ester can be hydrolyzed with an aqueous base such as NaOH in water. The resulting acid can be coupled to the appropriate substituted 3-(aminomethyl)-pyridin-2-one (e.g. 3-(amino methyl)-4, 6-dimethylpyridin- 2(lH)-one as depicted in Scheme 9') using standard amino acid coupling conditions such as PYBOP in DMSO. The resulting thioether may be oxidized to the corresponding sulfoxide or sulfone by using the appropriate equivalents of an oxidant such as m-CPBA in a solvent such as DCM. The ¾ chloro group may be replaced with an alternative R group in an additional Step 10 or after Step 5 or prior to amide coupling. Examples of alternative R groups include substituents that can be incorporated by using palladium couplings such as a Buchwald reaction to give amine groups (e.g. morpholino). The R6 substituent may be subject to subsequent suitable modifications to give an alternative Rs substituent. A representative sampling of such modifications includes protecting group removal followed by additional amide coupling reactions, reductive amination reactions or alkylation reactions.
Figure imgf000119_0001
following a general route that utilizes well-established chemistry. Starting with a substituted aniline such as methyl 3-amino-5-chloro-2-methylbenzoate, the aniline can be converted to a phenol using a Sandmeyer reaction such as treatment with aqueous NaN02 solution in a aqueous acid such as 50% H2SO4. The phenol can be alkylated using an alkylating agent such as tetrahydro-2H-pyran-4-yl 4- methylbenzenesulfonate in the presence of an appropriate base such as cesium carbonate in as polar solvent such as DMF optionally heating to a temperature such as 80 °C. The ester can be hydrolyzed with an aqueous base such as NaOH in water. The resulting acid can be coupled to the appropriate substituted 3-(aminomethyl)-pyridin-2-one using standard amino acid coupling conditions such as PYBOP in DMSO. The R6 chloro group may be replaced with an alternative R{ group in an additional after Step 5 or prior to amide coupling. Examples of alternative Regroups include substituents that can be incorporated by using palladium couplings such as a Buchwald reaction to give amine groups (e.g. morpholino). The R6 substituent may be subject to subsequent suitable modifications to give an alternative ¾ substituent. A representative sampling of such modifications includes protecting group removal followed by additional amide coupling reactions, reductive amination reactions or alkylation.
[0675] Compounds of the present invention inhibit the histone methyltransferase activity of EZH2 or a mutant thereof and, accordingly, in one aspect of the invention, certain compounds disclosed herein are candidates for treating, or preventing certain conditions and diseases. The present invention provides methods for treating conditions and diseases the course of which can be influenced by modulating the methylation status of histones or other proteins, wherein said methylation status is mediated at least in part by the activity of EZH2. Modulation of the methylation status of histones can in turn influence the level of expression of target genes activated by methylation, and/or target genes suppressed by methylation. The method includes administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, polymorph, solvate, or stereoisomeror thereof.
[0676] Unless otherwise stated, any description of a method of treatment includes uses of the compounds to provide such treatment or prophylaxis as is described in the specification, as well as uses of the compounds to prepare a medicament to treat or prevent such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models.
[0677] In still another aspect, this invention relates to a method of modulating the activity of the EZH2, the catalytic subunit of the PRC2 complex which catalyzes the mono- through tri-methylation of lysine 27 on histone H3 (H3-K27) in a subject in need thereof. For example, the method comprises the step of administering to a subject having a cancer expressing a mutant EZH2 a therapeutically effective amount of a compound described herein, wherein the compound(s) inhibits histone methyltransferase activity of EZH2, thereby treating the cancer.
[0678] For example, the cancer is selected from the group consisting of follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) of germinal center B cell-like (GCB) subtype. For example, the cancer is lymphoma, leukemia or melanoma. Preferably, the lymphoma is non- Hodgkin's lymphoma (NHL), follicular lymphoma or diffuse large B-cell lymphoma. Alternatively, the leukemia is chronic myelogenous leukemia (CML), acute myeloid leukemia, acute lymphocytic leukemia or mixed lineage leukemia.
[0679] For example, the precancerous condition is myelodysplastic syndromes (MDS, formerly known as preleukemia). [0680] For example, the cancer is a hematological cancer.
[0681 ] The compound(s) of the present invention inhibit the histone methyltransferase activity of EZH2 or a mutant thereof and, accordingly, the present invention also provides methods for treating conditions and diseases the course of which can be influenced by modulating the methylation status of histones or other proteins, wherein said methylation status is mediated at least in part by the activity of EZH2. In one aspect of the invention, certain compounds disclosed herein are candidates for treating, or preventing certain conditions and diseases. Modulation of the methylation status of histones can in turn influence the level of expression of target genes activated by methylation, and/or target genes suppressed by methylation. The method includes administering to a subject in need of such treatment, a therapeutically effective amount of a compound of the present invention.
[0682] As used herein, a "subject" is interchangeable with a "subject in need thereof, both of which refer to a subject having a disorder in which EZH2-mediatEd protein methylation plays a part, or a subject having an increased risk of developing such disorder relative to the population at large. A "subject" includes a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In one embodiment, the mammal is a human. A subject in need thereof can be one who has been previously diagnosed or identified as having cancer or a precancerous condition. A subject in need thereof can also be one who has (e.g., is suffering from) cancer or a precancerous condition. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a precancerous condition. A subject in need thereof can have refractory or resistant cancer (i.e., cancer that doesn't respond or hasn't yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof has cancer recurrence following remission on most recent therapy. In some embodiments, the subject in need thereof received and failed all known effective therapies for cancer treatment. In some embodiments, the subject in need thereof received at least one prior therapy. In a preferred embodiment, the subject has cancer or a cancerous condition. For example, the cancer is lymphoma, leukemia, melanoma, or rhabdomyosarcoma. Preferably, the lymphoma is non-Hodgkin's lymphoma, follicular lymphoma or diffuse large B-cell lymphoma. Alternatively, the leukemia is chronic myelogenous leukemia (CML). The precancerous condition is myelodysplastic syndromes (MDS, formerly known as preleukemia).
[0683] As used herein, "treating" or "treat" describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term "treaf ' can also include treatment of a cell in vitro or an animal model.
[0684] A compound of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes. As used herein, "preventing," "prevent," or "protecting against" describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.
[0685] Point mutations of the EZH2 gene at a single amino acid residue (e.g., Y641, A677, and A687) of EZH2 have been reported to be linked to lymphoma. More examples of EZH2 mutants and methods of detection of mutation and methods treatment of mutation-associated disorders are described in, e.g., U.S. Patent Application Publication No. US 20130040906, the entire content of which is incorporated herein by reference in its entirety.
[0686] One skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al, Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al. , Molecular Cloning, A Laboratory Manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al, Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al, Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al, The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th edition (1990). These texts can, of course, also be referred to in making or using an aspect of the invention.
[0687] As used herein, "combination therapy" or "co-therapy" includes the administration of a compound of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof, and at least a second agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
[0688] The present invention also provides pharmaceutical compositions comprising a compound of any Formula disclosed herein in combination with at least one pharmaceutically acceptable excipient or carrier.
[0689] A "pharmaceutical composition" is a formulation containing the compounds of the present invention in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
[0690] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit risk ratio.
[0691] "Pharmaceutically acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one such excipient.
[0692] A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral {e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. [0693] A compound or pharmaceutical composition of the invention can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, for treatment of cancers, a compound of the invention may be injected directly into tumors, injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., cancer, precancer, and the like) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.
[0694] The term "therapeutically effective amount", as used herein, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician. In a preferred aspect, the disease or condition to be treated is cancer. In another aspect, the disease or condition to be treated is a cell proliferative disorder.
[0695] For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, e.g. , of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50 ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
[0696] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation. [0697] The pharmaceutical compositions containing active compounds of the present invention may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.
[0698] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
[0699] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
[0700] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
[0701] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
[0702] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
[0703] The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.
[0704] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.
[0705] In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with the invention vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the growth of the tumors and also preferably causing complete regression of the cancer. Dosages can range from about 0.01 mg kg per day to about 5000 mg kg per day. In preferred aspects, dosages can range from about 1 mg kg per day to about 1000 mg/kg per day. In an aspect, the dose will be in the range of about 0.1 mg/day to about 50 g/day; about 0.1 mg/day to about 25 g/day; about 0.1 mg/day to about 10 g/day; about 0.1 mg to about 3 g/day; or about 0.1 mg to about 1 g/day, in single, divided, or continuous doses (which dose may be adjusted for the patient's weight in kg, body surface area in m2, and age in years). An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. For example, regression of a tumor in a patient may be measured with reference to the diameter of a tumor. Decrease in the diameter of a tumor indicates regression. Regression is also indicated by failure of tumors to reoccur after treatment has stopped. As used herein, the term "dosage effective manner" refers to amount of an active compound to produce the desired biological effect in a subject or cell.
[0706] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
[0707] The compounds of the present invention are capable of further forming salts. All of these forms are also contemplated within the scope of the claimed invention.
[0708] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the compounds of the present invention wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2- hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.
[0709] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present invention also encompasses 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 such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-memylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ration other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.
[0710] It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.
[0711] The compounds of the present invention can also be prepared as esters, for example, pharmaceutically acceptable esters. For example, a carboxylic acid function group in a compound can be converted to its corresponding ester, e.g., a methyl, ethyl or other ester. Also, an alcohol group in a compound can be converted to its corresponding ester, e.g., acetate, propionate or other ester.
[0712] The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognize the advantages of certain routes of administration.
[0713] The dosage regimen utilizing the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
[0714] Techniques for formulation and administration of the disclosed compounds of the invention can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.
[0715] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present invention are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present invention. The examples do not limit the claimed invention. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present invention.
[0716] In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the invention to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.
[0717] Compounds designed, selected and/or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.
[0718] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.
[0719] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.
Examples
Example 1 Syntheses of compounds of the invention
General experimental
NMR
[0720] Ή-NMR spectra were taken using CD ¾ unless otherwise stated and were recorded at 400 or 500 MHz using a Varian or Oxford instruments magnet (500 MHz) instruments. Multiplicities indicated are s=singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sxt = sextet, m = multiplet, dd =doublet of doublets, dt = doublet of triplets; br indicates a broad signal.
LCMS and HPLC
[0721] Mass: Waters Acquity Ultra Performance LC. HPLC: Products were analyzed by Shimadzu SPD-20A with 150 4.5mm YMC ODS-M80 column or 150 x 4.6mm YMC-Pack Pro C 18 column at 1.0 ml min. Mobile phase was MeC :H20=3:2 (containing 0.3% SDS and 0.05% H3PO4). Products were purified by HPLC/MS (MeOH-H20 containing 0.1 % ammonium hydroxide) using Waters AutoPurification System with 3100 Mass Detector.
3-(Aminomethyl)-4,6-dimethyl-l,2-dihydropyridin-2-one HCl salt
Figure imgf000130_0001
[0722] To a solution of 2-cyanoacetamide (8.40 g, 100 mmol) and acetylacetone (10.0 g, 100 mmol) in H20 (200 mL) was added K2CO3 (4.00 g, 28.9 mmol). The mixture was stirred at RT for 22 hours. Then the precipitated solid was filtered with Buchner funnel, washed with ice cold H20, and dried under vacuum pressure to give 4,6-dimethyl-2-oxo-l,2-dihydropyridme-3-carbonitrile (13.5 g, 91% yield).
[0723] To a solution of 4,6-dimethyl-2-oxo-l,2-dihydropyridine-3-carbonitrile (10.0 g, 67.5 mmol) in MeOH (1.50 L) and cone. HCl (30 mL) was added 10% Pd(OH)2 (19 g) under N2 atmosphere. The N2 gas was displaced by ¾ gas and the mixture was stirred for 26 hours at RT under hydrogen atmosphere. The H2 gas was displaced by N2 gas. The mixture was filtered through Celite, washed with MeOH and concentrated. The residue was triturated with EtOH, collected with Buchner funnel, and dried under vacuum pressure to give the titled compound as a white solid (11.5 g, 90%). Ή NMR (400 MHz, DMSO-d6): δ ppm 11.86 (brs, 1H), 5.98 (s, 1H), 3.78 (m, 2H), 2.20 (s, 3H), 2.16 (s, 3H).
3-(Aminomethyl)-6-methyl-4-propyl-l,2-dihydropyridin-2- ne HCl salt
Figure imgf000131_0001
[0724] To a stirred solution of i-BuOK (20.0 g, 179 mmol) and cyanoacetamide (16.5 g, 196 mmol) in DMSO (300 mL) was added (3E)-3-hepten-2-one (20.0 g, 178 mmol). The reaction mixture was stirred at 23 °C for 30 minutes and then additional i-BuOK (60.0 g, 712 mmol) was added to the reaction mixture. The reaction mixture was placed under oxygen atmosphere and stirred for 16 h. The reaction mixture was then purged with argon and was cooled to 0 °C. The mixture was diluted with aq. HCl and the resultant precipitate was collected. The solid was washed with water and dried to give 6-methyl-2-oxo-4-propyl-l,2-dihydropyridine-3-carbonitrile (15.0 g, 47%).
To a stirred solution of 6-memyl-2-oxo-4-propyl-l,2-dihydropyridine-3-carbonitrile (15.0 g, 85.1 mmol) in methanol (600 mL) and concentrated HCl (15 mL) was added Pd(OHh (15.0 g). The mixture was stirred for 48 hours under ¾ atmosphere. The reaction mixture was filtered and filtrate was concentrated in vacuo. Ethanol was added to the residue, the resultant precipitate was collected and dried to give the titled compound as a white solid (13.0 g, 60%). 'H-NMR (400 MHz, CDC13) δ ppm; 11.86 (br. s., 1H), 6.00 (s, 1H), 3.78 (q, J= 5.5 Hz, 2H), 3.61 (br. s, 2H), 2.46 (m, 2H), 2.17 (s, 3H), 1.50 (sxt, .7= 7.4 Hz, 2H), 0.91 {t, J= 7.4 Hz, 3H).
6-Methyl-2-oxo-4-(2-propyI)-l,2-dihydropyridine-3-carbonitrile
Figure imgf000131_0002
[0725] To a solution of 2-cyanoacetamide (35.1 g, 417 mmol) and i-BuOK (42.5 g, 379 mmol) in DMSO (631 mL) was added 5-methyl-3-hexen-2-one (50.0 mL, 379 mmol) under N2 atmosphere. The mixture was stirred at 23°C for 30 min and then additional /-BuO (127 g, 1137 mmol) was added. The N2 gas was displaced by O2 gas and the mixture was stirred for 45 h at 23°C under oxygen. The mixture was cooled to 0°C, diluted with H20 (200 mL) and 5N HCl (227 mL, slowly added). The mixture was stirred for 15 min at 0°C and the solid was collected with Buchner funnel. The solid was washed with ¾0 (1500 mL) and dried with hot-air (55°C, 16h) to give 6-methyl-2- oxo-4-(propan-2-yl)-l,2-dihydropyridine-3-carbonitrile as a white solid (26.6 g, 40%). ¾ NMR (400 MHz, CDCI3) δ ppm; 6.14 (s, 1H), 3.25-3.29 (m, 1H), 2.45 (s, 3H), 1.26 (d, J= 6.8 Hz, 6H); LC-MS: m/z 177.1 [M+H]+, 198.9 [M+Na .
3-(Aminomethyl)-6-methyI-4-(2-propyl)-l,2-dihydropyridin-2-one HCl salt
Figure imgf000131_0003
[0726] To a solution of 6-methyl-2-oxo-4-(2-propyl)-l,2-a¾hya opyridine-3-carbonitrile (5.00 g, 28.4 mmol) and in MeOH (400 mL) and cone. HCl (8.8 mL) was added 10% Pd(OH)2 (5.17 g, 3.68 mmol) under N2 atmosphere. The N2 gas was displaced by H2 gas and the mixture was stirred for 24 h at 23 °C under hydrogen. The ¾ gas was displaced by N2 gas and the mixture was filtrated through celite, washed with MeOH and the filtrate was concentrated. The residue was triturated with EtOH- TBME, the solid was collected with Buchner funnel and dried in vacuo to give the titled compound as a white solid (6.15 g, 100%). Ή NMR (400 MHz, DMSO-ds): δ ppm 11.9 (br-s, 1H), 8.03 (br-s, 2H), 6.12 (s, 1H), 3.82-3.84 (m, 2H), 3.08-3.12 (m, 1H), 2.19 (s, 3H), 1.12 (d, J= 6.8 Hz, 6H).
6-Methyl-2-oxo-4-(trifluoromethyl)-l,2-diliydropyridine-3-carboiiitrile
Figure imgf000132_0001
[0727] To a solution of 2-cyanoacetamide (14.0 g, 166 mmol) and trifluoroacetylacetone (20.0 mL, 166 mmol) in H20 (332 mL) was added K2C03 (6.60 g, 47.9 mmol). The mixture was stirred at 23°C for 15 h. The precipitated solid was collected with Buchner funnel, washed with ice cold H20, and dried with hot air (60 °C, 16 h) to give the titled compound as a white solid (17.6 g, 52%). Ή NMR (400 MHz, DMSO-d6): δ ppm 2.38 (s, 3H), 6.66 (s, 1H).
3-(Aminomethyl)-6-methyl-4-(trifluoromethyl)-l,2-dihydropyridin-2-oiie hydrochloride HC1
salt
Figure imgf000132_0002
[0728] To a solution of 6-methyl-2-oxo-4-(trifluoromethyl)-l,2-dihydropyridine-3-carbonitrile (400 mg, 1.98 mmol) in MeOH (19.8 mL) and cone. HC1 (436 uL) was added 10% Pd(OH)2 (361 mg, 0.257 mmol) under N2 atmosphere. The N2 gas was displaced by H2 gas and the mixture was stirred for 18 h at 23°C under hydrogen. The H2 gas was displaced by N2 gas. The mixture was filtrated through Celite, washed with MeOH and the filtrate was concentrated. The residue was triturated with MeOH-Et20, collected with Buchner funnel, and dried in vacuo to give the titled compound as a white solid (433 mg, 100%). Ή NMR (400 MHz, DMSO-d6): δ ppm 2.31 (s, 3H), 3.88 (s, 2H), 6.43 (s, 1H).
5-Fluoro-l,4,6-trimethyl-2-oxo-l,2-dihydropyridiiie-3-carbonitrile
Figure imgf000132_0003
[0729] The title compound was prepared (0.430 g, 38%) following the same procedure for the preparation of 5-fluoro-4-isopropyl-6-methyl-2-oxo-l,2-dihydropyridine-3-carbonitrile and purified by silica gel chromatography (50% to 100% EtOAc-heptane). Ή-NMR (400 MHz): δ ppm 3.56 (s, 3H), 2.43 (d, J = 2. \ Hz, 3H), 2.41 (d, J = 8.4 Hz, 3H); MS (ESI) [M+H]+ 181.1. 3-(Aminomethyl)-5-fluoro-l,4,6-trimethyIpyridin-2(lH)-one
Figure imgf000133_0001
[0730] The titled compound was prepared (0.440 g, 100% yield) following the same procedure for the preparation of 3-(aminomethyl)-5-fluoro-4-isopropyl-6-methylpyridin-2(lH)-one. Ή NMR (400 MHz, CD3OD): 5 ppm 3.75 (s, 2H), 3.S2 (s, 3H), 2.36 (d, = 3.2 Hz, 3H), 2.23 (d, J = 2.1 Hz, 3H); MS (ESI) [M+H]+ 185.1.
3-(Aminomethyl)-l,4,6-trimethyIpyridin-2(lH)-one
Figure imgf000133_0002
[0731] The titled compound was prepared (200 mg, 100% yield) following the same procedure for the preparation of 3-(aminomethyl)-5-fluoro-4-isopropyl-6-methylpyridin-2(lH)-one. Ή-NMR (400 MHz): δ ppm 5.90 (s, 1H), 3.75 (s, 2H), 3.51 (s, 3H), 2.30 (s, 3H), 2.19 (s, 3H); MS (ESI) [M+H]+ 167.1.
2-((6-Methyl-2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)methyl)isoindoline-l,3-dione
Figure imgf000133_0003
[0732] A solution of phthalic anhydride (0.140 g, 0.948 mmol), triethylamine (0.264 mL, 1.90 mmol) and 3-(aminomethyl)-6-methyl-4-(trifluoromethyl)pyridin-2(lH)-one hydrochloride (0.230 g, 0.948 mmol) in acetic acid (2.71 mL, 47.4 mol) was heated under microwave irradiation at 100 °C for 1 h. LC-MS showed a single peak corresponding to the desired product. The reaction mixture was poured into water and the precipitated solid was collected by filtration, washed with water and dried to provide the titled compound (265 mg, 83% yield). 1 H-NMR (400 MHz, DMSO-d6): δ ppm 7.83 (s, 4H), 6.29 (s, 1H), 4.74 (s, 2H), 2.24 (s, 3H); MS (ESI) [M+H]+ 337.2.
2-((l,6-Dimethyl-2-oxo-4-(trifluoromethyl)-l,2-dihydropyridin-3-yl)methyl)isoindoline-l,3- dione
Figure imgf000133_0004
[0733] Cesium carbonate (257 mg, 0.788 mmol) was added to a suspension of 2-((6-methyl-2-oxo- 4-(trifluoromethyl)-l,2-dmydropyridin-3-yl)methyl)isoindoline-l,3-dione (265 mg, 0.788 mmol) in DMSO (2.34 mL) at 23°C. The reaction mixture immediately turned to yellow. And after stirring for 16 h at 23°C, methyl iodide (49.3 ]i , 0.788 mmol) was added and the yellow color turned to light yellow color. After stirring for 1 h, LCMS showed the reaction was done. The reaction mixture was poured into ice water and filtered, washed with ether and dried to give the titled compound (250 mg, 91% yield). Ή-NMR (400 MHz, CD3OD): δ ppm 7.79 (m, 4H), 6.51 (s, 1H), 4.88 (s, 2H), 3.51 (s, 3H), 2.48 (s, 3H); MS (ESI) [M+H]+ 351.2.
S-iAminometliylJ-ije-dimethyW-itrifluorometh lipyridiii- ilH^one
Figure imgf000134_0001
[0734] Hydrazine hydrate (106 μΐ,, 2.14 mmol) was added to a suspension of 2-((l,6-dimethyl-2- oxo-4-(rrifluoromemyl)-l,2-dihydropyridin-3-yl)methyl)isoindoline-l,3-dione (250 mg, 0.714 mmol) in ethanol (4.2 mL) and the reaction mixture was heated at 80 °C for 2 h. LC-MS showed the reaction was completed so the mixture was cooled to ambient temperature, filtered to remove the precipitated solid. The filtrate was then concentrated and azeotroped with DMF to give the crude titled compound (178 mg, 113%). The crude was used directly without further purification for next step. MS (ESI) [M+H]+ 221.1.
Figure imgf000134_0002
[0735] Step 1: Synthesis of methyl 5-(((trans)-4-((tert- butoxycarbonyl)armno)cyclohexyl)(ethyl)amino)-4,-hydroxy-4-methyl-[l -biphenyl]-3-carboxylate [0736] To a stirred solution of methyl 5-bromo-3-(((trans)-4-((tert- butoxycarbonyl)amino)cyclohexyl)(emyl)arriino)-2-methylbenzoate (lOg, 21.3 mmol, see, e.g., WO2012142504 (Attorney Docket No. 41478-507001 WO)) and (4-hydroxyphenyl)boronic acid (3.5g, 25.3 mmol) in a mixture of dioxane (225 mL) and water (75 mL), Na2C03 (8.01 g, 75.5 mmol) was added and the solution was purged with argon for 30 min. Then Pd(PPh3 (2.4 g, 2.07 mmol) was added and argon was purged again for another 15 min. Reaction mass was heated at 100 °C for 4 h. On completion, reaction mixture was diluted with water and extracted with ethyl acetate. Combined organic layer was dried over sodium sulfate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (8.9 g, 87% yield).
[0737] Step 2: Synthesis of methyl 5-(((trans)-4-((tert-butoxycarbonyl)amino) cyclohexyl)
(ethyl)amino)-4'-(2-methoxyethoxy)-4-methyl-[l, -biphenyl]-3-carboxylate
[0738] To a stirred solution of methyl 5-(((trans)-4-((tert- butoxycarbonyl)armno)cyclohexyl)(ethyl)amino)-4'-hydroxy-4-methyl-[l,r-biphenyl]-3-carboxylate (0.6 g, 1.24 mmol) and l-bromo-2-methoxyethane (0.519 g, 3.73 mmol) in acetonitrile (6 mL), CS CO3 (0.485 g, 1.49 mmol) was added and reaction was stirred at 80 °C for 12 h. On completion, water was added to it and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by column chromatography to afford the title compound (0.6 g, 76.5% yield).
[0739] Step 3: Synthesis of tert-butyl ((trans)-4-((5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl) carbamoyl)-4'-(2-methoxyethoxy)-4-methyl-[l,l'-biphenyl]-3-yl(ethyl)-amino)-cyclohexyl) carbamate
[0740] Aqueous NaOH (0.066 g, 1.66 mmol in 5 mL H20) was added to a solution of 5-(((trans)-4- ((tert-butoxycarbonyl)armno)cyclohexyl)(ethyl)amino)-4'-(2-methoxyethoxy)-4-methyl-[ 1,1'- biphenyl]-3-carboxylate (0.6 g, 1.11 mmol) in EtOH (10 mL) and stirred at 60 °C for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and the residue was acidified using citric acid using to pH 4 was adjusted using citric acid. Extraction was carried out using 10% methanol in DCM. Combined organic layers were dried, concentrated giving respective acid (0.5 g, 85.6% yield).
[0741] The above acid (0.5 g, 0.95 mmol) was then dissolved in DMSO (5 mL) and 3- (aminomethyI)-4,6-dimethylpyridin-2(lH)-one (0.288 g, 1.90 mmol) and triethyl amine (0.096g, 0.950 mmol) was added to it. The reaction mixture was stirred at room temperature for 15 min before PyBop (0.741g, 1.42 mmol) was added to it and stirring was continued for overnight at room temperature. After completion of the reaction, reaction mass was poured into ice and extraction was carried out using 10 % MeOH DCM. Combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain crude material which then purified by column chromatography to afford the title compound (0.45 g, 71.8% yield).
[0742] Step 4: Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-5-(((trans)-4- (dimethylamino)-cyclohexyl)-(ethyI)-amino)-4'-(2-methoxyethoxy)-4-methyI-[l,l'-biphenyl] -3- carboxamide
[0743] To a stirred solution of tert-butyl((trans)-4-((5-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)carbamoyI)-4'-(2-methoxyethoxy)-4-methyI-[ 1 , 1 '-biphenyl]-3- yl)(ethyl)amino)cyclohexyl)carbamate (0.45 g, 0.681 nimol) in DCM (5 mL) at 0 °C, TFA (1 mL) was added and reaction was stirred for 2 K at room temperature. After completion, reaction was concentrated to dryness. The residue was then basified with Na2 X (aq.) to pH 8 and the aqueous layer extracted with 20% methanol in DCM. The combined organic layers were dried over Na2S04 and the solvent removed under reduced pressure to give Boc-deprotected compound (0.3 g, 78.7% yield).
[0744] To a stirred solution of Boc-deprotected compound (0.3 g, 0.535 mmol) in dichloromethane (3 mL) was added formaldehyde solution (35-41% aq.) (0.056 g, 1.87 mmol) at 0 °C and stirred for 20 min. Then, NaBH(OAc)3 (0.28 g, 1.33 mmol) was added and stirred for 2 h at 0 °C. On completion of the reaction, water was added and extracted with 20% methanol in DCM. The combined organic layers were dried over Na2S04 and the solvent was removed under reduced pressure. The crude compound was purified by prep. HPLC to afford the title compound (0.1 g, 31.7% yield).
[0745] LCMS: 589.75 (M+l)+; TFA-salt: Ή NMR (DMSO-i¾, 400 MHz) 6 11.47 (brs, 1H), 9.48 (brs, 1H), 8.21 (brs, 1H), 7.57 (d, 2H, J=8.0 Hz), 7.40 (s, 1H), 7.23 (s, 1H), 7.03 (d, 2H, J=8.8 Hz), 5.87 (s, 1H), 4.29 (d, 2H, J=4.4 Hz), 4.14-4.12 (m, 2H), 3.69-3.66 (m, 2H), 3.32 (s, 3H), 3.13 (m, 4H), 2.69-2.68 (m, 6H), 2.24 (s, 3H), 2.21 (s, 3H), 2.11 (s, 3H), 1.96 (m, 4H), 1.44 (m, 4H), 0.85 (t, 3H, J=6.8 Hz).
Compound 3:
[0746] Synthesis of N-((4,6-dimethyl-2-oxo-l ,2-dihydropyridin-3-yl)methyl)-5-(((trans)-4- (dimethylamino)cyclohexyl)(ethyl)amino)-4'-(2-hydroxyethoxy)-4-methyl-[l,r-biphenyl]-3- carboxamide
Figure imgf000136_0001
[0747] Step 1: Synthesis of methyl 5-(((trans)-4-((tert-butoxycarbonyl)amino)
cyclohexyl)(ethyl)amino)-4'-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methyl-[l,l'-biphenyl]-3- carboxylate
[0748] To a stirred solution of methyl 5-(((trans)-4-((tert- butoxycarbonyl)amino)cyclohexyl)(ethyl)amino)-4'-hydroxy-4-methyl-[l,l'-biphenyl]-3-carboxylate (0.8 g, 1.65 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (1.97 g, 8.29 mmol) in acetonitnle (10 mL), CS2CO3 (1.61 g, 4.97 mmol) was added and reaction was stirred at 80 °C for 12h. On completion, reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude compound was purified by column chromatography to afford the title compound (0.7 g, 70% yield).
[0749] Step 2: Synthesis of tert-butyl ((trans)-4-((5-(((4,6-dmiethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)carbamoyl)-4'-(2-hydroxyethoxy)-4-methyl-[ 1 , 1 '-biphenyi]-3 - yl)(ethyl)amino)cyclohexyl)carbamate
[0750] Protocol as for 2, Step 3, with methyl 5-(((trans)-4-((tert-butoxycarbonyl)amino) cyclohexyl)(ethyl)amino)-4'-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-methyl-[l, -biphenyl]-3- carboxylate (0.7g, 1.09 mmol) and 3-(amino methyl)-4, 6-dimethylpyridin-2(lH)-one (0.291g, 1.91 mmol) to afford the tide compound (0.45 g, 61.8% yield).
[0751] Step 3: Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-5-(((trans)-4- (dimethylamino)cyclohexyl)(ethyl)amino)-4'-(2-hydroxyethoxy)-4-methyl-[ 1 , 1 '-biphenyl]-3- carboxamide
[0752] To a stirred solution of tert-butyl ((trans)-4-((5-(((4,6-dimemyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)carbamoyl)-4'-(2-hydroxyethoxy)-4-methyl-[ 1 , 1 '-biphenyl]-3- yl)(ethyl)amino)cyclohexyl)carbamate (0.45 g, 0.59 mmol) in DCM (5 mL) at 0 °C, TFA (1 mL) was added and reaction was stirred for 2 h at room temperature. After completion, the reaction was concentrated to dryness. The residue was then basified with Na2C03 (aq.) to pH 8 and the aqueous layer was extracted with 20% methanol in DCM. The combined organic layers were dried over Na2S0 and the solvent was removed under reduced pressure to give Boc-deprotected compound (0.3 g, 76.9% yield).
[0753] To a stirred solution of the Boc-deprotected compound (0.3 g, 0.45 mmol) in dichloromethane (3 mL) was added formaldehyde solution (35-41% aq.) (0.05 g, 1.59 mmol) at 0 °C and stirred for 20 min. Then NaBH(OAc)3 (0.24 g, 1.13 mmol) was added and the resulting mixture was stirred for 2h at 0 °C. On completion of the reaction, water was added and extracted with 20% methanol in DCM. The combined organic layers were dried over Na2S04 and the solvent was removed under reduced pressure. The crude compound was purified by prep. HPLC to afford the title compound (0.1 g, 32.1% yield).
[0754] LCMS: 575.55 (M + 1)+; TFA-salt: Ή NMR (DMSO-<¾, 400 MHz) δ 11.50 (brs, 1H), 9.52 (brs, 1H), 8.23 (brs, 1H), 7.58 (d, 2H, J=8.4 Hz), 7.45 (s, 1H), 7.26 (s, 1H), 7.02 (d, 2H, J=8.4 Hz), 5.87 (s, 1H), 4.30-4.29 (m, 2H), 4.03-4.00 (m, 2H), 3.75-3.72 (m, 2H), 3.22 -3.12 (m, 3H), 2.93 (m, 1H), 2.69 (m, 6H), 2.25 (s, 3H), 2.21 (s, 3H), 2.11 (s, 3H), 1.97 (m, 4H), 1.45 (m, 4H), 0.85 (t, 3H, J=6.8 Hz).
Compound 4
[0755] Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(((trans)-4-
Figure imgf000138_0001
[0756] Step 1: Synthesis of methyl 3-(((trans)-4-((tert-butoxycarbonyl)amino)
cyclohexyl)(ethyl)arnmo)-5-(6-hydroxypyridin-3-yl)-2-methylberrzoate
[0757] To a stirred solution of methyl 5-bromo-3-(((trans)-4-((tert- butoxycarbonyl)amino)cyclohexyl)(ethyl)amino)-2-methylbenzoate (2 g, 4.27 mmol) and (6- hydroxypyridin-3-yl)boronic acid (1.06 g, 7.69 mmol) in dioxane/water mixture (16:4 mL), Na2C03 (1.63 g, 15.38 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (0.25 g, 0.21 mmol) was added and argon was purged again for 10 min. The reaction mass was heated at 100 °C for 3h. On completion, the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined organic layers were dried over Na9S04 and the solvent was removed under reduced pressure and the resulting crude material was purified by column chromatography on silica gel to afford the title compound (0.9 g, 43.6% yield).
[0758] Step 2: Synthesis of methyl 3-(((trans)-4-((tert-butoxycarbonyl)amino)
cyclohexyl)(ethyl)amino)-5-(6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)-2- methylbenzoate [0759] To a stirred solution of methyl 3-(((trans)-4-((tert-butoxycarbonyl)amino)
cyclohexyl)(ethyl)amino)-5-(6-hydroxypyridin-3-yl)-2-methylbenzoate (0.9 g, 1.86 mmol) and (2- bromoethoxy)(tert-butyl)dimethylsilane (1.33 g, 5.59 mmol) in DMF (10 mL), potassium t-butoxide (0.25 g, 2.23 mmol) was added and reaction was stirred at room temperature for 12 h. On completion, water was added and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude compound was purified by column chromatography to afford the title compound (0.7 g, 63.6% yield).
[0760] Step 3: Synthesis of tert-butyl ((trans)-4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)carbamoyl)-5-(6-(2-hydroxyethoxy)pyridin-3-yl)-2- methylphenyl)(ethyl)amino)cyclohexyl)carbamate
[0761] Protocol as for 2, Step 3, with methyl 3-(((trans)-4-((tert-butoxycarbonyl)amino) cyclohexyl)(ethyl)ammo)-5-(6-(2-((tert-butyldimemylsilyl)oxy)emoxy)pyridin-3-yl)-2- methylbenzoate (0.7 g, 1.09 mmol) and 3-(amino methyl)-4, 6-dimethylpyridin-2(lH)-one (0.24 g, 1.59 mmol) to afford the title compound (0.4 g, 56.2% yield).
[0762] Step 4: Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(((trans)-4- (dimethylamino)cyclohexyl)(emyl)amino)-5-(6-(2-hydroxyethoxy)pyridin-3-yl)-2-methylbenzamide [0763] Protocol as for 3, Step 3, with tert-butyl ((trans)-4-((3-(((4,6-dimethyl-2-oxo-l,2- dihydropyrid n-3-yl)methyl)carbamoyl)-5-(6-(2-hydroxyethoxy)pyridin-3-yl)-2- methylphenyl)(ethyl)amino)cyclohexyl)carbamate (0.4 g, 0.62 mmol) to afford the title compound (0.11 g, 42.0% yield).
[0764] LCMS: 576.60 (M+l)+; TFA-salt: 'H NMR (DMSO-<¾, 400 MHz) δ 11.46 (bs, 1H), 9.51 (bs, 1H), 8.16 (s, 1H), 7.97 (s, 1H), 7.80 (d, 1H, J=8.8 Hz), 7.32 (s, 1H), 7.16 (s, 1H), 6.48 (d, 1H, J=9.6 Hz), 5.87 (s, 1H), 4.28 (d, 2H, J=5.2 Hz), 4.05-4.02 (m, 2H), 3.67-3.64 (m, 2H), 3.12 (m, 3H), 2.75 (m, 1H), 2.69-2.68 (m, 6H), 2.21 (s, 3H+3H), 2.11 (s, 3H), 1.96-1.91 (m, 4H), 1.43 (m, 4H), 0.83 (t, 3H, J=6.8 Hz).
Compound 5:
[0765] Synthesis of N-((4,6-dimethyl-2-oxo-l ,2-dihydropyridin-3-yl)methyl)-3-(((trans)-4- (dimethylamino)cyclohexyl)(emyl)amino)-5-(6-(2-methoxyethoxy)pyridin-3-yl)-2-methylbenzamide
Figure imgf000140_0001
[0766] Step 1: Synthesis of methyl 3-(((trans)-4-((tert-butoxycarbonyl)amino)
cyclohexyl)(ethyl)amino)-5-(6-(2-methoxyethoxy)pyridin-3-yl)-2-methylbenzoate
[0767] To a stirred solution of methyl 3-(((trans)-4-((tert-butoxycarbonyl)amino)
cyclohexyl)(ethyl)amino)-5-(6-hydroxypyridin-3-yl)-2-methylbenzoate (0.3 g, 0.62 mmol) and 1- bromo-2-methoxyethane (0.259 g, 1.86 mmol) in DMF (3 mL), was added KOtBu (0.083 g, 0.75 mmol) and the resulting reaction mixture was stirred at 22 °C for 2 h. On completion, water was added and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2S04 and concentrated in vacuo. The crude compound was purified by column chromatography over basic alumina to afford the title compound (0.3 g, 89.3% yield).
[0768] Step 2: Synthesis of tert-but l ((trans)-4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)carbamoyl)-5-(6-(2-methoxyethoxy)pyridin-3-yl)-2- methylphenyl)(ethyl)amino)cyclohexyl)carbamate
[0769] Protocol as for 2, Step 3 with methyl 3-(((trans)-4-((tert-butoxycarbonyl)amino) cyclohexyl)(ethyl)amino)-5-(6-(2-methoxyethoxy)pyridin-3-yl)-2-methylbenzoate_(0.3 g, 0.55 mmol) and 3-(amino methyl)-4, 6-dimethylpyridin-2(lH)-one (0.14 g, 0.95 mmol) to afford the title compound (0.2 g, 54.7% yield).
[0770] Step 3: Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridm-3-yl)methyl)-3-(((trans)-4- (dimethylamino)cyclohexyl)(ethyl)amino)-5-(6-(2-methoxyethoxy) pyridine-3-yl)-2- methylbenzamide
[0771] Protocol as for 3, Step 3 with tert-butyl ((trans)-4-((3-(((4,6-dimethyl-2-oxo-l,2- dihydropyridin-3-yl)methyl)carbamoyl)-5-(6-(2-methoxyethoxy)pyridin-3-yl)-2- methylphenyl)(ethyl)amino)cyclohexyl)carbamate to afford the title compound (0.1 g, 59.9% yield). [0772] LCMS: 590.65 (M + 1)+; TFA-salt: Ή NMR (DMSO-<¾, 400 MHz) δ 11.48 (brs, 1H), 9.56 (bs, 1H), 8.17 (m, IH), 7.99 (s, 1H), 7.80 (d, 1H, J=9.6 Hz), 7.34 (m, 1H), 7.18 (m, 1H), 6.48 (d, 1H, J=9.6 Hz), 5.87 (s, IH), 4.28 (d, 2H, J=4.8 Hz), 4.16-4.14 (m, 2H), 3.62-3.60 (m, 2H), 3.24 (s, 3H), 3.13 (ra, 4H ), 2.69-2.68 (m, 6H), 2.21 (s, 6H+3H), 2.05-1.92 (m, 4H), 1.44 (m, 4H), 0.83 (t, 3H, J=6.8 Hz).
Compound 6:
[0773] Synthesis of N-((4,6-diinethyl-2-oxo-l,2-dihydropyridrn-3-yl)methyl)-5-(((trans)-4- (dimethylammo)cyclohexyl)(ethyl)armno)-4'-(2-(2-methoxyethoxy)ethoxy)-4-raethyl-[ 1,1'-
Figure imgf000141_0001
[0774] Step 1-3: Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-5-(((trans)-
4-(dimethylamino)cyclohexyl)(ethyl)amino)-4'-(2-(2-methoxyethoxy)ethoxy)-4-raethyl-[l,r- biphenyl]-3-carboxamide
[0775] Protocol as for 2, Steps 2-4, starting with methyl 5-(((trans)-4-((tert- butoxycarbonyl)amino)cyclohexyl)(ethyl)aniino)-4'-hydroxy-4-methyl-[l, -biphenyl]-3-carboxylate and 1 -bromo-2-(2-methoxyethoxy)ethane.
[0776] LCMS: 633.65 (M+l)+; TFA-salt: 'HNMR (DMSO-<¾, 400 MHz) δ 11.46 (brs, IH), 8.17 (brs, IH), 7.53 (d, 2H, J=8.0 Hz), 7.31 (s, IH), 7.14 (s, IH), 7.01 (d, 2H, J=8.0 Hz), 5.86 (s, IH), 4.28 (d, 2H, J=3.6 Hz), 4.12 (s, 2H), 3.75 (s, 2H), 3.59 (d, 2H, J=4.8 Hz), 3.46 (t, 2H, J=4.0 Hz), 3.25 (s, 3H), 3.16-2.98 (m, 2H), 2.72-2.60 (m, 2H), 2.20 (s, 3H), 2.15-2.01 (brs, 12H), 1.89-1.68 (m, 5H), 1.48-1.26 (m, 2H), 1.26-1.04 (m, 2H), 0.82 (t, 3H, J=6.0 Hz).
Compound 6b [0777] Synthesis of 5-(((trans)-4-(dimethylammo)cyclohexyl)(ethyl)amino)-N-((4-methoxy-6- methyl-2-oxo- 1 ,2-dihyd^opyridin-3-yl)memyl)-4'-(2-methoxyethoxy)-4-methyl-[ 1 , l'-biphenyl]-3-
Figure imgf000142_0001
[0778] Step 1: Synthesis of 2-amino-6-methyl-4-oxo-4H-pyran-3-carbonitrile
[0779] To a stirred solution of NaH (60% 19.03 g, 476 mmol) in THF (400 mL), malononitrile
(31.4g, 476 mmol) was added drop wise at -10 °C and stirred it at same temperature for 20 min. Then
4-methyleneoxetan-2-one (40 g, 476 mmol) was added at -10 °C over period of 15 min. and reaction was stirred at same temperature for lh. On completion, reaction was neutralized with dilute HCl (aq.) and concentrated to dryness to give the title compound (50 g, 70% yield).
[0780] Step 2: Synthesis of 4-hydroxy-6-methyl-2-oxo-l,2-dihydropyridine-3-carbonitrile
[0781] A suspension of 2-amino-6-methyl-4-oxo-4H-pyran-3-carbonitrile (50 g, 333 mmol) in 10%
HCl (600 mL) was heated under reflux for 4h. The precipitate was collected by filtration and washed with water and then recrystallized from MeOH to afford the title compound (45 g, 90% yield).
[0782] Step 3: Synthesis of 4-methoxy-6-methyl-2-oxo-l,2-dihydropyridine-3-carbonitrile
[0783] To a stirred solution of 4-hydroxy-6-methyl-2-oxo-l,2-dihydropyridine-3-carbonitrile (2 g,
13.24 mmol)) in DMF (10 mL) at 0 °C, KOtBu (1.48 g, 13.2 mmol) and methyl iodide (1.88 g, 13.2 mmol) were added. The resulting reaction mass was stirred at room temperature for 12h. On completion, reaction mixture was concentrated to dryness. The residue was diluted with 20%
MeOH/DCM and filtered and the filtrate was washed well with 20% MeOH/DCM. The filtrate was concentrated under reduced pressure to afford crude material which was purified by silica gel column chromatography to afford the title compound (1 g, 46.1% yield).
[0784] Step 4: Synthesis of 3-(aminomethyl)-4-methoxy-6-methylpyridin-2(lH)-one [0785] To a solution of 4-hydroxy-6-methyl-2-oxo-l,2-dihydropyridine-3-carbonitrile (0.3 g, 1.82 mmol) in methanol (5 mL), catalytic amount of Raney Nickel and ammonia solution (1 mL) were added. Reaction mass was stirred at room temperature under hydrogen pressure (balloon pressure) for 3h. On completion of reaction, reaction mass was filtered through celite, washed with methanol and the filtrate was concentrated under reduced pressure to afford the title compound (0.3 g, 97.7%).
[0786] Step 5: Synthesis of tert-butyl ((trans)-4-(ethyl(5-(((4-methoxy-6-methyl-2-oxo-l,2- dihydropyridin-3-yl)methyl)carbamoyl)-4'-(2-methoxyethoxy)-4-methyl-[l,r-biphenyl]-3- yl)amino)cyclohexyl)carbamate
[0787] Protocol as for 2, Step 3, Part 2 with 3-(aminomethyl)-4-methoxy-6-methylpyridin-2(lH)- one (0.3 g, 0.88 mmol) and 3-(((trans)-4-((tert-butoxycarbony])amino)cyclohexyl)amino)-5-(2- methoxyethoxy)-2-methylbenzoic acid (0.3 g, 1.77 mmol) to afford the title compound (0.07 g, 16.1% yield).
[0788] Step 6: Synthesis of 5-(((trans)-4-(dimethylamino)cyclohexyl)(ethyl)amino)-N-((4- methoxy-6-methyl-2-oxo- 1 ,2-dmydropyridin-3-yl)methyl)-4'-(2-methoxyethoxy)-4-methyl-[ 1,1'- biphenyl] -3 -carboxamide
[0789] Protocol as for 2, Step 4 with tert-butyl ((trans)-4-(ethyl(5-(((4-methoxy-6-methyl-2-oxo- l,2-dihydropyridm-3-yl)methyl)carbamoyl)-4'-(2-methoxyethoxy)-4-methyl-[l, -biphenyl]-3- yl)amino)cyclohexyl)carbamate (0.07 g, 0.14 mmol) to afford the title compound (0.02 g, 24% yield).
[0790] LCMS: 605.5 (M+l)+; TFA-salt: ]H NMR (DMSO-i¾, 400 MHz) δ 11.43 (brs, IH), 8.22 (s, 2H), 7.97 (t, IH, J=2.0 Hz), 7.53 (d, 2H, J=8 Hz), 7.30 (s, IH), 7.13 (s, IH), 7.00 (d, 2H, J=8.0 Hz), 6.09 (s, IH), 4.23 (d, 2H, J= 4.0 Hz), 4.12 (t, 2H, 4.0 Hz), 3.80 (s, 3H), 3.67 (t, 2H, J=4.0 Hz), 3.32 (s, 3H), 3.09 (q, 2H, J=6.8 Hz), 2.19 (t, 12H, J=8.0 Hz), 1.81 (t, 4H, J=12.8 Hz), 1.38 (q, 2H, J=12.0 Hz), 1.17 (q, 2H, J=12.0 Hz), 0.83 (t, 3H, J=6.8 Hz). IH merged into the solvent peak.
Figure imgf000143_0001
Figure imgf000144_0001
[001] Step 1: Synthesis of methyl 5-bromo-3-(((trans)-4-((tert-butoxycarbonyl)-(methyl)-amino)- cyclohexyl)(ethyl)amino)-2-methylbenzoate
[002] To a stirred solution of methyl 5-bromo-3-(((trans)-4-((tert- butoxycarbonyl)amino)cyclohexyl)(ethyl)amino)-2-methylbenzoate (3 g, 6.41 mmol, see, e.g., WO2012142504) in THF (30 mL), NaH (0.184 g, 7.69 mmol) was added at 0 °C and stirred it at same temperature for 20 min. Then methyl iodide (9.10 g, 64.10 mmol) was added at 0 °C and reaction was stirred for overnight at room temperature. On completion, reaction was quenched with ice water and extracted with dichloromethane. The combined organic layers were washed with water, dried, concentrated under reduced pressure. The crude compound was purified by column chromatography to afford the crude title compound that was used without further purification (3 g, 97.4% yield).
[003] Step 2: Synthesis of methyl 3-(((trans)-4-((tert-butoxycarbonyl)-(methyl)-amino)- cyclohexyl)-(ethyl)amino)-5-(3-hydroxyprop-l-yn-l-yl)-2-methylbenzoate
[004] To a stirred solution of methyl S-bromo-3-(((trans)-4-((tert-butoxycarbonyl)-(methyl)- amino)-cyclohexyl)(ethyl)amino)-2-methylbenzoate (2 g, 4.14 mmol) in dry toluene was added Cul (0.015 g, 0.079 mmol), PPh3 (0.043 g, 0.165 mmol), PdCl2(PPh3)2 (0.058 g, 0.082 mmol), N,N- diisopropyl amine (1.08 g, 10.78 mmol) and reaction was purged with argon for 15 min. prop-2-yn- ] -ol (0.46 g, 8.29 mmol) was added to it reaction was heated at 80 °C at sealed condition for 5 h. On completion, it was quenched with water and extracted with ethyl acetate. Organic layer was dried over Na2S04. The crude compound was purified by column chromatography to afford the title compound (1.2 g, 63.2% yield).
[005] Step 3: Synthesis of methyl 5-(3-bromoprop-l-yn-l-yl)-3-(((trans)-4-((tert-butoxy carbonyl)-(methyl)amino)cyclohexyl)(ethyl)amino)-2-methylbenzoate:
[006] To a stirred solution of methyl 3-(((trans)-4-((tert-butoxycarbonyl)-(methyl)-amino)- cyclohexyl)-(ethyl)amino)-5-(3-hydroxyprop-l-yn-l-yl)-2-methylbenzoate (1.2 g, 2.62 mmol) in
DC (15 mL), PPh3 (1.37 g, 5.22 mmol) and CBr4 (1.7 g, 5.10 mmol) were added at 0 °C and reaction was stirred for 4 h at room temperature. On completion, reaction was quenched with ice water and extracted with dichloromethane. The combined organic layers were washed with water, dried, concentrated under reduced pressure. The crude material was purified by column chromatography to afford the title compound (0.5 g, 38.5% yield).
[007] Step 4: Synthesis of methyl 3-(((trans)-4-((tert-butoxycarbonyl)(methyl)amino) cyclohexyI)(eth I)amino)-2-methyί-5-(3-nlO holmo rop-l-yn-l-yl)benzoate
[008] To a stirred solution of methyl 5-(3-bromoprop-l-yn-l-yl)-3-(((trans)-4-((tert-butoxy carbonyl)-(methyl)amino)cyclohexyl)(ethyl)amino)-2-methylbenzoate (1 equiv.) in D F, morpholine (5 equiv.) was added and reaction was stirred for 12 h at room temperature. On completion, the reaction was quenched with ice water and extracted with dichloromethane. The combined organic layers were washed with water, dried, concentrated under reduced pressure to afford desired crude title compound that was used in the next step without further purification
(98.7% yield)
[009] Step S: Synthesis of tert-butyl ((trans)-4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydro pyridin-3- yI)methyl)carbamoyI)-2-methyl-5-(3-morpholinoprop-l -yn-1 -yl)
phenyI)(ethyl)amino)cyclohexyl)(methyl)carbamate
[010] NaOH (1.5 eq.) was added to a solution of methyl 3-(((trans)-4-((tert- butoxycarbonyl)(methyl)amino)cyclohexyl)(ethyl)amino)-2-methyl-5-(3-morpholinoprop-l-yn-l- yl)benzoate (1 equiv.) in EtOH: ¾0 (9: 1) and stirred at 60 °C for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and acidified using dilute HCI up to pH 6 and pH 4 was adjusted using citric acid. Extraction was carried out using 10% methanol in DCM. Combined organic layers were dried concentrated giving respective acid.
[011] The above acid (1 equiv.) was then dissolved in DMSO and 3-(amino methyl)-4, 6- dimethylpyridin-2(lH)-one (2 equiv.) and triethyl amine (1 equiv.) was added to it. The reaction mixture was stirred at room temperature for 15 min before PyBop (1.5 equiv.) was added to it and stirring was continued for overnight at room temperature. After completion of the reaction, the reaction mass was poured into ice and extraction was carried out using 10 % MeOH/DCM. The combined organic layers were dried over Na2S04 and concentrated under reduced pressure to obtain crude material which then purified first by water followed by acetonitrile washing to afford desired title compound (69.4% yield).
[012] Step 6: Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3- (ethyl((trans)-4-(methylamino)cyclohexyl)amino)-2-methyl-5-(3-morpholinoprop -1-yn-l- yl)benzamide
[013] To a stirred solution of tert-butyl((trans)-4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydro pyridin-3- yl)methyl)carbamoyl)-2-methyl-5-(3-morpholinoprop-l-yn-l-yl)
phenyl)(ethyl)amino)cyclohexyl)(methyl)carbamate (1 equiv.) in DCM at 0 °C, TFA (3 equiv.) was added and reaction was stirred for 2 h at room temperature. After completion, reaction was concentrated to dryness. The residue was then basifled with Na2COj (aq.) to pH 8 and the aqueous layer was extracted with 20% methanol in DCM. The combined organic layers were dried over Na2S0 and solvent was removed under reduced pressure to afford the title compound (99% yield) which was used in the next reaction without further purification.
[014] Step 7: Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3- (emyI((trans)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)arnino)-2-methyl-5-(3- morpholinoprop- 1 -yn- 1 -yl)benzamide
[015] To a stirred solution of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3- (ethyl((trans)-4-(methylamino)cyclohexyl)amino)-2-methyl-5-(3-morpholinoprop -1-yn-l- yl)benzamide (1 equiv.) in dichloroethane, 2-methoxyacetaldehyde (10 equiv.) and acetic acid (6 equiv.) was added at 0 °C and stirred for 20 min. Then NaBH(OAc)3 (3 equiv.) was added and stirred for 2h at 0 °C. On completion of reaction, water was added and extracted with 20% methanol in DCM. Combined organic layers were dried over a2S0 and solvent removed under reduced pressure. The crude compound was purified by prep. HPLC to afford target molecule (0.1 g, 33.6% yield).
[016] LCMS: 606.65 (M+l)+; TFA salt: Ή NMR (DMSO-<¾ 400 MHz) 5 11.50 (brs, 1H), 9.22 (brs, 1H), 8.18 (t, 1H), 7.24 (s, 1H), 7.09 (s, 1H), 5.86 (s, 1H), 4.26-4.25 (m, 4H), 3.66-3.59 (m, 4H), 3.48-3.36 (m, 3H), 3.29-3.17 (m, 7H), 3.04-3.01 (m, 3H), 2.69-2.68 (m, 4H), 2.20 (s, 3H), 2.19 (s, 3H), 2.1 1 (s, 3H), 2.00-1.92 (m, 2H), 1.82-1.73 (m, 3H), 1.46 (m, 4H), 0.78 (t, 3H, J=6.4 Hz).
Alternative Synthetic Scheme for Compound 2:
Figure imgf000146_0001
[017] Step A: Synthesis of 4-(prop-2-yn-l-yl)morpholine: [018] To a stirred solution of propargyl bromide (50 g, 420 mmol) in acetone (300 mL), CS2CO3 (136.5 g, 420 mmol) was added at 0 °C. Then morpholine (36.60 g, 420 mmol) in acetone (200 mL) was added dropwise and reaction was stirred at room temperature for 16 h. On completion, the reaction mass was filtered and the filtrate was concentrated under reduced pressure to afford the title compound (50 g, crude). The isolated compound was used directly in the subsequent coupling step without further purification.
[019] Step 1: Synthesis of methyl 5-bromo-3-(ethyl((trans)-4-(methylamino) cyclohexyl) amino )- 2-methylbenzoate:
[020] To a stirred solution of methyl 5-bromo-3-(((trans)-4-((tert- butoxycarbonyl)(methyl)amino)cyclohexyl)(ethyl)amino)-2-methylbenzoate (30 g, 62.24 mmol) in methanol (100 mL) at 0 °C, methanolic HC1 (500 mL) was added and reaction was stirred for 2 h at room temperature. After completion, reaction was concentrated to dryness. The residue was basified with Na2C03 (aq.) to pH 8 and aqueous layer was extracted with 10% methanol in DCM (200 mL x 3). Combined organic layers were dried over Na2S04 and solvent removed under reduced pressure to afford the title compound as colorless oil (25 g, crude). The isolated compound was used in the next step without further purification.
[021] Step 2: Synthesis of methyl 5-bromo-3-(ethyl((trans)-4-((2-methoxyethyl)-(methyl)-amino) cyclohexyl) amino)-2-methylbenzoate:
[022] To a stirred solution of crude methyl 5-bromo-3-(ethyl((trans)-4-(methylamino) cyclohexyl)amino)-2-methylbenzoate (25 g, 65.44 mmol), l-bromo-2-methoxyethane (18.19 g, 130.8 mmol) in acetonitrile (250 mL), K2C03 (18.06 g, 130.8 mmol) and KI (6.51 g, 39.21 mmol) were added. The resulting reaction mass was stirred at 65 °C for 16 h. On completion, reaction mixture was diluted with water (300 mL) and extracted with DCM (500 mL x 3). The combined organic layers were washed with water, dried over Na2S04 and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to afford the title compound (20 g, 69.3% yield).
[023] Ή NMR (DMSO-cfe 400 MHz) δ 7.55 (s, 1H), 7.45 (s, 1H), 3.82 (s, 3H), 3.32 (m, 4H), 3.20 (s, 3H), 3.05 (q, 2H), 2.61 (m, 1H), 2.32 (s, 3H), 2.30 (m, 1H), 2.15 (s, 3H), 1.77-1.67 (m, 4H), 1.37- 1.31(m, 2H), 1.24-1.18 (m, 2H), 0.78 (t, 3H, J=6.8 Hz).
[024] Step 3: Synthesis of methyl 3-(ethyl((trans)-4-((2-methoxyethyl)-(methyl)-amino)- cyclohexyl)-amino)-2-methyl-5-(3-morpholinoprop-l-yn-l-yl)benzoate:
[025] The solution of methyl 5-bromo-3-(ethyl((trans)-4-((2-methoxyethyl)-(methyl)-amino) cyclohexyl) amino)-2-methylbenzoate (30 g, 68.02 mmol), 4-(prop-2-yn-l-yl) morpholine (25.51 g,
204 mmol) and triethylamine (20.61 g, 204 mmol) in DMF (300 mL) was bubbled through Argon for
20 min. Then Cul (3.87 g, 20.36 mmol) and Pd (PPh3)4 (7.85 g, 6.79 mmol) were added and Argon was bubbled through for further 20 min. The reaction mixture was heated at 105 °C for 4 h and then cooled to room temperature. The reaction was quenched with water (100 mL) and the aqueous phase was extracted with 10 % MeOH/DCM (400 mL x 3). The combined organic extracts were dried over Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography to afford the title compound (21 g, 63.7% yield).
[026] Ή M (DMSO-i¾, 400 MHz) δ 7.46 (s, 1H), 7.32 (s, 1H), 3.82 (s, 3H), 3.62-3.57 (m, 6H), 3.50 (s, 2H), 3.35-3.32 (m, 2H), 3.21 (s, 3H), 3.17 (m, 1H), 3.05 (q, 2H), 2.61-2.58 (m, 2H), 2.38 (s, 3H), 2.33 (m, 1H), 2.18 (m, 2H), 1.77-1.70 (m, 4H), 1.36-1.20 (m, 4H), 0.77 (t, 3H, J=6.8 Hz), 3H merged in solvent peak.
[027] Step 4: Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3- (ethyl((trans)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)-2-methyl-5-(3- morpholinoprop-1 -yn-1 -yl)benzamide:
[028] Aqueous NaOH (2.59 g, 64.91 mmol in 10 mL Η2θ) was added to a solution of methyl 3- (ethyl((tram)-4-((2-methoxyethyl)-(methyl)-amino)-cyclohexyl)-amino)-2-methyl-5-(3- morpholinoprop-l-yn-l-yl)benzoate (21 g, 43.29 mmol) in EtOH (100 mL) and stirred at 60 °C for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and the residue was acidified using dilute HC1 up to pH 4 using citric acid. Extraction was carried out using 10 % MeOH/DCM (200 mL x 3). Combined organic layers were dried concentrated giving respective acid (15.5 g, 76% yield).
[029] To the solution of above acid (15.5 g, 32.90 mmol) in DMSO (50 mL), 3-(amino methyl)- 4,6-dimethylpyridin-2(lH)-one (10 g, 65.80 mmol) and triethyl amine (23 mL, 164.5 mmol) were added. The reaction mixture was stirred at room temperature for 15 min before PyBop (25.66 g, 49.34 mmol) was added to it at 0 °C and further stirred for overnight at room temperature. After completion, the reaction mass was poured into ice water (100 mL) and extraction was carried out using 10 % MeOH/DCM (200 mL x 3). Combined organic layers were dried over a2S04 and concentrated under reduced pressure. The crude compound was purified by column chromatography over basic alumina eluting with MeOH:DCM to afford the title compound (11 g, 55.3% yield).
[030] LCMS: 606.50 (M + 1)+; Ή NMR (MeOD, 400 MHz) δ 7.23 (s, 1H), 7.09 (s, 1H), 6.11 (s, 1H), 4.46 (s, 2H), 3.74-3.72 (m, 4H), 3.51 (s, 2H), 3.47 (t, 2H, J=5.6 Hz,), 3.32 (s, 3H), 3.07 (q, 2H, J=7.2 Hz), 2.64-2.63 (m, 7H), 2.38 (m,lH), 2.37 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H), 2.25 (s, 3H), 1.89-1.86 (m, 4H), 1.50-1.30 (m, 4H), 0.83 (t, 3H, J=7.2 Hz).
Compound 7 [031] Synthesis of N-((4,6-dimethyl-2-oxo-l,2-a ya opyridm-3-yl)methyl)-3-(ethyl((trans)-4-((2- methoxyethyl)(methyl)amino)cyclohexyl)amino)-2-methyl-5-(3-(4-methylpiperazin-l-yl)pro^
Figure imgf000149_0001
[032] Step 1: Synthesis of methyl 3-(((trans)-4-((tert-butoxycarbonyl)(methyl)
ammo)cyclohexyl)(ethyl)amino)-2-methyl-5-(3-(4-m
[033] Protocol as for 8, Step 4 with methyl 5-(3-bromoprop-l-yn-l-yl)-3-(((trans)-4-((tert- butoxycarbonyl)(methyl)amino)cyclohexyl)(ethyl)amino)-2-methylbenzoate and N-methylpiperidine (5 equiv.) to afford the title compound (99% yield)
[034] Step 2: Synthesis of tert-butyl((trans)-4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)carbamoyl)-2-methyl-5-(3-(4-methylpiperazin-l -yl)prop- 1 -yn- 1 - yl)phenyl)(ethyl)amino)cyclohexyl)(methyl)carbamate
[035] Protocol as for 8, Step 5 with methyl 3-(((trans)-4-((tert-butoxycarbonyl)(methyl) amino)cyclohexyl)(ethyl)armno)-2-methyl-5-(3-(4-memylpiperazin-l-yl)prop-l-yn-l-yl)berizoate and 3-(aminomethyl)-4, 6-dimethylpyridin-2(lH)-one (2 equiv.) to afford the tide compound (73.4% yield)
[036] Step 3: Synthesis of N-((4,6-dimethyl-2-oxo-l>2-dihydropyridin-3-yl)methyl)-3-
(emyl((trans)-4-(methylamino)cyclohexyl)amino)-2-methyl-5-(3-(4-methylpiperazin-l-yl)prop-l-yn- l-yl)benzamide
[037] Protocol as for 8, Step 6 with tert-butyl((trans)-4-((3-(((4J6-dimethyl-2-oxo-l,2- dihydropyri Un-3-yl)methyl)carbamoyl)-2-methyl-5-(3-(4-methylpiperazin-l-yl)prop-l-yn-l- yl)phenyl)(ethyl)amino)cyclohexyl)(methyl)carbamate to afford the title compound (89.7% yield) [038] Step 4: Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3- (emyl((trans)-4-((2-methoxyethyl)(methyl)ammo)cyclohexyl)amino)-2-methyl-5-(3-(4- methylpiperazin- 1 -yl)prop- 1 -yn- 1 -yl)benzamide
[039] Protocol as for 8, Step 7 with N-((4,6-dimethyl-2-oxo-l ,2-dihydropyridin-3-yl)methyl)-3- (emyl((trans)-4-(methylamino)cyclohexyl)amino)-2-methyl-5-(3-(4-methylpiperazm-l-y])pro^ l-yl)benzamide to afford the title compound (0.07 g, 18.1% yield).
[040] LCMS: 619.65 (M + 1)+; TFA-salt: Ή NMR (DMSO-i¾, 400 MHz) δ 11.50 (brs, 1H), 9.28 (brs, lH), 8.17 (t, 1H), 7.17 (s, lH), 7.01 (s, 1H), 5.87 (s, 1H), 4.25 (d, 2H, J=4.8 Hz), 3.66 (m, 2H), 3.62 (m, 2H), 3.44-3.36 (m, 3H), 3.31 (s, 3H), 3.17-3.02 (m, 8H), 2.79 (s, 3H), 2.69-2.68 (m, 4H), 2.61 (m, 2H), 2.19 (s, 6H), 2.11 (s, 3H), 1.96-1.92 (m, 2H), 1.83 (m, 2H), 1.46 (m, 4H), 0.78 (t, 3H, J=6.4 Hz).
Compound 8
[041] Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(ethyl((trans)-4-((2- methoxyethyl)(methyl)amino)cyclohexyi)amino)-5-(3-hydroxy-3-methylbut-l-yn-l-yl)-2- methylbenzamide
Figure imgf000150_0001
[042] Step 1: Synthesis of methyl 3-(((trans)-4-((tert-butoxycarbonyl)(methyl)amino) cyclohexyl)(ethyl)amino)-5-(3-hydroxy-3-methylbut-l-yn-l-yl)-2-methylbenzoate
[043] To a stirred solution of methyl 5-bromo-3-(((trans)-4-((tert- butoxycarbonyl)(memyl)amino)cyclohexyl)(ethyl)ammo)-2-methylbenzoate (lg, 2.07 mmol) in DMF (10 mL), Cul (0.118 g, 0.62 mmol), Pd(PPh3)4 (0.239 g, 0.21 mmol), triethyl amine (0.84 mL, 6.2 mmol) were added and the reaction was purged with argon for 15 min. 2-methylbut-3-yn-2-ol (0.523 g, 6.22mmol) was added and the reaction was heated at 100 °C in a sealed tube for 6 h. On completion, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over Na2S04. The crude compound was purified by column chromatography to afford the title compoun (0.8 g, 80% yield).
[044] Steps 2-4: Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3- (ethyl((trans)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)-5-(3-hydroxy-3-methylbut-l- yn- 1 -yl)-2-methylbenzamide
[045] Protocol as for 8, Steps 5-7 starting with methyl 3-(((trans)-4-((tert- butoxycarbonyl)(methyl)amino) cyclohexyl)(ethyl)amino)-5-(3-hydroxy-3-methylbut-l-yn-l-yl)-2- methylbenzoate (0.8 g, 1.64 mmol) to afford the title compound (0.11 g, 17.5% yield).
[046] LCMS: 565.90 (M + 1)+; TFA-salt: Ή NMR (DMSO-<¾, 400 MHz) δ 11.45 (brs, 1H), 9.14 (brs, IH), 8.17 (t, 1H, J=4.4 Hz), 7.11 (s, 1H), 6.94 (s, 1H), 5.86 (s, 1H), 5.08-5.05 (m, 1H), 4.96- 4.93 (m, IH), 4.25 (d, 2H, J=5.2 Hz), 3.81-3.77 (m, 3H), 3.45-3.22 (m, 6H),3.03-3.01 (m, 3H), 2.68- 2.67 (m, 4H), 2.19 (s, 3H+3H), 2.11 (s, 3H), 2.02-1.91 (m, 2H), 1.84 (m, 2H), 1.44 (s, 6H), 0.77 (t, 3H, J=6.8 Hz). IH merged in solvent peak.
Compound 9
[047] Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(ethyl((trans)-4-((2-
Figure imgf000151_0001
[048] Step 1: Synthesis of methyl 3-(((trans)-4-((tert-butoxycarbonyl)(methyl)
ammo)cyclohexyl)(ethyl)amino)-5-fluoro-2-methylbenzoate
[049] Protocol as for 8, Step 1 with methyl 3-(((trans)-4-((tert-butoxycarbonyl)amino) cyclohexyl)(ethyl)amino)-5-fluoro-2-methylbenzoate (1 g, 2.45 mmol, see, e.g., co-owned US Provsional Application 61/714145 filed on October 15, 2012 (Attorney Docket No. 41478- 514P02US)) in DMF as solvent (10 mL) to afford the title compound 0.95 g, 95% yield).
[050] Steps2-4: Synthesis of N-((4>6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3- (ethyl((trans)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)-5-fluoro-2-methylbenzamide [051] Protocols as for 8, Steps 5-7 starting with methyl 3-(((trans)-4-((tert- butoxycarbonyl)(methyI) amino)cyclohexyl)(ethyl)amino)-5-fluoro-2-methylbenzoate (0.95 g, 2.25 mmol) to afford the title compound (0.05 g, 4.6% yield).
[052] LCMS: 501.40 (M + 1)+; TFA-salt: Ή NMR (DMSO-rfA 400 MHz) δ 11.47 (brs, IH), 9.25 (s, IH), 8.17 (t, IH), 7.02 (d, IH, J=10.8 Hz), 6.76 (d, IH, J=6.8 Hz), 5.86 (s, IH), 4.25 (d, 2H, J=5.2 Hz), 3.62 (m, 2H), 3.37 (s, 3H), 3.29-3.25 (m, 3H), 3.03-3.01 (m, 2H), 2.69-2.68 (m, 4H), 2.19 (s, 3H), 2.14 (s, 3H), 2.11 (s, 3H), 1.97-1.92 (m, 2H), 1.83 (m, 2H), 1.49-1.44 (m, 4H), 0.79 (t, 3H, J=6.8 Hz).
Compound 10:
[053] Synmesis of N-((4,6-dimemyl-2-oxo-l,2-dmydropyridm-3-yl)me l)-3-(ethyl((tr<
Figure imgf000152_0001
[054] Step 1: Synthesis of methyl 3-(((trans)-4-((tert-butoxycarbonyl)amino) cyclohexyl)amino)- 2-methylbenzoate
[055] To a stirred solution of methyl 3-amino-2-methylbenzoate (4.1 g, 24.82 mmol) and tert-butyl (4-oxocyclohexyl)carbamate (6.35 g, 29.80 mmol) in dichloroethane (40 mL), acetic acid (8.94 g, 149 mmol) was added and reaction stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydnde (15.8 g, 74.5 mmol) was added at 0 °C and reaction was stirred at room temperature for 16 h. On completion, the reaction was quenched with a2C03 (aq.) the organic phase was separated and the aqueous phase was extracted with DCM. The combined organic layers were washed with water, dried, concentrated under reduced pressure. The crude material obtained was purified by column chromatography to afford the title compound (3.1 g, 34.8% yield).
[056] Step 2: Synthesis of methyl 3-(((trans)-4-((tert-butoxycarbonyl)(methyl)
amino)cyclohexyl)(ethyl)amino)-2-methylbenzoate
[057] To a stirred solution of methyl 3-(((trans)-4-((tert-butoxycarbonyl)amino)
cyclohexyl)amino)-2-methylbenzoate (2.9 g, 8.01 mmol) and acetaldehyde (0.53 g, 12.01 mmol) in dichloroethane (30 mL), acetic acid (2.88 g, 48.0 mmol) was added and reaction stirred at room temperature for 20 min. Then sodium triacetoxyborohydride (5.1 g, 24.05 mmol) was added at 0 °C and reaction was stirred at room temperature for 2h. On completion, the reaction was quenched with Na2C03 (aq.), the organic phase was separated and the aqueous phase was extracted with DCM. The combined organic layers were washed with water, dried, concentrated under reduced pressure and the crude material was purified by column chromatography to afford the title compound (2.8 g, 61% yield).
[058] Step 3-6: Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3- (ethyl((trans)-4-((2-memoxyemyl)(memyl)amino)cyclohexyl)amino)-2-methylbenzamide
[059] Protocol as for 11, Steps 1-4 starting from methyl 3-(((trans)-4-((tert-butoxycarbonyl)- amino)-cyclohexyl)-(ethyl)-amino)-2-methylbenzoate (1.2 g, 3.08 mmol) to afford the title compound (O.lg, 4.3% yield).
[060] LCMS: 483.40 (M + 1)+; TFA-salt: Ή NMR (DMSO-<¾, 400 MHz) 8 11.45 (brs, 1H), 9.30 (brs, 1H), 8.04 (s, 1H), 7.18 (m, 2H), 6.98 (m, 1H), 5.86 (s, 1H), 4.27 (m, 2H), 3.62 (m, 2H), 3.46- 3.30 (m, 6H), 3.17-3.09 (m, 2H), 2.69 (m, 4H), 2.21(s, 3H), 2.20 (s, 3H), 2.11 (s, 3H), 1.98-1.87 (m, 4H), 1.45 (m, 4H), 0.79 (t, 3H).
Compound 11:
[061] Synthesis of N-((4,6-dime l-2-oxo-l,2-dmydropyridin-3-yl)methyl)-3-(ethyl((trans)-4-((2-
Figure imgf000153_0001
[062] Step 1: Synthesis of methyl 3-(((trans)-4-((tert-butoxycarbonyl)(methyl)
amino)cyclohexyl)(ethyl)amino)-5-methoxy-2-methylbenzoate
[063] Protocol as for 8, Step 1 with methyl 3-(((trans)-4-((tert-butoxycarbonyl)
amino)cyclohexyl)(ethyl)amino)-5-methoxy-2-methylbenzoate (see, e.g., WO2012/142513 (Attorney
Docket No. 41478-508001WO)). [064] Steps 2-4: Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3- (emyl((1rans)-4-((2-memoxyethyl)(methyl)ammo)cycloh^
[065] Protocol as for 8, Steps 5-7 starting from methyl 3-(((trans)-4-((tert-butoxycarbonyl)(rnethyl) amino)cyclohexyl)(ethyl)amino)-5-methoxy-2-methylbenzoate.
[066] LCMS: 513.55 (M + 1)+; TFA-salt: Ή NMR DMSO-d6, 400 MHz) δ 11.49 (brs, IH), 9.27 (s, IH), 8.07 (s, IH), 6.74 (brs, IH), 6.58 (s, IH), 5.87 (s, IH), 4.26 (d, 2H, J=4.0 Hz), 3.72 (s, 3H), 3.62 (brs, 2H), 3.50-2.90 (m, 9H), 2.68 (d, 3H, J=3.6 Hz), 2.20 (s, 3H), 2.1 1 (s, 6H), 2.04-1.87 (m, 4H), 1.56-1.38 ( , 4H), 0.80 (bit, 3H, J=6.4 Hz).
Compound 12:
[067] Syndesis of N-((4,6-dimeftyl-2-oxo-l,2-daydrop^
Figure imgf000154_0001
[068] Step 1: Synthesis of methyl 3-(((trans)-4-((tert-butoxycarbonyl)amino)
cyclohexyl)(ethyl)amino)-5-(2-methoxyethoxy)-2-methylbenzoate
[069] Protocol as for 10, Steps 1-2 with methyl 3-arnino-5-(2-methoxyethoxy)-2-methylbenzoate.
[070] Steps 2-5: Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3- (emyl((trans)-4-((2-memoxyemyl)(memyl)amino)cyclohexyl)amino)-5-(2-methoxyethoxy)-2- methylbenzamide
[071] Protocol as for 11, Steps 1-4 starting from methyl 3-(((trans)-4-((tert-butoxycarbonyl)ammo) cyclohexyl)(ethyl)amino)-5-(2-methoxyethoxy)-2-methylbenzoate
[072] LCMS: 557.60 (M + 1)+; TFA-salt: Ή NMR (DMSO-rf*, 400 MHz) δ 11.47 (brs, IH), 9.19 (s, IH), 8.05 (s, IH), 6.73 (s, IH), 6.56 (s, IH), 5.86 (s, IH), 4.25 (d, 2H, J=3.6 Hz), 4.05 (brs, 2H), 3.63 (brs, 4H), 3.30 (d, 3H, J=6.4 Hz), 3.25-2.93 (m, 3H), 2.68 (d, 4H, J=3.6 Hz), 2.19 (s, 3H), 2.11 (s, 6H), 2.03-1.69 (m, 4H), 1.53-1.38 (m, 4H), 0.80 (brt, 3H, J=6.4 Hz). 3H merged in solvent peak.
Compound 13: [073] Synthesis of N-((4,6-dimethyl-2-oxo-l ,2-dihydropyridin-3-yl)methyl)-3-(ethyl((trans)-4- memoxyemylXmemyl)ammo)cyclohexyl)amino)-2-memyl-5-(2-^^
Figure imgf000155_0001
[074] Step 1: Synthesis of methyl 3-(((trans)-4-((tert-butoxycarbonyl)amino)
cyclohexyl)(ethyl)amino)-2-methyl-5-(2-morpholmoethoxy)benzoate
[075] Protocol as for 10, Steps 1-2 with methyl 3-amino-2-methyl-5-(2- moφholinoethoxy)benzoate.
[076] Steps 2-5: Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-
(ethyl((trans)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)-2-methyl-5-(2- moφholinoetho y)benzamide
[077] Protocol as for 11, Steps 1-4 starting from methyl 3-(((trans)-4-((tert-butoxycarbonyl)amino) cyclohe l)(ethyl)amino)-2-methyl-5-(2-mo holinoetho y)benzoate
[078] LCMS: 612.55 (M + 1)+; TFA-salt: Ή R (DMSO-<¾, 400 MHz) δ 11.45 (brs, IH), 9.09 (s, IH), 8.48 (s, IH), 8.01 (s, IH), 6.77 (s, IH), 6.67 (s, IH), 5.87 (s, IH), 4.44 (brs, 2H), 4.27 (d, 2H, J=3.2 Hz), 4.00-3.89 (m, 6H), 3.64-3.47 (m, 6H), 3.38 (q, 2H, J=6.4 Hz), 3.42-3.23 (m, 6H), 3.14- 3.00 (m, 4H), 2.98-2.79 (m, 2H), 2.21 (s, 3H), 2.11 (s, 3H), 1.99 (brs, IH), 1.90-1.78 (m, 2H), 1.70- 1.59 (m, 2H), 1.53-1.37 (m, 3H), 0.81 (brt, 3H, J=6.4 Hz).
Compound 14:
[079] Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(ethyl((trans)-4-((2- metho yeth l)(methyl)amino)cyclohexyl)amino)-2-methyl-5-(3-moφholίno ro oxy)benzamide
Figure imgf000156_0001
[080] Step 1 : Synthesis of methyl 3-(((trans)-4-((tert-butoxycarbonyl)amino)
cyclohexyl)(ethyl)amino)-2-methyl-5-(3-morpholinopropoxy)benzoate
[081] Protocol as for 10, Steps 1-2 with methyl 3-ammo-2-methyl-5-(3- morpholinopropoxy)benzoate.
[082] Steps 2-5: Synthesis of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-
(ethyl((trans)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)-2-methyl-5-(3- mo holino ro oxy)benzamide
[083] Protocol as for 1 1, Steps 1-4 starting from methyl 3-(((trans)-4-((tert-butoxycarbonyl)amino) cyclohexyl)(ethyl)amino)-2-methyl-5-(3-mo holino ropoxy)benzoate
[084] LCMS: 626.75 (M + 1)+; TFA-salt: Ή NMR (DMSO-i¾, 400 MHz) δ 1 1.45 (brs, 1 H), 8.48 (s, 2H), 8.03 (s, 1H), 6.72 (s, 1H), 6.59 (s, 1H), 5.87 (s, 1H), 4.26 (d, 2H, J=3.2 Hz), 4.03 (m, 2H), 3.93 (m, 5H), 3.65-3.57 (m, 2H), 3.55 (t, 2H, J=4.4 Hz), 3.46 (m, 4H), 3.17 (s, 3H), 3.13-3.05 (m, 3H), 3.05-2.91 (m, 3H), 2.67-2.54 (m, 1H), 2.19 (s, 3H), 2.18-2.09 (m, 3H), 2.1 1 (s, 3H), 2.09-1.98 (m, 4H), 1.88-1.76 (m, 2H), 1.41 (q, 2H, J=l 1.2 Hz), 1.35-1.20 (m, 2H), 0.79 (t, 3H, J=6.4 Hz).
Figure imgf000156_0002
[085] Compounds 15-26 were synthesized from common intermediate 5-bromo-N-((4,6-dimethyl- 2-oxo- l,2-dihydropyridin-3-yl)methyl)-3-(ethyl((trans)-4-((2- methoxyethyl)(methyl)ammo)cyclohexyl)amino)-2-methylbenzamide following standard Suzuki coupling protocols outlined above. [086] Step 1: Synthesis of 5-bromo-N-((4,6-dimethyl-2-oxo-li2-dihydropyridin-3-yl)methyl)-3- (emyl((ttans)-4-((2-methoxyemyl)(methyl)ammo)cyclohexyl)aniino)-2-memylbenzamide
[087] Following the original protocol for making Compound 157, Step 7, 5-bromo-N-((4,6- dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(ethyl((trans)-4-
(methylamino)cyclohexyl)amino)-2-methylbenzamide (2.5 g, 4.98 mmol) was converted to afford the desired compound (1.6 g, 57.8% yield).
[088] Step 2: General Suzuki coupling conditions:
[089] To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3- (ethyl((trans)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)-2-methylbenzamide (1 equiv.) and boronic acid/ester (1.2 equiv.) in dioxane/water mixture, Na2C03 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPIi3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The comibined reaction mixture was heated at 100 °C for 2 h. On completion, the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined organic layers were dried over Na2S04 and the solvent removed under reduced pressure to afford crude material which was purified by column chromatography/ prep. HPLC to afford the desired targets. The analytical data for Compounds 15-26 are provided in the table below.
Compound
Step 2 Yield Data
#
LCMS: 574.45 (M + 1)+; TFA-salt: Ή NMR (DMSO- d6, 400 MHz) δ 11.48 (brs, 1H), 9.34 (brs, 1H), 9.00 (s, 1H), 8.53 (d, 1H, J=7.6 Hz), 8.22 (s, 1H), 7.78 (d, 1H, J=8.0 Hz), 7.56 (s, 1H), 7.40 (s, 1H), 5.87 (s, 1H), 4.31
15 (0.12 g, 46.7%) (d, 2H, J=4.0 Hz), 3.62 (m, 2H), 3.48-3.42 (m, 1H),
3.25-3.15 (m, 4H), 2.76 (m, 1H), 2.68 (m, 6H), 2.26 (s, 3H), 2.22 (s, 3H), 2.11 (s, 3H), 1.99-1.90 (m, 4H), 1.48 (m, 4H), 0.84 (t, 3H, J=6.8 Hz), 3H merged in solvent peak.
LCMS: 590.65 (M + 1)+; TFA-salt: 'H NMR (DMSO- d6, 400 MHz) δ 11.45 (s, 1H), 8.42 (s, 1H), 8.16 (t,
1H), 7.98-7.95 (m, 1H,), 7.35 (s, 1H), 7.18 (s, 1H), 6.89
16 (0.06 g, 28.5%) (d, 1H, J=8.8 Hz), 5.86 (s, 1H), 4.29 (d, 2H, J=4.8 Hz),
3.89 (s, 3H), 3.20 (s, 3H), 3.10-3.08 (m, 2H), 2.66-2.63 (m, 1H), 2.50 (m, 1H), 2.33-2.25 (m, 1H), 2.21 (m,
6H), 2.13 (s, 3H), 2.11 (s, 3H), 1.83-1.68 (m, 4H),
1.41-1.14 (m, 4H), 1.07 (s, 3H), 0.82 (t, 3H, J=6.8 Hz).
LCMS: 591.50 (M + 1)+; TFA-salt: Ή NMR (DMSO- d6, 400 MHz) δ 11.47 (brs, 1H), 9.13 (brs, 1H), 8.79 (s, 1H), 8.38 (s, 1H), 8.20 (s, 1H), 7.81 (s, 1H), 7.61 (s,
17 (0.06 g, 22.9%) 1H), 5.87 (s, 1H), 4.30 (d, 2H, J=4.4 Hz), 3.95 (s, 3H),
3.61 (m, 2H), 3.37-3.31 (m, 4H), 3.27-3.12 (m, 4H),
2.80 (m, 1H), 2.69-2.68 (m, 2H), 2.25 (s, 3H), 2.22 (s, 3H), 2.11 (s, 3H), 1.98-1.91 (m, 4H), 1.48 (m, 4H),
0.83 (t, 3H, J=6.8 Hz).
Figure imgf000158_0001
Figure imgf000159_0001
Methyl 3-((2,6-ft-a«i-dimethylpi eridin-4-yl)(ethyl)amino)-5-fluoro-2-methylbenzoate
Figure imgf000159_0002
[090] The titled compound was prepared (0.940 g, 100% yield) following the same procedure for the preparation of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-((2,6-ira«i- dimemylpiperidin-4-yl)(ethyl)amino)-5-fluoro-2-methylbenzamide. Ή-NMR (400 MHz): δ ppm 7.27 (dt, J = 8.6, 2.6 Hz, 1H), 6.98 (dt, J = 9.7, 1.9 Hz, 1H), 3.90 (d, J = 2.2 Hz, 3H), 3.54 (m, 1H), 3.05 (q, J = 7.0 Hz, 2H), 3.06 (m, 1H), 2.96 (m, 1H), 2.42 (s. 3H), 1.85 (td, J = 12.7, 4.6 Hz, 1H), 1.76 (d, / = 1.8 Hz, 1H), 1.68 (m, 1H), 1.23 (q, /= 12.2 Hz, 1H), 1.20 (dd, .7 = 6.8, 1.6 Hz, 3H), 1.12 (dd, = 6.0, 1.8 Hz, 3H), 0.86 (td, / = 7.0, 1.8 Hz, 3H); MS (ESI) [M+H]+ 323.3.
iert-Butyl 4-(ethyl(5-fluoro-3-(methoxycarbonyl)-2-methylphenyl)amino)-2,6-i/"aiis- dimethylpiperidine-l-
Figure imgf000159_0003
[091] Methyl 3-((2,6-irajw-dimethylpiperidm-4-yl)(ethyl)amm^
(0.938 g, 2.91 mmol), Boc20 (1.69 mL, 7.27 mmol) and TEA (2.43 mL, 17.46 mmol) was dissolved in DCM (18.7 mL, 291 mmol) at rt and the reaction mixture was stirred for overnight. MS showed reaction was done. The reaction mixture was diluted with ethylacetate and water. The separated aqueous layer was extracted once more with ethylacetate. The combined organic phase was dried over magnesium sulfate, filtered and evaportaed. The residue was purified by silica gel chromatography (1%- to 20% EtO Ac/heptane) to give the titled compound as a colorless oil (1.17 g, 95% yield). Ή NMR (400 MHz, CDC¾): δ ppm 7.31 (dd, J = 8.9, 2.7 Hz, IH), 6.99 (dd, J = 10.0, 2.7 Hz, IH), 4.27 (m, IH), 3.90 (s, 3H), 3.65 (m, IH), 3.34 (m, IH), 3.00 (m, 2H), 2.45 (s. 3H), 1.86 (m, 2H), 1.78 (m, IH), 1.48 (q, J = 6.6 Hz, IH), 1.45 (s, 9H), 1.34 (d, J = 6.7 Hz, 3H), 1.18 (d, J = 6.8, 3H), 0.84 (t, /= 7.0, 3H); MS (ESI) [M+H]+ 424.4.
3-((l-(iert-Butoxycarbonyl)-2,6-<rans-dimethylpiperidin-4-yl)(ethyl)amino)-5-fluoro-2- methylbenzoic acid
Figure imgf000160_0001
[092] The titled compound was prepared (1.18 g, 96% yield) following the same procedure for the preparation of 3-[ethyl(l-methylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzoic acid. Ή NMR (400 MHz): δ ppm 7.48 (dd, J = 8.9, 2.8 Hz, IH), 7.05 (dd, J = 9.8, 2.6 Hz, IH), 4.28 (m, IH), 3.67 (m, IH), 3.36 (m, IH), 3.02 (m, 2H), 2.53 (s. 3H), 1.89 (m, 2H), 1.80 (m, IH), 1.50 (q, = 6.9 Hz, IH), 1.47 (s, 9H), 1.36 (d, J = 6.8 Hz, 3H), 1.20 (d, J = 6.8 Hz, 3H), 0.84 (t, = 7.0, 3H); MS (ESI) [M+H]+ 410.4.
tert-Butyl 4-(ethyl(5-fluoro-3-(((5-fluoro-l,4,6-trimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)carbamoyl)-2-methylphenyl)amino)-2,6-ira»s-dimethylpiperidine-l- carboxylate
Figure imgf000160_0002
[093] The titled compound was prepared (76.0 mg, 62% yield) following the same procedure for the preparation of W-[(4,6-dimethyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl]-3-[ethyl(l - methylpiperidin-4-yl)amino]-2-methyl-5-(trifiuoromethyl)benzamide. Ή-NMR (400 MHz): δ ppm 7.06 (bt, J = 6.0 Hz, IH), 6.84 (dd, J = 10.5, 2.0 Hz, IH), 6.80 (d, J = 7.2 Hz, IH), 4.55 (d, J = 5.4 Hz, 2H), 4.29 (m, 1H), 3.63 (q, J = 6.4 Hz, 1H), 3.54 (s, 3H), 3.36 (m, 1H), 3.00 (m , 2H), 2.43 (d, J - 5.5 Hz, 3H), 2.36 (d, /= 3.2 Hz, 3H), 2.25 (s, 3H), 1.87 (m, 2H), 1.78 (m, 1H), 1.49 (m, 1H), 1.46 (s, 9H), 1.35 (d, J = 2.8 Hz, 3H), 1.19 (d, J = 6.8 Hz, 3H), 0.85 (t, J = 6.8 Hz, 3H); MS (ESI) [M+H]+ 575.5.
i^Butyl 4-(ethyl(5-fluoro-2-methyI-3-(^
yl)methyl)carbamoyl)phenyl)amino)-2,6-ira«s-dimethyIpiperidine-l- carboxylate
Figure imgf000161_0001
[094] The titled compound was prepared (56.0 mg, 47% yield) following the same procedure for the preparation of A^-[(4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-3-[ethyl(l- methylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzamide. Ή- MR (400 MHz): δ ppm 7.12 (s, 1H), 6.85 (d, J = 9.0, 2H), 6.00 (s, 1H), 4.54 (d, J = 5.3 Hz, 2H), 4.31 (m, 1H), 3.63 (q, J = 5.7 Hz, 1H), 3.54 (s, 3H), 3.42 (m, 1H), 3.07 (m , 2H), 2.39 (s, 3H), 2.35 (s, 3H), 2.30 (brs, 3H), 1.87 (m, 2H), 1.81 (m, 1H), 1.49 (m, 1H), 1.46 (s, 9H), 1.36 (d, J = 6.3 Hz, 3H), 1.20 (d, / = 6.7 Hz, 3H), 0.89 (bs, 3H); MS (ESI) [M+H]+ 557.5.
i^ButyI 4-((3-(((l,6-dimethyI-2-oxo^-(Mfluorom
yl)methyl)carbamoyl)-5-fluoro-2-methyIphenyl)(ethyl)amino)-2,6-frans-dimethyIpiperidine-l- carboxylate
Figure imgf000161_0002
[095] The titled compound was prepared (150 mg, 95% yield) following the same procedure for the preparation of Af-[(4,6-Dimethyl-2-oxo-l, 2-dihydropyridin-3-yl)methyl]-3-[ethyl(l- memylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzamide. 1 H-NMR (400 MHz, CD3OD): δ ppm 7.01 (dd, J = 10.6, 2.5 Hz, 1H), 6.82 (dd, J = 8.3, 2.8 Hz, 1H), 6.50 (s, 1H), 4.56 (s, 2H), 4.20 (m, 1H), 3.70 (q, J = 4.6 Hz, 1H), 3.61 (s, 3H), 3.48 (m, 1H), 3.04 (m , 2H), 2.50 (s, 3H), 2.25 (s, 3H), 1.89 (m, 3H), 1.52 (m, 1H), 1.44 (s, 9H), 1.33 (d, = 6.6 Hz, 3H), 1.20 (d, J = 7.0 Hz, 3H), 1.17 (d, J = 7.0 Hz, 3H), 0.84 (t, J = 7.0 Hz, 3H); MS (ESI) [M+H]+ 612.8.
iert-Butyl 4-(ethyl(5-fluoro-3-(((4-isopropyl-6-methyl-2-oxo-l,2-dihydropyridin-3- yl)methyI)carbamo l)-2-methylphenyl)amino)-2,6-ira»s-dimethylpiperidine-l-carboxylate
Figure imgf000162_0001
[096] The titled compound was prepared (50.0 mg, 41% yield) following the same procedure for the preparation of iV-[(4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-3-[ethyl(l- methylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzamide. Ή-NMR (400 MHz) δ ppm 7.10 (t, J = 6.0 Hz, IH), 6.82 (m, 2H), 6.08 (s, IH), 4.59 (m, 2H), 4.28 (m, IH), 3.63 (m, IH), 3.52 (m, 2H), 3.35 (m, IH), 2.99 (m, 2H), 2.29 (s, 3H), 2.24 (s, 3H), 1.85 (m, 2H), 1.74 (m, 1 H), 1.48 (m, IH), 1.46 (s, 9H), 1.34 (d, 7 = 6.71 Hz, 3H), 1.22 (dd, .7 = 6.83, 0.08 Hz, 6H), 1.18 (4 7 = 6.87 Hz, 3H), 0.83 (t, J = 7.00 Hz, 3H); MS (ESI) [M+H]+ 571.5.
tert-Butyl 4-(ethyl(5-fluoro-2-methyl-3-(((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3- yl)methyl)carbamoyl)phenyl)amino)-2,6-/cii/is-dimethylpiperidine-l-carboxylate
Figure imgf000162_0002
[097] The titled compound was prepared (64.0 mg, 53% yield) following the same procedure for the preparation of Af-[(4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yI)methyl]-3-[ethyI(l- methylpiperidin-4-yI)amino]-2-methyl-5-(trifluoromethyl)benzamide. Ή-NMR (400 MHz) δ ppm 7.19 (t, = 6.0 Hz IH) 6.81 (m, 2H) 5.97 (s, IH) 4.55 (m, 2H) 4.28 (m, IH) 3.64 (m, IH) 3.50 (m, IH) 3.35 (m. IH) 2.98 (m, 2H) 2.69 (m, 2H) 2.25 (s, 6H) 1.84 (m, IH), 1.76 (m, IH), 1.64 (m, 3H) 1.46 (m, 10H) 1.34 (d, J = 6.68 Hz, 3H) 1.18 (d, J = 6.87 Hz, 3H) 1.02 (t, J = 7.34 Hz, 3H) 0.84 (t, J = 7.1 Hz 3H); MS (ESI) [M+H]+ 571.5.
3-((2,6-<rans-Dimethylpiperidin^-yl)(ethyl)amino)-S-fluoro-iV-((5-fluoro-l,4,6-trimethyl-2-oxo- l,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide hydrochloride
Figure imgf000162_0003
[098] 7¾rt-butyl 4-(e l(5-fluoro-3-(((5-fluoro-l,4,6-trimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)carbamoyl)-2-methylphenyl)amino)-2,6-iran.s^ (75.0 mg,
0.131 mmol) was dissolved in in dichloromethane (1 mL) and 4N HC1 in 1,4-dioxane (1.63 mL, 6.53 mmol) was added at rt and the mixture was stirred at room temperature for 3 h. The reaction mixture was then concentrated, azeotroped with MeOH several times to give the titled compound as a solid (67.0 mg, 100 % yield). Ή-NM (400 MHz, DMSO-ds): δ ppm 8.80 (bs, 1H), 8.27 (t, J = 4.9 Hz, 1H), 7.10 (d, J = 9.3 Hz, 1H), 6.80 (d, J = 9.3 Hz, 1H), 4.33 (t, J = 3.9 Hz, 2H), 3.72 (m, 2H), 3.43 (s, 3H), 3.34 (m, 1H), 2.99 (m, 2H), 2.32 (d, J = 3.5 Hz, 3H), 2.24 (d, J = 2.2 Hz, 3H), 2.12 (s, 3H), 1.83 (m, 2H), 1.70 (m, 1H), 1.45 (m, 1H), 1.27 (d, J = 7.2 Hz, 3H), 1.21 (d, .7 = 6.2 Hz, 3H), 0.79 (t, J = 6.7 Hz, 3H); MS (ESI) [M+H]+ 475.3.
3-((2,6-irans-Dimethylpiperidin-4-yl)(ethyl)amino)-5-fluoro-2-methyl-Ar-((1,4,6-trimethyl-2- oxo-l,2-dihydropyridin-3-yI)methyl)benzamide dihydrochloride
Figure imgf000163_0001
[099] The titled compound was prepared (52.0 mg, 100% yield) following a similar procedure for the preparation of 3-((2,6-ira«s-dimethylpiperidm^-yl)(ethyl)amino)-5-fluoro-N-((5-fluoro- 1 ,4,6- trimethyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide hydrochloride. Ή-NMR (400 MHz, DMSO-d6): δ ppm 8.85 (bs, 2H), 8.16 (s, 1H), 7.10 (d, J = 11.1 Hz, 1H), 6.79 (d, J = 7.4 Hz, 1H), 6.04 (s, 1H), 4.30 (t, J = 4.6 Hz, 2H), 3.71 (m, 2H), 3.41 (s, 3H), 3.33 (m, 1H), 2.99 (m, 2H), 2.30 (s, 3H), 2.20 (s, 3H), 2.13 (s, 3H), 1.83 (m, 2H), 1.70 (m, 1H), 1.48 (m, 1H), 1.27 (d, / = 6.7 Hz, 3H), 1.21 (d, / = 6.1 Hz, 3H), 0.79 (t, J = 6.7 Hz, 3H); MS (ESI) [M+H]+ 457.4.
3-((2,6 -Dimethylpiperidln-4-yl)(ethyl)amino)-5-fluoro-iV-((4-isopropyl-6-methyl-2-oxo- l,2-dihydropyridin-3-yl)methyl)-2-met ylbenzamide dihydrochloride
Figure imgf000163_0002
[0100] The titled compound was prepared (40.0 mg, 97% yield) following a similar procedure for the preparation of 3-((2,6-irani-dimethylpiperidin-4-yl)(ethyl)amino)-5-fluoro-N-((5-fluoro-l,4,6- trimemyl-2-oxo-l,2-dihydropyridin-3-yl)memyl)-2-memylbenzarnide hydrochloride. Ή-NMR (400 MHz, DMSO-rf6) δ ppm 8.78 (bm, 2H), 8.14 (m, IH), 7.05 (d, J = 10.6 Hz, IH), 6.72 (d, / = 9.6 Hz, IH), 5.97 (s, IH), 4.26 (m, 2H), 3.65 (bm, 2H), 3.27 (bm, IH), 3.15 (bm, 2H), 2.95 (bm, 2H), 2.09 (s, 6H), 1.80 (m, 2H), 1.65 (m, IH), 1.41 (m, IH), 1.22 (d, J = 7.0 Hz, 3H), 1.17 (d, /= 6.6 Hz, 3H), 1.07 (d, J = 6.8 Hz, 6H), 0.74 (t, J = 6.67 Hz, 3H); MS (ESI) [M+H]+ 471.4.
3-((2,6-irans-Dimethylpiperidin-4-yl)(ethyl)amino)-5-fluoro-2-methyl-iV-((6-methyl-2-oxo-4- propyl-l,2-dihydropyridin-3-yl)methyl)benzamide
Figure imgf000164_0001
[0101] The titled compound was prepared (60.0 mg, 76% yield) following a similar procedure for the preparation of 3-((2,6-(raHi-dimethylpiperidm-4-yl)(ethyl)amino)-5-fluoro-N-((5-fluoro-l,4,6- trimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide hydrochloride and purification by reverse phase HPLC. Ή-NMR (400 MHz, CD3OD) δ ppm 6.96 (dd, J = 10.3, 2.3 Hz, IH), 6.76 (dd, J = 8.0, 1.6 Hz, IH), 6.10 (s, IH), 4.43 (s, 2H), 3.48 (m, IH), 3.16 (m, IH), 3.04 (m, 3H), 2.64 (m, 2H), 2.22 (s, 3H), 2.19 (s, 3H), 1.81 (m, IH), 1.73 (m, 2H), 1.61 (m, 2H), 1.24 (m, IH), 1.19 (d, J = 7.14 Hz, 3H), 1.09 (d, J = 6.1 Hz, 3H), 0.99 (t, J = 7.4 Hz, 3H), 0.83 (t, J = 7.00 Hz, 3H); MS (ESI) [M+H]+ 471.4.
iert-Butyl 4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-fIuoro-2- methylphenyl)(ethyl)amino)-2,6-ira«s-diniethylpiperidine-l-carboxylate
Figure imgf000164_0002
[0102] The titled compound was prepared (526 mg, 74% yield) following the same procedure for the preparation of JV-[(4,6-Dimetiyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-3-[ethyl(l- memylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzamide and purification by reverse phase HPLC. 'H NMR (400 MHz): δ ppm 7.12 (t, J = 4.7 Hz, 1H), 6.83 (dd, J = 4.7, 2.4 Hz, 2H), 5.98 (s, IH), 4.53 (d, J = 5.9 Hz, 2H), 4.28 (m, IH), 3.62 (m, IH), 3.37 (m, IH), 3.00 (m, 2H), 2.41 (s. 3H), 2.27 (s, 3H), 2.25 (s, 3H), 1.87 (m, 2H), 1.78 (m, IH), 1.49 (q, J = 6.7 Hz, IH), 1.46 (s, 9H), 1.34 (d, J = 6.7 Hz, 3H), 1.18 (d, J = 7.2 Hz, 3H), 0.84 (t, J = 7.2, 3H); MS (ESI) [M+H]+ 543.5. Ai-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-((2,6-fra«^dimethylpiperidin-4 yl)(ethyl)amino)-5-fluoro-2-methylbenzamide dihydrochloride
Figure imgf000165_0001
[0103] The titled compound was prepared (500 mg, 100% yield) following a similar procedure for the preparation of 3-((2,6-trans-dimethylpiperidin-4-yl)(ethyl)ammo)-5-fluoro-N-((5-fluoro-l,4,6- trimethyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide hydrochloride. This is the dihydrocloride form of the same compound made earlier, see JV-[(4,6-Dimethyl-2-oxo-l,2- dihydropyridin-3-yl)memyl]-3-((2,6-tians-dimemylpiperidin-4-yl](ethyl)ammo)-5-fluoro-2- methylbenzamide.
A'-^.e-Dimeth l^-o o-l^-dihydrop ridin-S-ylJmethy -S-iethylil-methyl^^-frfl/is^ dimethylpiperidin-4-yl)amiiio)-5-fluoro-2-methyIbeiizainide
Figure imgf000165_0002
[0104] The titled compound was prepared (83.0 mg, 87% yield) following a similar procedure for the preparation of methyl 3-[ethyl(l-methylpiperidin-4-yl)amino]-2-methyl-5- (trifluoromethyl)benzoate. Ή-NMR (400 MHz): δ ppm 7.13 (t, 7 = 6.1 Hz, 1H), 6.83 (dd, 7 = 10.4, 2.8 Hz, 1H), 6.77 (dd, J = 8.0, 2.4 Hz, 1H), 5.95 (s, 1H), 4.53 (d, J = 6.2 Hz, 2H), 3.50 (s, 1H), 3.27 (brs, 1H), 3.08 (brs, 1H), 3.03 (q, J = 6.8 Hz, 2H), 2.40 (s. 3H), 2.33 (bis, 3H), 2.24 (s, 3H), 2.23 (s, 3H), 1.72— 1.62 (m, 3H), 1.09 (brs, 3H), 1.00 (brs, 3H), 0.85 (t, J = 7.2, 3H); MS (ESI) [M+H]+ 457.4.
^-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(ethyl(l-ethyl-2,6- <ra7is- amide
Figure imgf000165_0003
[0105] To a stirred solution of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)metliyl)-3-((2,6- trans-dimethylpiperidm-4-yl)(ethyl)ammo)-5-fluoro-2-methylbenzarnide dihydrochloride (150 mg, 0.291 mmol) in MeOH (2 mL, 49.4 mmol) and acetic acid (0.017 mL, 0.291 mmol) was added acetaldehyde (0.164 mL, 2.91 mmol) and sodium triacetoxyborohydride (185 mg, 0.873 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. MS showed the reaction was completed. The reaction was quenched with saturated aq. NaHC03 until pH 8-9. The separated aq. Phase was extracted with DCM. The combined org. phase was concentrated to give 120 mg crude material. Purification by reverse phase HPLC/MS provided the titled compound (103 mg, 75 % yield). Ή-NMR (400 MHz, CD3OD): δ ppm 7.01 (dd, J = 9.7, 2.9 Hz, 1H), 6.81 (dd, J = 8.5, 2.9 Hz, 1H), 6.11 (s, 1H), 4.46 (s, 2H), 3.53 (brs, 2H), 3.21 (m, 1H), 3.07 (q, J = 6.5, 2H), 2.37 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H), 1.86-1.77 (m. 4H), 1.45 (d, J = 12.3 Hz, 2H), 1.14 (bs, 6H), 1.09 (brs, 3H), 0.86 (t, / = 7.1, 3H); MS (ESI) [M+H]+ 471.4.
5-Bromo-2-methyl-3-nitrobenzoic acid
Figure imgf000166_0001
[0106] To a stirred solution of 2-methyl-3-nitrobenzoic acid (5.00 g, 27.6 mmol) in H2SO4 (20 mL) was added l,3-dibromo-5,5-dimethylhydantoin (4.34 g, 15.20 mmol) at 0°C. The reaction mixture was stirred at 0°C for 5 hours. The reaction mixture was poured onto ice cold water, the resultant precipitated solid was collected, washed with water and dried in vacuo to give the titled compound as a white solid (7.28 g, quantitative yield). Ή-NMR (400 MHz, DMSO-d*) δ ppm; 8.31 (s, 1H), 8.17 (s, 1H), 2.43 (s, 3H).
Methyl 5-bromo-2-methyl-3-nitrobenzoate
Figure imgf000166_0002
[0107] To a stirred solution of 5-bromo-2-methyl-3-mtrobenzoic acid (7.28 g, 28.0 mmol) in DMF (100 mL) was added sodium carbonate (11.9 g, 112 mmol) and methyl iodide (15.9 g, 112 mmol). The reaction mixture was stirred at 60 °C for 8 hours. After completion of the reaction, the reaction mixture was filtered and washed with ethyl acetate. The combined filtrate was washed with water and the aqueous phase was re-extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound as a solid. (7.74 g, quantitative yield). ]H-NMR (400 MHz, CDC13) δ (ppm); 8.17 (s, 1H), 7.91 (s, 1H), 3.96 (s, 3H), 2.59 (s, 3H).
Methyl 3-amino-5-bromo-2-methylbenzoate
Figure imgf000167_0001
[0108] To a stirred solution of methyl 5-bromo-2-methyl-3-nitrobenzoate (7.60 g, 27.7 mmol) in aq. EtOH (100 mL of EtOH and 20 mL of ¾θ) was added ammonium chloride (4.4S g, 83.1mmol) and iron (4.64 g, 83. lmmol). The reaction mixture was stirred at 80°C for 5 hours. Then the mixture was filtered through Celite and the Celite bed was washed with ethyl acetate. The combined filtrate was concentrated in vacuo. The resultant residue was dissolved in ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (twice). The combined organic layer dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the titled compound as a brown oil (6.67 g, 99%). 'H-NMR (400 MHz, CDC13) δ ppm; 7.37 (s, 1H), 6.92 (s, 1H), 3.94 (s, 3H), 3.80 (brs, 2H), 2.31 (s, 3H).
Methyl 5-bromo-2-methyl-3-[(oxan-4-yl)amino]benzoate
Figure imgf000167_0002
[0109] To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (40.2 g, 165 mmol) in CH2CI2 (500 mL) and AcOH (60 mL) was added dihydro-2H-pyran-4-one (17.3 g, 173 mmol) and sodium triacetoxyborohydride (73.6 g, 330 mmol). The reaction mixture was stirred at RT for 20 hours. Then saturated NaHC03 aq. was added and the mixture was separated. The aqueous layer was extracted with 0¾(¾ and the combined organic layer was concentrated in vacuo. The residue was triturated with ethyl ether, and resultant precipitate was collected to afford the titled compound as a white solid (39.1 g, 72%). Ή-NMR (400 MHz, DMSO-d6) S ppm; 7.01 (s, 1H), 6.98 (s, 1H), 5.00 (d, J = 7.6 Hz, 1H), 3.84-3.87 (m, 2H), 3.79 (s, 3H), 3.54-3.56 (m, 1H), 3.43 (m, 2H), 2.14 (s, 3H), 1.81- 1.84 (m, 2H), 1.47-1.55 (m, 2H).
Methyl 5-bro hylbenzoate
Figure imgf000167_0003
[0110] To a stirred solution of methyl 5-bromo-2-methyl-3-[(oxan-4-yl)amino]benzoate (39.1 g, 119 mmol) in CH2C12 (400 mL) and AcOH (40 mL) was added acetaldehyde (24.7 g, 476 mmol) and sodium triacetoxyborohydride (79.6 g, 357 mmol). The reaction mixture was stirred at RT for 24 hours. Then saturated NaHC03 aq. was added and the mixture was separated. The aqueous layer was extracted with CH2CI2 and the combined organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (S1O2 Heptane/EtOAc = 3/1) to give the titled compound as a viscous oil (44.1 g, quantitative yield). Ή-NMR (400 MHz, DMSO-ds) δ ppm; 7.62 (s, 1H), 7.52 (s, 1H), 3.80 (m, 5H), 3.31 (m, 2H), 2.97-3.05 (m, 2H), 2.87-2.96 (m, 1H), 2.38 (s, 3H), 1.52-1.61 (m, 2H), 1.37-1.50 (m, 2H), 0.87 (t, J= 6.8 Hz, 3H).
Methyl 3-[ethyl(oxan-4-yl)aminol-2-methyl-S-(tetramethyl-l,3,2-dioxaboroIan-2-yl)benzoate
Figure imgf000168_0001
[0111] To a stirred solution of methyl 5-bromo-3-[ethyl(oxan-4-yl)amino]-2-methylbenzoate (2.93 g, 8.23 mmol) and bis(pinacolato)diboron (2.72 g, 10.7 mmol) in DMSO (40 mL) was added potassium acetate (3.07 g, 31.3 mmol) and Pd(dppf)Cl2 (672 mg, 0.823 mmol). The reaction mixture was stirred at 80 °C for 2.5 hours. After cooling to RT, ethyl acetate and water were added to the mixture. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water (twice) and brine. The organic layer was dried over MgS04 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (S1O2; Heptane/ethyl acetate =5/1 to 2/1) to give the titled compound as a yellow oil (2.92 g, 88% yield). Ή-NMR (400 MHz, CDC13) δ ppm; 7.99 (s, 1H), 7.66 (s, 1H), 3.90-3.98 (m, 2H), 3.89 (s, 3H), 3.25-3.37 (m, 2H), 3.09 (q, J = 7.1 Hz, 2H), 2.92-3.02 (m, 1H), 2.54 (s, 3H), 1.57-1.76 (m, 4H), 1.35 ppm (s, 12H), 0.85(t, J = 7.1 Hz, 3H).
Methyl S-bromo-3-{[fr«ns-4-(dimethylamino)cyclohexyl]amino}-2-methylbenzoate
Figure imgf000168_0002
[0112] To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (5.00 g, 20.5 mmol) in CH2CI2 (100 mL) and AcOH (5 mL) was added 4-(dimethylamino)cyclohexan-l-one (3.76 g , 26.6 mmol) and sodium triacetoxyborohydride (13.0 g, 61.5 mmol). The reaction mixture was stirred at RT for 4 hours. Then saturated NaHC(¾ aq. was added and the mixture was separated. The aqueous layer was extracted with CH2C12 (2 x 50 mL) and the combined organic layers were concentrated in vacuo. The residue was purified by silica gel column chromatography (NH-S1O2
heptane/EtOAc=l/l) to give the titled compound as a brown oil (2.10 g, 28%). 1 H-NMR (500MHz, CDCI3) 5 ppm; 7.20 (d, J = 1.9 Hz, 1H), 6.81 (d, J = 1.9 Hz, 1H), 3.87 (s, 3H), 3.58 (d, J = 7.3 Hz, IH), 3.20 (m, IH), 2.30 (s, 6H), 2.20 (s, 3H), 2.16-2.26 (m, 3H), 1.97 (m, 2H), 1.34-1.46 (m, 2H), 1.14-1.25 (m, 2H); MS (ESI) [M+H]+ 369.2, 371.2.
Methyl 5-bromo-3-{ [/rans-4-(dimethylamino)cycIohexyI] (eth l)amino}-2-methylbenzoate
Figure imgf000169_0001
[0113] To a stirred solution of Methyl 5-bromo-3-{[iran4'-4-(dimethylammo)cyclohexyl]amino}-2- methylbenzoate (2.10 g, 5.69 mmol) in C¾C¾ (40 mL) and AcOH (2 mL) was added acetaldehyde (626 mg, 14.2 mmol) and sodium tnacetoxyborohydride (3.62 g, 17.1 mmol). The reaction mixture was stirred at RT for 3 hours and then saturated NaHCXb aq. was added and the mixture was separated. The aqueous layer was extracted with CH2CI2 and the combined organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH-Si02 heptane/ethylacetate=3/2) to give the titled compound as a yellow oil (824 mg, 36%). 'HNMR (400 MHz, CDCI3) δ ppm; 7.67 (d, J = 2.0 Hz, IH), 7.33 (d, J = 2.0 Hz, IH), 3.89 (s, 3H), 3.03 (q, J = 7.0 Hz, 2H), 2.57-2.69 (m, IH), 2.42 (s, 3H), 2.24 (s, 6H), 2.07-2.18 (m, IH), 1.88 (m, 4H), 1.09- 1.44 (m, 4H), 0.85 (t, J = 7.0 Hz, 3H); MS (ESI) [M+HJ+ 397.3, 399.3.
Methyl 3-((iJ-ans-4-aminocyclohexyl)(ethyl)amino)-5-bromo-2-methylbenzoate
Figure imgf000169_0002
[0114] Methyl 5-bromo-3-((4-frani-((tert-butoxycarbonyl)amino)cyclohexyl)(ethyl)amino)-2- methylbenzoate (1.00 g, 2.13 mmol) was dissolved in DCM (1 mL) at rt. Then 4 M HC1 in 1,4- dioxane (8 mL, 32.0 mmol) was added drop wise during 10 min at rt. After stirring additional 10 min, TLC (20% E/H) showed reaction was done, and no SM at Rf=0.55 and there is only a baseline. The mixture was then concentrated and re-dissolved in 10 mL DCM and treated with sodium bicarbonate (0.447 g, 5.33 mmol) with stirring for 15 min (bubbling was observed). The mixture was then filtered through celite washing with DCM, the filtrate was concentrated to give the titled compound (0.780 g, 100% yield). Ή-NMR (400 MHz, CD3OD): 8 ppm 7.62 (d, J= 2.1 Hz, IH), 7.44(d, J= 2.1 Hz, IH), 3.85 (s, 3H), 3.07 (q, J= 7.0 Hz, 2H), 3.00 (m, IH), 2.72 (m,lH), 2.38 (s, 3H), 1.95 (m, 4H), 1.49 (m, 2H), 1.33 (m, 2H), 0.83 (t, J= 7.0 Hz, 3H); MS (ESI) [M+H]+ 369.2,
371.2. Methyl S-bromo-S-^-i/'a/is-idimethylammoJcyclohexylJiethy^aminoJ-l-inethylbenzoate
Figure imgf000170_0001
[0115] To a solution of Methyl 3-((ira«i-4-aminocyclohexyl)(ethyl)amino)-5-bromo-2- methylbenzoate (0.787 g, 2.13 mmol) in methanol (3 mL) and DCM (5 mL) was added formaldehyde (37% in water, 0.793 mL, 10.7 mmol) at 0°C and stirred for 10 min. Then sodium triacetoxyborohydride (1.81 g, 8.52 mmol) was added and the mixture was stirred for 30 min at 0°C and then at rt for 30 min. MS showed reaction is done. The reaction mixture was quenched with sat. NaHC03, extracted with 8xDCM until TLC (10% 7N NH3 in MeOH/DCM) showed no product at Rf=0.35. The combined org. phase was dried (Na2S04), filtered, concentrated and chromatography (25.0 g column, 5% MeOH/DCM and then 10% 7N NH3 in MeOH/DCM isocratic) purification gave the titled compound (850 mg, 100% yield). Ή- MR (400 MHz, CD3OD): δ ppm 7.60 (d, J= 2.1 Hz, 1 H), 7.42 (d, = 2.1 Hz, 1 H), 3.84 (s, 3H), 3.06 (q, = 7.0 Hz, 2 H), 2.67 (m,lH), 2.37 (s, 3H), 2.35 (m, 1H), 2.31 (s, 6H), 1.91 (m, 4H), 1.40 (m, 2H), 1.24 (m, 2H), 0.82 (t, / = 7.0 Hz, 3H); MS (ESI) [M+H]+ 397.3, 399.3.
5-Bromo-3-((4-»-««s-(dimetliylammo)cyclohexyl)(ethyl)amino)-2-methylbenzoic acid
Figure imgf000170_0002
[0116] The titled compound was prepared (820 mg, 100% yield) following the same procedure for the preparation of 3-[ethyl(l-memylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)berizoic acid. MS (ESI) [M+H]+ 383.3, 385.3. The crude compound was used without further purification for the next step reaction.
5-Bromo-3-((4-fra«^(dimethyIamino)cyclohexyl)(ethyl)amino)-/Y-((4-isopropyl-6-methyl-2-oxo- l,2-dihydropyridin-3-yl)methyl)-2-meth
Figure imgf000170_0003
[0117] The titled compound was prepared (110 mg, 86% yield) following the same procedure for the preparation of At[(4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-3-[ethyl(l- methylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzamide. 1 H-NMR (500 MHz, CD3OD) δ ppm 7.31 (d, J = 2.0 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 6.24 (s, 1H), 4.51 (s, 2H), 3.47-3.41 (m, 1H), 3.08 (q, / = 7.0 Hz, 2H), 2.75-2.67 (m, 1H), 2.32 (s, 6H), 2.28 (s, 3H), 2.34-2.26 (m, 1H), 2.22 (s, 3H), 1.98-1.88 (m, 4H), 1.49-1.39 (m, 2H), 1.30-1.24 (m, 2H), 1.23 (d, J = 7.0 Hz, 6H), 0.85 (t, J = 7.0 Hz, 3H); MS (ESI) [M+H]+ 545.4, 547.4.
5-Bromo-iV-[(4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-3-|ethyl(oxan-4-yl)amino]-2- methylbenzamide
Figure imgf000171_0001
[0118] To a stirred solution of methyl 5-bromo-3-[ethyl(oxan-4-yl)amino]-2-methylbenzoate (31.0 g, 87.0 mmol) in ethanol (100 mL) was added aq. NaOH (2N, 100 mL). The reaction mixture was stirred at 60 C for 3 hours. After cooling to rt, the reaction mixture was concentrated in vacuo, and the resultant residue was dissolved in ethyl acetate and water. The aqueous layer was acidified with aq. KHSO4, extracted with ethyl acetate (300 mL, twice), concentrated in vacuo to give 5-bromo-3- [ethyl(oxan-4-yl)amino]-2-methylbenzoic acid as a crude product (28.0g, 97%).
To a stirred solution of 5-bromo-3-[ethyl(oxan-4-yl)amino]-2-methylbenzoic acid (5.00 g, 14.6 mmol) and 3-(aminomethyl)-4,6-dimethyl-l,2-dihydropyridin-2-one HCl salt (3.31 g, 17.5 mmol) in DMSO (50 mL) was added PYBOP (11.4 g, 21.9 mmol) and Hunig's base (7.63 mL, 43.8 mmol). The reaction mixture was stirred at RT for 4 hours. The reaction mixture was quenched with water, and the resultant precipitate was collected, washed with water (2 x 100 mL) and ethyl ether (20 mL). The collected solid was dried under vacuum pressure to give the titled compound as a white solid (5.70 g, 82%). 1 H-NMR (400 MHz, DMSO-d6) δ ppm; 11.47 (s, 1H), 8.23 (brs, 1H), 7.30 (s, 1H), 7.08 (s, 1H), 5.85 (s, 1H), 4.23 (d, /= 4.4 Hz, 2H), 3.81 (d, J= 10.4 Hz, 2H), 3.20-3.26 (m, 2H), 3.00-3.07 (m, 1H), 2.91-2.96 (m, 2H), 2.18 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H), 1.58-1.60 (m, 2H), 1.45-1.50 (m, 2H), 0.78 (t, J= 6.8 Hz, 3H) ; MS (ESI) [M+H]+ 476.3, 478.3.
5-Bromo-3-[ethyl(oxan-4-yl)amino]-2-methyl-N-{[6-methyl-2-oxo-4-(2-propyl)-l,2- dihydropyridin-3-yl]methyl}benzamide
Figure imgf000172_0001
[0119] To a stirred solution of methyl 5-bromo-3-[ethyl(oxan-4-yl)amino]-2-methylbenzoate (31.0 g, 87.0 mmol) in ethanol (100 mL) was added aq. NaOH (2N, 100 mL). The reaction mixture was stirred at 60 C for 3 hours. After cooling to rt, the reaction mixture was concentrated in vacuo, and the resultant residue was dissolved in ethyl acetate and water. The aqueous layer was acidified with aq. HSO4, extracted with ethyl acetate (300 mL, twice), concentrated in vacuo to give 5-bromo-3- [ethyl(oxan-4-yl)amino]-2-methylbenzoic acid as a crude product (28.0 g, 97%).
To a stirred solution of 5-bromo-3-[ethyl(oxan-4-yl)amino]-2-methylbenzoic acid (3.00 g, 8.77 mmol) and 3-(Aminomethyl)-6-methyl-4-(propan-2-yl)-l,2-dihydropyridin-2-one HC1 salt (2.47 mg, 11.4 mmol) in DMSO (40 mL) was added PYBOP (6.84 mg, 13.1 mmol) and Hunig's base (7.63 mL, 43.8 mmol). The reaction mixture was stirred at RT for 17 hours. The reaction mixture was quenched with water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water (twice) and brine. The organic layer was dried over MgS0 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (S1O2; ethylacetate MeOH=6/l). Fractions containing target material were collected and concentrated in vacuo. The residue was re-purified by silica gel column chromatography (NH- S1O2;
Heptane/ethylacetate =1/1 to ethylacetate methanol=10/l ) to give the titled compound as a white amorphous solid (5.45 g, quantitative yield). Ή-NMR (400 MHz, CDC13) δ ppm; 10.54 (brs, 1H), 7.21 (d, J = 2.2 Hz, 1H), 7.17 (d, J = 2.2 Hz, 1H), 7.04-7.10 (m, 1H), 6.05 (s, 1H), 4.57 (d,J = 6.2 Hz, 2H), 3.91-3.99 (m, 2H), 3.47-3.56 (m, 1H), 3.27-3.36 (m, 2H), 3.02 (q, J = 7.2 Hz, 2H), 2.87- 2.98 (m, 1H), 2.27 (s, 3H), 2.24(s, 3H), 1.61-1.70 (m,4H), 1.21 (d, J = 7.0 Hz, 6H), 0.85(t, J = 7.2 Hz, 3H).
S-Bromo-S-lethyKo an^-y aminol-Z-methyl-Af-fld-methyl^-o o^-itrifluoromethyl)-!^- dihydropyridin-3-yl] methyl} benzamide
Figure imgf000172_0002
[0120] To a stirred solution of 5-bromo-3-fethyl(oxan-4-yl)araino]-2-methylbenzoic acid (500 mg, 1.46 mmol) and 3-(Aminomemyl)-6-methyl-4-(trifluoromethyl)-l,2-dihydropyridin-2-one hydrocMoride (461 mg, 1.90 mmol) in DMSO (11 mL) was added PYBOP (1.14 g, 2.19 mmol) and Hunig's base (0.763 mL, 4.38 mmol). The reaction mixture was stirred at RT for 15 hours. The reaction mixture was quenched with water, diluted with EtOAc, and partitioned. The organic layer was washed with water, brine, dried over N 2S04, filtered, and concentrated. The residue was purified by silica gel column chromatography (NH-Si02, EtOAc/heptane = 1/1 to EtOAc only) to give the titled compound (563 mg, -89% purity, 65%). Ή-NMR (400 MHz, DMSO-d6) δ ppm; 7.23 (d, = 2.0 Hz, lH), 7.19 (d, J = 2.0 Hz, 1H), 6.82 (t, J = 6.4 Hz, 1H), 6.35 (s, 1H), 4.71 (d, J = 6.4 Hz, 2H), 3.92-3.97 (m, 2H), 3.27-3.34 (m, 2H), 3.03 (q, J = 7.2 Hz, 2H), 2.89-2.95 (m, 1H), 2.39 (s, 3H), 2.27 (s, 3H), 1.62-1.68 (m, 4H), 0.86 (t, /= 7.2 Hz, 3H).
5-Bromo-2-(methoxymethyl)pyridine
Figure imgf000173_0001
[0121] To a stirred solution of (5-bromo-2-pyridyl)methanol (1.50 g, 7.98 mmol) and Mel (600 uL, 9.58 mmol) in DMF (10 mL) was added NaH (60% in oil, 400 mg, 9.98 mmol) at 0°C. The reaction mixture was stirred at rt for 3.5 hours. The reaction mixture was quenched with water, diluted with EtOAc, and partitioned. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel column chromatography (NH-Si02; ethyl acetate heptane=l/8) to give the titled compound as a white solid (1.52 g, 94%). Ή-NMR (400 MHz, CDCI3) δ ppm; 8.62 (d, J= 2.4 Hz, 1H), 7.82 (dd, J= 2.4, 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 4.54 (s, 2H), 3.48 (s, 3H).
2-(Methoxymethyl)-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine
Figure imgf000173_0002
[0122] To a stirred solution of 5-bromo-2-(methoxymethyl)pyridine (700 mg, 3.46 mmol) and bis(pinacolato)diboron (968 mg, 3.81 mmol) in 1,2-dimethoxyethane (10 mL) was added potassium acetate (1.02 g, 10.4 mmol) and Pd(dppf)Cl2- CH2C12 complex (595 mg, 0.692 mmol). The reaction mixture was stirred at 80 °C for 3 hours. The mixture was cooled to rt, diluted with EtOAc, and filtered through Celite pad. The filtrate was washed with water (twice), dried over Na2SO,», filtered, and concentrated to give the titled compound as a crude product (1.6 g, -50% purity (as quantitative yield)). Ή-NMR (400 MHz, CDC13) δ ppm; 8.88 (s, 1H), 8.07 (d, / = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 4.61 (s, 2H), 3.48 (s, 3H), 1.25 (s, 12H).
3-[Ethyl(oxan-4-yl)amino]-5-[6-(methoxymethyl)pyridin-3-yl]-2-methyl-A'-{[6-methyl-2-oxo-4-
(2-propyl)-l,2-dihydropyridin-3-yl]methyl}benzamide
Figure imgf000174_0001
[0123] To a stirred solution of 5-brorao-3-[ethyl(oxan-4-yl)amino]-2-methyl-N-{[6-methyl-2-oxo- 4-(propan-2-yl)-l,2-dihydropyridin-3-yl]methyl}benzamide (125 mg, 0.198 mmol) and a crude product of 2-(Memoxymethyl)-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (160 mg, ~50% purity, 0.317 mmol) in 1,4-dixoxane (2 mL) and H20 (0.4 mL) was added Pd(PPh3) (23.0 mg, 0.02 mmol) and sodium carbonate (76.0 mg, 0.713 mmol). The reaction mixture was stirred at 100 °C for 3 hours. The mixture was cooled to rt, diluted with EtOAc, and filtered through Celite pad. The filtrate was washed with water (twice), dried overNa2S04, filtered, and concentrated. The residue was purified by silica gel column chromatography (NH-S1O2; heptane/ethyl acetate =1/2 to EtOAc only) and (SiOz; EtOAc only to EtOAc/MeOH = 5/1 + 5% TEA), and by PTLC (Si02; EtOAc, 6 developments). The mixture was triturated with EtOAc-hexane to give the titled compound as a white solid (33.4 mg, 31%). Ή-NMR (400 MHz, CDC13) δ ppm; 9.88-9.90 (m, 1H), 8.69 (d, J = 2.4 Hz, 1H), 7.81 (dd, J = 2.4, 8.0 Hz, 1Ή), 7.44 (d, J = 8.0 Hz, 1H), 7.28-7.29 (m, 1H), 7.24-7.25 (m, 1H), 7.09-7.12 (m, 1H), 6.03 (s, 1H), 4.61 (s, 2H), 4.60-4.61 (m, 2H), 3.94-3.97 (m, 2H), 3.50-3.58 (m, 1H), 3.50 (s, 3H), 3.29-3.36 (m, 2H), 3.10 (q, J = 6.8 Hz, 2H), 2.99-3.03 (m, 1H), 2.34 (s, 3H), 2.23 (s, 3H) 1.66-1.73 (m, 4H), 1.22 (d, J = 6.8 Hz, 6H), 0.90 (t, J = 6.8 Hz, 3H); MS (ESI) [M+H]+ 547.4; HPLC 98.0% purity.
7V-[(4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyI]-3-[ethyl(oxan-4-yl)amino]-5-(6- methoxypyridin-3-yl)-2-methylbenzamide
Figure imgf000174_0002
[0124] To a stirred solution of 5-bromo-N-[(4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyI]-3- [ethyl(oxan-4-yl)amino]-2-methylbenzamide (100 mg, 0.210 mmol) and 2-methoxy-5- pyridineboronic Acid (51 mg, 0.336 mmol) in 1,4-dixoxane (2 mL) and ¾θ (0.4 mL) was added Pd(PPli3)4 (25 mg, 0.0216 mmol) and sodium carbonate (80 mg, 0.756 mmol). The reaction mixture was stirred at 100 °C for 4 hours. The mixture was cooled to rt, diluted with EtOAc, and filtered through Celite pad. The filtrate was washed with water (twice) and brine, dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel column chromatography (NH-S1O2; heptane/ethyl acetate =1/1 ~ EtOAc to EtOAc/MeOH = 10/1). The mixture was triturated with EtOAc-hexane to give the titled compound as a white solid (66.7 mg, 63%). Ή-NMR (400 MHz, CDCI3) δ ppm; 10.7-10.8 (m, 1H), 8.29 (d, = 2.8 Hz, 1H), 7.70 (dd, J = 2.8, 8.8 Hz, 1H), 7.25 (d, = 1.6 Hz, 1H), 7.20 (d, J = 1.6 Hz, 1H), 7.13 (t, J = 6.0 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 5.91 (s, 1H), 4.55 (d, J = 6.0 Hz, 2H), 3.95 (s, 3H), 3.93-3.96 (m, 2H), 3.28-3.36 (m, 2H), 3.10 (q, J = 7.2 Hz, 2H), 2.96-3.03 (m, 1H), 2.41 (s, 3H), 2.34 (s, 3H), 2.17 (s, 3H) 1.68-1.72 (m, 4H), 0.89 (t, J = 7.2 Hz, 3H); MS (ESI) [M+H]+ 505.5; HPLC 99.3% purity.
4-{[5-(Tetram }morpholine
Figure imgf000175_0001
[0125] To a stirred solution of 4-[(5-bromopyridin-2-yl)methyl]nK^holine (500 mg, 1.94 mmol) and bis(pinacolato)diboron (542 mg, 2.13 mmol) in 1 ,2-dimethoxyethane (5 mL) was added potassium acetate (571 mg, 5.82 mmol) and Pd(dppf)Ci2 (400 mg, 0.235 mmol). The reaction mixture was stirred at 80 °C for 1.5 hours. The mixture was cooled to rt, evaporated, diluted with EtOAc, and filtered through Celite pad. The filtrate was washed with water (twice), brine, dried over Na2S04, filtered, and concentrated to give the titled compound as a crude product (934 mg, -60% purity (as quantitative yield)). Ή- MR (400 MHz, CDC¾) δ ppm; 8.63 (d, J = 2.4 Hz, 1H), 7.79 (dd, J = 2.4, 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 3.71-3.78 (m, 4H), 3.61 (s, 2H), 2.45-2.58 (m, 4H), 1.26 (s, 12H).
3-[Ethyl(oxan-4-yl)amino]-2-methyl-N-{[6-methyl-2-oxo-4-(trifluoromethyl)-l,2- dihydropyridin-3-yl]methyl}-5-[6-(morpholin-4-ylmethyl)pyridin-3-yl)ben2amide
Figure imgf000175_0002
[0126] To a stirred solution of 5-bromo-3-[ethyl(oxan-4-yl)amino]-2-methyl-N-{[6-methyl-2-oxo- 4-(1rifluoromethyl)-l,2-dihydropyridm-3-yl]methyl}benzamide (274 mg, ~89% purity, 0.46 mmol) and a crude mixture of 4-{[5-(tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]methyl}mo holine (470 mg, -60% purity, 0.927 mmol) in 1,4-dixoxane (4.6 mL) and H20 (0.92 mL) was added Pd(PPh3)4 (53.0 mg, 0.0459 mmol) and sodium carbonate (176 mg, 1.66 mmol). The reaction mixture was stirred at 100 °C for 3 hours. The mixture was cooled to rt, evaporated, diluted with EtOAc, and filtered through Celite pad. The filtrate was washed with water (twice), brine, dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel column chromatography (NH-S1O2; EtOAc only to EtOAc MeOH = 5/1) and (Si02; EtOAc only to EtOAc/MeOH = 5/1 + 5% TEA). The mixture was triturated with EtjO-hexane to give the titled compound as a white solid (28.0 mg, 9.7%). Ή-NMR (400 MHz, CDC13) δ ppm; 8.41 (d, J = 2.4 Hz, 1H), 7.64 (dd, J = 2.4, 8.0 Hz, 1H), 7.30-7.40 (m, 2H), 7.22 (s, 1H), 7.18 (s, 1H), 6.26 (s, 1H), 4.77 (d, J = 6.4 Hz, 2H), 3.94-3.97 (m, 2H), 3.66-3.77 (m, 4H), 3.49 (s, 2H), 3.26-3.38 (m, 2H), 3.10 (q, / = 6.8 Hz, 2H), 2.94-3.05 (m, 1H), 2.42-2.49 (m, 4H), 2.39 (s, 3H), 2.31 (s, 3H) 1.66-1.73 (m, 4H), 0.90 (t, J = 6.8 Hz, 3H); MS (ESI) [M+H]+ 628.6; HPLC 95.4% purity.
l-[ -oI
Figure imgf000176_0001
[0127] To a stirred solution of 4-bromo-2-fluorobenzyl alcohol (818 mg, 3.99 mmol) and triethylamine (0.666 mL, 4.79 mmol) in CH2C12 (6.8 mL) was added MsCl (0.340 mL, 4.39 mmol) drop wise at 0°C. The reaction mixture was stirred at 0 C for 3 hours. The mixture was quenched with water, diluted with EtOAc, and partitioned. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated.
[0128] To a stirred solution of the crude mesylate and triethylamine (2.22 mL, 16.0 mmol) in DMF (6.8 mL) was added 3-hydroxyazetidine hydrochloride (655 mg, 5.99 mmol). The reaction mixture was stirred at 23°C for 14 hours. The reaction mixture was quenched with water, diluted with ethyl acetate, and partitioned. The organic layer was washed with water and brine, dried over Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography (NH-S1O2; ethyl acetate/heptane=l/l-2/l) to give the titled compound (698 mg, 67% yield). Ή-NMR (400 MHz, CDCI3) δ ppm; 7.17-7.27 (m, 3H), 4.42-4.47 (m, 1H), 3.61-3.67 (m, 4H), 2.95-2.99 (m, 2H), 1.90-2.05 (m, 1H).
l-{[2-Fluoro-4-(tetramethyl-l,3,2-dioxaboroIan-2-yl)phenyl]methyl}azetidin-3-ol
Figure imgf000176_0002
[0129] To a stirred solution of l-[(4-bromo-2-fluorophenyl)methyl]azetidin-3-ol (348 mg, 1.34 mmol) and bis(pinacolato)diboron (374 mg, 1.47 mmol) in 1 ,2-dimethoxyethane (3 mL) was added potassium acetate (394 mg, 4.02 mmol) and Pd(dppf)Cl2 (273 mg, 0.335 mmol). The reaction mixture was stirred at 80 °C for 2 hours. The mixture was cooled to rt, evaporated, diluted with EtOAc, and filtered through Celite pad. The filtrate was washed with water (twice), brine, dried over a2S04, filtered, and concentrated to give the titled compound as a crude product (650 mg, ~63% purity (as quantitative yield)).
V-[(4,6-Dimethyl-2-oxo-l,2-dihydropyridiii-3-yI)methyI]-3-[ethyl(oxan-4-yl)amino]-5-{3-fluoro-
4-[(3-hydroxyazetidin-l-yl)methyI)phenyl}-2-methylbeiizamide
Figure imgf000177_0001
[0130] To a stirred solution of 5-bromo-N-[(4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-3- [ethyl(oxan-4-yl)amino]-2-methylbenzamide (203 mg, 0.426 mmol) and a crude mixture of l-{[2- fluoro-4-(tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]methyl}azetidin-3-ol (350 mg, -63% purity, 0.67 mmol) in 1,4-dixoxane (4 mL) and ¾0 (0.8 mL) was added Pd(PPh3) (48 mg, 0.0415 mmol) and sodium carbonate (160 mg, 1.51 mmol). The reaction mixture was stirred at 100 °C for 3 hours. The mixture was cooled to rt, evaporated, diluted with EtOAc, and filtered through Celite pad. The filtrate was washed with water (twice), brine, dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel column chromatography (NH-S1O2; EtOAc only to EtOAc MeOH = 5/1), (SiO¾; EtOAc only to EtOAc/MeOH = 5/1 + 5% TEA) and by PTLC (S1O2; EtOAc/MeOH = 20/1 6 developments). The mixture was triturated with EtOAc-hexane to give the titled compound as a white solid (74.1 mg, 31%). Ή-NMR (400 MHz, CDCI3) δ ppm; 7.33 (t J = 6.0 Hz, 1H), 7.13- 7.30 (m, 5H), 5.91 (s, 1H), 4.56 (d, = 6.0 Hz, 2H), 4.34-4.38 (m, 1H), 3.94-3.98 (m, 2H), 3.56- 3.60 (m, 2H), 3.56 (s, 2H), 3.29-3.36 (m, 2H), 3.09 (q, = 7.2 Hz, 2H), 3.01-3.03 (m, 1H), 2.91-2.94 (m, 2H), 2.43 (s, 3H), 2.38 (s, 3H), 2.13 (s, 3H), 1.68-1.74 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H); MS (ESI) [M+Hf 577.6; HPLC 95.0% purity.
iV-(2-HydroxyethyI)-4-(tetramethyl-l,3,2-dioxaboroIaii-2-yl)benzamide
Figure imgf000177_0002
[0131] To a stirred solution of 4-bromobenzoic acid (2.00 g, 9.95 mmol) and 2-aminoethan-l-ol (912 mg, 14.9 mmol) in THF (200 mL) was added HATU (6.81 g, 17.9 mmol) and Hunig's base (5.20 mL, 29.9 mmol). The reaction mixture was stirred at RT for 2 hours. Then, the reaction mixture was quenched with water. The mixture was concentrated in vacuo, and the resultant residue was dissolved in ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (twice), and the combined organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (S1O2; Heptane/ethyl acetate =1/1) to give JV-(2-hydroxyethyl)benzamide as a white solid (1.70 g, 70%).
To a stirred solution of iV-(2-hydroxyethyl)benzamide (1.70 g, 6.96 mmol) and bis(pinacolato)diboron (2.12 g, 8.36 mmol) in 1 ,2-dimethoxyethan (40 mL) was added potassium acetate (2.05 g, 20.9 mmol) and Pd(dppf)Ci2 (255 mg, 0.348 mmol). The reaction mixture was stirred at 80 °C for 4 hours. After cooling to RT, the mixture was filtered through Celite pad. The filtrate was concentrated in vacuo, the resultant residue was purified by silica gel column chromatography (S1O2; Heptane/ethyl acetate =1/1) to give the titled compound as a brown solid (1.20 g, 59%). Ή-
N R (400 MHz, CDCI3) δ ppm; 7.87 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 6.71 (brs, 1H), 3.80-3.88 (m, 2H), 3.6Ό-3.69 (m, 2H), 1.35 (s, 12H); MS (ESI) [M+Hf 292.2.
/Y-[(4,6-Dimethyl-2-oxo-l,2-dihydropyridin -yl)methyl]-3-[ethyl(oxan-4-yl)amino]-5-{4-[(2-
Figure imgf000178_0001
[0132] To a stirred solution of 5-bromo-N-[(4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-3- [ethyl(oxan-4-yl)amino]-2-methylbenzamide (200 mg, 0.419 mmol) and N-(2-hydroxyethyl)-4- (tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (196 mg, 0.673 mmol) in 1,4-dixoxane (4.2 mL) and H20 (0.8 mL) was added Pd(PPh3)4 (49 mg, 0.0424 mmol) and sodium carbonate (160 mg, 1.51 mmol). The reaction mixture was stirred at 100 DC for 2 hours. The mixture was cooled to rt, evaporated, and diluted with EtOAc. The mixture was washed with water (twice), brine, dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel column chromatography (NH-S1O2; EtOAc only to EtOAc MeOH = 10/1-5/1), (S1O2; EtOAc only to EtOAc/MeOH = 10/1- 5/1). The mixture was triturated with CH2Cl2-Et20-hexane to give the titled compound (122.2 mg, 52%). Ή-NMR (400 MHz, CDC13) δ ppm; 7.75-7.79 (m, 1H), 7.70 (br-s, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.30-7.33 (m, 4H), 5.63 (s, 1H), 4.52 (d, J = 6.4 Hz, 2H), 4.12-4.18 (m, 1H), 3.92-3.98 (m, 4H), 3.72-3.75 (m, 2H), 3.29 (m, 2H), 3.11 (q, J = 1.2 Hz, 2H), 2.98-3.03 (m, 1H), 2.41 (s, 3H), 2.37 (s, 3H), 1.90 (s, 3H), 1.66-1.73 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H); MS (ESI) [M+H]+ 561.5; HPLC 95.8% purity.
3-(EthyI(oxan-4-yl)arnino]-5-{4-[(2-hydroxyethyl)carbamoyI]phenyl}-2-rnethyl-/V-{[6-methyl-2- oxo-4-(propan-2-yI)-l,2-dihydropyridin-3-yI]methyl}benzamide
Figure imgf000179_0001
[0133] To a stirred solution of 5-bromo-3-[ethyl(oxan-4-yl)amino]-2-metliyl-N-{[6-methyl-2-oxo- 4-(propan-2-yl)-l,2-dihydropyridin-3-yl]methyl}benzamide (250 mg, -80% purity, 0.396 mmol) and N-(2-hydroxyethyl)-4-(tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (184 mg, 0.634 mmol) in 1,4-dixoxane (4 iriL) and ¾0 (0.8 mL) was added Pd(PPh3)4 (40 mg, 0.0346 mmol) and sodium carbonate (151 mg, 1.43 mmol). The reaction mixture was stirred at 100 °C for 2 hours. The mixture was cooled to rt, evaporated, and diluted with EtOAc. The mixture was washed with water (twice), brine, dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel column chromatography ( H-S1O2; EtOAc only to EtOAc/MeOH = 10/1-5/1). The mixture was triturated with CH2Ci2-EtOAc-hexane to give the titled compound as a white solid (176 mg, 75% yield). Ή- NMR (400 MHz, CDC13) δ ppm; 7.85 (t, J = 6.4 Hz, 1H), 7.67 (t, J = 5.2 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.26-7.30 (m, 4H), 5.89 (s, 1H), 4.61 (d, /= 6.4 Hz, 2H), 3.91-4.02 (m, 3H), 3.84-3.89 (m, 2H), 3.64-3.68 (m, 2H), 3.51-3.56 (m, 1H), 3.29-3.36 (m, 2H), 3.09 (q, J = 6.8 Hz, 2H), 2.97-3.03 (m, 1H), 2.40 (s, 3H), 2.02 (s, 3H), 1.64-1.68 (m, 4H), 1.18 (d, J = 6.8 Hz, 6H), 0.88 (t, J = 6.8 Hz, 3H); MS (ESI) [M+H]+ 589.5; HPLC 96.7% purity.
V-[(4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-3-[ethyl(oxan-4-yl)araino]-2-methyl-5- {6-l(4-raethyl-l,4-diazepan-l-yl)methyl]pyridin-3-yI}benzamide)
Figure imgf000179_0002
[0134] To a stirred solution of 5-bromo-N-[(4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-3- [ethyl(oxan-4-yl)amino]-2-methylbenzamide (2.00 g, 4.20 mmol) and [5-(tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl]methanol (1.18 g, 5.04 mmol) in 1,4-dixoxane (40 mL) and ¾0 (4 mL) was added Pd(PPh3)4 (485 mg, 0.420 mmol) and sodium carbonate (1.34 g, 12.6 mmol). The reaction mixture was stirred at 80 °C for 2 hours. Then, the reaction mixture was filtered through celite pad. The filtrate was concentrated in vacuo, the resultant residue was purified by silica gel column chromatography (NH-S1O2; heptatne/ethylacetate =1/5 to ethyl acetate only) to give N-[(4,6- dimethy]-2-oxo-l,2-dihydropyridin-3-yl)methyl]-3-[ethyl(oxan-4-yl)ainino]-5-[6- (hydroxymethyl)pvridin-3-yl]-2-methylbenzamide as a white solid (800 mg, 37% yield).
To a stirred solution of N-[(4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-3- [ethyl(oxan-4-yl)amino]-5-[6-(hydroxymet yl)pyridin-3-yl]-2-methylbenzamide (200 mg, 0.396 mmol) in (%(¾ (4 mL) was added methanesulfonyl chloride (54.4 mg, 0.475 mmol) and Hunig's base (206 uL, 1.1 mmol). The reaction mixture was stirred at RT for 30 minutes. Then 1-methyl- homopiperazine (226 mg, 1.98 mmol) was added to the reaction mixture, and the resultant mixture was stirred at RT for 1 hour. The mixture was quenched with water, and concentrated in vacuo. The residue was purified by silica gel column chromatography ( H-Si02 ethylacetate/MeOH=20/l) to give the titled compound as a white solid (25.1 mg). Ή-NMR (400 MHz, CDC13) δ ppm; 8.63 (dd, J = 2.3, 0.8 Hz, 1H), 7.75 (dd, / = 8.2, 2.3 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.25 (d, / = 2.0 Hz, 1H), 7.20 (t, J = 5.9 Hz, 1H), 5.91 (s, 1H), 4.56 (d, J = 5.9 Hz, 2H), 3.96 (m, 2H), 3.80 (s, 2H), 3.26-3.36 (m, 2H), 3.09 (q, / = 7.0 Hz, 2H), 2.95-3.05 (m, 1H), 2.75-2.82 (m, 4H), 2.60-2.71 (m, 4H), 2.39 (s, 3H), 2.36 (s, 3H), 2.34 (s, 3H), 2.14 (s, 3H), 1.79-1.89 (m, 4H), 1.64-1.74 (m, 2H), 0.89 (t, J = 7.0 Hz, 3H); MS (ESI) [M+H]+ 601.6; HPLC 93.4% purity.
A^-[(4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-3-|ethyl(oxan-4-yl)ainino]-2-methyl-5-
[6-(pyrrolidin-l-ylmethyl)pyridin-3-yl]benzamide
Figure imgf000180_0001
[0135] To a stirred solution of 5-bromo-N-[(4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-3- [ethyl(oxan-4-yl)amino]-2-methylbenzamide (2.00 g, 4.20 mmol) and [5-(tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl]methanol (1.18 g, 5.04 mmol) in 1,4-dixoxane (40 mL) and H2O (4 mL) was added Pd(PPh3)4 (485 mg, 0.420 mmol) and sodium carbonate (1.34 g, 12.6 mmol). The reaction mixture was stirred at 80 °C for 2 hours. Then, the reaction mixture was filtered through Celite pad. The filtrate was concentrated in vacuo, the resultant residue was purified by silica gel column chromatography (NH-Si02; heptane/ethylacetate =1/5 to ethyl acetate only) to give N-[(4,6- dimethyl- 2-oxo- l,2-dihydropyridin-3-yl)methyl]-3-[ethyl(oxan-4-yl)amino]-5-[6- (hydroxymethyl)pyridin-3-yl]-2-methylbenzamide as a white solid (800 mg, 37%).
To a stirred solution of N-[(4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-3- [ethyl(oxan-4-yl)amino]-5-[6-(hydroxymethyl)pyridin-3-yl]-2-methylbenzamide (200 mg, 0.396 mmol) in (¾<¾ (4 mL) was added methanesulfonyl chloride (68.1 mg, 0.595 mmol) and Hunig's base (206 uL, 1.19 mmol). The reaction mixture was stirred at RT for 30 minutes. Then pyrrolidine (141 mg, 1.98 mmol) was added to the reaction mixture, and the resultant mixture was stirred at RT for 4 days. The mixture was quenched with water, and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH-S1O2; heptane/ethyl acetate=l/5 to ethyl acetate only) to give the titled compound as a white solid (21.0 mg, 9.5% yield).Ή-NMR (400 MHz, CDC¾) δ ppm; 8.67 (d, J = 2.0 Hz, 1H), 7.75 (dd, J = 8.2, 2.0 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.15 (t, J = 5.7 Hz, 1H), 5.92 (s, 1H), 4.56 (d, J = 5.7 Hz, 2H), 3.96 (m, 2H), 3.64 (s, 2H), 3.28-3.39 (m, 2H), 3.10 (q, J = 7.0 Hz, 2H), 3.02 (m, 1H), 2.46 (m, 4H), 2.41 (s, 3H), 2.35 (s, 3H), 2.19 (s, 3H), 1.68-1.75 (m, 4H), 1.61 (m, 2H), 1.46 (m, 2H), 0.90 (t, J = 7.0 Hz, 3H); MS (ESI) [M+H]+ 558.6; HPLC 96.3% purity.
iV-[(4,6-0imethyI-2-oxo-1,2-dihydropyridin-3-yI)methylJ-3-[ethyl(oxan-4-yl)amino]-2-methyI-5-
Figure imgf000181_0001
[0136] To a stirred solution of 5-bromo-N-[(4,6-dimethyl-2-oxo-l,2-dmydropyridin-3-yl)methyl]-3- [ethyl(oxan-4-yl)amino]-2-methylbenzamide (2.00 g, 4.20 mmol) and [5-(tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl]methanol (1.18 g, 5.04 mmol) in 1,4-dixoxane (40 mL) and ¾0 (4 mL) was added Pd(PPl¾)4 (485 mg, 0.420 mmol) and sodium carbonate (1.34 g, 12.6 mmol). The reaction mixture was stirred at 80 °C for 2 hours. Then, the reaction mixture was filtered through Celite pad. The filtrate was concentrated in vacuo, the resultant residue was purified by silica gel column chromatography (NH-S1O2; heptane/ethylacetate =1/5 to ethyl acetate only) to give N-[(4,6- dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-3-[ethyl(oxan-4-yl)amino]-5-[6- (hydroxymethyl)pyridin-3-yl]-2-methylbenzamide as a white solid (800 mg, 37%).
To a stirred solution of N-[(4,6-dimemyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-3- [ethyl(oxan-4-yl)amino]-5-[6-(hydroxymethyl)pyridin-3-yl]-2-methylbenzamide (200 mg, 0.396 mmol) in CH2CI2 (4 mL) was added methanesulfonyl chloride (54.4 mg, 0.475 mmol) and Hunig's base (206 uL, 1.19 mmol). The reaction mixture was stirred at RT for 30 minutes. Then piperidine (169 mg, 1.98 mmol) was added to the reaction mixture, and the resultant mixture was stirred at RT for 1 hour. The mixture was quenched with water, and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH-S1O2; heptane/ethyl acetate=l/5 to ethyl acetate/MeOH=20/l) to give the titled compound as a white solid (81.2 mg, 35.9% yield). Ή-NMR (400 MHz, CDCb) δ ppm; 8.64 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 8.2, 2.0 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.17-7.22 (m, 1H), 5.90 (s, IH), 4.56 (d, J = 8.0 Hz, IH), 4.54 (d, J= 8.0 Hz, IH), 3.94 (m, 2H), 3.61 (s, 2H), 3.27-3.36 (m, 2H), 3.09 (q, J = 7.0 Hz, 2H), 2.96-3.04 (m, IH), 2.40 (m, 4H), 2.39 (s, 3H), 2.34 (s, 3H), 2.14 (s, 3H), 1.70 (m, 2H), 1.50-1.63 (m, 6H), 1.38-1.49 (m, 2H), 0.89 (t, J = 7.0 Hz, 3H); MS (ESI) [M+H]+ 572.5; HPLC 97.6% purity.
3-[Ethyl(oxan-4-yl)amino]-5-[6-(hydroxymethyI)pyridin-3-yl]-2-methyl-7V-{|6-methyl-2-oxo-4- de
Figure imgf000182_0001
[0137] To a stirred solution of 5-bromo-3-[ethyl(oxan-4-yl)amino]-2-methyl-N-{[6-methyl-2-oxo- 4-(2-propyl)-l,2-dihydropyridin-3-yl]methyl}benzamide (1.50 g, 2.97 mmol) and [5-(tetramethyl- l,3,2-dioxaborolan-2-yl)pyridin-2-yl]methanol (1.89g, 8.03mmol) in 1,4-dioxane (20 mL) and water (5 mL) was added Pd(PPri3)4 (515 mg, 0.446 mmol) and sodium carbonate (1.14 g, 10.7 mmol). The reaction mixture was stirred at 80 °C for 2 hours. Then, [5-(tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl]methanol (800mg, 3.40mmol), Pd(PPh3)4 (200 mg, 0.173 mmol) and sodium carbonate (630 mg, 5.94 mmol) were added and stirred at 80°C for 14 hours. After coolmg to RT, ethyl acetate and water were added to the mixture. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water (twice) and brine. The organic layer was dried over MgS04 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (1; NH-Si02j ethyl acetate/MeOH =50/1 to 6/1, 2; S1O2; ethyl acetate/MeOH =8/1 to 5/1) to give the titled compound as a white solid (457 mg, 29%). Ή-NMR (400M Hz, CDCI3) δ ppm; 10.51 (br. s., IH), 8.60 (s, IH), 7.64-7.73 (m, IH), 7.24-7.27(m, IH), 7.17-7.24 (m, IH), 7.11-7.17 (m, 2H), 6.07 (s, IH), 4.69 (br. s., 2H), 4.61 (d, J = 6.2 Hz, 2H), 3.84- 4.02 (m, 3H), 3.53-3.65 (m, IH), 3.28-3.40 (m, 2H), 3.10 (q, / = 7.0 Hz, 2H), 2.96-3.06 (m, IH), 2.36 (s, 3H), 2.27(s, 3H), 1.65-1.76 (m, 4H), 1.24 (d, J = 7.0 Hz, 6H), 0.90 (t, J = 7.0 Hz, 3H). 3-[EthyI(oxan-4-yI)amino]-2-methyI-5-{6-[(4-methyl-l,4-diazepan-l-yl)methyI]pyridiii-3-yl}-iV- {[6-methyI-2-oxo-4-(2-propyI)-l,2-dihydropyridin-3-yI]methyl}benzamide
Figure imgf000183_0001
[0138] To a stirred solution of 3-[ethyl(oxan-4-yl)amino]-5-[6-(hydroxymethyl)pyridin-3-yl]-2- methyl-N-{[6-methyl-2-oxo-4-(2-propyl)-l,2-dihydropyria^n-3-yl]methyl}benzamide (200 mg, 0.375 mmol) in CH2CI2 (4 mL) was added methanesulfonyl chloride (51.6 mg, 0.451 mmol) and Hunig's base (195 uL, 1.13 mmol). The reaction mixture was stirred at RT for 1 hour. Then 1- methyl-homopiperazine ( 129 mg, 1.13 mmol) was added to the reaction mixture, and the resultant mixture was stirred at RT for 1 hour. The mixture was quenched with water, and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH-S1O2 ethyl acetate only to ethyl acetate MeOH=15/l) to give the titled compound as a white solid (81.3 mg, 34.5% yield). Ή- NMR (400 MHz, CDC13) δ ppm; 8.65 (d, J = 2.3 Hz, 1H), 7.76 (dd, J = 8.2, 2.3 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.23 (d, J = 2.0 Hz, lH), 7.12 (t, J = 5.9 Hz, 1H), 6.03 (s, 1H), 4.61 (d, J = 5.9 Hz, 2H), 3.95 (m, 2H), 3.81 (s, 2H), 3.54 (m, 1H), 3.27-3.37 (m, 2H), 3.10 (q, J = 6.8 Hz, 2H), 3.01 (m, 1H), 2.76-2.84 (m, 4H), 2.60-2.71 (m, 4H), 2.37 (s, 3H), 2.33 (s, 3H), 2.22 (s, 3H), 1.84 (m, 2H), 1.67-1.74 (m, 4H), 1.21 (d, 7= 7.0 Hz, 6H), 0.85-0.90 (t, J = 6.8 Hz, 3H); MS (ESI) [M+H]+ 629.6; HPLC 91.7% purity.
3-[Ethyl(oxan-4-yl)amino]-5-(6-{[(35)-3-hydroxypiperidin-l-yl)methyl}pyridin-3-yl)-2-methyl- iV-{[6-methyl-2-oxo-4-(2-propyl)-l,2-dihydropyridin-3-yl]methyl}benzamide
Figure imgf000183_0002
[0139] To a stirred solution of 3-[ethyl(oxan-4-yl)amino]-5-[6-(hydroxymethyl)pyridin-3-yl]-2- methyl-N-{[6-methyl-2-oxo-4-(2-propyl)-l,2-dihydropyridin-3-yl]methyl}benzamide (200 mg, 0.375 mmol) in CH2CI2 (4 mL) was added methanesulfonyl chloride (51.6 mg, 0.451 mmol) and Hunig's base (195 uL, 1.13 mmol). The reaction mixture was stirred at RT for 1 hour. Then (5)-3- hydroxypiperidine HCl salt (258 mg, 1.88 mmol) was added to the reaction mixture, and the resultant mixture was stirred at RT for 1 hour. The mixture was quenched with water, and concentrated in vacuo. The residue was purified by silica gel column chromatography (NH-S1O2; ethyl acetate/MeOH=20/l) to give the titled compound as a white solid (39.9 mg, 17.3% yield). 'H-NMR (400 MHz, CDC13) δ ppm; 8.63-8.66 (m, 1H), 7.74 (dd, J = 8.2, 2.3 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.17 (t, J = 5.9 Hz, 1H), 6.02 (d, J = 0.8 Hz, 1H), 4.61 (d, J = 5.9 Hz, 2H), 3.91-3.98 (m, 2H), 3.82 (brs, 1H), 3.66 (s, 1H), 3.65 (s, 1H), 3.52 (m, 1H), 3.26-3.36 (m, 2H), 3.09 (q, J = 7.0 Hz, 2H), 2.95-3.05 (m, 1H), 2.52 (m, 3H), 2.35-2.41 (m, 1H), 2.34 (s, 3H), 2.19 (s, 3H), 1.74-1.88 (m, 4H), 1.67-1.73 (m, 2H), 1.56 (m, 2H), 1.20 (d, / = 7.0 Hz, 6H), 0.89 (t, J= 7.0 Hz, 3H); MS (ESI) [M+H]+ 616.6; HPLC 97.4% purity.
5-Bromo-2-[(l-methylpiperidin-4-yl)oxy]pyridine
Figure imgf000184_0001
[0140] To a stirred solution of 4-hydroxy-l-methylpiperidine (175 mg, 1.52 mmol) in THF (8.0 mL) was added NaH (60%, 60.8 mg, 1.52 mmol). The reaction mixture was stirred for lOmin. 2, 5- dibromopyridine (300 mg, 1.27 mmol) was added at 0 °C and stirred under reflux for 9.5 hours. After cooling to RT, ethyl acetate and water were added to the mixture. The organic layer was washed with water and brine. The organic layer was dried over MgS04 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH-S1O2; Heptane/ethyl acetate =5/1 to 1/1) to give the titled compound as a colorless oil (309 mg, 90%). Ή- NMR (400 MHz, CDCI3) δ ppm; 8.15 (d, J = 2.6 Hz, lH), 7.62 (dd, = 8.8, 2.6 Hz, 1H), 6.63 (d, J = 8.8 Hz, lH), 4.95-5.04 (m, 1H), 2.63-2.76 (m, 2H), 2.23-2.36 (m, 2H), 2.30 (s, 3H), 1.98-2.08 (m, 2H), 1.75-1.87 (m, 2H).
Methyl 3-[ethyl(oxan-4-yl)amino]-2-methyl-5-{6-[(l-methylpiperidin-4-yl)oxy]pyridin-3- yl}benzoate
Figure imgf000184_0002
[0141] To a stirred solution of methyl 3-[ethyl(oxan-4-yl)amino]-2-methyl-5-(tetramethyl- 1,3,2- dioxaborolan-2-yl)benzoate (110 mg, 0.273 mmol) and 5-bromo-2-[(l-methylpiperidin-4- yl)oxy]pyridine (96.1 mg, 0.355 mmol) in 1,4-dioxane (2.5 mL) and water (0.5 mL) was added Pd(PPh3)4 (47.3 mg, 0.0410 mmol) and sodium carbonate (104 mg, 0.982 mmol). The reaction mixture was stirred at 80 °C for 4 hours. After cooling to RT, ethyl acetate and water were added to the mixture. The mixture was filtered and partitioned. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine. The organic layer was dried over MgSO* and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH-S1O2; heptane/ethyl acetate =3/1 to 1/1) to give the titled compound as a colorless oil (70.1 mg, 55%). Ή-NMR (400 MHz, CDC¾) δ ppm; 8.33 (d, J = 2.6 Hz, 1H), 7.77 (dd, J = 8.6, 2.6 Hz, lH), 7.73 (d, J = 1.8 Hz, 1H), 7.41 (d, J = 1.8 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 5.05-5.15 (m, 1H), 3.92-4.02 (m, 2H), 3.92(s, 3H), 3.29-3.38 (m, 2H), 3.11 (q, J = 7.0 Hz, 2H), 2.97-3.06 (m, 1H), 2.69-2.79 (m, 2H), 2.53 (s, 3H), 2.32(s, 3H), 2.24-2.37 (m, 2H), 2.03-2.14 (m, 2H), 1.80-1.93 (m, 2H), 1.63-1.77 (m, 4H), 0.90 (t, / = 7.0 Hz, 3H).
AM(4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yI)methy^
Figure imgf000185_0001
[0142] To a stirred solution of methyl 3-[ethyl(oxan-4-yl)amino]-2-methyl-5-{6-[(l- methylpiperidin-4-yl)oxy]pyridin-3-yl}benzoate (70.1 mg, 0.150 mmol) in ethanol (2 mL) was added aq. NaOH (5N, 150 uL). The reaction mixture was stirred at 90 C for 1 hour. After cooling to 0 C, the reaction mixture was neutralized with 5N-HC1. The mixture was concentrated in vacuo, and dried under vacuum pressure to give the crude product of 3-[ethyl(oxan-4-yl)amino]-2-methyl-5-{6-[(l- methylpiperidin-4-yl)oxy]pyridin-3-yl}ben2oic acid.
To a stirred solution of the crude carboxylic acid and 3-(aminomethyl)-4,6-dimethyl-l,2- dihydropyndin-2-one HC1 salt (42.4 mg, 0.225 mmol) in DMSO (2 mL) was added PYBOP (117 mg, 0.225 mmol) and Hunig's base (131 uL, 0.750 mmol). The reaction mixture was stirred at RT for 17 hours. The reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (10ml, twice), and the combined organic layer was washed with water (twice) and brine. The organic layer was dried over MgS04 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH-S1O2 ethyl acetate/MeOH=50/l to 10/1) to give the crude compound. The crude compound was suspended with ethyl acetate and heptane. The resultant precipitated solid was collected by filtration. The solid was dried under vacuum pressure to give the titled compound as a white solid (56.7 mg, 64%). Ή-NMR (400 MHz, CDCI3) δ ppm; 10.23 (br. s., 1H), 8.27 (d, J = 2.6 Hz, 1H), 7.70 (dd, J = 8.4, 2.6 Hz, 1H), 7.25 (d, J = 1.8 Hz, 1H), 7.20 (d, J = 1.8Hz, 1H), 7.10 (t, / = 5.9 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 5.91 (s, 1H), 5.03-5.12 (m, 1H), 4.55 (d, J = 5.9 Hz, 2H), 3.92-3.99 (m, 2H), 3.27-3.37 (m, 2H), 3.09 (q, J = 7.0 Hz, 2H), 2.95- 3.05 (m, 1H), 2.68-2.79 (m, 2H), 2.41 (s, 3H), 2.33(s, 3H), 2.32(s, 3H), 2.26-2.36 (m, 2H), 2.19 (s, 3H), 2.03-2.12 (m, 2H), 1.80-1.91(m, 2H), 1.62-1.76 (m, 4H), 0.89 (t, / = 7.0 Hz, 3H); MS (ESI) [M+Hf 588.7 ; HPLC 97.0% purity. 1 -Methylazetidin-3-ol
Ια¾.
[0143] To a stirred solution of benzyl 3-hydroxyazetidine-l-carboxylate (134 mg, 0.646 mmol) in THF (5.0 mL) was added lithium aluminum hydride (75.0 mg, 0.968 mmol) at 0 C and stirred under reflux for 2 hours. After cooling to 0 °C, water (75 uL), 5N NaOH aq. (75 uL) and water (225 uL) were added to the mixture and stirred at r.t. for 30min. The precipitated solid was removed by filtration. The filtrate was concentrated in vacuo. The residue was used for next step without further purification, (a colorless oil, 107 mg, quantitative yield). Ή-NMR (400 MHz, CDC13) δ ppm; 4.35- 4.43 (m, lH), 3.63-3.68 (m, 2H), 2.88-2.96 (m, 2H), 2.35 (s, 3H).
5-Bromo-2-[(l-methylazetidin-3-yl)oxy]pyridine
Figure imgf000186_0001
[0144] To a stirred solution of crude l-methylazetidin-3-ol (107 mg, 1.23 mmol) in THF (5.0 mL) was added NaH (60%, 64.1 mg, 1.60 mmol). The reaction mixture was stirred for 15min. 2, 5- dibromopyridine (292 mg, 1.23 mmol) was added at 0 C and the mixture was stirred under reflux for 17 hours. After cooling to rt, ethyl acetate and water were added to the mixture. The organic layer was washed with water and brine. The organic layer was dried over MgS04 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH- S1O2; Heptane/ethyl acetate =6/1 to 2/1) to give the titled compound as a colorless oil (38.8 mg, 25% yield). Ή-NMR (400 MHz, CDC13) δ ppm; 8.14 (d, J = 2.6 Hz, 1H), 7.64 (dd, J = 8.8, 2.6 Hz, lH), 6.66 (d, J = 8.8 Hz, 1H), 5.12-5.20 (m, 1H), 3.71 -3.87 (m, 2H), 3.02-3.17 (m, 2H), 2.40 (s, 3H).
Methyl 3-[ethyl(oxan-4-yl)amino]-2-methyl-5-{6-[(l-methylazetidin-3-yl)oxy]pyridin-3-
Figure imgf000186_0002
[0145] To a stirred solution of methyl 3-[ethyl(oxan-4-yl)amino]-2-methyl-5-(tetramethyl-l,3,2- dioxaborolan-2-yl)benzoate (77.2 mg, 0.192 mmol) and 5-bromo-2-[(l-methylazetidin-3- yl)oxy]pyridine (38.8 mg, 0.160 mmol) in 1,4-dioxane (2.0 mL) and water (0.5 mL) was added Pd(PPh3)4 (27.7 mg, 0.0240 mmol) and sodium carbonate (60.9 mg, 0.575 mmol). The reaction mixture was stirred at 80 °C for 1.5 hours. After cooling to RT, ethyl acetate and water were added to the mixture. The mixture was filtered and partitioned. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine. The organic layer was dried over MgS04 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH-Si02, heptane/ethyl acetate =3/1 to 1/1) to give the titled compound as a colorless oil (33.1 mg, 47%). Ή-NMR (400 MHz, CDC13) 5 ppm; 8.31 (dd, J = 2.6, 0.7 Hz, 1H), 7.78 (dd, J = 8.8, 2.6 Hz, 1H), 7.72 (d, J = 2.2 Hz, 1H), 7.40 (d, J = 1.8 Hz, 1H), 6.79- 6.85 (m, 1H), 5.22-5.30 (m, 1H), 3.93-4.00 (m, 2H), 3.92 (s, 3H), 3.83-3.89 (m, 2H), 3.28-3.38 (m, 2H), 3.06-3.21 (m, 4H), 2.95-3.06 (m, 1H), 2.53 (s, 3H), 2.43 (s, 3H), 1.63-1.78 (m, 4H), 0.90 (t, J = 7.1 Hz, 3H).
A?-[(4,6-Dimethyl-2-oxo-l,2-dihydropyridiii-3-yl)raethyl]-3-|ethyl(oxan-4-yl)amino]-2-methyl-5-
Figure imgf000187_0001
[0146] To a stirred solution of methyl 3-[ethyl(oxan-4-yl)amino]-2-methyl-5-{6-[(l-methylazetidin- 3-yl)oxy]pyridin-3-yl}benzoate (33.1 mg, 0.0753 mmol) in methanol (600 uL) was added aq. NaOH (5N, 150 uL). The reaction mixture was stirred at 60 C for 1 hour. After cooling to RT, the reaction mixture was concentrated in vacuo, and dried under vacuum pressure to give the crude 3- [emyl(oxan-4-yl)amino]-2-methyl-5-{6-[(l-methylazetidin-3-yl)oxy]pyridin-3-yl}benzoic acid sodium salt.
To a stirred solution of the crude carboxylic acid sodium salt and 3-(aminomethyl)-4,6- dimethyl-1 ,2-dihydropyridin-2-one HC1 salt (21.3 mg, 0.113 mmol) in DMSO (300 uL) was added PYBOP (98.0 mg, 0.188 mmol) and Hunig's base (39.4 uL, 0.226 mmol). The reaction mixture was stirred at RT for 21 hours. The reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (1 mL, twice), and the combined organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH-S1O2 ethylacetate MeOH=10/l) to give the titled compound as a white solid (11.6 mg, 28%). ]H-NMR (400 MHz, CDCI3) δ ppm; 8.25 (d, J = 2.0 Hz, 1H), 7.71 (dd, J = 8.8, 2.0 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 7.20 (d, J = 1.6 Hz, 1H), 7.18 ft / = 5.9 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 5.93 (s, 1H), 5.17-5.28 (m, 1H), 4.56 (d, J = 5.9 Hz, 2H), 3.95 (m, 2H), 3.79-3.87 (m, 2H), 3.27-3.37 (m, 2H), 3.05-3.18 (m, 4H), 2.94-3.04 (m, 1H), 2.39-2.44 (s x 2, 6H), 2.34 (s, 3H), 2.19 (s, 3H), 1.62-1.72 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H); MS (ESI) [M+H]+ 560.6 ; HPLC 71.0% purity.
l-(5-Iodopyridin-2-yl)-4-methyl-l,4-diazepane
Figure imgf000187_0002
[0147] To a stirred solution of 2-bromo-5-iodopyridine (200 mg, 0.704 mmol) and 1 -methyl homopiperazine (121mg, 1.06mmol) in NMP (3 mL) was added potassium carbonate (146 mg, 1.06 mmol). The reaction mixture was irradiated with Microwave at 150°C for 2 hours. After completion of the reaction, ethyl acetate and water were added to the mixture. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with water (twice) and brine. The organic layer was dried over MgSQ} and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH-S1O2; heptane/ethyl acetate =6/1 to 2/1) to give the titled compound as a white solid (187 mg, 83%). 'H-NMR (400 MHz, CDC13) 8 ppm; 8.23- 8.28 (m, 1H), 7.60 (dd, J = 9.0, 2.4 Hz, 1H), 6.33 (d, J = 9.0 Hz, 1H), 3.74-3.81 (m, 2H), 3.55-3.63 (m, 2H), 2.63-2.70 (m, 2H), 2.51-2.59 (m, 2H), 2.37 (s, 3H), 1.96-2.04 (m, 2H).
Methyl 3-[ethyl(oxan-4-yl)amino]-2-methyl-5-[6-(4-methyl-l,4-diazepan-l-yI)pyridin-3- yljbenzoate
Figure imgf000188_0001
[0148] To a stirred solution of methyl 3-[ethyl(oxan-4-yl)amino]-2-methyl-5-(tetramethyl-l,3,2- dioxaborolan-2-yl)benzoate (180 mg, 0.446 mmol) and l-(5-iodopyridin-2-yl)-4-methyl-l,4- diazepane (184 mg, 0.580 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added Pd(PPii3)4 (77.4 mg, 0.067 mmol) and sodium carbonate (170 mg, 1.61 mmol). The reaction mixture was stirred at 80 °C for 14.5 hours. After cooling to RT, ethyl acetate and water were added to the mixture. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water (twice) and brine. The organic layer was dried over MgS04 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (1; SiOi; heptane/ethyl acetate =3/1 to 1/1, 2; S1O2; heptane/ethyl acetate =1/1 to ethyl acetate/MeOH =8/1 to CHC¾/MeOH =5/1) to give the titled compound as a colorless oil (25.5 mg, 12% yield). 1 H-NMR (400 MHz, CDCI3) δ ppm; 8.38 (d, J = 2.4 Hz, 1H), 7.72 (d, J = 1.8 Hz, 1H), 7.68 (dd, J = 8.8, 2.4 Hz, 1H), 7.41 (d, J = 1.8 Hz, 1H), 6.56 (d, J = 8.8 Hz, 1H), 3.86-4.01 (m, 4H), 3.92(s, 3H), 3.64- 3.68 (m, 2H), 3.29-3.38 (m, 2H), 3.10 (q, J = 7.0 Hz, 2H), 2.96-3.06 (m, 1H), 2.75-2.84 (m, 2H), 2.60-2.70 (m, 2H), 2.51 (s, 3H), 2.43 (s, 3H), 2.05-2.17 (m, 2H), 1.61-1.80 (m, 4H), 0.90 ppm (t, J = 7.0 Hz, 3H).
iV-[(4,6-DimethyI-2-oxo-l,2-dihydropyridin-3-yl)niethyl]-3-[ethyl(oxan-4-yl)amino]-2-methyl-S- [6-(4-methyl-l,4-diazepan-l-yl)pyridin-3-yI]benzamide
Figure imgf000189_0001
[0149] To a stirred solution of methyl 3-[ethyl(oxan-4-yl)amino]-2-memyl-5-[6-(4-methyl-l,4- diazepan-l-yl)pyridin-3-yl]benzoate (25.5 mg, 0.055 mmol) in ethanol (2 mL) was added aq. NaOH (5N, 44 uL). The reaction mixture was stirred at 90°C for 1.5 hour. After cooling to 0 C and neutralized with aq. 5N-HC1, the reaction mixture was concentrated in vacuo, and dried under vacuum pressure to give the crude 3-fethyl(oxan-4-yl)amino]-2-methyl-5-[6-(4-methyl-l,4-diazepan- l-yl)pyridin-3-yl]benzoic acid sodium salt.
To a stirred solution of the crude carboxylic acid sodium salt and 3-(aminomethyi)-4,6- dimethyl-l,2-dihydropyridin-2-one HC1 salt (13.4 mg, 0.071 rnmol) in DMSO (2 mL) was added PYBOP (42.7 mg, 0.082 rnmol) and Hunig's base (47.6 uL, 0.273 rnmol). The reaction mixture was stirred at RT for 15 hours. The reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (10 mL, twice), and the combined organic layer was washed with water (twice) and brine. The organic layer was dried over MgSOi and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH-Si02 ethyl acetate MeOH=50/l to 10/1) to give the crude compound. The crude compound was suspended with ethyl acetate and heptane. The resultant precipitated solid was collected by filtration. The solid was dried under vacuum pressure to give the titled compound as a white solid (9.20 mg, 28%). H-NMR (400 MHz, CDC13) δ ppm; 9.74 (br. s., 1H), 8.32 (d, J = 2.6 Hz, 1H), 7.61 (dd, J = 8.8, 2.6 Hz, 1H), 7.26 (br. s, 1H), 7.19 (d, J = 1.8 Hz, 1H), 7.04-7.09 (m, 1H), 6.51 (d, 7 = 8.8 Hz, 1H), 5.91 (s, 1H), 4.54 (d, J = 5.9 Hz, 2H), 3.92-3.99 (m, 2H), 3.82-3.89 (m, 2H), 3.63-3.69 (m, 2H), 3.27-3.38 (m, 2H), 2.95-3.13 (m, 3H), 2.68-2.76 (m, 2H), 2.55-2.62 (m, 2H), 2.41 (s, 3H), 2.39 (s, 3H), 2.32 (s, 3H), 2.20 (s, 3H), 1.99-2.09 (m, 2H), 1.62-1.77 (m, 4H),0.88 (t, J = 7.0 Hz, 3H). ; MS (ESI) [M+H]+ 587.7 ; HPLC 95.0% purity.
l l
Figure imgf000189_0002
[0150] To a stirred solution of (4-bromophenyl)methanol (2.00 g, 10.6 mmol) in C¾C12 (40 mL) was added methanesulfonyl chloride (1.46 g, 12.8 mmol) and Hunig's base (5.54 mL, 31.8 mmol). The reaction mixture was stirred at RT for 1 hour. Then piperidin-4-ol (5.36 g, 53.0 mmol) was added to the reaction mixture, and the resultant mixture was stirred at RT for 16 hours. The mixture was quenched with water, and concentrated in vacuo. The residue was dissolved in ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (100 mL, twice), and the combined organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH-Si02; heptane/ethyl acetate=l/3) to give the titled compound as a brown oil (1.97 g, 69% yield). Ή-NMR (400 MHz, CD ¾) δ ppm; 8.61 (d, J = 2.3 Hz, 1H), 7.78 (dd, J = 8.2, 2.3 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 3.73 (m, 1H), 3.60 (s, 2H), 2.72-2.82 (m, 2H), 2.19-2.29 (m, 2H), 1.90 (m, 2H), 1.55-1.68 (m, 2H); MS (ESI) [M+H]+ 271.1, 273.1.
Methyl 3-lethyl(oxan-4-yl)amino]-5-{6-[(4-hydroxypiperidin-l-yl)methyl]pyridin-3-yl}-2- methylbenzoate
Figure imgf000190_0001
[0151] To a stirred solution of methyl 3-[ethyl(oxan-4-yl)amino]-2-methyl-5-(tetramethyl-l,3,2- dioxaborolan-2-yl)benzoate (480 mg, 1.19 mmol) and l-[(5-bromopyridin-2-yl)methyI]piperidin-4-ol (484 mg, 1.79 mmol) in 1,4-dioxane (10 mL) and ¾0 (2.5 mL) was added Pd(PPh3)4 (138 mg, 0.119 mmol) and sodium carbonate (378 mg, 3.57 mmol). The reaction mixture was stirred at 80 °C for 4 hours. Then, the reaction mixture was filtered through Celite pad. The filtrate was concentrated in vacuo, the resultant residue was purified by silica gel column chromatography ( H-Si02;
ethylacetate only) to give the titled compound as a colorless oil (520 mg, 93%). ]H-NMR (400 MHz, CDC¾) 5 ppm; 8.76 (d, J = 2.3 Hz, 1H), 7.84 (dd, J = 8.4, 2.3 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.49 (brs, 1H), 7.47 (brs, 1H), 3.98 (m, 2H), 3.94 (s, 3H), 3.74 (m, 1H), 3.72 (s, 2H), 3.36 (m, 2H), 3.14 (q, J = 6.8 Hz, 2H), 2.99-3.09 (m, 1H), 2.73-2.87 (m, 2H), 2.56 (s, 3H), 2.20-2.34 (m, 2H), 1.94 (m, 2H), 1.64-1.80 (m, 6H), 0.93 (t, J = 6.8 Hz, 3H); MS (ESI) [M+H]+ 468.4.
3-[Ethyl(oxan-4-yl)amino]-5-{6-[(4-hydroxypiperidin-l-yl)methyl)pyridin-3-yl}-2-methyl-iV- {[ ide
Figure imgf000190_0002
[0152] To a stirred solution of methyl 3-[ethyl(oxan-4-yl)amino]-5-{6-[(4-hydroxypiperidin-l- yl)methyI]pyridin-3-yl}-2-methylbenzoate (520 mg, 1.1 1 mmol) in methanol (10 mL) was added NaOH (5 N, 1 mL). The reaction mixture was stirred at 60 C for 1 hour. After cooling to rt, the reaction mixture was concentrated in vacuo, and dried under vacuum pressure to give the crude 3- [ethyl(oxan-4-yl)amino]-5-{6-[(4-hydroxypiperid acid sodium salt.
To a stirred solution of the crude carboxylic acid sodium salt and 3-(aminomethyl)-6-methyl- 4-(2-propyl)-l,2-dihydropyridin-2-one HC1 salt (361 mg, 1.67 mmol) in DMSO (5 mL) was added PYBOP (145 mg, 2.78 mmol) and Hunig's base (580 uL, 3.33 mmol). The reaction mixture was stirred at RT for 20 hours. The reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (10 mL, twice), and the combined organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH-SiO? Ethyl acetate/MeOH=10/l) to give the titled compound as a white solid (250 mg, 37%). !H- MR (400 MHz, CD<¾) δ ppm; 8.68 (d, J = 2.0 Hz, 1H), 7.77 (dd, J = 7.8, 2.0 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H), 7.13 (t, J = 5.9 Hz, 1H), 6.04 (s, 1H), 4.62 (d, = 5.9 Hz, 2H), 3.96 (m, 2H), 3.73 (m, 1H), 3.68 (s, 2H), 3.55 (m, 1H), 3.27-3.43 (m, 2H), 3.11 (q, J = 7.0 Hz, 2H), 2.97- 3.06 (m, 1H), 2.77-2.87 (m, 2H), 2.35 (s, 3H), 2.24 (s, 3H), 2.21-2.31 (m, 2H), 1.85-1.99 (m, 2H), 1.64-1.75 (m, 6H), 1.23 (s, 3H), 1.22 (s, 3H), 0.90 (t, J = 7.0 Hz, 3H); MS (ESI) [M+H]+ 616.7 ; HPLC 97.4% purity.
l-[(4-Bromo-2-fluorophenyl)methyl]piperidin-4-ol
Figure imgf000191_0001
[0153] To a stirred solution of (4-bromo-2-fluorophenyl)methanol (2.00 g, 9.76 mmol) in CH2C¾ (40 mL) was added methanesulfonyl chloride (1.34 g, 11.7 mmol) and Hunig's base (5.09 mL, 29.3 mmol). The reaction mixture was stirred at RT for 3 hours. Then piperidin-4-ol (4.94 g, 48.8 mmol) was added to the reaction mixture, and the resultant mixture was stirred at RT for 16 hours. The mixture was quenched with water, and concentrated in vacuo. The residue was dissolved in ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (100 mL, twice), and the combined organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH-S1O2; heptane/ethyl acetate=l/2) to give the titled compound as a pale yellow solid (1.97 g, 70%). Ή-NMR (400 MHz, CDC¾) δ ppm; 7.24-7.31 (m, 2H), 7.19-7.23 (m, IH), 3.70 (m, IH), 3.53 (m, 2H), 2.70-2.79 (m, 2H), 2.15-2.25 (m, 2H), 1.89 (m, 2H), 1.52-1.64 (m, 2H); MS (ESI) [M+H]+ 288.1, 290.0.
Methyl 3-[ethyl(oxan-4-yl)amino]-5-{3-fluoro-4-[(4-hydroxypiperidiii-l-yl)methyl]phenyl}-2- methylbenzoate
Figure imgf000192_0001
[0154] To a stirred solution of methyl 3-[ethyl(oxan-4-yl)ammo]-2-methyl-5-(tetramethyl-l33,2- dioxaborolan-2-yl)benzoate (430 mg, 1.07 mmol) and l-[(4-bromo-2-fluorophenyl)methyl]piperidin- 4-ol (461 mg, 1.60 mmol) in 1,4-dioxane (8 mL) and ¾0 (2 mL) was added Pd(PPh3)4 (124 mg, 0.107 mmol) and sodium carbonate (340 mg, 3.21 mmol). The reaction mixture was stirred at 80 °C for 6 hours. Then, the reaction mixture was filtered through Celite pad. The filtrate was concentrated in vacuo, the resultant residue was purified by silica gel column chromatography (NH-Si02; ethyl acetate) to give the titled compound as a colorless oil (461 mg, 89%). Ή-NMR (400 MHz, CDC13) δ ppm; 7.42-7.48 (m, 2H), 7.28-7.37 (m, 2H), 7.19-7.24 (m, 1H), 3.98 (m, 2H), 3.93 (s, 3H), 3.71 (m, 1H), 3.63 (s, 2H), 3.29-3.40 (m, 2H), 3.13 (q, J = 7.0 Hz, 2H), 2.97-3.07 (m, 1H), 2.71-2.86 (m, 2H), 2.55 (s, 3H), 2.15-2.29 (m, 2H), 1.92 (m, 4H), 1.65-1.80 (m, 4H), 0.92 (t, J = 7.0 Hz, 3H); MS (ESI) [M+H]+ 485.4.
^-[(4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-3-[ethyI(oxan-4-yl)ammo]-5-{3-flnoro- 4-[(4-hydroxypiperidin-l-yl)methyl]phenyl}-2-methylbenzamide
Figure imgf000192_0002
[0155] To a stirred solution of methyl 3-[ethyl(oxan-4-yl)amino]-5-{3-fluoro-4-[(4- hydroxypiperidin-l-yl)methyl]phenyl}-2-methylbenzoate (461 mg, 1.11 mmol) in methanol (10 mL) was added aq. NaOH (5 N, 1 mL). The reaction mixture was stirred at 60 C for 1 hour. After cooling to rt, the reaction mixture was concentrated in vacuo, and dried under vacuum pressure to give the crude 3-[ethyl(oxan-4-yl)amino]-5-{3-fluoro-4-[(4-hydroxypiperidin-l-yl)methyl]phenyl}-2- methylbenzoic acid sodium salt.
To a stirred solution of the crude carboxylic acid sodium salt and 3-(aminomethyl)-4,6- dimethyl-l,2-dihydropyridin-2-one HC1 salt (269 mg, 1.43 mmol) in DMSO (4 mL) was added PYBOP (1.24 mg, 2.38 mmol) and Hunig's base (497 uL, 2.85 mmol). The reaction mixture was stirred at RT for 20 hours. The reaction mixture was quenched with water. The mixture was extracted with ethyl acetate (10 mL, twice), and the combined organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH-SiO? Ethyl acetate/MeOH=20/l) to give the titled compound as a white solid (208 mg, 36%). Ή-NMR (400 MHz, CDC13) δ ppm; 7.32- 7.37 (m, 1H), 7.19-7.31 (m, 4H), 7.14 (dd, J = 11.1, 1.8 Hz, 1H), 5.90 (s, 1H), 4.55 (d, J = 5.9 Hz, 2H), 3.94 (m, 2H), 3.60-3.69 (m, 1H), 3.55 (s, 2H), 3.31 (m, 2H), 3.09 (q, J = 7.0 Hz, 2H), 2.95-3.04 (m, 1H), 2.71-2.81 (m, 2H), 2.39 (s, 3H), 2.34 (s, 3H), 2.14-2.23 (m, 2H), 2.12 (s, 3H), 1.83 (m, 2H), 1.66-1.72 (m, 4H), 1.50-1.62 (m, 2H), 1.25 (t, J = 7.0 Hz, 3H); MS (ESI) [M+H]+ 605.6 ; HPLC 99.7% purity.
Azetidin-3-ol 2,2,2-trifluoroacetate
T F!M0H
[0156] To a stirred solution of tert-butyl 3-hydroxyazetidine-l-carboxylate (3.44 g, 19.9 mmol) in DCM (10 mL) at rt was carefully added TFA (10 mL, 130 mmol). After a total of 1.5 h reaction, the solvents were removed in vacuo to give crude title compound (6.65 g, 35.5 mmol, 179 % yield, contains residual TFA) as a light yellow oil. This was used for next step without further purification. Ή-NMR (400 MHz, DMSO-d6) δ ppm: 8.6 (bs, 2H), 4.52 (m, 1H), 4.06 (m, 2H), 3.73 (m, 2H).
Figure imgf000193_0001
[0157] To crude azetidin-3-ol 2,2,2-trifluoroacetate (6.65 g, 19.9 mmol, containing an estimated 2.93 g of residual TFA) with magnetic stirrer was added triethylamine (6.77 mL, 48.5 mmol) portion wise over 5 min (carefully, exothermic) to give a biphasic mixture. Then acetonitrile (5 mL) was added (one layer formed) followed by 2,5-dibromopyridine (500 mg, 2.11 mmol). The reaction mixture was heated at 80°C for 16 h. After cooling to room temperature, the reaction mixture was diluted with water (30 mL), extracted with EtO Ac-Heptane (1 : 1, 5 x 30 mL). The combined extracts were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. Purification by silica gel column chromatography (30% to 100% EtO Ac-Heptane) gave the titled compound (108 mg, 22% yield) as a colorless glassy film. Ή-NMR (400 MHz, C6D6) δ ppm: 8.25 (dd, J= 2.4, 0.6 Hz,
1H), 7.12 (dd, J= 8.8, 2.3 Hz, 1H), 5.54 (dd, J= 8.8, 0.6 Hz, 1H), 4.06 (m, 1H), 3.77 (m, 2H), 3.43- 3.67 (m, 2H); MS (ESI) [M+Hf 229.0.
Figure imgf000193_0002
[0158] To a solution of hydrochloride salt of l-methylazetidin-3-ol (442 mg, 3.57 mmol) in DMF (10 mL) was added NaH in mineral oil (60%, 286 mg, 7.15 mmol) at 0 °C and the resulting mixture was stirred for 0.5 h. Then dibromopyrazine (1.0 g, 4.20 mmol) was added portion wise. The reaction mixture was slowly warmed up to room temperature and stirred for 14 h. The reaction was quenched by addition of saturated aqueous solution of NK Cl and the mixture was extracted with EtOAc (3 X 40 mL). The combined org. phase was washed with brine, dried over Na2S04, filtered and concentrated under vacuum. The crude mixture was purified by flash chromatography (S1O2, 30% to 100% EtOAc : Heptane) to give the titled compound (230 mg, 26%). Ή-NMR (400 MHz): δ ppm 8.15 (d, /= 1.2 Hz, 1H), 8.03 (d, J= 1.2 Hz, 1H), 5.17 (ddd, J
3.79 (m, 2H), 3.16-3.12 (m, 2H), 2.42 (s, 3H).
Figure imgf000194_0001
[0159] The titled compound was prepared (450 mg, 27% yield) in the same manner as described for 2-bromo-5-((l-methylpiperidin-4-yl)oxy)pyrazine. Ή- MR (400 MHz): δ ppm 8.15 (d, J= 1.2 Hz, 1H), 7.99 (d, J= 1.6 Hz, 1H), 5.00 (dddd, J= 8.0, 8.0, 4.0, 4.0, 1H), 2.79-2.66 (m, 2H), 2.35-2.26 (m, 2H), 2.32 (s, 3H), 2.08-2.02 (m, 2H), 1.90-1.81 (m, 2H).
Figure imgf000194_0002
[0160] To a solution of (5-bromopyridin-2-yl)methanol (0.474 g, 2.52 mmol) in THF (30 mL, 366 mmol) and DMF (10 mL, 129 mmol) at 0 °C was added sodium hydride (60% in mineral oil, 0.202 g, 5.04 mmol) and the reaction mixture was stirred at room temperature for 1 h. After cooling the reaction mixture to 0 °C, methyl iodide (0.158 mL, 2.52 mmol) was added. The reaction was stirred at room temperature for 2 h, and LCMS showed there was no more starting material was left. The reaction mixture was cooled to 0 °C, quenched with MeOH and concentrated. The crude product was purified by silica gel chromatography using ethylacetate/heptane to give the titled compound (35.0 mg, 6.87 % yield). 'H- M (400 MHz): δ ppm 8.59 (d, J = 2.4 Hz, 1H), 7.79 (dd, J = 8.1, 2.4 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 4.50 (s, 2H), 3.44 (s, 3H); MS (ESI) [M+H]+ 202.0.
l-Methyl-4-((5-(4,4,5, -yl)methyl)piperazine
Figure imgf000194_0003
[0161] In a sealed tube was added l-((5-bromopyridin-2-yl)methyl)-4-methylpiperazine (500 mg, 1.85 mmol), bis(pinacolato)diboron (564 mg, 2.22 mmol), potassium acetate (272 mg, 2.78 mmol) and 1,4-dioxane (8 mL, 93.5 mmol). The mixture was degassed by bubbling through N2 for 15 min. Then tricyclohexylphosphme (67.5 mg, 0.241 mmol) and tris(dibenzylideneacetone)dipalladium(0) (85.0 mg, 0.093 mmol) was added and degassed again for 15 min. The dark mixture was then sealed under N2 and heated for 8 h at 80 °C. MS (must use Flowlnjection) showed desired mass of 318 (M+H) and no SM peak of 270/272. The reaction mixture was filtered through celite and washed with dioxane (10 mL) and then EtOAc (10 mL). The combined greenish dark yellow filtrate was concentrated and dried under vacuum overnight to give the product as a crude viscous yellow oil (1.33 g, 227% yield). HNMR is good for crude. The crade material was used directly without further purification. Ή-NMR (400 MHz) δ ppm: 8.91 (s, 1H), 8.04 (d, J= 7.6 Hz, 1H), 7.40 (d, J= 7.6 Hz, 1H), 3.71 (s, 2H), 2.61 (bs, 8H), 2.36 (s, 3H), 1.36 (s, 12H); MS (ESI) [M+Hf 318.3.
2-(Methoxymethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine
Figure imgf000195_0001
[0162] The titled compound was prepared (90.0 mg, 209% yield) in the same manner as described for l-methyl-4-((5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)niethyl)piperazine as a light yellow oil. The crude material was used directly without further purification. MS (ESI) [M+H] 250.3.
l-(5-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)azetidin-3-ol
Figure imgf000195_0002
[0163] The titled compound was prepared (270 mg, 213% yield) in the same manner as described for l-methyl-4-((5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)piperazine as a light yellow semi-crystalline solid. The crude material was used directly without further purification. MS (ESI) [M+H]+ 277.3.
teri-Butyl 4-((5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)piperazine-l-
Figure imgf000195_0003
[0164] The titled compound was prepared (1.18 mg, 232% yield) in the same manner as described for l-methyl-4-((5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)piperazine as crude oil. The crude material was used directly without fiirther purification. MS (ESI) [M+H]+ 404.4.
l-(5-(4,4,S,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperidin-4-ol
Figure imgf000196_0001
[0165] The titled compound was prepared (320 mg, 180% yield) in the same manner as described for l-methyl-4-((5-(4,4,5,5-tetramethyl-l,3,2-d1oxaborolan-2-yl)pyridm-2-yl)memyl)piperazme as a yellow-orange semi-crystalline solid. The crude material was used directly without further purification. MS (ESI) [M+H]+ 304.2.
2-(4- ethylpiperazin-l-yl)-S-(4,4,5,5-tetramethyl-l,3,2-dioxaborolaii-2-yl)pyrazine
Figure imgf000196_0002
[0167] The titled compound was prepared (420 mg, 237% yield) in the same manner as described for 1 -methyl-4-((5-(4,4,5,5-tetramethyl- 1 , 3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)piperazine as a red oil. The crude material was used directly without further purification. MS (ESI) [M+H]+ 305.3.
2-((l-MethyIazetidin-3-yl)oxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazine
Figure imgf000196_0003
[0168] The titled compound was prepared (360 mg, 216% yield) in the same manner as described for l-methyl-4-((5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl) methyl)piperazine as a light yellow semi-crystalline solid. The crude material was used directly without further purification. MS (ESI) [M+Hf 292.2.
2-((l-Methylpiperidin-4-yl)oxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolaii-2-yl)pyrazine
Figure imgf000196_0004
[0169] The titled compound was prepared (260 mg, 128% yield) in the same manner as described for l-methy]-4-((5-(4,4,5,5-tetramethyl-l,3)2-dioxaborolan-2-yl)pyridin-2-yl) methyl)piperazine as a light yellow semi-crystalline solid. The crude material was used directly without further purification. MS (ESI) [M+H]+ 320.2.
2-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyrazine
Figure imgf000196_0005
[0170] The titled compound was prepared (77.0 mg, 40% yield) in the same manner as described for l-methyl-4-((5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl) methyl)piperazine as a light dark oil. The crude material was used directly without further purification. MS (ESI) [M+H]+ 275.1.
2,6-irans-Dimethylpiperidiii-4-one
Figure imgf000197_0001
[0171] To a solution of l-benzyl-2,6-iraras-dimethylpiperidin-4-one (4.80 g, 22.1 mmol) in MeOH (100 mL) was added wet 10% Pd/C (1.0 g) under N2 atmosphere. The N2 gas was displaced by ¾ gas and the mixture was stirred for 18 h at rt under hydrogen. The ¾ gas was replaced with >½ gas. The mixture was filtered through Celite, washed with MeOH and concentrated in vacuo. The crude material was used directly without further purification.
iert-Butyl 2, l-carboxylate
Figure imgf000197_0002
[0172] To a stirred solution of 2,6-<ra«i-dimethylpiperidin-4-one ( 1.20 g, crude) and di-fert-butyl dicarbonate (10.3 g, 47.2 mmol) in DCM (15 mL) was added triethylamine (15.0 mL, 108 mmol). The reaction mixture was stirred at rt for 20 hours. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (Heptane/EtOAc = 3/1) to give the titled compound as white solid (1.40 g, 65% yield). Ή-NMR (400 MHz) δ ppm: 4.40 (m, 2H), 2.86 (dd, J = 6.8, 18.0 Hz, 2H), 2.39 (dd, J= 1.6, 17.6 Hz, 2H), 1.51 (s, 9H), 1.27 (d, J= 6.4 Hz, 6H).
fert-Butyl 4-((5-bromo-3-(methoxycarbonyl)-2-methylphenyl)amino)-2,6-ira«s- dimethylpiperidine-l-carboxylate
Figure imgf000197_0003
[0173] To a solution of methyl 3-amino-5-bromo-2-methylbenzoate (3.65 g, 15.0 mmol) and tert- butyl 2,6-ira«i-dimethyl-4-oxopiperidine-l-carboxylate (3.00 g, 13.2 mmol) in 1,2-dichloroethane (18 mL, 228 mmol) at rt was added acetic acid (6 mL, 105 mmol) and the mixture was stirred for 15 min. Then sodium triacetoxyborohydride (8.39 g, 40.0 mmol) was added and the mixture was stirred for overnight (17 h). TLC (20% E/H) showed Rf=0.35 for aniline, Rf=0.25 for ketone and Rf=0.45 for a new spot. And there is no SM ketone (limiting SM) left. The mixture was quenched by slow addition of sat. aHCOj until the mixture was a pH about 8. The separated aq. phase was extracted with 3xEtOAc. The combined org. phase was dried (Na2S04), filtered and concentrated to give a light yellow oil. The oil was purified by flash column chromatography (S1O2, 15% EtOAc:Heptane) to give the titled compound as a semi-pure white solid (2.65 g, 41% yield). The crude material was used directly without further purification. This material was used directly without further purification. MS (ESI) [M+H]+ 455.3, 457.3.
tert-Butyl 4-((5-bromo-3-(methoxycarbonyI)-2-methylphenyl)(ethyl)amino)-2,6-i 'e«s- dimethylpiperidine-l-carboxylate
Figure imgf000198_0001
[0174] To a solution of tert-butyl 4-((5-bromo-3-(methoxycarbonyl)-2-methylphenyl)amino)-2,6- trans-dunethylpiperidine-l-carboxylate (2.65 g, 5.81 mmol) and acetaldehyde (0.657 mL, 11.6 mmol) in 1 ,2-dichloroethane (15 mL, 190 mmol) at room temperature was added acetic acid (1.99 mL, 34.9 mmol) and the resulting mixture stirred for 10 min. Then sodium triacetoxybororhydride (3.70 g, 17.4 mmol) was added and stirred at room temperature for 3 h. The mixture was quenched by slow addition of saturated aqueous NaHC03 until the mixture was a pH 8. The aqueous phase was extracted with EtOAc. The combined organic phases were dried with Na2S04, filtered and concentrated in vacuo to a light yellow oil. The oil was purified by flash column chromatography (Si02, 10% EtOAc:Heptane) to give the titled compound as a colorless oil (1.81 g, 64% yield). Ή- NMR(400 MHz) 5 ppm: 7.73 (d, J= 2.1 Hz, 1H), 7.35 (d, J = 2.1 Hz, 1H), 4.27 (m, 1H), 3.90 (s, 3H), 3.66 (m, 1H), 3.35 (m, 1H), 2.92-3.10 (m, 2H), 2.45 (s, 3H), 1.75-1.95 (m, 3H), 1.48 (m, 1H), 1.46 (s, 9H), 1.35 (d, J= 6.7 Hz, 3H), 1.20 (d, J = 6.7 Hz, 3H), 0.85 (t, J= 7.0 Hz, 3H); MS (ESI) [M+H]+ 483.3, 485.4.
5-Bromo-3-((l-(tert-butoxycarbonyl)-2,6-<ra«s-dimethylpiperidin-4-yl)(ethyl)amino)-2- methylbenzoic acid
Figure imgf000198_0002
[0175] The titled compound was prepared (1.75 g, 100% yield) following the same procedure for the preparation of 3 ethyl(l-memylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzoic acid. Ή-NMR (400 MHz) δ ppm: 7.87 (d, , 7= 2.1 Hz, 1H), 7.37 (d, J= 2.1 Hz, 1H), 4.25 (m, 1H), 3.64 (m, 1H), 3.33 (m, 1H), 2.90-3.10 (m, 2H), 2.49 (s, 3H), 1.71-1.92 (m, 3H), 1.47 (m, 1H), 1.44 (s, 9H), 1.33 (d, 6.7 Hz, 3H), 1.17 (d, J= 6.7 Hz, 3H), 0.84 (t, J= 7.0 Hz, 3H); MS (ESI) [M+H]+ 469.3, 471.3.
iert-Butyl 4-((5-bromo-3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)earbamoyl)-2- methylphenyyiethyliamino -dimethylpiperidlne-l-carboxylate
Figure imgf000199_0001
[0176] The titled compound was prepared (2.10 g, 93% yield) following the same procedure for the preparation of V-[(4,6-Dimethyl-2-oxo-l,2-dihyd^opyridin-3-yl)methyl]-3-[ethyl(l-methylpiperidin- 4-yl)amino]-2-methyl-5-(trifluoromethyl)benzamide. Ή-NMR (400 MHz) δ ppm: 7.18 (s, 2H), 5.95 (s, 1 H), 4.50 (d, J= 5.9 Hz, 2H), 4.25 (m, 1H), 3.60 (m, 1H), 3.31 (m, 1 H), 2.98 (m, 2H), 2.37 (s, 3H), 2.23 (s, 6H), 1.82 (m, 2H), 1.74 (m, 1H), 1.44 (m, 1H), 1.43 (s, 9H), 1.31 (d, J= 6.7 Hz, 3H), 1.15 (d, J = 6.1 Hz, 3H), 0.81 (t, J= 6.7 Hz, 3H); MS (ESI) [M+H]+ 603.5, 605. 5.
iert-B tyl 4-((3-(((4,6-dlmethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(6- methoxypyridin-3-yl)-2-methylphenyl)(ethyl)amino)-2,6-<rani-dimethylpiperidine-l- carboxylate
Figure imgf000199_0002
[0177] A solution of tert-butyl 4-((5-bromo-3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)carbamoyl)-2-methylphenyl)(ethyl)amino)-2,6-ira«s-dimethylpiperidine-l-carboxylate (100 mg, 0.166 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (58.4 mg, 0.249 mmol) and sodium carbonate (61.5 mg, 0.58 mmol) in 1 ,4-dioxane (1 mL, 1 1.7 mmol) and water (0.2 mL, 1 1.1 mmol) was degassed by bubbling for 15 min. Then Pd(PhjP (19.1 mg, 0.017 mmol) was added and degassed again for 10 min. The mixture was then sealed and heated at 100 °C for 4.5 h. MS showed reaction was done. The mixture was diluted with 5 mL water, extracted with 3xEtOAc, dried (Na2S04), filtered and concentrated. The oil was purified by flash column chromatography (SK¾, 10% to 100% EtOAc:Heptane) to give the titled compound (88 mg, 84% yield). Ή-NMR (400 MHz) δ ppm: 8.31 (d, /= 2.4 Hz, 1H), 7.72 (dd, J= 2.4, 8.5 Hz, 1H), 7.27 (s, 1H), 7.24 (bs, 1H), 6.80 (d, J= 8.5 Hz, 1H), 5.94 (s, 1H), 4.56 (d, J= 5.8 Hz, 2H), 4.29 (bs, 1H), 3.98 (s, 3H), 3.65 (m, 1H), 3.44 (m, 1H), 3.07 (m, 2H), 2.43 (s, 3H), 2.36 (s, 3H), 2.21 (s, 3H), 1.75-1.98 (m, 3H), 1.55 (m, 1H), 1.46 (s, 9H), 1.35 (d, /= 6.4 Hz, 3H), 1.20 (d, J= 6.7 Hz, 3H), 0.89 (bs, 3H); MS (ESI) [M+H]+ 632.5.
teri-Butyl 4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methyl-5- (6-(morpholiDomethyl)pyridin-3-yl)phenyI)(ethyI)amino)-2,6-<r«ns-dimet yIpiperidine-l- carboxylate
Figure imgf000200_0001
[0178] The titled compound were obtained (116 mg, 100% yield) following a similar procedure for the preparation of ierf-butyl 4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)memyl)carbamoyl)-5-(6-methoxypyridin-3-yl)-2-methylphenyl)(emyl)amino)-2,6-ira«i- dimethylpiperidine-l-carboxylate. Ή-NMR (400 MHz, CD3OD) δ ppm: 8.71 (d, J= 2.0 Hz, 1H), 8.04 (dd, J= 2.0, 8.3 Hz, 1H), 7.61 (d, /= 7.8 Hz, 1H), 7.49 (d, = 1.5 Hz, 1H), 7.37 (d, J= 2.0 Hz, 1H), 4.50 (s, 2H), 4.21 (m, 1H), 3.71 (m, 6H), 3.59 (m, 1H), 3.13 (m, 2H), 2.53 (m, 2H), 2.40 (s, 3H), 2.35 (s, 3H), 2.25 (s, 3H), 1.89 (m, 2H), 1.58 (m, 1H), 1.45 (s, 9H), 1.35 (d, J= 6.9 Hz, 3H), 1.25 (d, J= 7.2 Hz, 3H), 0.89 (t, d, J= 6.9 Hz, 3H); MS (ESI) [M+H]+ 701.6.
teri-Butyl 4-((5-(3-((l-(teri-butoxycarbonyl)-2,6-ira«s-dimethylpiperidin-4-yl)(ethyl)amino)-S- (((4,6-dimethyI-2-oxo-l,2-dihydropyridin-3-yI)methyl)carbamoyl)-4-methylphenyl)pyridin-2-
Figure imgf000200_0002
[0179] The titled compound was prepared (133 mg, 100% yield) as semi-pure compound following a similar procedure for the preparation of fert-butyl 4-((3-(((4,6-dimethyl-2-oxo- 1 ,2-dihydropyridin- 3-yl)methyl)carbamoyl)-5-(6-methoxypyridin-3-yl)-2-methylphenyl)(ethyl)amino)-2,6-fra«i- dimethylpiperidine-l-carboxylate. MS (ESI) [M+H]+ 800.8. The product was carried on to next step without further purification.
tert-Butyl 4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methyl-5- (6-((4-methylpiperazin-l-yl)methyl)pyridiii-3-yl)phenyl)(ethyl)aniino)-2,6-ft-flns-
Figure imgf000201_0001
[0180] The titled compound was prepared (68.0 mg, 58% yield) as semi-pure compound following the similar procedure for the preparation of iert-butyl 4-((3-(((4,6-dimethyl-2-oxo-l,2- dihydropyridin-3-yl)methyl)carbamoyl)-5-(6-methoxypyridin-3-yl)-2-methyIphenyl)(ethyI)amino)- 2,6-ira«s-dimethylpiperidine-l-carboxylate. MS (ESI) [M+H]+ 714.7. The product was carried on to next step without further purification.
iert-Butyl 4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methyl-5- (<^4-methylpiperazin-l-yl)pyridin-3-yl)phenyl)(eth^
carboxylate
Figure imgf000201_0002
[0181] The titled compound were obtained (100 mg, 87% yield) following a similar procedure for the preparation of iert-butyl 4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)carbamoyl)-5-(6-methoxypyridin-3-yl)-2-methylphenyl)(ethyl)amino)-2,6-irans- dimethylpiperidine-l-carboxylate. Ή-NM (500 MHz) δ ppm; 12.20 (br, s, 1H), 8.35 (d, J= 2.4Hz, 1H), 7.62 (dd, /= 2.4, 8.8 Hz, 1H), 7.23 (d, J= 2.0Hz, 1H), 7.21 (d, J= 1.5Hz, 1H), 7.17 (t, J = 5.9Hz, 1H), 6.85 (d, /= 8.8Hz, 1H), 5.92 (s, 1H), 4.56 (d, J= 5.9Hz, 2H), 4.26 (m, 1H), 3.64 (m, 1H), 3.58 (t, J= 4.9Hz, 4H), 3.43 (m, 1H), 2.97-3.11 (m, 2H), 2.54 (t, J= 4.9Hz, 4H), 2.40 (s, 3H), 2.16 (s, 3H), 2.13 (s, 3H), 2.14 (s, 3H), 1.75-1.93 (m, 3H), 1.50 (m, 1H), 1.45 (s, 9H), 1.33 (d, /= 6.8Hz, 3H), 1.18 (d, 7 = 6.8Hz, 3H), 0.85 (t, J= 7.3Hz, 3H); MS (ESI) [M+Hf 700.7.
iV-((4,6-DimethyI-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-((2,6-ira«s-dimethylpiperidiu-4- yl)(ethyl)amino)-5-(6-methoxypyridin-3-yl)-2-methylbenzamide
Figure imgf000202_0001
[0182] A solution of 4 M HCl (3 mL, 12.0 mmol) in dioxane was added to a solution of iert-butyl 4- ((3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridm-3-yl)methyl)carbamoyl)-5-(6-memoxypyri methylphenyl)(ethyl)amino)-2,6-ira«s-dimethylpiperidine-l-carboxylate (88.0 mg, 0.139 mmol) in DCM (2 mL) at rt and an immediate white precipitate was observed. MS after 1 h showed reaction was done. TLC (50% E/H) showed no SM at Rf=0.3 and there is only a baseline. The mixture was concentrated and purified by reverse phase HPLC to give the titled compound (39.6 mg, 54% yield). Ή-NMR (400 MHz, CD3OD) 5 ppm; 8.30 (d, J = 2.6 Hz, 1H), 7.88 (dd, /= 2.3, 8.8 Hz, 1H), 7.39 (s, 1H), 7.26 (d, J= 1.5 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.08 (s, 1H), 4.45 (s, 2H), 3.90 (s, 3H), 3.55 (m, 1H), 3.26 (m, 1H), 3.17 (m, 3H), 2.36 (s, 3H), 2.28 (S, 3H), 2.21 (s, 3H), 1.93 (bd, J= 12.3 Hz, 1H), 1.80 (m, 2H), 1.25 (m, 1H), 1.24 (d, J= 7.0 Hz, 3H), 1.13 (d, J= 6.1 Hz, 3H), 0.87 (t, J= 7.0 Hz, 3H); MS (ESI) [M+H]+ 532.4.
AL((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)^-((2,6-frans-dimethylpiperidin-4- yl)(ethyl)amino)-2-methyl-5-(6-(morphoIinomethyI)pvridin-3-yI)benzamide
Figure imgf000202_0002
[0183] The titled compound was obtained (30.0 mg, 30% yield) following a similar procedure for the preparation of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-((2,6-irani- chmemylpiperidm-4-yl)(ethyl)amino)-5-(6-methoxypyridin-3-yl)-2-methylbenzamide. Ή-NMR (400 MHz, CD3OD) δ ppm; 8.67 (d, J= 2.4 Hz, 1H), 8.01 (dd, J= 2.4, 8.0 Hz, 1H), 7.57 (d, J= 8.2 Hz, 1H), 7.46 (s, 1H), 7.33 (s, 1H), 6.08 (s, 1H), 4.46 (s, 2H), 3.67 (m, 6H), 3.55 (m, 1H), 3.31 (m, 1H), 3.14 (m, 3H), 2.49 (m, 4H), 2.36 (s, 3H), 2.30 (S, 3H), 2.21 (s, 3H), 1.90 (m Hz, 1H), 1.78 (m, 2H), 1.25 (m, 1H), 1.24 (d, J= 7.0 Hz, 3H), 1.13 (d, J= 6.1 Hz, 3H), 0.87 (t, J= 7.0 Hz, 3H); MS (ESI) [M+H]+ 601.6.
iV-((4,6-Dimethyl-2-oxo-l,2-dihydropvridin-3-yI)methyl)-3-((2,6-<TOni-dimethylpiperidin-4- yl)(ethyl)amino)-2-methyl-5-(6-(piperazin-l-ylmethyl)pyridin-3-yl)benzamide
Figure imgf000203_0001
[0184] The titled compound was obtained (27.0 mg, 27% yield) following a similar procedure for the preparation of N-((4,6-dimethyl-2-oxo-l !2-dihydropyridin-3-yl)methyl)-3-((2,6-irani- dimemylpiperidin-4-yl)(emyl)ammo)-5-(6-methoxypyridin-3-yl)-2-methylbenzamide. Ή-NMR (400 MHz, CDjOD) δ ppm; 8.67 (d, J= 2.3 Hz, IH), 8.01 (dd, J= 2.3, 8.2 Hz, IH), 7.58 (d, J= 8.2 Hz, IH), 7.45 (d, J= 1.8 Hz, IH), 7.32 (d, J= 1.8 Hz, IH), 6.08 (s, IH), 4.46 (s, 2H), 3.66 (s, 2H), 3.47 (m, IH), 3.25 (m, 2H), 3.13 (m, 2H), 3.05 (m, IH), 2.84 (m, 4H), 2.49 (m, 4H), 2.36 (s, 3H), 2.30 (S, 3H), 2.21 (s, 3H), 1.95 (m Hz, IH), 1.75 (m, 2H), 1.25 (m, IH), 1.20 (d, = 7.0 Hz, 3H), 1.09 (d, /= 6.1 Hz, 3H), 0.87 (X, J= 6.7 Hz, 3H); MS (ESI) [M+H]+ 600.6.
A-((4,6-Diraethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-((2,6-fra«s-(limethylpiperidm^ yl)(ethyl)a beiizamide
Figure imgf000203_0002
[0185] The titled compound was obtained (35.0 mg, 59% yield) following the similar procedure for the preparation of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-((2,6-frani- dimethylpiperidin-4-yl)(emyl)amino)-5-(6-methoxypyridin-3-yl)-2-memylbenzarmde. Ή-NMR (400 MHz, CDjOD) δ ppm; 8.66 (d, J = 1.5 Hz, IH), 8.00 (dd, J= 2.1, 8.2 Hz, IH), 7.55 (d, J = 8.2 Hz, IH), 7.44 (bs, IH), 7.31 (bs, IH), 6.08 (s, IH), 4.46 (s, 2H), 3.68 (s, 2H), 3.45 (m, IH), 3.30 (m, 2H), 3.14 (m, 2H), 2.98 (m, IH), 2.50 (m, 7H), 2.36 (s, 3H), 2.29 (S, 3H), 2.25 (s, 3H), 2.21 (s, 3H), 1.85 (m, IH), 1.75 (m, 2H), 1.25 (m, IH), 1.19 (d, J= 7.0 Hz, 3H), 1.05 (d, J= 6.1 Hz, 3H), 0.86 (t, J = 6.7 Hz, 3H); MS (ESI) [M+H]+ 614.6.
jV-((4,6-Dimethyl-2-oxo-l,2-dihydropyri<Un-3-yl)me ^
yl)(ethyl)amino)-2-methyl-5-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzaraide
Figure imgf000204_0001
[0186] The titled compound was obtained (106 mg, 54% yield) following the similar procedure for the preparation of N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-((2,6-ira«s- dimemylpiperidin-4-yl)(ethyl)amino)-5-(6-methoxypyridin-3-yl)-2-methylbenzamide. Ή-NMR (500 MHz, CD3OD) δ ppm; 8.34 (d, J= 2.5Hz, 1H), 7.81 (J= 2.5, 9.3 Hz, 1H), 7.40 (d, 7= 1.5 Hz, 1H), 7.26 (d, J = 1.5 Hz, 1H), 6.90 (d, J= 9.3 Hz, 1H), 6.12 (s, 1H), 4.50 (s, 2H), 3.60 (m, 4H), 3.49 (m, 1H), 3.26 (m, 1H), 3.15 (m, 2H), 3.06 (m, 1H), 2.57 (m, 4H), 2.40 (s, 3H), 2.36 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H), 1.90 (m, 1H), 1.78 (m, 2H), 1.28 (m, 1H), 1.23 (d, J= 6.9 Hz, 3H), 1.12 (d, J= 6.4 Hz, 3H), 0.90 (t, J= 6.9 Hz, 3H); MS (ESI) [M+H]+ 600.5.
3-((4-fr««s-Aminocyclohexyl)(ethyl)amino)-5-bromo-A'-((4,6-dimethyl-2-oxo-l,2- dih de
Figure imgf000204_0002
[0187] The titled compound was prepared following a similar procedures described for 3-((2,6- trans-dimemylpiperidin-4-yl)(ethyl)amino)-5-fluoro-N-((5-fluoro-l,4,6-trimethyl-2- dihydropyridin-3-yl)methyl)-2-methylbenzamide hydrochloride followed by silica gel chromatography purification (10% 7N NH3/MeOH in DCM) (440 mg, 100%). Ή-NMR (500 MHz, CD3OD) δ ppm 7.30 (d, J= 2.0 Hz, 1H), 7.17 (d, J= 2.0 Hz, 1H), 6.10 (s, 1H), 4.46 (s, 2H), 3.07 (q, J= 7.0 Hz, 2H), 2.75-2.68 (m, 1H), 2.60-2.53 (m, 1H), 2.37 (s, 3H), 2.25 (s, 3H), 2.22 (s, 3H), 1.90- 1.84 (m, 2H), 1.84-1.78 (m, 2H), 1.50-1.41 (m, 2H), 1.14-1.05 (m, 2H), 0.85 (t, J= 7.0 Hz, 3H); MS (ESI) [M+H]+ 489.3.
5-Bromo-7V-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-((4-i>'ans-
(dimethylamino)cycIohexyl)(ethyl)amino)-2-methylbenzamide
Figure imgf000205_0001
[0188] The titled compound was prepared following a similar procedures described for the preparation of methyl 3 -[ethyl( 1 -methylpiperidin-4-yl)ammo]-2-methyl-5-(trifluoromethyl)benzoate followed by silica gel chromatography purification (10% 7N NH3 MeOH in DCM) (335 mg, 72%). 1 H-NMR (500 MHz, CD3OD) δ ppm 7.31 (d, 2.0 Hz, IH), 7.17 (D, 2.0 Hz, IH), 6.11 (s, IH), 4.46 (s, 2H), 3.08 (q, 7.0 Hz, 2H), 2.75-2.67 (m, IH), 2.38 (s, 3H), 2.28 (s, 6H), 2.25 (s, 3H), 2.29-2.23 (m, IH), 2.21 (s, 3H), 1.98-1.85 (m, 4H), 1.49-1.39 (m, 2H), 1.28-1.19 (m, 2H), 0.86 (t, = 7.0 Hz, 3H); MS (ESI) [M+H]+ 519.4.
5-Bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-iV-((4-isopropyl-6-methyl-2-oxo-l,2- dihydropyridin-3-yl)methyl)-2-methylbenzamide
Figure imgf000205_0002
[0189] The titled compound was prepared (361 mg, 31% yield) following the same procedures for the preparation of 5-bromo-N-((4, 6-dimethyl-2-oxo- 1 , 2-dihydropyridin-3-yl) methyl)-3-(ethyl (tetrahydro-2H-pyran-4-yl) ammo)-2-methylbenzamide. 1 H-NMR (400 MHz) δ ppm; 13.8 (br, s, IH), 7.20 (s, IH), 7.08 (t, 5.4Hz, IH), 5.09 (s, IH), 4.60 (d, = 5.9 Hz, 2H), 3.96 (br, d, /= 11.2 Hz, 2H), 3.52 (m. IH), 3.32 (m, 2H), 3.06 (m, 2H), 2.96 (m, IH), 2.30 (s, 3H), 2.27 (s, 3H), 1.64- 1.72 (m, 4H), 1.22 (d, 6.4 Hz, 6H), 0.88 (t, 7.3 Hz, 3H) ); MS (ESI) [M+H]+ 504.4.
iV-((4,6-Dimethyl-2-oxo-l,2-dihydropyridiii-3-yl)methyl)-3-((4-trans- (dimethyIamino)cyclohexyl)(ethyl)amino)-2-methyl-S-(6-(morpholiriomethyl)pyridiri-3-
Figure imgf000205_0003
[0190] The titled compound was obtained (64.0 mg, 67% yield) as a light yellow solid following a similar procedure for the preparation of tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)carbamoyl)-5-(6-methoxypyridin-3-yl)-2-methylpheny])(ethyl)amino)-2,6-//-e«i- dimethylpiperidine-l-carboxylate followed by reverse phase HPLC/MS purification. Ή-NMR (500 MHz, CDjOD) δ ppm 8.68 (d, = 2.0 Hz, 1H), 8.03 (dd, J= 8.0 Hz, J= 2.0 Hz, 1H), 7.60 (d, J= 8.0 Hz, 1H), 7.46 (d, J= 2.0 Hz, 1H), 7.34 (d, J= 2.0 Hz, 1H), 6.10 (s, 1H), 4.50 (s, 2H), 3.71 (m, 4H), 3.68 (s, 2H), 3.17 (q, J= 7.0 Hz, 2H), 2.82-2.75 (m, 1H), 2.54-2.50 (m, 4H), 2.39 (s, 3H), 2.34 (s, 3H), 2.24 (s, 9H), 2.23-2.16 (m, 1H), 1.98-1.90 (m, 4H), 1.51-1.41 (m, 2H), 1.27-1.17 (m, 2H), 0.90 (t, 7= 7.0 HZ, 3H); MS (ESI) [M+H]+ 615.6.
V-((4,6-DimethyI-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-((4-i-««s- (dimethyIamino)cycloliexyI)(ethyl)amino)-S-(6-(metIioxymethyI)pyridm-3-yl)-2- methylbenzamide
Figure imgf000206_0001
[0191] The titled compound was obtained (64.0 mg, 67% yield) as a light yellow solid following a similar procedure for the preparation of tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)carbamoyl)-5-(6-methoxypyridm-3-yl)-2-methylphenyl)(ethyl)amino)-2,6-<rani- dimethylpiperidine-l-carboxylate followed by reverse phase HPLC/MS purification. 1 H-NMR (500 MHz, CD3OD) δ ppm; 8.66 (d, J= 2.2 Hz, 1H), 8.03 (dd, J = 2.2 and 8.0 Hz, 1H), 7.54 (d, J= 8.0 Hz, 1H), 7.43 (d, J= 2.0 Hz, 1H), 7.30 (d, J= 2.0 Hz, 1H), 6.08 (s, 1H), 4.55 (s, 2H), 4.45 (s, 2H), 3.44 (s, 3H), 3.14 (q, J= 7.0 Hz, 2H), 2.75 (m, 1H), 2.36 (s, 3H), 2.29 (s, 9H), 2.21 (s, 3H), 2.19- 2.25 (m, 1H), 1.93 (m, 4H), 1.45 (m, 2H), 1.23 (m, 2H), 0.86 (t, = 7.0 HZ, 3H); MS (ESI) [M+H]+ 560.5.
iV-((4,6-Dimethyl-2-oxo-l,2-dihydropyridm-3-yl)methyl)-3-((4-/rans- (dimethylamino)cyclohexyI)(ethyI)ammo)-5-(6-(3-hydroxyazetidin-l-yl)pyridin-3-yI)-2- methylbenzamide
Figure imgf000207_0001
[01 2] The titled compound was obtained (31.0 mg, 27% yield) as a light yellow solid following a similar procedure for the preparation of tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-l ,2-dihydropyridin-3- yl)methyl)carbamoyl)-5-(6-methoxypyridin-3-yl)-2-methylphenyl)(ethyl)amino)-2,6-irans- dimethylpiperidine-1 -carboxylate followed by reverse phase HPLC/MS purification. 1 H-NMR (400 MHz, CD3OD) 5 ppm: 8.20 (d, J= 2.4 Hz, 1H), 7.77 (dd, J= 8.5, 2.4 Hz, 1H), 7.33 (d, J= 1.8 Hz, 1H), 7.20 (d, J= 1.8 Hz, 1H), 6.48 (d, J= 8.5 Hz, 1H), 6.10 (s, 1H), 4.70 (m, 1H), 4.48 (s, 2H), 4.28 (dd, J= 9.4, 6.4 Hz, 2H), 3.82 (dd, J= 9.4, 4.5 Hz, 2H), 3.14 (q, J= 7.0 Hz, 2H), 2.75 (m, 1H). 2.38 (s, 3H), 2.29 (s, 3H), 2.24 (s, 6H), 2.23 (s, 3H), 2.17-2.26 (m, 1H), 1.93 (m, 4H), 1.44 (m, 2H), 1.21 (m, 2H), 0.88 (t, J= 7.0 Hz, 3H); MS (ESI) [M+H]+ 587.6.
V-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-((4-trans- (dimethylamino)cyclohexyl)(ethyl)amino)-5-(6-(4-hydroxypiperidin-l-yl)pyridin-3-yl)-2- methylbenzamide
Figure imgf000207_0002
[0193] The titled compound was obtained (51.0 mg, 54% yield) as a white solid following a similar procedure for the preparation of tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)carbamoyl)-5-(6-methoxypyridin-3-yl)-2-methylphenyl)(ethyl)amino)-2,6-ira«i- dimethylpiperidine-1 -carboxylate followed by reverse phase HPLC/MS purification. 1 H-NMR (400 MHz, CD3OD) δ ppm: 8.28 (d, J = 2.6 Hz, 1H), 7.75 (dd, J= 9.0, 2.6 Hz, 1H), 7.34 (d, J= 1.8 Hz, 1H), 7.22 (d, J= 1.8 Hz, 1H), 6.87 (d, J= 8.8 Hz, 1H), 6.08 (s, 1H), 4.47 (s, 2H), 4.07 (dt, J= 13.5, 4.1 Hz, 2H), 3.82 (m, 1H), 3.13 (m, 4H), 2.75 (m, 1H), 2.38 (s, 3H), 2.29 (s, 3H), 2.23 (s, 9H), 2.16- 2.25 (m, 1H), 1.91 (m, 6H), 1.39-1.56 (m, 4H), 1.21 (m, 2H), 0.88 (t, J= 6.9 Hz, 3H); MS (ESI) [M+H]+ 615.6. Ar-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-((4-ira«s- (dimethylamino)cyclohexyl)(ethyI)amino)-2-methyl-5-(S-(4-methylpiperaziii-l-yl)pyraziii-2- yl)benzamide
Figure imgf000208_0001
[0194] The titled compound was obtained (18.0 mg, 19% yield) as a light yellow glassy film material following a similar procedure for the preparation of tert-butyl 4-((3-(((4,6-dimethyl-2-oxo- l,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(6-methoxypyridin-3-yl)-2- memylphenyl)(etiiyl)amiino)-2,6-ira«s-dimethylpiperidine-l-carboxylate followed by reverse phase HPLC/MS purification. Ή-NMR (400 MHz, CD3OD) δ ppm: 8.54 (s, 1H), 8.24 (s, 1H), 7.77 (d, J = 1.5 Hz 1H), 7.56 (d, J= 1.2 Hz, 1H), 6.11 (s, 1H), 4.49 (s, 2H), 3.68 (m, 4H), 3.15 (q, J= 6.9 Hz, 2H), 2.75 (m, 1H), 2.57 (m, 4H), 2.39 (s, 3H), 2.35 (s, 3H), 2.31 (s, 3H), 2.25 (s, 6H), 2.24 (s, 3H), 2.19-2.25 (m, 1H), 1.94 (m, 4H), 1.45 (m, 2H), 1.22 (m, 2H), 0.88 (t, J= 6.9 Hz, 3H); MS (ESI) [M+H 615. 7.
A'-((4,6-Diraethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-((4-irans- (dimethylamino)cyclohexyI)(ethyl)amino)-5-(6-formylpyridin-3-yl)-2-methylbenzaniide
Figure imgf000208_0002
[0195] A microwave vial was charged with 5-bromo-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)-3-((4-irewi-(dimemylarnino)cyclohexyl)(ethyl)amino)-2-methylbenzamide (286 mg, 0.553 mmol), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)picolinaldehyde (193 mg, 0.829 mmol), sodium carbonate (205 mg, 1.934 mmol), 1,4-dioxane (3340 ΐ , 39.0 mmol) and water (667 μΐ,, 37.0 mmol). The suspension was bubbled with N2 for 5 min and Ρΰ(Ρ1¾Ρ)4 (63.9 mg, 0.055 mmol) was added. The reaction mixture was bubbled with N2 for additional 5 minutes, sealed and heated to 100 °C for 45 min under microwave condition. After cooling to room temperature the mixture was diluted with water (15 mL) and extracted with 10% MeOH/DCM (3 x 50 mL). The combined organic layers were dried ( a2S04) and concentrated. The residue was purified by silica gel column chromatography ( 12 g column, 7N NH3 in MeOH DCM = 5-20%) to give the titled compound as a semi-pure yellow solid (260 mg, 87 % yield). MS (ESI) [M+H]+ 544.4. This semi-pure product was used without further purification for next step.
At((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-((4-(?-ens- (dimethylamino)cyclohexyl)(ethyl)amino)-2-methyl-5-(6-((4-methyl-l,4-diazepan-l-
Figure imgf000209_0001
[0196] The titled compound was prepared (19.0 mg, 32 % yield) following the same procedure described for N-((4,6-dimethyl-2-oxo-l ,2-dihydropyridin-3-yl)methyl)-3-(ethyl(l -ethyl-2,6-trans- dimethylpiperidin-4-yl)amino)-5-fluoro-2-methylbenzamide. Ή-NMR (400 MHz, CD3OD) δ ppm 8.64 (dd, J= 2.42, 0.86 Hz, 1 H), 8.00 (dd, /= 8.14, 2.35 Hz, 1 H), 7.60 (d, J= 8.1 Hz, 1 H), 7.42 (d, J= 2.02 Hz, 1 H), 7.29 (d, J= 1.8 Hz, 1H), 6.08 (s, lH), 4.46 (s, 2H), 3.80 (s, 2H), 3.14 (m, 2H), 2.78 (m, 7H), 2.72 (m, 2H), 2.38 (s, 3H), 2.36 (s, 3H), 2.36-2.29 (m, 2H), 2.29 (s, 9H), 2.21 (s, 3 H), 1.93 (m, 4H), 1.86 (m, 2H), 1.45 (m, 1H), 1.22 (m, 2H), 0.86 (t, J= 7.7 Hz, 3H); MS (ESI) [M+H]+ 642.6.
^-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-((4-/ra«s- (dimethylamino)cyclohexyl)(ethyl)amino)-5-(6-(((S)-3-hydroxypiperidin-l-yl)methyl)pyridin-3- l)-2-mefhylbenzamide
Figure imgf000209_0002
[0197] The titled compound was prepared (10.0 mg, 20 % yield) as a white solid following the same procedure described for N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(ethyl(l-ethyl- 2,6- fra«i-dimethylpiperidin-4-yl)amino)-5-fluoro-2-methylbenzamide. Ή-NMR (400 MHz, CD3OD) 5 ppm; 8.65 (d, = 2.2 Hz, 1H), 8.00 (dd , J= 1.3 Hz, 2.4 Hz, 1H), 7.56 (d , 7= 8.1 Hz, 1H), 7.42 (d, J= 1.66 Hz, 1H), 7.30 (d, J = 1.65 Hz, 1H), 6.08 (s, 1H), 4.46 (s, 2H), 3.67 (m, 3H), 3.14 ( m, 2H), 2.78 (m, 2H), 2.36 (s, 3H), 2.32 (s, 6H), 2.29 (s, 3H), 2.25-2.40 (m, 1H), 2.21 (s, 3H), 2.14 (m,lH), 1.93 (d, J= 9.8 Hz, 4H), 1.75 (m, 1H), 1.44 (m, 4H), 1.21 (m, 5H), 0.86 (t, J= 7.7 Hz, 3H); MS (ESI) [M+H]+ 629.6. AL((4,6-DimethyI-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-((4-/r«n^ amino)cyclohexyl)(ethyl)amino)-5-(6-(((S)-3-hydroxypyrrolidiii-l-yl)niethyl)pyridin- 3-yl)-2-methyIbenzamide
Figure imgf000210_0001
[01 8] The titled compound was prepared (7.00 mg, 15 % yield) as a white solid following the same procedure described for N-((4,6-dime&yl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(ethyl(l-ethyl- 2,6- trans-dimethylpiperidin-4-yl)amino)-5-fluoro-2-methylbenzamide. 'H-NMR (400 MHz, CD3OD) δ ppm; 8.65 (d, J= 2.4 Hz, 1H), 8.00 (dd, , J= 1.4, 2.4 Hz, 1H), 7.56 (d, J= 7.5 Hz, 1H), 7.42 (d, J= 1.9 Hz, 1H), 7.29 (d, J = 1.8 Hz, 1H), 6.08 (s, 1H), 4.45 ( s, 2H), 4.32 (m, 1H), 3.78 (q, J= 13.9, 8.25 Hz, 2H), 3.14 (q, .7=7.0 Hz, 2H), 2.80 (m, 3H), 2.54 (m, 2H), 2.36 (s, 3H), 2.29 (s, 3H), 2.22 (s, 6H), 2.21 (s, 3H), 2.14 (m, 1H), 1.91 (m, 4H), 1.76 (m, 1H), 1.44 (m, 2H), 1.21 ( m, 4H), 0.86 (t, J= 7.1 Hz, 3H); MS (ESI) [M+H]+ 615.6.
iV-((4-isopropyl-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)metliyl)-3-((4-trans- (dimethylamino)cyelohexyl)(ethyl)amino)-5-(6-(((S)-3-hydroxypyrrolidin-l-yl)methyl)pyridin-
3-yl)-2-methylbenzamide
Figure imgf000210_0002
[0199] The titled compound was prepared following a procedure similar to that described for Compound 148 above.
iV-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-((4-<-a«s- (dimethylamino)cyclohexyl)(ethyI)ammo)-5-(6-((3-hydroxyazetidin-l-yl)methyl)pyridiii-3-yl)-2- methylbenzamide
Figure imgf000211_0001
[0200] The titled compound was prepared (7.00 mg, 12 % yield) as a white solid following the same procedure described for N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(ethyl(l-ethyl- 2,6- trans-dimethylpiperidin-4-yl)amino)-5-fluoro-2-methylbenzamide. Ή-NMR (400 MHz, CD3OD) δ ppm 8.66 (d, 7= 2 Hz, IH) 7.99 (dd, 7= 2.6, 2.4 Hz, IH) 7.44 (d, 7 = 7.9 Hz, IH), 7.42 (d, J = 1.8 Hz, IH), 7.29 (d, 7= 1.8 Hz, 1 H), 6.08 (s, IH), 4.46 (s, 2H), 4.35 (m, 1 H), 3.79 (bs, 2H), 3.67 (m, 2H), 3.14 (m, 2H), 3.05 (m, 2H), 2.75 (m, IH), 2.36 (s, 3H), 2.29 (s, 3H), 2.27 (s, 6H), 2.21 (s, 3H), 1.92 (m, 4H), 1.44 (m, 2H), 1.23 (m, 3H), 0.86 (t, 7 = 7.0 Hz, 3H); MS (ESI) [M+H]+ 601.6. iV-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-
Figure imgf000211_0002
[0201] The titled compound was obtained (1 1.2 mg, 21% yield) following a similar procedure for the preparation of ferf-butyl 4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)memyl)carbamoyl)-5-(6-memoxyp)ridin-3-yl)-2-methylphenyl)(ethyl)amino)-2,6-irani- dimethylpiperidine-l-carboxylate followed by reverse phase HPLC/MS purification. Ή-NMR (400 MHz, CD3OD) δ ppm: 8.57 (7=1.2 Hz, IH), 8.21 (J =1.2 Hz, IH), 7.83 (d, =1.8 Hz IH), 7.61 (d, 7 =1.8 Hz, IH), 6.21 (7=0.9 Hz, IH), 4.52 (s, 2H), 3.97 (s, 3H), 3.88 (bd, 7=1 1.6 Hz, 2H), 3.44 (m, IH), 3.32 (m, 2H), 3.13 (q, 7=7.0 Hz, 2H), 3.07 (m, IH), 2.31 (s, 3H), 2.24 (s, 3H), 1.72 (m, 2H), 1.62 (m, 2H), 1.21 9d, 7=6.7 Hz, 6H), 0.86 (t, 7=7.0 Hz, 3H); MS (ESI) [M+H]+ 534.4.
iV-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(ethyI(tetrahydro-2H-pyran-4- yl)amino)-2-metliyl-5-(5-(trifluoromethyl)pyrazin-2-yl)benzamide
Figure imgf000212_0001
[0202] The titled compound was prepared (5.10 mg, 8.1% yield) following a similar procedure for the preparation of tert-buryl 4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)carbamoyl)-5-(6-methoxypyridin-3-yl)-2-methylphenyl)(ethyl)amino)-2,6-irans- dimethylpiperidine-l-carboxylate followed by reverse phase HPLC/MS purification. ' H-NMR (400 MHz): δ ppm 10.30 (bs, 1H), 9.05 (d, =1.2 Hz, 1H), 8.92 (d, J = 0.8 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.24 (t, J = 6.0 Hz 1H), 5.95 (s, 1H), 4.57 (d, J = 6.0 Hz, 2H), 3.97 (bd, J = 7.9 Hz, 2H), 3.37-3.31 (m, 2H), 3.15 (q, J = 7.0 Hz 2H), 3.06 (dddd, J = 7.4, 7.4, 7.4, 7.4 Hz, 1H), 2.43 (s, 3H), 2.40 (s, 3H), 2.22 (s, 3H), 1.74-1.66 (m, 4H), 0.91 (t, J = 7.0 Hz 3H); MS (ESI) [M+H]+ 544.5.
iV-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(ethyI(tetrahydro-2H-pyran-4- yl)amino)-2-methyl-5-(5-((l-methylpiperidin-4-yl)oxy)pyraziii-2-yl)benzaiiiide
Figure imgf000212_0002
[0203] The titled compound was prepared (28.0 mg, 22% yield) following a similar procedure for the preparation of tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)carbamoyl)-5-(6-methoxypyridin-3-yl)-2-methylphenyl)(ethyl)amino)-2,6-ir«ns- dimethylpiperidine-l-carboxylate followed by reverse phase HPLC/MS purification. 1 H-NMR (400 MHz): δ ppm 8.39 (d, J= 1.2 Hz, 1 H), 8.17 (d, J= 1.2 Hz, 1 H), 7.68 (d, J= 1.2 Hz, 1 H), 7.58 (d, J = 1.6 Hz, 1 H), 7.20 (t, J= 5.6 Hz, 1 H), 5.91 (s, 1 H), 5.07-5.03 (m, 1 H), 4.56 (d, J= 5.8 Hz, 2 H), 3.94 (br d, J= 11.3 Hz, 2 H), 3.32 (ddd, J= 11.1, 11.1, 2.8 Hz, 2 H), 3.11 (q, 7= 7.0 Hz 2 H), 3.04 (dddd, J= 9.4, 9.4, 4.9, 4.9 Hz, 1 H), 2.76-2.69 (m, 2 H), 2.40 (s, 3 H), 2.36 (s, 3 H), 3.33-3.28 (m, 2 H), 2.32 (s, 3 H), 2.15 (s, 3 H), 2.09-2.05 (m, 4 H), 1.86 (dddd, J= 12.5,12.5, 3.7, 3.7 Hz, 2 H), 1.74-1.64 (m, 2 H), 0.88 (t, J= 7.0 Hz, 3 H); MS (ESI) [M+H]+ 589.6.
iV-((4,6-Dimethyl-2-oxo-l,2-diliydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4- yl)amino)-2-methyl-S-(5-((l-methyIazetidin-3-yl)oxy)pyrazin-2-yl)benzamide
Figure imgf000213_0001
[0204] The titled compound was obtained (21.0 mg, 18% yield) following the same procedure for the preparation of tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)carbamoyl)-5-(6-methoxypvridm-3-yl)-2-methylphenyl)(ethyl)amino)-2,6- rani- dimethylpiperidine-l-carboxylate followed by reverse phase HPLC/MS purification. Ή NMR (400 MHz): δ ppm 8.39 (d, J= 1.2 Hz, 1H), 8.21 (d, J= 1.6 Hz, 1H), 7.69 (d, J= 2.0 Hz, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.22 (t, J= 6.0 Hz 1H), 5.91 (s, 1H), 5.21 (dddd, J= 5.9, 5.9, 5.9, 5.9 Hz, 1H), 4.56 (d, J= 5.8 Hz, 2H), 3.94 (bd, 7= 1 1.3 Hz, 2H), 3.83-3.80 (m, 2H), 3.32 (ddd, J= 1 1.1, 1 1.1, 3.2 Hz, 2H), 3.17-3.09 (m, 4H), 3.06 (dddd, J= 10.1, 10.1 , 5.0, 5.0 Hz, 1H) 2.41 (s, 3 H), 2.40 (s, 3H), 2.36 (s, 3H), 2.15 (s, 3H), 1.74-1.64 (m, 4H), 0.88 (t, /= 7.0 Hz, 3H); MS (ESI) [M+H]+ 561.5.
iY-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-
Figure imgf000213_0002
[0205] The titled compound was obtained (23.0 mg, 34% yield) following a similar procedure for the preparation of tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)memyl)carbamoyl)-5-(6-methoxypyridin-3-yl)-2-methylphenyl)(ethyl)amino)-2,6-ira«i- dimethylpiperidine-l-carboxylate followed by reverse phase HPLC/MS purification. Ή-NMR (400 MHz): δ ppm 8.40 (d, J= 1.2 Hz, 1H), 8.12 (d, J= 1.2 Hz, 1H), 7.69 (d, J= 2.0 Hz, 1H), 7.59 (d, J= 2.0 Hz, 1H), 7.24 (t, J= 6.0 Hz 1H), 5.91 (s, 1H), 5.27 (septet, J= 6.4 Hz, 1H), 4.56 (d, J= 5.6 Hz, 2H), 3.94 (br d, J= 11.2 Hz, 2H), 3.32 (ddd, J = 11.2, 11.2, 2.8 Hz, 2H), 3.12 (q, J = 7.2 Hz, 2H), 3.32 (dddd, J= 9.9, 9.9, 4.8, 4.8 Hz, 1H), 2.40 (s, 3H), 2.36 (s, 3H), 2.14 (s, 3H), 1.73-1.66 (m, 4H), 1.38 (s, 3H), 1.37 (s, 3H), 0.89 (t, J= 7.0 Hz, 3H); MS (ESI) [M+H]+ 534.5.
Methyl 3-{[ira«s-4-(dimethyIamino)cyclohexyl](ethyl)amino}-2-methyl-5-[3-(morpholin-4-yl)-l- propyn-l-yl]benzoate
Figure imgf000214_0001
[0206] To a stirred solution of methyl 5-bromo-3-{[iraws-4-
(dimethylamino)eyclohexyl](ethyl)amino}-2-methylbenzoate (80 mg, 0.201 mmol) and 4-(l-propyn- 3-yl)morpholine (0.051ml, 0.4 mmol) in DMF (4 mL) was added Pd(PPh3)4 (23.0 mg, 0.0199 mmol), Cul (7.60 mg, 0.0399mmol), and triethylamine (0.056 mL, 0.399 mmol). The reaction mixture was stirred at 80 °C for 1.5 hours. The mixture was cooled to rt, diluted with EtOAc and water, and filtered through celite pad. The filtrate was partitioned. The organic layer was washed with water and brine, dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel column chromatography (NH-Si02; EtOAc heptane = 1/3-1/1 to EtOAc only) to give the titled compound as a crude product (73.2 mg, -76% purity, 64%). Ή-NMR (400 MHz, CD ¾) δ ppm; 7.68 (br-s, 1H), 7.29 (br-s, 1H), 3.89 (s, 3H), 3.77-3.80 (m, 4H), 3.50 (s, 2H), 3.03 (q, J = 6.8 Hz, 2H), 2.60-2.67 (m, 5H), 2.47 (s, 3H), 2.26 (s, 6H), 2.13-2.20 (m, 1H), 1.85-1.91 (m, 4H), 1.17-1.36 (m, 4H), 0.84 (t, J = 6.8 Hz, 3H); MS (ESI) [M+H]+ 442.4.
7V-l(4,6-Dimethyl-2-oxo-l,2-dihydropyridiii-3-yl)methyl]-3-{[<rani-4- (dimethylamino)cyclohexyl](ethyl)amino}-2-met yl-5-[3-(morpholin-4-yl)prop-l-yn-l- yl]benzamide
Figure imgf000214_0002
[0207] To a stirred solution of methyl 3-{[;ran -4-(dimethylamino)cyclohexyl](ethyl)amino}-2- methyl-5-[3-(morpholin-4-yl)-l-propyn-l-yl]benzoate (56.2 mg, 0.127 mmol) in ethanol (1.5 mL) was added aq. NaOH (5 N, 0.051 mL). The reaction mixture was stirred at 70 C for 1.5 hours. After cooling to rt, the reaction mixture was concentrated in vacuo, azeotroped with toluene (twice), and dried in vacuo.
To a stirred solution of the crude 3-{[ira«i-4-(dimethylamino)cyclohexyl](ethyl)amino}-2- methyI-5-[3-(morpholin-4-yI)-l-propyn-l-yl]benzoic acid and 3-(aminomethyl)-4,6-dimethyl-l,2- dihydropyridin-2-one HC1 salt (31.1 mg, 0.165 mmol) in DMSO (2 mL) was added PYBOP (100 mg, 0.191 mmol) and Hunig's base (0.066 mL, 0.381 mmol). The reaction mixture was stirred at RT for 14h. The reaction mixture was quenched with water, diluted with CHCI3, and partitioned. The organic layer was washed with water and brine, dried over Na2S0 , filtered, and concentrated. The residue was purified by silica gel column chromatography (NH-S1O2; EtOAc to EtOAc/MeOH = 10/1-5/1). The mixture was triturated with EtOAc-hexane to give the titled compound (34.7 mg, 49%). The compound was purified again by PTLC ( H-S1O2; EtOAc/MeOH = 10/1 4 developments) and triturated with EtOAc-hexane to give the compound with higher purity as a white solid. lH- MR (400 MHz, DMSO-d6) 5 ppm; 7.15 (s, 1H), 7.13 (s, 1H), 7.03 (t, J = 6.4 Hz, IH), 5.92 (s, 1H), 4.51 (d, J= 6.4 Hz, 2H), 3.73-3.86 (m, 4H), 3.48 (s, 2H), 3.01 (q, J = 7.2 Hz, 2H), 2.62-2.66 (m, 5H), 2.40 (s, 3H), 2.29 (s, 3H), 2.25 (s, 6H), 2.23 (s, 3H), 2.11-2.19 (m, IH), 1.82-1.87 (m, 4H), 1.12-1.42 (m, 4H), 0.83 (t, J= 7.2 Hz, 3H) ; MS (ESI) [M+H]+ 562.6; HPLC 95.4% purity.
l
Figure imgf000215_0001
[0208] To a stirred solution of 3-bromo- 1-propyne (ca. 9.2 M, 865 uL, 7.96 mmol) in acetone (8 mL) was added cesium carbonate (2.85 g, 8.76 mmol) and 1-methyl-homopiperazine (1.00 g, 8.76 mmol). The reaction mixture was stirred at RT for 18 hours. Then the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the titled compound as a brown oil (887 mg, 61%). •HNMR (400 MHz, CDCI3) δ ppm; 3.38 (s, IH), 3.37 (s, IH), 2.76-2.84 (m, 4H), 2.63-2.70 (m, 4H), 2.37 (s, 3H), 1.85 (s, IH), 1.79-1.89 (m, 2Η).
Methyl 3-{[ireHi-4-(dimethylamino)cyclohexyl](ethyl)amino}-2-methyl-5-[3-(4-methyl-l,4-
Figure imgf000215_0002
[0209] To a stirred solution of methyl 5-bromo-3-{[iraro-4-
(dimethylamino)cyclohexyl](ethyl)amino}-2-methylbeiizoate (295 mg, 0.742 mmol) and l-methyl-4- (l-propyn-4-yl)-l,4-diazepane (338 mg, 2.23 mmol) in DMF (7.4 mL) was added Pd(PPh3)4 (171 mg, 0.148 mmol), Cul (28 mg, 0.148 mmol), and triethylamine (0.31 mL, 2.23 mmol). The reaction mixture was stirred at 80 °C for 2 hours. The mixture was cooled to rt, diluted with EtOAc and water, and filtered through Celite pad. The filtrate was partitioned. The organic layer was washed with water and brine, dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel column chromatography (NH-S1O2; EtOAc/heptane = 1/2-1/1 to EtOAc only) to give the titled compound as a crude product (120 mg, 72% purity, 35%). Ή-NMR (400 MHz, CDC13) δ ppm; 7.29-7.33 (m, 2H), 3.89 (s, 3H), 3.58 (s, 2H), 3.03 (q, J = 7.2 Hz, 2H), 2.85-2.90 (m, 4H), 2.62-2.71 (m, 5H), 2.47 (s, 3H), 2.38 (s, 3H), 2.25 (s, 6H), 2.13-2.20 (m, 1H), 1.84-1.90 (m, 6H), 1.13-1.40 (m, 4H), 0.84 (t, J = 7.2 Hz, 3H); MS (ESI) [M+H]+ 469.5.
iV-[(4,6-DimethyI-2-oxo-l,2-dihydropyridin-3-yl)methylJ-3-{[ft-a«i-4- (dimethylamino)cyclohexyl](ethyl)amino}-2-methyl-S-[3-(4-methyl-l,4-diazepan-l-yl)-l- propyn-l-yl]benzamide
Figure imgf000216_0001
[0210] To a stirred solution of methyl 3-{[irani-4-(dimethylamino)cyclohexyl](ethyl)amino}-2- methyl-5-[3-(4-methyl-l ,4-diazepan-l-yI)-l-propyn-l-yl]benzoate (120 mg, 0.256 mmol) in ethanol (4 mL) was added aq. NaOH (5N, 0.150 mL). The reaction mixture was stirred at 70°C for 2 hours. After cooling to rt, the reaction mixture was neutralized with 2N-HC1 (0.25 mL), concentrated in vacuo, azeotroped with toluene (twice), and dried in vacuo.
To a stirred solution of the crude 3-{[irafji-4-(dimethylamino)cyclohexyl](ethyl)amino}-2- methyl-5-[3-(4-methyl-l,4-diazepan-l-yl)-l-propyn-l-yl]benzoic acid and 3-(aminomethyl)-4,6- dimethyl-l,2-dihydropyridin-2-one HC1 salt (63.0 mg, 0.333 mmol) in DMF (4 mL) was added PYBOP (200 mg, 0.384 mmol) and Hunig's base (0.179 mL, 1.02 mmol). The reaction mixture was stirred at RT for 14h. The mixture was directly evaporated. The residue was purified by silica gel column chromatography (NH-Si02; EtOAc to EtOAc/MeOH = 10/1-5/1) to give the titled compound (101 mg, 67%). The compound was purified again by PTLC (NH-Si02; EtOAc/MeOH = 10/1 4 developments) and triturated with TBME-hexane to give the compound with higher purity as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm; 7.13-7.16 (m, 1H), 7.13 (s, 1H), 7.12 (s, 1H), 5.92 (s, 1H), 4.50 (d, J = 6.0 Hz, 2H), 3.55 (s, 2H), 3.01 (q, J = 7.2 Hz, 2H), 2.84-2.90 (m, 4H), 2.69- 2.73 (m, 4H), 2.59-2.65 (m, 1H), 2.39 (s, 3H), 2.37 (s, 3H), 2.30 (s, 3H), 2.24 (s, 6H), 2.22 (s, 3H), 2.12-2.17 (m, 1H), 1.84-1.89 (m, 6H), 1.13-1.40 (m, 4H), 0.83 (t, .7 = 7.2 Hz, 3H); MS (ESI) [M+H]+ 589.6 ; HPLC 93.5% purity.
3-((tert-Butyldiphenylsilyl)oxy)-l-(prop-2-yn-l-yl)azetidine
Figure imgf000216_0002
[021 1] To a stirred solution of 3-((iert-butyldiphenylsilyl)oxy)azetidine (935 mg, 3.00 mmol) and Hunig base (786 mL, 4.50 mmol) in DCM (10 mL) at -78°C was added propargyl bromide (267 mL, 3.00 mmol) slowly. After 5 min, the reaction was warmed up to 23°C slowly and stirred for 1 h. The reaction was quenched with sat. aq. NaHC03 and water, the aq. phase was extracted with DCM, the combined organic extracts was dried over Na2S0 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane/EtOAc = 3/1) to give the titled compound as colorless oil (588 mg, 49% yield). Ή-NMR (400 MHz) δ ppm: 7.63 (m, 4H), 7.40 (m, 6H), 4.42 (dddd, /= 5.6 Hz, 1H), 3.45 (ddd, J= 2.4, 6.0, 6.0 Hz, 2H), 3.28 (d, J= 2.4 Hz, 2H), 3.19 (ddd, J= 2.0, 6.0, 6.0 Hz, 2H), 2.27 (t, J= 2.4 Hz, 1H), 1.06 (s, 9H).
Methyl 5-(3-(3-((tefi-butyldiphenylsilyl)oxy)azetidin-l-yl)prop-l-yn-l-yl)-3-((4-ft-a«s-
Figure imgf000217_0001
[0212] The solution of 3-((ieri-butyldiphenylsilyl)oxy)-l-(prop-2-yn-l-yl)azetidine (584 mg, 1.67 mmol), methyl 5-bromo-3-((4-ira«i-(dimethylamino)cyclohexyl)(ethyl)amino)-2-methylbenzoate (604 mg, 1.52 mmol) and triethylamine (2.10 mL, 15.2 mmol) in DMF (15 mL) was bubbled through N2 for 10 min. Then Cul (28.9 mg, 152 mmol) and Pd(PPh3)4 (88.0 mg, 0.076 mmol) were added and N2 was bubbled through for another 10 min. The reaction mixture was heated at 100 °C for 6 h and then cooled down to rt. The reaction was quenched with sat. aq. NaHCOs and water and the separated aq. phase was extracted with TBME. The combined organic extracts were dried over Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography (10% 7 N NH3 in MeOH DCM) to give the titled compound as pale brown foam (709 mg, 70% yield). Ή-NMR (400 MHz) δ ppm: 7.58 (m, 5H), 7.39 (m, 7H), 4.40 (dddd, J= 6.0 Hz, 1 H), 3.83 (s, 3H), 3.49 (s, 2H), 3.42 (m, 2H), 3.36 (m, 2H), 3.05 (ddd, J= 6.8 Hz, 2H), 2.65 (m, 1H), 2.44 (s, 3H), 2.25 (s, 6H), 2.23 (m, 1H), 1.89 (br. d. J= 9.6 Hz, 4H), 1.37 (m, 2H), 1.19 (m, 2H), 0.99 (s, 9H), 0.82 (t, J= 6.8 Hz, 3H); MS (ESI) [M+Hf 666.6.
3-((4-ira«i-(Dimethylamino)cyclohexyl)(ethyl)ammo)-5-(3-(3-hydroxyazetidin-l-yl)prop-l-yn-
Figure imgf000217_0002
[0213] To the solution of methyl 5-(3-(3-((tert-butyldiphenylsilyl)oxy)azetidin-l-yl)prop-l-yn-l- yl)-3-((4-rra)js-(dimethylamino)cyclohexyl)(ethyl)amino)-2-methylbenzoate (696 mg, 1.05 mmol) in EtOH (10 mL) was added 1.0 N NaOH aq. solution (3.2 mL, 3.20 mmol). The reaction mixture was heated at 60 °C for 6 h. After cooling to 23 °C, 1.0 N aq. HC1 (3.3 mL, 3.30 mmol) was added. The mixture was concentrated in vacuo to give the titled compound as crude products. MS (ESI) [M+H]+ 414.4.
3-((4-<ra«s^(Dimethylamlno)cyclohexyl)(ethyl)amino)-5-(3-(3-hydroxyazetidin-l-yl)prop-l-yn- l-yl)-N-((4-i zamide
Figure imgf000218_0001
[0214] To a stirred solution of 3-((4-ira«s-(dimethylamino)cyclohexyl)(ethyl)amino)-5-(3-(3- hydroxyazetidm-l-yl)prop-l-yn-l-yl)-2-methylbenzoic acid (crude, 432 mg, 1.05 mmol) and 3- (aminomethyl)-4-isopropyl-6-methylpyridin-2(lH)-one (162 mg, 0.90 mmol) in DMSO (5 mL) was added EDC (258 mg, 1.45 mmol) and HOBT (206 mg, 1.35 mmol). The reaction mixture was stirred at 23 °C for 20 h. A fraction of the mixture was purified by HPLC to give the titled compound as white solid (16.7 mg). 'H-NMR (400 MHz) δ ppm: 7.25 (d, J= 1.6 Hz, 1H), 7.10 (d, J= 1.2 Hz, 1H), 6.24 (s, 1H), 4.51 (s, 2H), 4.36 (dddd, J= 6.4 Hz, 1H), 3.64 (dd, J= 2.0, 6.4 Hz, 2H), 3.52 (s, 2H), 3.44 (m, 1H), 3.17 (dd, J= 2.0, 6.4 Hz, 2H), 3.08 (ddd, J= 6.8 Hz, 2H), 2.69 (m, 1H), 2.28 (s, 6H), 2.26 (s, 6H), 2.23 (m, 1H), 1.92 (m, 4H), 1.43 (m, 2H), 1.23 (d, J= 6.8 Hz, 6H), 1.24 (m, 2H), 0.84 (t, = 6.8 Hz, 3H). 13C-NMR (400 MHz) δ ppm: 172.26, 166.06, 163.28, 151.26, 145.72, 140.51, 135.90, 129.27, 126.36, 121.68, 121.28, 105.95, 85.86, 84.79, 64.88, 63.19, 63.00, 62.30, 47.16, 42.07, 41.74, 35.86, 31.08, 29.63, 28.45, 23.03, 19.01, 15.55, 13.78; MS (ESI) [M+H 576.6.
Figure imgf000218_0002
[0215] To a stirred solution of piperidine (388 mg, 4.56 mmol) in acetone (10 mL) was added CS2CO3 (1490 mg, 4.56 mmol) followed by drop wise addition of 3-bromoprop-l-yne (542 mg, 4.56 mmol). After stirring over weekend at r.t., the reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was partitioned between ethyl ether and aqueous NaH(X>3 solution. The separated organic layer was dried and evaporated to give the titled compound (389 mg, 69 % yield) as an orange-brown oil. 1 H-NMR (400 MHz) δ ppm; 3.27 (d, J = 2.5 Hz, 2H), 2.45-2.53 (m, 4H), 2.22 (t, J= 2.6 Hz, 1H), 1.58-1.64 (m, 4H), 1.39-1.45 (m, 2H).
Figure imgf000218_0003
[0216] The titled compound was prepared (423 mg, 61 %) following the same procedure described for l -(prop-2-yn-l-yl)piperidme. Ή-NMR (400 MHz) δ ppm; 3.39 (d, J= 2.6 Hz, 2H), 2.58-2.62 (m, 4H), 2.19 (t, J= 4.1 Hz, 1H), 1.77-1.80 (m, 4H).
(5)-l-(Prop-2-yn-l-yl)piperidin-3-ol
^ + H — p
[0217] The titled compound was prepared (138 mg, 46%) following the same procedure described for l -(prop-2-yn-l -yl)piperidine. Ή-NMR (400 MHz) δ ppm; 3.78-3.83 (m, 1H), 3.28 (t, J= 2.6 Hz , 2H), 2.68 (bd, J = 10Hz, 1H), 2.38-2.49 (m, 3H), 2.24 (t, J= 2.5 Hz , 1H), 1.42-1.83 (m, 4H).
3,5-« DimethyI-l-(prop-2-yn-l-yl)piperazine
[0218] A solution of 2,6-ds-dimethylpiperazine (1920 mg, 16.8 mmol) in DCM (10 mL) was added to a solution of 3-bromoprop-l -yne (500 mg, 4.20 mmol) in DCM (10 mL) at -78 °C and the mixture was stirred for 30 min and then warmed to rt. MS showed reaction was completed shown by strong desired peak of 153 (M+H) and excess SM peak of 1 15 (M+H). TLC (10% 7N N¾ in
MeOH/DCM) showed Rf=0.6 for new spot and Rf=0.4 for SM amine. The mixture was concentrated and chromatography (50 g column, 10% MeOH/DCM and then 5% 7N N¾ in MeOH DCM) purification gave the titled compound (0.550 g, 86% yield). Ή-NMR (400 MHz) δ ppm; 4.84 (bs, 1H), 3.31 (d, J = 2.4 Hz , 2H), 2.98 (m, 2H), 2.79 (dd d, J = 2.1 , 1 1.3 Hz, 2H), 2.26 (t, J= 2.4 Hz , 1H), 1.89 (dd, J= 10.4, 10.7 Hz 2H), 1.10 (d, J= 6.4 Hz, 6H); MS (ESI) [M+H]+ 153.1.
l-(ier<-Butyldiphenylsilyl)-2,6-cis-dimethyl-4-(prop-2-yn-l-yl)piperazine
Figure imgf000219_0001
[0219] The titled compound was prepared (138 mg, 46%) following the same procedure described for tert-butyl 4-(ethyl(5-fluoro-3-(methoxycarbonyl)-2-methylphenyl)amino)-2,6-;rani- dimethylpiperidine-l-carboxylate. Ή-NMR (400 MHz): δ ppm 4.16 (bs, 2H), 3.33 (m, 2H), 2.62 (m, 2H), 2.43 (m, 2H), 2.25 (bs, 1H), 1.52 (s, 9H), 1.37 (s, J = 6.7 Hz, 3H); MS (ESI) [M+H]+ 253.2.
A^-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-((4-freHs- (dimethylamino)cyclohexyl)(ethyl)amino)-5-(3 -3-hydroxypiperidin-l-yl)prop-l-yn-l-yl)-2- methylbenzamide
Figure imgf000220_0001
[0220] The titled compound was prepared (27.0 mg, 43% yield) in the same procedure as described for the preparation of 3-((4-frans-(dimethylamino)cyclohexyl)(ethyl)amino)-5-(3-(3- hydroxyazetidin- 1 -yl)prop- 1 -yn- 1 -yl)-N-((4-isopropyl-6-methyl-2-oxo-l ,2-dihydropyridin-3- yl)methy])-2-methylbenzamide in three step sequences. The titled compound was purified by reverse phase HPLC/MS. Ή-NM (400 MHz, CD3OD) δ ppm 7.19 (d, J= 1.2 Hz, IH), 7.05 (d, J= 1.6 Hz, IH), 6.07 (s, IH), 4.42 (s, 2H), 3.63-3.70 (m, IH), 3.48 (d, J= 1.8 Hz, 2H), 3.04 (q, J= 7.0 Hz, 2H), 2.96-3.01 (m, IH), 2.75-2.78 (m, IH), 2.62-2.68 (m, IH), 2.34 (s, 3H), 2.22 (s, 3H), 2.22 (s, 6H), 2.21 (s, 3H), 2.08-2.22 (m, 3H), 1.72-1.90 (m, 6H), 1.13-1.59 (m, 6H), 0.80 (t, J= 7.1 Hz, 3H).
Figure imgf000220_0002
7V-((4,6-Diraethyl-2-oxo-l,2-dihydropyridin-3-yl)raethyl)-3-((4-fra«s- (diraethylamino)cyclohexyl)(ethyl)amino)-5-(3-(3-hydroxyazetidin-l-yl)prop-l-yn-l-yl)-2-
Figure imgf000220_0003
[0221] The titled compound were prepared (64.0 mg, 41% yield) in a similar manner as described for the preparation of 3-((4-ira«i-(dimethylamino)cyclohexyl)(ethyl)amino)-5-(3-(3- hydroxyazetidin- 1 -yl)prop- 1 -yn- 1 -yl)-N-((4-isopropyl-6-methyl-2-oxo- 1 ,2-dihydropyridin-3- yl)methyl)-2-methylbenzamide in three step sequences. The titled compound was purified by reverse phase HPLC MS. Ή-NMR (400 MHz, CD3OD) δ ppm 7.22 (d, J= 1.3 Hz, IH), 7.08 (d, J = 1.6 Hz, IH), 6.07 (s, IH), 4.42 (s, 2H), 4.32 (m, IH), 3.58-3.62 (m, 2H), 3.48 (s, 2H), 3.12-3.16 (m, 2H), 3.04 (q, J= 7.0 Hz, 2H), 2.60-2.69 (m, IH), 2.34 (s, 3H), 2.23 (s, 3H), 2.22 (s, 6H), 2.21 (s, 3H), 2.13-2.20 (m, IH), 1.84-1.90 (m, 4H), 1.34-1.44 (m, 2H), 1.10-1.22 (m, 2H), 0.80 (t, 7= 6.8 Hz, 3H). MS (ESI) [M+H]+ 548.7.
A^-^^-Dimethyl^-oxo-l^-dihydropyridin-S-y^methy^-S-iethylitetrahydro^H-pyran^- yI)araino)-2-methyl-5-(3-(piperidin-1-yl)prop-l-yn-l-yl)benzamide
Figure imgf000221_0001
[0222] The titled compound were prepared (33.0 mg, 50% yield) in a similar mariner as described for the preparation of 3-((4 -(dimethylamirio)cyclohexyl)(ethyl)amino)-5-(3-(3- hydroxyazetidin-l-yl)prop-l-yn-l-yl)-N-((4-isopropyl-6-methyl-2-oxo-l,2-dmydropyridin-3- yl)methyl)-2-methylbenzamide in three step sequences. The titled compound was purified by reverse phase HPLC/MS. Ή-NMR (400 MHz, CD3OD): δ ppm 7.26 (d, J = 1.6 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 6.10 (s, 1H), 4.45 (s, 2H), 3.90 (m, 2H), 3.46 (s, 2H), 3.35 (m, 2H), 3.10—2.98 (m, 3H), 2.60 (bs, 4H), 2.37 (s, 3H), 2.27 (s, 3H), 2.24 (s, 3H), 1.65 (m, 8H), 1.48 (bs, 2H), 0.84 (t, J= 7.0 Hz, 3H); MS (ESI) [M+H]+ 519.4.
Af-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyraii-4-
Figure imgf000221_0002
[0223] The titled compound were prepared (30.0 mg, 23% yield) in a similar manner as described for the preparation of 3-((4-i aHs-(dimethylamino)cyclohexyl)(ethyl)amino)-5-(3-(3- hydroxyazetidin- 1 -yl)prop- 1 - n- 1 -yl)-N-((4-isopropyl-6-methyl-2-oxo- 1 ,2-dihydropyridin-3- yl)methyl)-2-methylbenzamide in three step sequences. The titled compound was purified by reverse phase HPLC/MS. Ή-NMR (400 MHz, CD3OD): δ ppm 7.25 (d, J = 1.5 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 6.10 (s, 1H), 4.44 (s, 2H), 3.90 (m, 2H), 3.60 (s, 2H), 3.34 (m, 2H), 3.10—2.98 (m, 3H), 2.71 (bs, 4H), 2.36 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H), 1.85 (m, 4H), 1.70—1.55 (m, 4H), 0.83 (t, J = 6.8 Hz, 3H); MS (ESI) [M+H]+ 505.5.
5-(3-(4-(iert-Butyldiphenylsilyl)-3,5-cis-dimethyIpiperazin-l-yl)prop-l-yn-l-yl)-3- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((4-isopropyl-6-methyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)-2-methylbemamide
Figure imgf000221_0003
[0224] The titled compound were prepared (40.0 mg, 15% yield) in a similar mariner as described for the preparation of 3-((4-/ra«i-(dimethylamino)cyclohexyl)(ethyl)amino)-5-(3-(3- hydroxyazetidin-l-yl)prop-l-yn-l-yl)-N-((4-isopropyl-6-methyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)-2-methylbenzamide in three step sequences. The titled compound was purified by reverse phase HPLC/MS. Ή-NMR (400 MHz, CD3OD): δ ppm 7.25 (d, J = 1.7 Hz, 1H), 7.09 (d, J = 1.4 Hz, 1H), 6.23 (d, J = 0.9 Hz, 1H), 4.50 (s, 2H), 4.09 (m 2H), 3.90 (m, 2H), 3.53 (s, 2H), 3.43 (m, 1H), 3.36 (m, 2H), 3.08 (t, J = 6.9 Hz, 2H), 3.01 (m, 1H), 2.74 (m, 2H), 2.38 (dd, / = 11.5, 4.1 Hz, 2H), 2.28 (s, 3H), 2.27 (s, 3H), 1.7—1.58 (m, 4H), 1.47 (s, 9H), 1.31 (d, J = 6.7 Hz, 6H), 1.23 (d, J = 6.9 Hz, 6H), 0.84 (t, J = 6.9 Hz, 3H); MS (ESI) [M+H]+ 676.7.
5-(3-(cis-3,5-Dimethylpiperazin-l-yl)prop-l-yn-l-yl)-3-(ethyl(tetrahydro-2H-pyran-4- yl)amino)-N-((4-i -methylbenzamide
Figure imgf000222_0001
[0225] To a solution of 5-(3-(4-(tert-butyldiphenylsilyl)-3,5 is-dimethylpiperazin-l-yl)prop-l-yn- l-yl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((4-isopropyl-6-methyl-2-oxo-l,2- dihydropyridin-3-yl)methyl)-2-methylbenzamide (40 mg, 0.059 mmol) in DCM (381 uL, 5.918 mmol) was added 4 M HC1 in 1,4-dioxane (1480 ί, 5.918 mmol) at rt. The reaction was stirred at room temperature for 2 h. The reaction mixture was then concentrated and the residue was purified by reverse phase HPLC/MS to give the titled compound (33 mg, 97 % yield). 'H-NMR (400 MHz, CD3OD): δ ppm 7.27 (d, J = 1.5 Hz, 1H), 7.11 (d, J = 1.6 Hz, 1H), 6.23 (d, J = 0.6 Hz, 1H), 4.50 (s, 2H), 3.91 (m, 2H), 3.52 (s, 2H), 3.44 (q, J = 7.0 Hz, 1H), 3.34 (m, 2H), 3.07 (q, J = 6.9 Hz, 2H), 3.01 (m, 1H), 2.98 (m, 2H), 2.86 (m, 2H), 2.28 (s, 3H), 2.27 (s, 3H), 1.95 (t, / = 10.8 Hz, 2H), 1.70 (m, 2H), 1.60 (qd, J = 12.7, 4.2 Hz, 2H), 1.23 (d, J = 6.6 Hz, 6H), 1.09 (d, J = 6.4 Hz, 6H), 0.84 (t, J = 7.0 Hz, 3H); MS (ESI) [M+H]+ 576.5.
te«-Butyl 4-((3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(methoxycarbonyl)-4-
Figure imgf000222_0002
[0226] To a solution of methyl 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2- methylbenzoate (1.80 g, 5.05 mmol) and tert-butyl 4-efhynylpiperidine-l-carboxylate (1.80 g, 8.59 mmol) in DMF (40 ml) was added triethylamine (2.82 ml, 20.2 mmol) and Copper(I) iodide (0.096 g, 0.505 mmol). The reaction mixture was degassed by bubbling nitrogen for 15 min. Then tetrakis(triphenylphosphine)palladium(0) (0.292 g, 0.253 mmol) was introduced and degassed for additional 10 min by bubbling nitrogen. The reaction mixture was heated at 80 °C for 6 h. The reaction was quenched with sat. NaHC03, extracted with TBME (3x40 mL), dried over Na2S04, filtered and concentrated. The residue was purified by chromatography (0% to 40%
AcOEt/Heptane) to give the titled compound (2.40 g, 98% yield). Ή-NMR (500 MHz) δ ppm; 7.65 (s, 1H), 7.28 (s, 1H), 3.97 (brd, J= 11.3 Hz, 2H), 3.90 (s, 3H), 3.76 (m, 2H), 3.34 (dt, J= 2.0, 11.7 Hz, 2H), 3.24 (ddd, J= 3.4, 8.8, 12.2 Hz, 2H), 3.08 (brs, 2H), 2.98 (brs, 1H), 2.80 (dddd, =3.9, 3.9, 3.9, 3.9 Hz, 1 H), 2.52 (s, 3H), 1.87 (m, 2H), 1.60-1.74 (m, 6H), 1.48 (s, 9H), 0.89 (t, J= 6.8 Hz, 3H) ); MS (ESI) [M+H]+ 485.4.
5-((l-(iert-Butoxycarbonyl)piperidin-4-yl)ethynyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)ammo)-
2-methylbenzoic acid
Figure imgf000223_0001
[0227] To a solution of iert-butyl 4-((3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5- (methoxycarbonyl)-4-methylphenyl)ethynyl)piperidine-l-carboxylate (2.4 g, 4.95 mmol) in ethanol (20.0 mL) was added a solution of sodium hydroxide (0.565 g, 14.1 mmol) in water (3.0 ml) at rt. The reaction mixture was heated at 60 °C for 6 h. The reaction was quenched with 1 M HCl (5 mL) and then excess citric acid solution to adjust to the pH to 5. The mixture was concentrated to remove EtOH and the remaining aqueous phase was extracted with AcOEt (2x40 mL). The organic layers were combined, dried o erNa2S04, filtered and concentrated. The residue was purified by chromatography (10%-100% AcOEt/Heptane) to give the titled compound (2.30 g, 99% yield). Ή- NMR (500 MHz) δ ppm; 7.82 (s, 1H), 7.35 (s, 1H), 3.98 (brd, J= 11.3Hz, 2H), 3.77 (m, 2H), 3.35 (dt, J= 1.5, 11.3Hz, 2H), 3.25 (ddd, J= 3.4, 8.3, 12.2 Hz, 2H), 3.11 (brs, 2H), 3.00 (brs, 1H), 2.81 (dddd, J=3.9, 3.9, 3.9, 3.9 Hz, 1H), 2.60 (s, 3H), 1.88 (m, 2H), 1.60-1.78 (m, 6H), 1.48 (s, 9H), 0.90 (t, J= 6.8Hz, 3H); MS (ESI) [M+H]+ 471.4.
tert-Butyl 4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-5- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylpheuyl)ethynyl)piperidine-l-carboxylate
Figure imgf000223_0002
[0228] To a solution of 5-((l-(tert-butoxycarbonyl)piperidin-4-yl)ethynyl)-3-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-2-methylbenzoic acid ( 1.06 g, 2.25 mmol) in DMSO (5.8 mL) at rt was added triethylamine (0.90 mL, 6.44 mmol) and (4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methanaminium chloride (0.405 g, 2.15 mmol). The clear solution become heterogenous. Then HOBT (0.493 g, 3.22 mmol) and EDC (0.617 g, 3.22 mmol) were added and the resulting reaction mixture was stirred at rt overnight. The reaction was quenched with water (80 mL) and the slurry was stirred for 1 h at rt. The slurry was filtrated and the cake was washed with water (2x20 mL). The collected solid was dried under vacuum to give the titled compound (1.27 g, 98% yield). Ή- NMR (500 MHz, CD3OD) δ ppm; 7.22 (s, 1H), 7.08 (d, = 1.0 Hz 1H), 6.11 (s, 1H), 4.45 (s, 2H), 3.92 (brd, J= 10.8 Hz, 2H), 3.78 (dd, .7=4.4, 5.4 Hz, 1H), 3.75 (dd, .7=4.4, 5.4 Hz, 1H), 3.36 (t, J= 11.7 Hz, 2H), 3.21 (brt, .7=8.3 Hz, 2H), 3.07 (q, J= 7.3 Hz, 2H), 3.01 (dddd, ,7=3.9, 3.9, 11.3, 11.3 Hz, 1H), 2.84 (dddd, .7=3.4, 3.4. 3.9, 3.9 Hz, 1H), 2.38 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H), 1.88 (m, 2H), 1.70 ((brd, 7= 12.2 Hz, 2H), 1.60 (m, 4H), 1.47 (s, 9H), 0.87 (t, J= 7.3 Hz, 3H); MS (ESI) [M+H]+ 605.6.
tert-Butyl 4-((3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(((4-isopropyl-6-methyl-2-oxo-l,2- dihydropyridin-3-yl)methyl)carbamoyl)-4-methylphenyl)ethynyl)piperidine-l-carboxylate
Figure imgf000224_0001
[0229] The titled compound were prepared (491 mg, 34% yield) in a similar manner as described for the preparation of 3-((4-ira«i-(dimethylamino)cyclohexyl)(ethyl)amino)-5-(3-(3- hydroxyazetidin- 1 -yl)prop- 1 -yn- 1 -yl)-N-((4-isopropyl-6-methyl-2-oxo-l ,2-dihydropyridin-3- yl)methyl)-2-methylbenzamide. Ή-NMR (500 MHz, CD3OD) δ ppm; 8.22 (t, J= 4.9 Hz 1H), 7.22 (s, 1H), 7.06 (d, J= 1.0 Hz 1H), 6.24 (s, 1H), 4.52 (d, J= 4.4 Hz, 2H), 3.92 (br, d, J= 10.8 Hz, 2H), 3.75 (m, 2H), 3.45 (m, 1H), 3.34 (t, J= 11.7 Hz, 2H), 3.20 (br, d, J = 10.3 Hz, 2H), 3.07 (q, J= 7.3 Hz, 2H), 3.01 (m, 1H), 2.83 (m, 1H), 2.28 (s, 6H), 1.87 (m, 2H), 1.70 ((br, d, J= 11.3 Hz, 2H), 1.60 (m, 4H), 1.47 (s, 9H), 1.24 (d, J= 6.9 Hz, 6H), 0.85 (t, J= 6.9 Hz, 3H); MS (ESI) [M+H]+ 633.7.
3-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((4-isopropyl-6-methyl-2-oxo-l,2- dihydropyridin-3-yl)methyl)-2-methyl-5-(piperidin-4-ylethvnyl)benzamide
Figure imgf000225_0001
[0230] To a solution of tert-butyl 4-((3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(((4-isopropyl-6- metJiyl-2-oxo- 1 ,2-dihydropyridin-3 -yl)methyl)carbamoyl)-4-metbylphenyl)ethynyl)piperidine- 1 - oarboxylate (212 mg, 0.335 mmol) in DCM (2 mL) at rt was added 4 M HC1 in 1,4-dioxane (3 mL, 12.0 mmol) and the reaction mixture became cloudy. After stirring for 30 min, TLC (10% MeOH DCM) showed reaction was done, Rf=0.5 for SM and Rf=0.3 for new spot. The mixture was concentrated, redissolved in DCM and washed with sat. Na2S04. The aq. phase was extracted with 4xDCM until no more product was detected by TLC. The combined org. phase was dried (Na2S04), filtered and concentrated to give the titled compound as a brownish solid (257 mg, 144% yield). Assume 100% yield of 178 mg and go next step reaction without further purification. HNMR and MS showed it is desired with some minor impurities. Ή-NMR (400 MHz, CD3OD) δ ppm; 7.18 (d, J = 1.5 Hz 1H), 7.03 (d, J= 1.5 Hz, 1H), 6.20 (s, 1H), 4.47 (s, 2H), 3.88 (m, 2H), 3.45 (m, 1H), 3.31 (m, 2H), 2.93-3.15 (m, 5H), 2.79 (m, 3H), 2.24 (s, 6H), 1.98 (m, 3H), 1.40-1.75 (m, 6H), 1.19 (d, J= 6.7 Hz, 6H), 0.81 (t, J = 7.0 Hz, 3H); MS (ESI) [M+H]+ 533.5.
(^-3-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-((l-(2-hydroxypropyl)piperidin-4-yl)ethynyl)- V-((4-is amide
Figure imgf000225_0002
[0231] To 3-(ethyl(tetrahyaio-2H-pyran-4-yl)amino)-N-((4-isopropyl-6-memyl-2-oxo-l,2-dihydro pyridin-3-yl)methyl)-2-methyl-5-(piperidin-4-ylethynyl)benzamide (80 mg) in methanol (4.1 mL) was added (S)-2-methyloxirane (24 μL) in a sealed tube. The reaction mixture was heated at 65 °C for 3 hrs. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to give the titled compound (33.0 mg, 50% yield). 1 H-NMR (500 MHz, CD3OD) δ ppm; 7.21 (s, 1H), 7.06 (d, /= 1.0 Hz, 1H), 6.24 (s, 1H), 4.50 (s, 2H), 3.94 (m, 1H), 3.92 (br, d, J= 10.8 Hz, 2H), 3.46 (m, 1H), 3.35 (t, J= 11.7 Hz, 2H), 3.07 (q, J= 6.8 Hz, 2H), 3.01 (m, 1H), 2.90 (m, 1H), 2.84 (m, 1H), 2.64 (m, 1H), 2.3-2.42 (m, 3H), 2.28 (s, 6H), 1.94 (m, 2H), 1.67-1.80 (m, 4H), 1.60 (dq, J= 4.4, 11.7 Hz, 2H), 1.24 (d, J= 6.3 Hz, 6H), 1.15 (d, J= 6.4 Hz, 3H), 0.85 (t, J= 7.3 Hz, 3H); MS (ESI) [M+H]+ 591.5. (i)-3-(Ethyl(tetrahydro-2H-pyran-4-yl)amino)-^
iV-((4-isop amide
Figure imgf000226_0001
[0232] To 3-(ethyl(terj¾hydro-2H-pyran-4-yl)arnino)-N-((4-isopropyl-6-methyl-2-oxo-l,2-dihydro pyridm-3-yl)methyl)-2-met yl-5-(piperidin-4-ylethynyl)benzamide (80.0 mg) in methanol (4.1 mL) was added (R)-2-methyloxirane (24 μ¾ in a sealed tube. The reaction mixture was heated at 65 °C for 3 hrs. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to give the titled compound (33.0 mg, 50% yield). Ή-NMR (500 MHz, CD3OD) δ ppm; 7.21 (d, J = 1.0 Hz, 1H), 7.06 (d, J= 1.0 Hz, 1H), 6.24 (s, 1H), 4.50 (s, 2H), 3.94 (m, 1H), 3.92 (br, d, J= 10.8 Hz, 2H), 3.46 (m, 1H), 3.35 (t, J= 11.7 Hz, 2H), 3.07 (q, J= 6.8 Hz, 2H), 3.01 (m, 1H), 2.88 (m, 1H), 2.82 (m, 1H), 2.62 (m, 1H), 2.3-2.42 (m, 3H), 2.28 (s, 6H), 1.94 (m, 2H), 1.67-1.80 (m, 4H), 1.60 (dq, J= 4.4, 11.7 Hz, 2H), 1.24 (d, J= 6.9 Hz, 6H), 1.14 (d, J= 5.9 Hz, 3H), 0.85 (t, J= 6.9 Hz, 3H); MS (ESI) [M+H]+ 591.6.
Ar-((4,6-DimethyI-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4- yl)a de
Figure imgf000226_0002
[0233] To a solution of iert-butyl 4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)carbamoyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4- methylphenyl)ethynyl)piperidine-l-carboxylate (250 mg, 0.413 mmol) in DCM (3 mL) was added 4M HC1 in 1,4-dioxane (3 mL, 12.0 mmol) at 20 °C. The mixture was stirred at 20 °C for 1 h. LCMS indicated that the reaction was completed. The reaction mixture was directly concentrated and the residue was dissolved in DCM and then neutralized with sat. NaHC03/brine. The organic layer was dried ( ajSO^ and filtered. And the filtrate was concentrated. The residue was used for alkylation without further purification (209 mg, 100%). Ή-NMR (500 MHz, CD3OD) δ ppm 7.21 (bs, 1H), 7.07 (bs, 1H), 6.11 (s, 1H), 4.46 (s, 2H), 3.95-3.89 (m, 2H), 3.39-3.34 (m, 2H), 3.08 (q, J = 7.0 Hz, 2H), 3.06-2.98 (m, 3H), 2.79-2.72 (m, lH), 2.72-2.65 (m, 2H), 2.38 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H), 1.94-1.88 (m, 2H), 1.73-1.68 (m, 2H), 1.68-1.56 (m, 4H), 0.85 (t, J = 7.0 Hz, 3H); MS (ESI) [M+H]+ 505.5.
^-^(fi-Dimeth l-Z-oxo-l^-dih dro yridin-S- ^meth -S-ieth litetrahydro- H- ran^- yl)a amide
Figure imgf000227_0001
[0234] To a solution of N-((4,6-dimethyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl)-3- (emyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(piperidin-4-ylethynyl)benzamide (100 mg, 0.198 mmol) in methanol (5 mL) was added 35% formaldehyde in H20 (0.155 mL, 1.98 mmol) at 0 °C. After stirring at 0 °C for 10 min, sodium cyanobororhydride (24.9 mg, 0.396 mmol) was added. The resulting mixture was stirred at 0 °C for 1 h. LCMS indicated that the reaction was completed. The reaction was quenched with sat. NaHC03/brine and extracted with EtAOc Heptane. The organic layer was dried (NajSO^, filtered and concentrated. The residue was purified by chromatography (10 g column, MeOH/DCM=l :9, and then MeOH/7 M NH3 in MeOH/DCM=l : 1 :8) to afford the titled compound (96.0 mg, 93%). Ή-NMR (500 MHz, C¾OD) δ ppm 7.22 (bs, IH), 7.08 (bs, IH), 6.10 (s, IH), 4.46 (s, 2H), 3.94-3.87 (m, 2H), 3.35-3.30 (m, 2H), 3.07 (q, / = 7.0 Hz, 2H), 3.04-2.97 (m, IH), 2.79-2.71 (m, 2H), 2.67-2.58 (m, IH), 2.38 (s, 3H), 2.28 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H), 2.28-2.21 (m, 2H), 1.97-1.91 (m, 2H), 1.78-1.67 (m, 4H), 1.64-1.54 (m, 2H), 0.85 (t, J = 7.0 Hz, 3H); MS (ESI) [M+H]+ 519.4.
iV-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4- yl)amino)-5-((l-ethyIpiperidin-4-yl)ethynyl)-2-methylbenzamide
Figure imgf000227_0002
[0235] To a pear flask with A¾4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3- (ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(piperidin-4-ylethynyl)benzamide ( 100 mg, 0.198 mmol) in methanol (5 mL, 124 mmol) was added acetaldehyde (0.112 mL, 1.98 mmol) at 0 °C. After stirring at 0 °C for 10 min, sodium cyanobororhydride (24.9 mg, 0.396 mmol) was added. The mixture was stirred at 0 °C for 1 h. MS indicated that the reaction was completed. The reaction was quenched with sat. NaHC03 brine and extracted with EtAOc/Hept. The organic layer was dried (NajSO,,), filtered and concentrated. The residue was purified chromatography (10.0 g column, MeOH/DCM=l:9, then MeOH/7 M NH3 in MeOH/DCM=l:l:8) to afford the titled compound (90.0 mg, 85%). 1 H-NMR (500 MHz, CD3OD) δ ppm 7.21 (s, 1H), 7.07 (s, 1H), 6.11 (s, 1H), 4.46 (s, 2H), 3.95-3.88 (m, 2H), 3.37-3.33 (m, 2H), 3.07 (q, J = 7.0 Hz, 2H), 3.05-2.98 (m, 1H), 2.87-2.78 (m, 2H), 2.69-2.61 (m, 1H), 2.45 (q, J = 7.0 Hz, 2H), 2.38 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H), 2.28-2.20 (m, 2H), 1.99-1.93 (m, 2H), 1.79-1.67 (m, 4H), 1.64-1.55 (m, 2H), 1.11 (t, 7 = 7.0 Hz, 3H), 0.85 (t, J = 7.0 Hz, 3H); MS (ESI) [M+H]+ 533. 5.
iert-Butyl 4-((5-bromo-3-(methoxycarbonyl)-2-methylphenyl)amino)piperidine-l-carboxylate
Figure imgf000228_0001
[0236] The titled compound were prepared (1.75, 68% yield) in a similar manner as described for the preparation of iert-buty] 4-((3-(methoxycarbonyl)-2-methyl-5-
(trifluoromethyl)phenyl)amino)piperidine-l-carboxylate. 1 H-NMR (500 MHz) δ ppm 7.25 (s, 1H), 6.85 (s, IH), 4.05 (br, 2H), 3.88 (s, 3H), 3.49-3.41 (m, IH), 2.98 (t, J = 10 Hz, 2H), 2.23 (s, 3H), 2.09-2.02 (m, 2H), 1.48 (s, 9H), 1.44-1.34 (m, 2H); MS (ESI) [M+Hf 427.2, 429.2.
tert-Butyl 4-((5-bromo-3-(methoxycarbonyl)-2-methylphenyl)(ethyl)amino)piperidine-l- carboxylate
Figure imgf000228_0002
[0237] The titled compound were prepared (1.28 g, 87% yield) in a similar manner as described for the preparation of ieri-butyl 4-(ethyl(3-(methoxycarbonyl)-2-methyl-5-
(trifluoromethyl)phenyl)amino)piperidine-l-carboxylate. Ή-NMR (500 MHz) δ ppm 7.71 (d, J = 2.0 Hz, IH), 7.36 (d, J = 2.0 Hz, IH), 4.05 (br, 2H), 3.90 (s, 3H), 3.04 (q, J = 6.5 Hz, 2H), 2.90-2.84 (m, IH), 2.70 (t, J = 12.5 Hz, 2H), 2.45 (s, 3H), 1.78-1.70 (m, 2H), 1.55-1.47 (m, 2H), 1.46 (s, 9H), 0.89 (t, J = 6.5 Hz, 3H) MS (ESI) [M+H]+ 455.3, 457.3.
5-Bromo-3-((l-(iert-butoxycarbonyl)piperidln-4-yl)(ethyl)amino)-2-methylbenzoic acid
Figure imgf000229_0001
[0238] The titled compound were prepared (1.07 g, 100% yield) in a similar manner as described for the preparation of 3-[emyl(l-methylpiperidin-4-yl)amino]-2-memyl-5-(trifluoromethyl)berizoic acid. Ή-NMR (500 MHz) δ ppm 7.81 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 4.03 (m, 2H), 3.02 (q, J = 7.0 Hz, 2H), 2.89-2.83 (m, 1H), 2.73-2.66 (m, 2H), 2.47 (s, 3H), 1.77 .70 (m, 2H), 1.53-1.45 (m, 2H), 1.43 (s, 9H), 0.85 (t, J = 7.0 Hz, 3H); MS (ESI) [M+H]+ 441.3, 443.3.
tert-Buryl-4-((5-bromo-3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)carbamoyl)-2- methyIphenyI)(ethyI)amino)piperidine-l-carboxyIate
Figure imgf000229_0002
[0239] The titled compound was prepared (1.10 g, 77% yield) following the same procedure for the preparation of iV"-[(4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)memyl]-3-[emyl(l-methylpiperidin- 4-yl)amino]-2-methyl-5-(trifIuoromethyl)benzamide. Ή-NMR (500 MHz) δ ppm 7.36 (d, = 2.0. Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 6.11 (s, 1H), 4.46 (s, 2H), 4.04-3.98 (m, 2H), 3.07 (q, J = 7.0 Hz, 2H), 3.01-2.94 (m, 1H), 2.80-2.70 (m, 2H), 2.38 (s, 3H), 2.25 (s, 3H), 2.23 (s, 3H), 1.78-1.72 (m, 2H), 1.52-1.46 (m, 2H, 1.45 (s, 9H), 0.86 (t, = 7.0 Hz, 3H); MS (ESI) [M+H]+ 575.4, 7.4.
5-Bromo-7V-((4,6-dimethy)-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(ethyl(piperidin-4- yl)amino)-2-methylbenzamide
Figure imgf000229_0003
[0240] The titled compound was prepared (413 mg, 100% yield) following a similar procedure for the preparation of 3-((2,6 -dimethylpiperidin-4-yl)(ethyl)amino)-5-fluoro-N-((5-fluoro-l,4,6- trimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide hydrochloride followed by silica gel chromatography purification (10% 7N NH3 in MeOH/ DCM). Ή-NMR (500 MHz, CD3OD) δ ppm 7.33 (d, J = 2.0 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 6.10 (s, 1H), 4.45 (s, 2H), 3.09 (q, 7 = 7.5 Hz, 2H), 3.05-2.99 (m, 2H), 2.90-2.83 (m, 1H), 2.52-2.45 (m, 2H), 2.37 (s, 3H), 2.25 (s, 3H), 2.24 (s, 3H), 1.78-1.72 (m, 2H), 1.58-1.49 (m, 2H), 0.86 (t, 7 = 7.5 Hz, 3H); MS (ESI) [M+H]+ 475.3, 477.4.
5-Bromo-iV-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(ethyl(l-methylpiperidin-
Figure imgf000230_0001
[0241] The titled compound was prepared (400 mg, 84% yield) following a similar procedure for the preparation of methyl 3-[ethyl(l-methylpiperidin-4-yl)amino]-2-methyl-5- (trifluoromethyl)beri20ate. Ή-NMR (500 MHz, CD3OD) δ ppm 7.35 (d, 7 = 2.0 Hz, 1H), 7.20 (d, 7 = 2.0 Hz, 1H), 6.12 (s, 1H), 4.46 (s, 2H), 3.08 (q, 7 = 7.0 Hz, 2H), 2.90-2.84 (m, 2H), 2.85-2.79 (m, 1H), 2.37 (s, 3H), 2.26 (s, 3H), 2.25 (s, 3H), 2.23 (s, 3H), 2.08-2.01 (m, 2H), 1.80-1.74 (m, 2H)3 1.71-1.62 (m, 2H), 0.86 (t, 7 = 7.0 Hz, 3H); MS (ESI) [M+H]+ 489.3, 491.4.
iV-((4,6-Dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3-(ethyl(l-methylpiperidin-4- yl) ide
Figure imgf000230_0002
[0242] The titled compound were obtained (34.0 mg, 28% yield) following a similar procedure for the preparation of ieri-butyl 4-((3-(((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)carbamoyl)-5-(6-methoxypyridin-3-yl)-2-methylphenyl)(ethyl)amino)-2,6-ira«s- dimethylpiperidine-l-carboxylate. 'H-NMR (500 MHz, CD3OD) δ ppm 8.33 (d, 7 = 2.5 Hz, 1H), 7.81 (dd, 7 = 8.8, 2.5 Hz, 1H), 7.40 (d, 7= 2.0 Hz, 1H), 7.26 (d, 7= 2.0 Hz, 1H), 6.90 (d, 7= 8.8 Hz, 1H), 6.12 (s, 1H), 4.50 (s, 2H), 3.62-3.57 (m, 4H), 3.15 (q, 7 = 7.0 Hz, 2H), 2.94-2.89 (m, 1H), 2.892.84 (m, 2H), 2.60-2.56 (m, 4H), 2.40 (s, 3H), 2.36 (s, 3H), 2.31 (s, 3H), 2.26 (s, 3H), 2.25 (s, 3H), 2.10-2.03 (m, 2H), 1.86-1.80 (m, 2H), 1.75-1.66 (m, 2H), 0.90 (t, 7 = 7.0 Hz, 3H); MS (ESI) [M+H]+ 586.6.
[0243] Compounds 157-163 were synthesized by the methods similar to those described aabove. The analytical data for Compounds 157-163 are provided below. [0244] Compound 157: LCMS: 545.5 (M+l)+; TFA-salt: Ή NMR (DMSO-i¾, 400 MHz) δ 11.48 (brs, 1H), 8.96 (brs, 1H), 8.17 (s, 1H), 7.38-7.08 (m, 1H), 6.96 (s, 1H), 5.87 (s, 2H), 4.35 (s, 2H), 3.82 (d, 2H, J=10.4 Hz), 3.51 (t, 2H, J=10.4 Hz), 3.41-3.29 (m, IH), 3.27-3.06 (m, 4H), 3.05-2.89 (m, 3H), 2.88-2.76 (m, IH), 2.19 (s, 6H), 2.11 (s, 3H), 1.96 (m, 2H), 1.72 (q, IH, J=12 Hz), 1.65-
1.41 (m, 4H), 0.93 (brs, 2H), 0.85-0.73 (m, 5H).
[0245] Compound 158: LCMS: 559.6 (M+l)+; TFA-salt: Ή NMR (DMSO-i¾, 400 MHz) δ 11.47 (brs, IH), 9.36 (m, IH), 8.17 (brs, IH), 7.23-7.07 (m, IH), 6.97 (s, IH), 5.87 (s, IH), 4.24 (m, 2H), 3.84 (d, 2H, J=12.0 Hz), 3.61 (q, IH, J=8.0 Hz), 3.40-3.18 (m, 4H), 3.10-2.88 (m, 3H), 2.87-2.21 (m, 2H), 2.25-2.09 (m, 14H), 1.93 (m, 2H), 1.79-1.49 (m, 7H), 0.78 (t, 3H, J=6.8 Hz).
[0246] Compound 159: LCMS: 561.5 (M+l)+; TFA-salt: Ή NMR (DMSO-ife, 400 MHz) δ 11.48 (brs, IH), 10.41 (brs, IH), 8.17 (s, IH), 7.25-7.05 (m, 2H), 6.97 (s, IH), 5.87 (s, IH), 4.73 (d, 4H, J=6.4 Hz), 4.35 (s, IH), 4.25 (d, 2H, J=5.2 Hz), 3.82 (d, 2H, J=10.4 Hz), 3.47-3.30 (m, 2H), 3.20 (t, 2H, J=10.4 Hz), 3.13-2.78 (m, 6H), 2.19 (s, 6H), 2.11 (s, 3H), 2.03 (m, 2H), 1.78 (q, IH, J=12 Hz), 1.68-1.40 (m, 4H), 0.78 (t, 3H, J=6.8 Hz).
[0247] Compound 160: LCMS: 588.7 (M+l)+; Ή NMR (DMSO-<¾, 400 MHz) δ 11.45 (brs, IH),
8.15 (m, IH), 7.09 (s, IH), 6.92 (s, IH), 5.85 (s, IH), 4.24 (d, 2H, J=4.8 Hz), 3.92-3.83 (m, IH), 3.70-3.62 (m, IH), 3.38 (q, IH, J=7.2 Hz), 3.35-3.20 (m, IH), 3.17-30.6 (m, IH), 3.00 (q, 2H, J=7.2), 2.93-2.84 (m, IH), 2.18 (d, 2H, J=6.8 Hz), 2.22-207 (m, 15H), 1.99 (s, 3H), 1.90-1.70 (m, 6H), 1.64-
1.42 (m, 2H), 1.34 (q, 2H, J=12.0 Hz), 1.17-1.05 (m, 2H), 0.76 (t, 3H, J=6.8 Hz).
[0248] Compound 161: LCMS: 628.6 (M+l)+; Ή NMR (DMSO-J„, 400 MHz) δ 11.46 (brs, IH),
8.16 (t, IH, 4.8 Hz), 7.08 (s, IH), 6.9 (s, IH), 5.85 (s, IH), 4.24 (d, 2H, J=4.8 Hz), 3.16 (q, 2H, J=10.4 Hz), 2.99 (q, 2H, 6.8 Hz), 2.89-2.70 (m, 2H), 2.68-2.53 (m, 4H), 2.48-2.45 (m, IH), 2.20-2.03 (m, 15H), 1.89-1.70 (m, 6H), 1.65-1.54 (m, 2H), 1.40-1.36 (m, 2H), 1.11 (q, 2H, J=11.2 Hz), 0.76 (t, 3H, J=6.8 Hz).
[0249] Compound 162: LCMS: 574.5 (M+l)+; TFA-salt: Ή NMR (DMSO-ds, 400 MHz) δ 11.48 (brs, IH), 10.4-9.90 (m, IH), 8.16 (s, IH), 7.16 (s, IH), 7.01 (s, IH), 5.87 (s, 2H), 4.43 (brs, 2H), 4.25 (d, 2H, J=4.4 Hz), 4.25-3.97 (m, 4H), 3.82 (d, 2H, J=8.0 Hz), 3.23 (t, 2H, J=l 1.2 Hz), 3.20-2.95 (m, 4H), (2.95-2.73 (m, 4H), 2.19 (s, 6H), 2.11-1.99 (m, 5H), 1.80 (brs, 2H), 1.65-1.40 (m, 4H), 0.78 (t, 3H, J=6.8 Hz).
[0250] Compound 163: LCMS: 535.5 (M+l)+; TFA-salt: Ή NMR (DMSO-J«, 400 MHz) δ 8.32 (s, 2H), 7.95 (t, IH, J=4.4 Hz), 7.11 (s, IH), 6.93 (s, IH), 6.09 (s, IH), 4.19 (d, 2H, J=4.4 Hz), 3.83 (brs, 2H), 3.80 (s, 3H), 3.23 (t, 2H, J=10.8 Hz), 2.99 (q, 2H, J=7.2 Hz), 2.97-2.89 (m, IH), 2.68-2.52 (m, 2H), 2.22-2.15 (m, 9H), 2.13-2.03 (m, 2H), 1.88-1.68 (m, 2H), 1.65-1.54 (m, 4H), 1.53-1.42 (m, 2H), 0.77 (t, 3H, J=6.8 Hz). Example 2: Bioassay protocol and General Methods
Protocol for Wild-Type and Mutant PRC2 Enzyme Assays
[0251] General Materials. 5-adenosylmethionine (SAM), S-adenosylhomocyteine (SAH), bicine, KC1, Tween20, dimethylsulfoxide (DMSO) and bovine skin gelatin (BSG) were purchased from Sigma-Aldrich at the highest level of purity possible. Dithiothreitol (DTT) was purchased from EMD. H-SAM was purchased from American Radiolabeled Chemicals with a specific activity of SO Ci/mmol. 384-well streptavidin Flashplates were purchased from PerkinElmer.
[0252] Substrates. Peptides representative of human histone H3 residues 21 - 44 containing either an unmodified lysine 27 (H3K27meO) or dimethylated lysine 27 (H3K27me2) were synthesized with a C-terminal G( -biotin) linker-affinity tag motif and a C-terminal amide cap by 21st Century Biochemicals. The peptides were high-performance liquid chromatography (HPLC) purified to greater than 95% purity and confirmed by liquid chromatography mass spectrometry (LC-MS). The sequences are listed below.
H3K27meO: ATKAAR SAPATGGVKKPHRYRPGG (biotin)-amide (SEQ ID NO: 101) H3K27me2: AT AAR (me2)SAPATGGV KPHRYRPGG (biotin)-amide (SEQ ID NO: 102)
[0253] Chicken erythrocyte oligonucleosomes were purified from chicken blood according to established procedures.
[0254] Recombinant PRC2 Complexes. Human PRC2 complexes were purified as 4-component enzyme complexes co-expressed in Spodoptera frugiperda (sf9) cells using a baculovims expression system. The subunits expressed were wild-type EZH2 (NM_004456) or EZH2 Y641F, N, H, S or C mutants generated from the wild-type EZH2 construct, EED (NM_003797), Suzl2 (NMJH5355) and RbAp48 (NM_005610). The EED subunit contained an N-terminal FLAG tag that was used to purify the entire 4-component complex from sf9 cell lysates. The purity of the complexes met or exceeded 95% as determined by SDS-PAGE and Agilent Bioanalyzer analysis. Concentrations of enzyme stock concentrations (generally 0.3 - 1.0 mg/mL) was determined using a Bradford assay against a bovine serum albumin (BSA) standard.
[0255] General Procedure for PRC2 Enzyme Assays on Peptide Substrates. The assays were all performed in a buffer consisting of 20 mM bicine (pH = 7.6), 0.5 mM DTT, 0.005% BSG and 0.002% Tween20, prepared on the day of use. Compounds in 100% DMSO (1 uL) were spotted into polypropylene 384-well V-bottom plates (Greiner) using a Platemate 2 X 3 outfitted with a 384- channel pipet head (Thermo). DMSO (1 uL) was added to columns 11, 12, 23, 24, rows A - H for the maximum signal control, and SAH, a known product and inhibitor of PRC2 (1 uL) was added to columns 11,12, 23, 24, rows I - P for the minimum signal control. A cocktail (40 uL) containing the wild-type PRC2 enzyme and H3K27me0 peptide or any of the Y641 mutant enzymes and H3K27me2 peptide was added by Multidrop Combi (Thermo). The compounds were allowed to incubate with PRC2 for 30 min at 25 °C, then a cocktail (10 uL) containing a mixture of nonradioactive and 3H-SAM was added to initiate the reaction (final volume = 51 μΐ^). In all cases, the final concentrations were as follows: wild-type or mutant PRC2 enzyme was 4 nM, SAH in the minimum signal control wells was 1 mM and the DMSO concentration was 1%. The final concentrations of the rest of the components are indicated in Table 2, below. The assays were stopped by the addition of non-radioactive SAM (10 |iL) to a final concentration of 600 μΜ, which dilutes the 3H-SAM to a level where its incorporation into the peptide substrate is no longer detectable. 50 μί of the reaction in the 384-well polypropylene plate was then transferred to a 384- well Flashplate and the bion'nylated peptides were allowed to bind to the streptavidin surface for at least lh before being washed three times with 0.1% Tween20 in a Biotek ELx405 plate washer. The plates were then read in a PerkinElmer TopCount platereader to measure the quantity of 3H-labeled peptide bound to the Flashplate surface, measured as disintegrations per minute (dpm) or alternatively, referred to as counts per minute (cpm).
Table 2: Final concentrations of components for each assay variation based upon EZH2 identity (wild-type or Y641 mutant EZH2)
Figure imgf000233_0001
[0256] General Procedure for Wild-Type PRC2 Enzyme Assay on Oligonucleosome Substrate.
The assays were performed in a buffer consisting of 20 mM bicine (pH = 7.6), 0.5 mM DTT, 0.005% BSG, 100 mM KC1 and 0.002% Tween20, prepared on the day of use. Compounds in 100% DMSO (1 μί) were spotted into polypropylene 384-well V-bottom plates (Greiner) using a Platemate 2 X 3 outfitted with a 384-channel pipet head (Thermo). DMSO (l ΐ.) was added to columns 11, 12, 23, 24, rows A - H for the maximum signal control, and SAH, a known product and inhibitor of PRC2 (1 μϋ,) was added to columns 11,12, 23, 24, rows I - P for the minimum signal control. A cocktail (40 uL) containing the wild-type PRC2 enzyme and chicken erythrocyte oligonucleosome was added by Multidrop Combi (Thermo). The compounds were allowed to incubate with PRC2 for 30 min at 25 °C, then a cocktail (10 μί) containing a mixture of non-radioactive and 3H-SAM was added to initiate the reaction (final volume = 51 μϋ,). The final concentrations were as follows: wild-type PRC2 enzyme was 4 nM, non-radioactive SAM was 430 nM, 3H-SAM was 120 nM, chicken erythrocyte olignonucleosome was 120 nM, SAH in the minimum signal control wells was 1 mM and the DMSO concentration was 1%. The assay was stopped by the addition of non-radioactive SAM (10 uL) to a final concentration of 600 uM, which dilutes the 3H-SAM to a level where its incorporation into the chicken erythrocyte olignonucleosome substrate is no longer detectable. 50 uL of the reaction in the 384-well polypropylene plate was then transferred to a 384-well Flashplate and the chicken erythrocyte nucleosomes were immobilized to the surface of the plate, which was then washed three times with 0.1 % Tween20 in a Biotek ELx405 plate washer. The plates were then read in a PerkinElmer TopCount platereader to measure the quantity of 3H-labeled chicken erythrocyte ohgonucleosome bound to the Flashplate surface, measured as disintegrations per minute (dpm) or alternatively, referred to as counts per minute (cpm).
[0257] % Inhibition Calculation
[0258] Where dpm = disintegrations per minute, cmpd
the respective minimum and maximum signal controls.
[0259] Four-parameter IC5o fit
Figure imgf000234_0002
[0260] Where top and bottom are the normally allowed to float, but may be fixed at 100 or 0 respectively in a 3-parameter fit. The Hill Coefficient normally allowed to float but may also be fixed at 1 in a 3-parameter fit. Y is the % inhibition and X is the compound concentration.
[0261] IC50 values for the PRC2 enzyme assays on peptide substrates (e.g., EZH2 wild type andY641F) are presented in Tables 3A and 3B below.
[0262] WSU-DLCL2 Methylation Assay
[0263] WSU-DLCL2 suspension cells were purchased from DSMZ (German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany). RPMI/Glutamax Medium, Penicillin- Streptomycin, Heat Inactivated Fetal Bovine Serum, and D-PBS were purchased from Life Technologies, Grand Island, NY, USA. Extraction Buffer and Neutralization Buffer(5X) were purchased from Active Motif, Carlsbad, CA, USA. Rabbit anti-Histone H3 antibody was purchased from Abeam, Cambridge, MA, USA. Rabbit anti-H3K27me3 and HRP-conjugated anti-rabbit-IgG were purchased from Cell Signaling Technology, Danvers, MA, USA. TMB "Super Sensitive" substrate was sourced from BioFX Laboratories, Owings Mills, MD, USA. IgG-free Bovine Serum Albumin was purchased from Jackson ImmunoResearch, West Grove, PA, USA. PBS with Tween (10X PBST) was purchased from KPL, Gaithersburg, MD, USA. Sulfuric Acid was purchased from Ricca Chemical, Arlington, TX, USA. Immulon ELISA plates were purchased from Thermo, Rochester, NY, USA. V-bottom cell culture plates were purchased from Coming Inc., Corning, NY, USA. V-bottom polypropylene plates were purchased from Greiner Bio-One, Monroe, NC, USA.
[0264] WSU-DLCL2 suspension cells were maintained in growth medium (RPMI 1640 supplemented with 10% v/v heat inactivated fetal bovine serum and 100 units/niL penicillin- streptomycin) and cultured at 37 °C under 5% CC¾. Under assay conditions, cells were incubated in Assay Medium (RPMI 1640 supplemented with 20% v/v heat inactivated fetal bovine serum and 100 units/mL penicillin-streptomycin) at 37 °C under 5% CO2 on a plate shaker.
[0265] WSU-DLCL2 cells were seeded in assay medium at a concentration of 50,000 cells per mL to a 96-well V-bottom cell culture plate with 200 per well. Compound (Ιμΐ,) from 96 well source plates was added directly to V-bottom cell plate. Plates were incubated on a titer-plate shaker at 37 °C, 5% CO2 for 96 hours. After four days of incubation, plates were spun at 241 x g for five minutes and medium was aspirated gently from each well of cell plate without disturbing cell pellet. Pellet was resuspended in 200 L DPBS and plates were spun again at 241 x g for five minutes. The supernatant was aspirated and cold (4 °C) Extraction buffer ( 100 iL) was added per well. Plates were incubated at 4 °C on orbital shaker for two hours. Plates were spun at 3427 x g x 10 minutes. Supernatant (80 \i per well) was transferred to its respective well in 96 well V-bottom polypropylene plate. Neutralization Buffer 5X (20 L per well) was added to V-bottom polypropylene plate containing supernatant. V-bottom polypropylene plates containing crude histone preparation (CHP) were incubated on orbital shaker x five minutes. Crude Histone Preparations were added (2μί per well) to each respective well into duplicate 96 well ELISA plates containing 100
Figure imgf000235_0001
Coating Buffer (IX PBS + BSA 0.05% w/v). Plates were sealed and incubated overnight at 4 °C. The following day, plates were washed three times with 300 per well IX PBST. Wells were blocked for two hours with 300 μΐ per well ELISA Diluent ((PBS (IX) BSA (2% w/v) and Tween20 (0.05% v/v)). Plates were washed three times with IX PBST. For the Histone H3 detection plate, 100 μΐ^ ετ well were added of anti-Histone-H3 antibody (Abeam, abl791) diluted 1:10,000 in ELISA Diluent. For H3K27 trimethylation detection plate, 100 iL per well were added of anti- H3 27me3 diluted 1 :2000 in ELISA diluent. Plates were incubated for 90 minutes at room temperature. Plates were washed three times with 300
Figure imgf000235_0002
IX PBST per well. For Histone H3 detection, 100 μL of HRP -conjugated anti-rabbit IgG antibody diluted to 1 :6000 in ELISA diluent was added per well. For H3K27me3 detection, 100 μΐ^ of HRP conjugated anti-rabbit IgG antibody diluted to 1 :4000 in ELISA diluent was added per well. Plates were incubated at room temperature for 90 minutes. Plates were washed four times with IX PBST 300 ΐ. per well. TMB substratelOO μΐ, was added per well. Histone H3 plates were incubated for five minutes at room temperature. H3 27me3 plates were incubated for 10 minutes at room temperature. The reaction was stopped with sulfuric acid IN (100 \iL per well). Absorbance for each plate was read at 450 nm.
Figure imgf000236_0001
[0267] Each plate included eight control wells of DMSO only treatment (Minimum Inhibition) as well as eight control wells for maximum inhibition (Background wells).
[0268] The average of the ratio values for each control type was calculated and used to determine the percent inhibition for each test well in the plate. Test compound was serially diluted three-fold in DMSO for a total of ten test concentrations, beginning at 25 uM. Percent inhibition was determined and IC50 curves were generated using duplicate wells per concentration of compound. IC50 values for this assay are presented in Tables 3A and 3B below.
[0269] Percent Inhibition = 100-
Figure imgf000236_0002
[0270] Cell proliferation analysis
[0271] WSU-DLCL2 suspension cells were purchased from DSMZ (German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany). RPMI/Glutamax Medium, Penicillin- Streptomycin, Heat Inactivated Fetal Bovine Serum were purchased from Life Technologies, Grand Island, NY, USA. V-bottom polypropylene 384-well plates were purchased from Greiner Bio-One, Monroe, NC, USA. Cell culture 384-well white opaque plates were purchased from Perkin Elmer, Waltham, MA, USA. Cell-Titer Glo® was purchased from Promega Corporation, Madison, WI, USA. SpectraMax M5 plate reader was purchased from Molecular Devices LLC, Sunnyvale, CA,
USA.
[0272] WSU-DLCL2 suspension cells were maintained in growth medium (RPMI 1640 supplemented with 10% v/v heat inactivated fetal bovine serum and cultured at 37 °C under 5% CO2. Under assay conditions, cells were incubated in Assay Medium (RPMI 1640 supplemented with 20% v/v heat inactivated fetal bovine serum and 100 units/mL penicillin-streptomycin) at 37 °C under 5% co2.
[0273] For the assessment of the effect of compounds on the proliferation of the WSU-DLCL2 cell line, exponentially growing cells were plated in 384-well white opaque plates at a density of 1250 cell/ml in a final volume of 50 μΐ of assay medium. A compound source plate was prepared by performing triplicate nine-point 3-fold serial dilutions in DMSO, beginning at 10 mM (final top concentration of compound in the assay was 20 μΜ and the DMSO was 0.2%). A 100 nL aliquot from the compound stock plate was added to its respective well in the cell plate. The 100% inhibition control consisted of cells treated with 200 nM final concentration of staurosponne and the 0% inhibition control consisted of DMSO treated cells. After addition of compounds, assay plates were incubated for 6 days at 37 °C, 5% CO2, relative humidity > 90% for 6 days. Cell viability was measured by quantization of ATP present in the cell cultures, adding 35 μΐ of Cell Titer Glo® reagent to the cell plates. Luminescence was read in the SpectraMax M5. The concentration inhibiting cell viability by 50% was determined using a 4-parametric fit of the normalized dose response curves. IC50 values for this assay are also presented in Tables 3A and 3B below. The mass spectral data for these compounds are also listed in Tables 3 A and 3B below.
Table 3A
Figure imgf000237_0001
13 > 50.0 uM 611.82
14 17.08469 625.84
15 0.00486 0.34641 0.33988 573.77
16 0.00596 0.67511 0.28656 589.77
17 0.01288 0.50666 0.40245 590.76
18 0.00859 0.55322 574.76
19 0.00981 588.78
20 <0.005 590.76
21 0.01011 1.39074 0.84001 574.76
22 0.02825 1.03851 560.73
23 <0.005 0.40058 562.75
24 <0.005 661.88
25 0.0089 2.21876 0.64998 566.77
26 <0.005 0.138 0.087 657.89
157 <0.005 0.140 544.727
158 <0.005 0.215 558.754
159 <0.005 0.262 560.727
160 0.014 0.094 587.795
161 <0.005 0.034 627.783
162 0.012 573.769
163 <0.005 0.043 534.69
105 0.0084 0.325 0.150 518.69 Table 3B
Figure imgf000239_0001
146 0.16112 0.21694 <0.01 641.4417
128 1.55449 0.9747 <0.01 543.2457
127 0.52523 0.71702 <0.01 533.3002
150 0.37722 0.36055 <0.01 642.4257
145 0.08424 0.18514 <0.01 614.3944
147 0.07432 0.11609 <0.01 628.4101
148 0.5036 0.24287 <0.01 614.3944
151 0.61791 0.68226 <0.01 600.3788
131 0.30571 0.19355 j <0.01 560.3111
152 0.06 0.412 0.018 559.3522
143 0.018 0.276 <0.01 614.3944
144 0.092 1.539 <0.01 586.3631
149 0.02 0.316 <0.01 614.4057
132 0.177 0.526 0.02 588.3424
106 0.044 0.188 O.Ol 518.3257
107 0.028 0.0262 0.011 504.31
108 0.042 0.438 O.Ol 575.3835
101 0.126 0.536 .01 575.3835
105 0.058 0.325 .Ol 518.3257
104 0.066 0.549 O.Ol 532.3413
102 0.256 0.614 0.01 590.3832
103 0.232 0.745 O.Ol 590.3832
109 0.244 1.064 O.Ol 547.3522
110 2.007 2.452 .Ol 575.3835 142 0.699 1.996 627.3032
136 0.259 0.566 628.4101
137 0.056 0.505 586.3631
155 560.2999
111 0.014 0.201 <0.005 561.3679
112 0.179 0.798 588.4152
140 0.716 615.3785
153 0.476 604.3425
133 0.503 587.3472
134 559.3159
[0274] Example 3: Derivation of the Lowest Cytotoxic Concentration (LCC)
[0275] It is well established that cellular proliferation proceeds through cell division that results in a doubling of the number of cells after division, relative to the number of cells prior to division. Under a fixed set of environmental conditions (e.g., pH, ionic strength, temperature, cell density, medium content of proteins and growth factors, and the like) cells will proliferate by consecutive doubling (i.e., division) according to the following equation, provided that sufficient nutrients and other required factors are available.
j_
[0276] Nt = N0 x 2' (A.1)
where Nt is the cell number at a time point (t) after initiation of the observation period, No is the cell number at the initiation of the observation period, t is the time after initiation of the observation period and to is the time interval required for cell doubling, also referred to as the doubling time. Equation A.1 can be converted into the more convenient form of an exponential equation in base e, taking advantage of the equality, 0.693 = ln(2).
[0277] N, = Noe (A.2)
[0278] The rate constant for cell proliferation (kp) is inversely related to the doubling time as follows. 0.693
[0279] K = (A.3)
t D
[0280] Combining equation A.2 and A.3 yields,
Figure imgf000242_0001
[0282] Thus, according to equation A.4 cell number is expected to increase exponentially with time during the early period of cell growth referred to as log-phase growth. Exponential equations like equation A.4 can be linearized by taking the natural logarithm of each side.
[0283] (A.5)
[0284] Thus a plot of ln( t) as a function of time is expected to yield an ascending straight line with . slope equal to kp and y-intercept equal to ln(No).
[028S] Changes in environmental conditions can result in a change in the rate of cellular proliferation that is quantifiable as changes in the proliferation rate constant kp. Among conditions that may result in a change in proliferation rate is the introduction to the system of an antiproliferative compound at the initiation of the observation period (i.e., at t = 0). When an antiproliferative compound has an immediate impact on cell proliferation, one expects that plots of ln(Nt) as a function of time will continue to be linear at all compound concentrations, with diminishing values of kp at increasing concentrations of compound.
[0286] Depending on the mechanistic basis of antiproliferative action, some compounds may not immediately effect a change in proliferation rate. Instead, there may be a period of latency before the impact of the compound is realized. In such cases a plot of ln(Nt) as a function of time will appear biphasic, and a time point at which the impact of the compound begins can be identified as the breakpoint between phases. Regardless of whether a compound's impact on proliferation is immediate or begins after a latency period, the rate constant for proliferation at each compound concentration is best defined by the slope of the ln(Nt) vs. time curve from the time point at which compound impact begins to the end of the observation period of the experiment.
[0287] A compound applied to growing cells may affect the observed proliferation in one of two general ways: by inhibiting further cell division (cytostasis) or by cell killing (cytotoxicity). If a compound is cytostatic, increasing concentration of compound will reduce the value of kp until there is no further cell division. At this point, the rate of cell growth, and therefore the value of kp, will be zero. If, on the other hand, the compound is cytotoxic, then the value of kp will be composed of two rate constants: a rate constant for continued cell growth in the presence of the compound (kg) and a rate constant for cell killing by the compound (kd). The overall rate constant for proliferation at a fixed concentration of compound will thus be the difference between the absolute values of these opposing rate constants.
Figure imgf000243_0001
[0289] At compound concentrations for which the rate of cell growth exceeds that of cell killing, the value of kp will have a positive value (i.e., kp > 0). At compound concentrations for which the rate of cell growth is less than that for cell killing, the value of kp will have a negative value (i.e., kp < 0) and the cell number will decrease with time, indicative of robust cytotoxicity. When kg exactly matches kd then the overall proliferation rate constant, kp, will have a value of zero. We can thus define the lowest cytotoxic concentration (LCC) as that concentration of compound that results in a value of kp equal to zero, because any concentration greater than this will result in clearly observable cytotoxicity. Nota bene: at concentrations below the LCC there is likely to be cell killing occurring, but at a rate that is less than that of residual cell proliferation. The treatment here is not intended to define the biological details of compound action. Rather, the goal here is to merely define a practical parameter with which to objectively quantify the concentration of compound at which the rate of cell killing exceeds new cell growth. Indeed, the LCC represents a breakpoint or critical concentration above which frank cytotoxicity is observed, rather than a cytotoxic concentration per se. In this regard, the LCC can be viewed similar to other physical breakpoint metrics, such as the critical micelle concentration (CMC) used to define the concentration of lipid, detergent or other surfactant species above which all molecules incorporate into micellar structures.
[0290] Traditionally, the impact of antiproliferative compounds on cell growth has been most commonly quantified by the IC50 value, which is defined as that concentration of compound that reduces the rate of cell proliferation to one half that observed in the absence of compound (i.e., for the vehicle or solvent control sample). The IC50, however, does not allow the investigator to differentiate between cytostatic and cytotoxic compounds. The LCC, in contrast, readily allows one to make such a differentiation and to further quantify the concentration at which the transition to robust cytotoxic behavior occurs.
[0291] If one limits the observation time window to between the start of impact and the end of the experiment, then the data will generally fit well to a linear equation when plotted as ln(Nt) as a function of time {vide supra). From fits of this type, the value of kp can be determined at each concentration of compound tested. A rep lot of the value of kp as a function of compound concentration ([I]) will have the form of a descending isotherm, with a maximum value at [I] = 0 of k (defined by the vehicle or solvent control sample) and a minimum value at infinite compound concentration of km;n.
Figure imgf000244_0001
where Ilma is the concentration of compound yielding a value of kp that is midway between the values of kmax and kmm (note that the value of Imjd is not the same as the IC50, except in the case of a complete and purely cytostatic compound). Thus, fitting the replot data to equation A.7 provides estimates of kma¾ kmin and Imid- If a compound is cytostatic (as defined here), the value of krai„ cannot be less than zero. For cytotoxic compounds, kraj„ will be less than zero and the absolute value of kmjn will relate directly to the effectiveness of the compound in killing cells.
[0293] The fitted values derived from equation A.7 can also be used to determine the value of the LCC. By definition, when [I] = LCC, kp = 0. Thus, under these conditions equation A.7 becomes.
(^rnax ^min )
[0294] LCC (A.8)
1 +
l mid
[0295] Algebraic rearrangement of equation A.8 yields an equation for the LCC.
Figure imgf000244_0002
[0297] This analysis is simple to implement with nonlinear curve fitting software and may be applied during cellular assays of compound activity throughout the drug discovery and development process. In this manner, the LCC may provide a valuable metric for the assessment of compound SAR (structure-activity relationship).
[0298] Example 4: In vivo Assays
Mice
[0299] Female Fox Chase SCID* Mice (CB 17/Icr-.Pr/Wc IcrIcoCrl, Charles River Laboratories) or athymic nude mice (Crl:NU(Ncr)- ox Charles River Laboratories) are 8 weeks old and had a body-weight (BW) range of 16.0-21.1 g on Dl of the study. The animals are fed ad libitum water (reverse osmosis 1 ppm CI) and NTH 31 Modified and Irradiated Lab Diet® consisting of 18.0% crude protein, 5.0% crude fat, and 5.0% crude fiber. The mice are housed on irradiated Enrich- o'cobs™ bedding in static microisolators on a 12-hour light cycle at 20-22 °C (68-72 °F) and 40- 60% humidity. All procedures comply with the recommendations of the Guide for Care and Use of Laboratory Animals with respect to restraint, husbandry, surgical procedures, feed and fluid regulation, and veterinary care. Tumor Cell Culture
[0300] Human lymphoma cell lines line are obtained from different sources (ATCC, DSMZ), e.g., WSU-DLCL2 obtained from DSMZ. The cell lines are maintained at Piedmont as suspension cultures in RPMI-1640 medium containing 100 units/mL penicillin G sodium salt, 100 g/mL streptomycin, and 25 g/mL gentamicin. The medium is supplemented with 10% fetal bovine serum and 2 mM glutamine. The cells are cultured in tissue culture flasks in a humidified incubator at 37 °C, in an atmosphere of 5% CO2 and 95% air.
In Vivo Tumor Implantation
[0301] Human lymphoma cell lines, e.g., WSU-DLCL2 cells, are harvested during mid-log phase growth, and re-suspended in PBS with 50% Matrigel™ (BD Biosciences). Each mouse receives 1 x 107 cells (0.2 mL cell suspension) subcutaneously in the right flank. Tumors are cal pered in two dimensions to monitor growth as the mean volume approached the desired 80-120 mm3 range. Tumor size, in mm3, is calculated from:
2 x ί
Tumor volume =
2
where w = width and / = length, in mm, of the tumor. Tumor weight can be estimated with the assumption that 1 mg is equivalent to 1 mrtu of tumor volume. After 10-30 days mice with 108-126 mm3 tumors are sorted into treatment groups with mean tumor volumes of 117-119 mm3.
Test Articles
[0302] Test compounds are stored at room temperature and protected from light. On each treatment day, fresh compound formulations are prepared by suspending the powders in 0.5% sodium carboxymethylcellulose (NaCMC) and 0.1% Tweenm 80 in deionized water. Compound 141 (free base) is dissolved in sterile saline and the pH is adjusted to 4.5 with HC1 fresh every day. The vehicles, 0.5% NaCMC and 0.1% Tween* 80 in deionized water or sterile saline pH 4.5, are used to treat the control groups at the same schedules. Formulations are stored away from light at 4 °C prior to administration. Unless otherwise specified, compounds referered to and tested in this experiment are in their specific salt forms mentioned in this paragraph.
Treatment Plan
[0303] Mice are treated at compound doses ranging from 12.5 - 600 mg/kg and at TID (three time a day every 8h), BID (2 times a day every 12 h) or QD (once a day) schedules for various amounts of days by oral gavage or injections via the intraperitoneal route. Each dose is delivered in a volume of 0.2 mL/20 g mouse (10 mL/kg), and adjusted for the last recorded weight of individual animals. The maximal treatment length is 28 days.
Median Tumor Volume (MTV) and Tumor Growth Inhibition (TGI) Analysis
[0304] Treatment efficacy is determined on the last treatment day. MTV(n), the median tumor volume for the number of animals, n, evaluable on the last day, is determined for each group. Percent tumor growth inhibition (%TGI) can be defined several ways. First, the difference between the MTV(n) of the designated control group and the TV(n) of the drug-treated group is expressed as a percentage of the MTV(n) of the control group:
V MTY(n}eBarBl }
[0305] Another way of calculating %TGI is taking the change of the tumor size from day 1 to day n into account with n being the last treatment day.
%TGI = i x loo
HMTV„
AMTVmttrBl = MTV(n)contral- MTV(i}mi
^M7Versaced ~ MTV 1 treated ~ MTV{1)
Toxicity
[0306] Animals are weighed daily on Days 1-5, and then twice weekly until the completion of the study. The mice are examined frequently for overt signs of any adverse, treatment related side effects, which are documented. Acceptable toxicity for the maximum tolerated dose (MTD) is defined as a group mean BW loss of less than 20% during the test, and not more than 10% mortality due to TR deaths. A death is to be classified as TR if it is attributable to treatment side effects as evidenced by clinical signs and/or necropsy, or due to unknown causes during the dosing period. A death is to be classified as NTR if there is evidence that the death is unrelated to treatment side effects. NTR deaths during the dosing interval would typically be categorized as NTRa (due to an accident or human error) or NTRm (due to necropsy-confirmed tumor dissemination by invasion and/or metastasis). Orally treated animals that die from unknown causes during the dosing period may be classified as NTRu when group performance does not support a TR classification and necropsy, to rule out a dosing error, is not feasible. Sampling
[0307] On days 7 or 28 during the studies mice are sampled in a pre-specified fashion to assess target inhibition in tumors. Tumors are harvested from specified mice under RNAse free conditions and bisected. Frozen tumor tissue from each animal is snap frozen in liquid N2 and pulverized with a mortar and pestle.
Statistical and Graphical Analyses
[0308] All statistical and graphical analyses are performed with Prism 3.03 (GraphPad) for Windows. To test statistical significance between the control and treated groups over the whole treatment time course a repeated measures ANOVA test followed by Dunnets multiple comparison post test or a 2 way ANOVA test are employed. Prism reports results as non-significant (ns) at P >
0.05, significant (symbolized by "*") at 0.01 < P < 0.05, very significant ("**") at 0.001 < P < 0.01 and extremely significant ("***") at P < 0.001.
Histone Extraction
[0309] For isolation of histones, 60-90 mg tumor tissue is homogenized in 1.5 ml nuclear extraction buffer (10 mM Tris-HCl, 10 mM MgCl2, 25 mM KCl, 1 % Triton X-100, 8.6% Sucrose, plus a Roche protease inhibitor tablet 1836145) and incubated on ice for 5 minutes. Nuclei are collected by centrifugation at 600 g for 5 minutes at 4 °C and washed once in PBS. Supernatant is removed and histones extracted for one hour, with vortexing every 15 minutes, with 0.4 N cold sulfuric acid. Extracts are clarified by centrifugation at 10,000 g for 10 minutes at 4 °C and transferred to a fresh microcentrifuge tube containing lOx volume of ice cold acetone. Histones are precipitated at -20 °C for 2 hours-overnight, pelleted by centrifugation at 10,000 g for 10 minutes, and resuspended in water.
ELISA
[0310] Histones are prepared in equivalent concentrations in coating buffer (PBS+0.05%BSA) yielding 0.5 ng/ul of sample, and 100 ul of sample or standard is added in duplicate to 2 96-well ELISA plates (Thermo Labsystems, Immulon 4HBX #3885). The plates are sealed and incubated overnight at 4 °C. The following day, plates are washed 3x with 300 ul/well PBST (PBS+0.05% Tween 20; 10X PBST, KPL #51-14-02) on a Bio Tek plate washer. Plates are blocked with 300 ul/well of diluent (PBS+2%BSA+0.05% Tween 20), incubated at RT for 2 hours, and washed 3x with PBST. All antibodies are diluted in diluent. 100 uVwell of anti-H3K27me3 (CST #9733, 50% glycerol stock 1:1,000) or anti-total H3 (Abeam abl791, 50% glycerol 1:10,000) is added to each plate. Plates are incubated for 90 min at RT and washed 3x with PBST. 100 ul/well of anti-Rb-IgG- HRP (Cell Signaling Technology, 7074) is added 1:2,000 to the H3K27Me3 plate and 1:6,000 to the H3 plate and incubated for 90 min at RT. Plates are washed 4X with PBST. For detection, 100 ul/well of 1MB substrate (BioFx Laboratories, #TMBS) is added and plates incubated in the dark at RT for 5 min. Reaction is stopped with 100 ul/well IN H2SO4. Absorbance at 450 nm is read on SpectaMax M5 Microplate reader.
7 day PD study
[031 1] In order to test whether a compound can modulate the H3K27me3 histone mark in tumors in vivo, WSU-DLCL2 xenograft tumor bearing mice are treated with the compound at either 200 mg/kg BID or 400 mg kg QD or vehicle (BID schedule) for 7 days. There are 4 animals per group. Animals are euthanized 3 h after the last dose and tumor is preserved in a frozen state as described above. Following histone extraction the samples are applied to ELISA assays using antibodies directed against the trimethylated state of histone H3K27 (H3 27me3) or total histone H3. Based on these data the ratio of globally methylated to total H3K27 is calculated. The mean global methylation ratios for all groups as measured by ELISA indicate target inhibition range compared to vehicle.
28 day efficacy study in WSU-DLCL2 xenograft model
[0312] In order to test whether a compound could induce a tumor growth inhibition in vivo WSU- DLCL2 xenograft tumor bearing mice are treated with the compound at 12.5, 25 or 50 mg kg QD for 28 days via intraperitoneal injection. Tumor volume and body weights are determined twice a week. A parallel cohort of mice (n=4 per group) is treated at the same doses for 7 days, and mice are euthanized on day 7, 3 h after the last dose for tumor sampling and assessment of target inhibition. The result of the ELISA measuring global methylation of H3K27me3 normalized to total H3 is determined.
Efficacy study with increasing doses in WSU-DLCL2 xenograft model
[0313] In order to test whether a compound could induce an anti-tumor effect in vivo, WSU-DLCL2 xenograft tumor bearing mice are treated with a compound at, e.g., 37.5, 75 or 150 mg/kg TID for 28 days. There are 12 mice per group for the efficacy arm of the experiment. A parallel cohort is dosed for 7 days at the same doses and schedules for assessment of target inhibition after 7 days (n=6 per group). The tumor growth over the treatment course of 28 days for vehicle and compound treated groups is measured.
[0314] Histones are extracted from tumors collected after 7 days of dosing (parallel PD cohort) and at the end of the study on day 28 for the efficacy cohort (3h after the last dose for both cohorts). The H3K27me3 methyl mark is assessed for modulation with treatment in a dose dependent matter.
Efficacy study at different dose schedules [0315] To assess whether a compound would lead to tumor growth inhibition at other dosing schedules but TID a WSU-DLCL2 xenograft efficacy study is performed where TID, BID and QD schedules are compared side by side. There are 12 animals per group, and mice are treated for 28 days. The tumor growth over the treatment course of 28 days for vehicle and compound treated groups is measured.
[0316] On day 28 mice are euthanized and tumors are collected 3h after the last dose for assessment of target inhibition.
[0317] Example 5: Anti-cancer effect on the KARPAS-422 human diffused large B-Cell lymphoma mouse xenograft model
[0318] A test compound is analyzed for its anti-cancer activity in KARPAS-422 mouse xenograft model, which is a human diffused large B-Cell lymphoma xenograft model. 45 female of CAnN.Cg- Foxnlnu/CrlCrlj mice (Charles River Laboratories Japan) with KARPAS-422 tumors whose mean tumor volume (TV) reached approximately 150 mm3 are selected based on their TVs, and are randomly divided into five groups. The oral administration of compound (e.g., 80.5, 161, 322, and 644 mg kg) or vehicle is started on day 1. Compound is given once daily on day 1 and day 29 and twice daily everyday from day 2 to day 28. The administration volume (0.1 mL/10 g body weight) is calculated from the body weight before administration. The TV and body weight are measured twice a week. The design for this experiment is shown in Table 4.
Table 4 Dosin Scheme
Figure imgf000249_0001
[031 ] TV is calculated from caliper measurements by the formula for the volume of a prolate ellipsoid (LxW2)/2 where L and W are the respective orthogonal length and width measurements (mm).
[0320] Data are expressed as the mean ± standard deviation (SD). The differences in TV between the vehicle-treated and compound -treated groups are analyzed by a repeated measures analysis of variance (ANOVA) followed by the Dunnett-type multiple comparison test. A value of P < 0.05 (two sided) is considered statistically significant. Statistical analyses are performed using the Prism 5 software package version 5.04 (GraphPad Software, Inc., CA, USA).
[0321] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.
[0322] The invention can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

What is claimed is:
1. A compound of Formula III:
Figure imgf000251_0001
(III)
or a pharmaceutically acceptable salt thereof; wherein
R801 is Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3_8 cycloalkyl, 4-7 membered heterocycloalkyl containing 1 -3 heteroatoms, phenyl or 5- or 6-membered heteroaryl, each of which is substituted with 0-Cj_6 alkyl-Rx or NH-C].6 alkyl-Rx, wherein Rx is hydroxyl, 0-C]_3 alkyl or NH-Ci alkyl, and Rx is optionally further substituted with 0-Ci_3 alkyl or NH-C1.3 alkyl except when Rx is hydroxyl; and R801 is optionally further substituted;
each of R802 and R803, independently is H, halo, C alkyl, C].6 alkoxyl or C6-Cio aryloxy, each optionally substituted with one or more halo;
each of R804 and R805, independently is CM alkyl; and
R806 is -Qx-Tx, wherein Qx is a bond or C1.4 alkyl linker, Tx is H, optionally substituted C1.4 alkyl, optionally substituted C3-C8 cycloalkyl or optionally substituted 4- to 14-membered
heterocycloalkyl, provided that the compound is not
Figure imgf000251_0002
2. The compound of claim 1 , wherein Qx is a bond or methyl linker, and Tx is
tetrahydropyranyl, piperidinyl substituted by 1 , 2, or 3 C1-4 alkyl groups, or cyclohexyl substituted by N(Ci-4 alkyl)2 wherein one or both of the C alkyl is optionally substituted with Ci-6 alkoxy.
3. The compound of claim 1 , wherein R is cyclohexyl substituted by N(Ci.4 alkyl)2.
4. The compound of claim 1, wherein R
Figure imgf000252_0001
5. The compound of any of claims 1-4, wherein R801 is phenyl or 5- or 6-membered heteroaryl substituted with 0-Ci_6 alkyl-Rx.
6. The compound of claim 1, wherein the compound is of Formula IVa or IVb:
wherein Z' is CH or N, and Rsu is C2-3 alkyl-Rx.
7. The compound of claim 6, wherein R807 is -CH2CH2OH, -CH2CH2OCH3, or
-CH2CH2OCH2CH2OCH3.
8. The compound of any of claims 1-7, wherein R802 is methyl or isopropyl and R803 is methyl or methoxyl.
9. The compound of any of claims 1 -8, wherein R804 is methyl.
10. A compound of Formula I:
Figure imgf000253_0001
(I)
or a pharmaceutically acceptable salt thereof; wherein
R701 is H, F, OR707, NHR707, -(C≡C)-(CH2)n7-R708, phenyl, 5- or 6-membered heteroaryl, C3-8 cycloalkyl, or 4-7 membered heterocycloalkyl containing 1 -3 heteroatoms, wherein the phenyl, 5- or 6-membered heteroaryl, C3.8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is optionally substituted with one or more groups selected from halo, Ci-3 alkyl, OH, 0-Ci.6 alkyl, NH- Ci_6 alkyl, and, Ci_3 alkyl substituted with C3-8 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein each of the 0-Ci_6 alkyl and NH-Ci-6 alkyl is optionally substituted with hydroxyl, 0-Ci_3 alkyl or NH-Ci_3 alkyl, each of the 0-Ci-3 alkyl and NH-Ci_3 alkyl being optionally further substituted with 0-Q_3 alkyl or NH-Q. alkyl;
each of R702 and R703, independently is H, halo, C alkyl, Ci-6 alkoxyl or C6-Cio aryloxy, each optionally substituted with one or more halo;
each of R704 and R705, independently is C1-4 alkyl;
R706 is cyclohexyl substituted by N(Ci_4 alkyl)2 wherein one or both of the C alkyl is substituted with Ci_6 alkoxy; or R 706 is tetrahydropyranyl;
R707 is Ci_4 alkyl optionally substituted with one or more groups selected from hydroxyl, Ci-4 alkoxy, amino, mono- or di-Ci_4 alkylamino, C3-8 cycloalkyl, and 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the C3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is further optionally substituted with Q_3 alkyl;
R708 is Ci-4 alkyl optionally substituted with one or more groups selected from OH, halo, and Ci_4 alkoxy, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, or 0-Ci_6 alkyl, wherein the 4-7 membered heterocycloalkyl can be optionally further substituted with OH or Ci-6 alkyl; and d that the compound is not
Figure imgf000254_0001
or
Figure imgf000254_0002
1 1. The compound of claim 10, wherein R is cyclohexyl substituted by N(Ci_4 alkyl)2 wherein one of the C alkyl is unsubstituted and the other is substituted with methoxy.
12. The compound of claim 10, wherein R is
Figure imgf000254_0003
13. The compound of claim 10, wherein the compound is of Formula II:
Figure imgf000254_0004
(II).
14. The compound of any of claims 10-13, wherein R is methyl or isopropyl and R is methyl or methoxyl.
15. The compound of any of claims 10-14, wherein R704 is methyl.
16. The compound of any of claims 10-15, wherein R701 is OR707 and R707 is Ci- alkyl optionally substituted with OC¾ or morpholine.
17. The compound of any of claims 10-15, wherein R701 is H or F.
18. The compound of any of claims 10-15, wherein R701 is tetrahydropyranyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with methyl, methoxy, ethyl substituted with morpholine, or -OCH2CH2OCH3.
19. The compound of any of claims 10-18, wherein R708 is morpholine, piperidine, piperazine, pyrrolidine, diazepane, or azetidine, each of which is optionally substituted with OH or C]-6 alkyl.
20. The compound of any of claims 10-18, wherein R708 is morpholine
21. The compound of any of claims 10-18, wherein R708 is piperazine substituted with Ci-6 alkyl.
22. The compound of any of claims 10-18, wherein R708 is methyl, t-butyl or C(CH3)2OH.
23. A compound of Formul
Figure imgf000255_0001
(VI)
or a pharmaceutically acceptable salt thereof;
wherein
n5 is 0, 1, or 2; R501 is C(H) or N;
R502, R503, R504 and R505 are, independently for each occurrence, C alkyl;
R506 is cyclohexyl substituted by N(C]-4 alkyl)2 or piperidine substituted by 1 , 2, or 3 Cj.4 alkyl groups;
when R501 is C(H), R507 is morpholine; piperidine; diazepane; pyrrolidine; azetidine; O-Ci- alkyl; or O-heterocycle, wherein the heterocycle is a 4-7 membered heterocycle containing an oxygen or nitrogen, or both, and wherein the nitrogen can optionally be substituted with Ci-3 alkyl; wherein the piperidine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH, Ci-6 alkyl, or 0-Ci-3 alkyl;
or when R501 is C(H), R507 can be piperazine optionally further substituted with C1-6 alkyl, provided that R506 is piperidine substituted by 1 , 2, or 3 Ci„4 alkyl groups;
when R501 is N, R507 is morpholine; piperidine; piperazine; diazepane; pyrrolidine; azetidine; 0-Ci„6 alkyl; or O-heterocycle, wherein the heterocycle is a 4-7 membered heterocycle containing an oxygen or nitrogen, or both, and wherein the nitrogen can optionally be substituted with Ci-3 alkyl; wherein the piperidine, piperazine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH, Ci-6 alkyl, or 0-Ci_3 alkyl.
24. The compound of claim 23, wherein R50 ! is C(H), and R507 is piperidine; diazepane;
pyrrolidine; azetidine; 0-Ci_ alkyl; or O-heterocycle, wherein the heterocycle is a 4-7 membered heterocycle containing an oxygen or nitrogen, or both, and wherein the nitrogen can optionally be substituted with Ci_3 alkyl; wherein the piperidine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH, Ci-6 alkyl, or 0-Ci.3 alkyl.
25. The compound of claim 23, wherein R50' is C(H) and R507 is piperidine, diazepane, pyrrolidine, azetidine or O-Cj. alkyl, wherein the piperidine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH or Ci-6 alkyl.
26. The compound of claim 23, wherein R50' is C(H), R507 is piperazine optionally further substituted with Ci-6 alkyl, and R506 is piperidine substituted by 1 , 2, or 3 C alkyl groups.
27. The compound of claim 23, wherein R501 is N, and R507 is morpholine, piperidine, piperazine, diazepane, pyrrolidine, azetidine or 0-C]-6 alkyl, wherein the piperidine, piperazine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH or Ci-6 alkyl.
28. The compound of claim 23, wherein R502 is methyl or isopropyl, and R503 is methyl.
29 The compound of any of claims 23-28, wherein R is methyl.
The compound of any of claims 23-29, wherein R is ethyl.
31. The compound of any of claims 23-30 wherein R is
Figure imgf000257_0001
32. The compound of any of claims 23-30, R is
Figure imgf000257_0002
33. The compound of any of claims 23-32, wherein when R is C(H), R is piperidine or diazepane, which are substituted with OH or Ci_6 alkyl, or when R501 is N, R507 is piperidine, piperazine, or diazepane, which are optionally further substituted with OH or Ci.6 alkyl.
34. The compound of any of claims 23-33, wherein when R501 is C(H), R307 is piperidine substituted with Ci_6 alkyl, or when RM is N, R507 is piperidine substituted with OH or piperazine substituted with Ci_6 alkyl.
35. The compound of any of the claims 23-34, wherein when R501 is N, R507 is unsubstituted piperazine.
36. The compound of claims 23-35, wherein ¾ is 0 or 1.
37. The compound of claim 23, wherein when R501 is C(H) or N, R507 is 0-C,.6 alkyl or O- heterocycle, and n5 is 1.
38. The compound of claim 23, wherein when R501 is C(H), R507 is unsubstituted piperazine and R506 is piperidine substituted by 1, 2, or 3 Q_4 alkyl groups.
39. A compound of Formula VII:
Figure imgf000258_0001
(VII)
or a pharmaceutically acceptable salt thereof;
wherein
ri6 is 1 or 2;
R602, R603, R604 and R605 are, independently for each occurrence, Ci-4 alkyl;
R606 is cyclohexyl substituted by N(Ci-4 alkyl)2 or piperidine substituted by 1, 2, or 3 Q alkyl groups; and
R607 is morpholine, piperidine, piperazine, pyrrolidine, diazepane, azetidine or 0-Ci.6 alkyl, wherein the piperidine, diazepane or azetidine groups can be optionally further substituted with OH or C]_6 alkyl.
40. The compound of claim 39, wherein R602 is methyl or isopropyl and R603 is methyl.
41. The compound of claim 39 or 40, wherein R604 is methyl and R605 is ethyl.
42. The compound of any
The compound of any
Figure imgf000258_0002
44. The compound of any of claims 39-43, wherein R is piperidine or diazepane, each of which is substituted with OH or Ci-6 alkyl.
45. The compound of any of claims 39-43, wherein R607 is piperidine substituted with OH.
46. The compound of any of claims 39-45, wherein is 2.
47. A compound selected from those in Tables 1 A and IB, and pharmaceutically acceptable salts thereof.
48. A pharmaceutical composition comprising a compound of any of claims 1-47 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
49. A method of treating an EZH2-mediated disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of claims 1-47 or a pharmaceutically acceptable salt thereof.
50. The method of claim 49, wherein the EZH2 -mediated disorder is cancer.
51. The method of claim 50, wherein the cancer is lymphoma, leukemia or melanoma.
52. The method of claim 50, wherein the cancer is diffuse large B-cell lymphoma (DLBCL), non- Hodgkin's lymphoma (NHL), follicular lymphoma, chronic myelogenous leukemia (CML), acute myeloid leukemia, acute lymphocytic leukemia, mixed lineage leukemia, or myelodysplastic syndromes (MDS).
53. The method of claim 50, wherein the cancer is malignant rhabdoid tumor or INIl-defecient tumor.
54. A compound of any of claims 1 -47 for use in a method of treating an EZH2-mediated disorder.
55. Use of a compound of any of claims 1-47 for the manufacture of a medicament in the treatment of an EZH2-mediated disorder.
56. A pharmaceutical composition for treating an EZH2 -mediated disorder comprising a compound of any of claims 1-47 as a main ingredient.
PCT/US2013/065127 2012-10-15 2013-10-15 Substituted benzene compounds WO2014062733A2 (en)

Priority Applications (21)

Application Number Priority Date Filing Date Title
CN201380065683.2A CN105102432B (en) 2012-10-15 2013-10-15 The benzene compound being substituted
JP2015537019A JP6461803B2 (en) 2012-10-15 2013-10-15 Substituted benzene compounds
US14/435,704 US10092572B2 (en) 2012-10-15 2013-10-15 Substituted benzene compounds
CA2888021A CA2888021A1 (en) 2012-10-15 2013-10-15 Substituted n-((2-oxo-1,2-dihydropyridin-3-yl)-methyl)-benzamide compounds and their use in the treatment of ezh2-mediated disorders
EP13846696.6A EP2906537B1 (en) 2012-10-15 2013-10-15 Substituted benzene compounds
KR1020157012673A KR102057366B1 (en) 2012-10-15 2013-10-15 Substituted benzene compounds
AU2013331381A AU2013331381B2 (en) 2012-10-15 2013-10-15 Substituted benzene compounds
NZ706739A NZ706739A (en) 2012-10-15 2013-10-15 Substituted benzene compounds
EP20161557.2A EP3725314A1 (en) 2012-10-15 2013-10-15 Substituted benzene compounds
RU2015118145A RU2658919C2 (en) 2012-10-15 2013-10-15 Substituted benzene compounds
SG11201502803VA SG11201502803VA (en) 2012-10-15 2013-10-15 Substituted benzene compounds
MX2015004722A MX353929B (en) 2012-10-15 2013-10-15 Substituted benzene compounds.
UAA201504699A UA119136C2 (en) 2012-10-15 2013-10-15 Substituted benzene compounds
BR112015008480A BR112015008480A2 (en) 2012-10-15 2013-10-15 substituted benzene compounds
IL238197A IL238197A0 (en) 2012-10-15 2015-04-12 Substituted benzene compounds
PH12015500825A PH12015500825A1 (en) 2012-10-15 2015-04-15 Substituted benzene compounds
ZA2015/02560A ZA201502560B (en) 2012-10-15 2015-04-16 Substituted benzene compounds
HK16101355.9A HK1213264A1 (en) 2012-10-15 2016-02-04 Substituted benzene compounds
US16/120,702 US20190060322A1 (en) 2012-10-15 2018-09-04 Substituted benzene compounds
IL265437A IL265437A (en) 2012-10-15 2019-03-18 Substituted benzene compounds
US16/924,962 US11642348B2 (en) 2012-10-15 2020-07-09 Substituted benzene compounds

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US201261714140P 2012-10-15 2012-10-15
US201261714145P 2012-10-15 2012-10-15
US61/714,140 2012-10-15
US61/714,145 2012-10-15
US201361780703P 2013-03-13 2013-03-13
US61/780,703 2013-03-13
US201361786277P 2013-03-14 2013-03-14
US61/786,277 2013-03-14

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US14/435,704 A-371-Of-International US10092572B2 (en) 2012-10-15 2013-10-15 Substituted benzene compounds
US16/120,702 Continuation US20190060322A1 (en) 2012-10-15 2018-09-04 Substituted benzene compounds

Publications (2)

Publication Number Publication Date
WO2014062733A2 true WO2014062733A2 (en) 2014-04-24
WO2014062733A3 WO2014062733A3 (en) 2014-06-12

Family

ID=50475881

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2013/065126 WO2014062732A1 (en) 2012-10-15 2013-10-15 Substituted benzene compounds
PCT/US2013/065127 WO2014062733A2 (en) 2012-10-15 2013-10-15 Substituted benzene compounds

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/US2013/065126 WO2014062732A1 (en) 2012-10-15 2013-10-15 Substituted benzene compounds

Country Status (23)

Country Link
US (7) US10092572B2 (en)
EP (4) EP3628662A1 (en)
JP (4) JP6461803B2 (en)
KR (2) KR102057366B1 (en)
CN (3) CN105102432B (en)
AR (1) AR093244A1 (en)
AU (2) AU2013331381B2 (en)
BR (2) BR112015008480A2 (en)
CA (2) CA2888021A1 (en)
CL (2) CL2015000942A1 (en)
HK (2) HK1213264A1 (en)
IL (4) IL238135B (en)
MX (2) MX353929B (en)
MY (1) MY180311A (en)
NZ (2) NZ706739A (en)
PE (2) PE20150886A1 (en)
PH (2) PH12015500800A1 (en)
RU (2) RU2662436C2 (en)
SG (3) SG11201502803VA (en)
TW (2) TWI651303B (en)
UA (2) UA119136C2 (en)
WO (2) WO2014062732A1 (en)
ZA (2) ZA201502526B (en)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015506985A (en) * 2012-02-10 2015-03-05 コンステレーション・ファーマシューティカルズ・インコーポレイテッドＣｏｎｓｔｅｌｌａｔｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． Methyl group-modifying enzyme regulator, composition and use thereof
US9006242B2 (en) 2012-10-15 2015-04-14 Epizyme, Inc. Substituted benzene compounds
US9090562B2 (en) 2011-04-13 2015-07-28 Epizyme, Inc. Aryl- or heteroaryl-substituted benzene compounds
WO2016061507A1 (en) * 2014-10-16 2016-04-21 Epizyme, Inc. Method for treating cancer
US9376422B2 (en) 2011-04-13 2016-06-28 Epizyme, Inc. Dihidropyridin-2-one benzamine compounds
WO2016101956A2 (en) 2014-12-23 2016-06-30 University Of Copenhagen Treatment of cancer by inhibiting ezh2 activity
US9745305B2 (en) 2013-03-15 2017-08-29 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US9969716B2 (en) 2013-08-15 2018-05-15 Constellation Pharmaceuticals, Inc. Indole derivatives as modulators of methyl modifying enzymes, compositions and uses thereof
US10457640B2 (en) 2016-10-19 2019-10-29 Constellation Pharmaceuticals, Inc. Synthesis of inhibitors of EZH2
US10456407B2 (en) 2015-04-20 2019-10-29 Epizyme, Inc. Combination therapy for treating cancer
US10463671B2 (en) 2013-12-06 2019-11-05 Epizyme, Inc. Combination therapy for treating cancer
US10493076B2 (en) 2015-08-24 2019-12-03 Epizyme, Inc. Method for treating cancer
WO2020011607A1 (en) 2018-07-09 2020-01-16 Fondation Asile Des Aveugles Inhibition of prc2 subunits to treat eye disorders
US10577350B2 (en) 2015-08-28 2020-03-03 Constellation Pharmaceuticals, Inc. Crystalline forms of (R)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide
US10710987B2 (en) 2013-10-16 2020-07-14 Epizyme, Inc. Hydrochloride salt form for EZH2 inhibition
US10786511B2 (en) 2014-11-17 2020-09-29 Epizyme, Inc. Method for treating cancer
US11147819B2 (en) 2016-06-17 2021-10-19 Epizyme, Inc. EZH2 inhibitors for treating cancer
US11202781B2 (en) 2015-06-10 2021-12-21 Epizyme, Inc. EZH2 inhibitors for treating lymphoma
US11452727B2 (en) 2017-09-05 2022-09-27 Epizyme, Inc. Combination therapy for treating cancer
US11602529B2 (en) 2017-06-02 2023-03-14 Epizyme, Inc. Use of EZH2 inhibitors for treating cancer
US11642346B2 (en) 2017-03-31 2023-05-09 Epizyme, Inc. Combination therapy for treating cancer
US11642347B2 (en) 2014-06-17 2023-05-09 Epizyme, Inc. EZH2 inhibitors for treating lymphoma
US11786533B2 (en) 2016-06-01 2023-10-17 Epizyme, Inc. Use of EZH2 inhibitors for treating cancer
US11951108B2 (en) 2016-01-29 2024-04-09 Epizyme, Inc. Combination therapy for treating cancer

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2841142C (en) 2010-06-23 2020-12-15 Ryan D. Morin Biomarkers for non-hodgkin lymphomas and uses thereof
US9175331B2 (en) * 2010-09-10 2015-11-03 Epizyme, Inc. Inhibitors of human EZH2, and methods of use thereof
WO2013075084A1 (en) 2011-11-18 2013-05-23 Constellation Pharmaceuticals Modulators of methyl modifying enzymes, compositions and uses thereof
BR112015014090A2 (en) 2012-12-13 2017-07-11 Glaxosmithkline Llc homologous zeste inhibitor enhancer 2
US9701666B2 (en) 2012-12-21 2017-07-11 Epizyme, Inc. 1,4-pyridone bicyclic heteroaryl compounds
US20150344427A1 (en) * 2012-12-21 2015-12-03 Epizyme, Inc. 1,4-pyridone compounds
US10053463B2 (en) 2013-03-14 2018-08-21 Janssen Pharmaceutica Nv Substituted [1,2,4]triazolo[4,3-a]pyrazines as P2X7 modulators
JP6294953B2 (en) 2013-03-14 2018-03-14 ヤンセン ファーマシューティカ エヌ．ベー． P2X7 modulator
WO2014140075A1 (en) 2013-03-14 2014-09-18 Boehringer Ingelheim International Gmbh Substituted 2-aza-bicyclo[2.2.1]heptane-3-carboxylic acid (benzyl-cyano-methyl)-amides inhibitors of cathepsin c
TWI644671B (en) 2013-03-14 2018-12-21 比利時商健生藥品公司 P2x7 modulators
JO3509B1 (en) 2013-03-14 2020-07-05 Janssen Pharmaceutica Nv P2x7 modulators
RU2016104044A (en) 2013-07-10 2017-08-15 Глэксосмитклайн Интеллекчуал Проперти (Nо.2) Лимитед ZESTE Homolog Amplifier Inhibitors 2
WO2015010078A2 (en) 2013-07-19 2015-01-22 Epizyme, Inc. Substituted 6,5-fused bicyclic heteroaryl compounds
WO2015010049A1 (en) 2013-07-19 2015-01-22 Epizyme, Inc. Substituted benzene compounds
CN107074870B (en) 2014-09-12 2019-07-12 勃林格殷格翰国际有限公司 The spiro-compound inhibitor of cathepsin C
ES2714048T3 (en) 2014-09-12 2019-05-24 Janssen Pharmaceutica Nv P2X7 modulators
TW201718598A (en) 2015-08-27 2017-06-01 美國禮來大藥廠 Inhibitors of EZH2
JP2019514884A (en) * 2016-04-22 2019-06-06 ダナ−ファーバー キャンサー インスティテュート， インコーポレイテッド EZH2 inhibitors and their use
US20200262813A1 (en) * 2016-11-11 2020-08-20 Shanghai Haiyan Pharmaceutical Technology Co., Ltd. 1,5,7-trisubstituted isoquinoline derivatives, preparation thereof, and use thereof in medicines
US10266542B2 (en) 2017-03-15 2019-04-23 Mirati Therapeutics, Inc. EZH2 inhibitors
PL3746446T3 (en) 2018-01-31 2022-08-29 Mirati Therapeutics, Inc. Prc2 inhibitors
EA202190886A1 (en) 2018-09-28 2021-09-07 Янссен Фармацевтика Нв MONOACYLGLYCERINE LIPASE MODULATORS
MA53722A (en) 2018-09-28 2022-03-30 Janssen Pharmaceutica Nv MONOACYLGLYCEROL LIPASE MODULATORS
CN114555112A (en) 2019-08-22 2022-05-27 朱诺治疗学股份有限公司 Combination therapy of T cell therapy and ZESTE enhancer homolog 2(EZH2) inhibitors and related methods
CA3156100A1 (en) 2019-09-30 2021-04-08 Janssen Pharmaceutica Nv Radiolabelled mgl pet ligands
CN111303133A (en) * 2020-03-25 2020-06-19 清华大学 Small molecule compound for degrading EZH2 protein
KR20220157999A (en) 2020-03-26 2022-11-29 얀센 파마슈티카 엔.브이. monoacylglycerol lipase modulator

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4522811A (en) 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
US5763263A (en) 1995-11-27 1998-06-09 Dehlinger; Peter J. Method and apparatus for producing position addressable combinatorial libraries
WO2012142513A1 (en) 2011-04-13 2012-10-18 Epizyme, Inc. Substituted benzene compounds
WO2012142504A1 (en) 2011-04-13 2012-10-18 Epizyme, Inc. Aryl-or heteroaryl-substituted benzene compounds
US20130040906A1 (en) 2010-09-10 2013-02-14 Kevin W. Kuntz Inhibitors of Human EZH2, and Methods of Use Thereof

Family Cites Families (73)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0733729A (en) 1993-07-26 1995-02-03 Kirin Brewery Co Ltd Production of n-cyano-n'-substituted-arylcarboxyimidamide compound
CA2155662A1 (en) 1993-12-27 1995-07-06 Fumihiro Ozaki Anthranilic acid derivative
DE19516776A1 (en) 1995-05-10 1996-11-14 Boehringer Ingelheim Int Chromatin regulatory genes
US5741819A (en) 1995-06-07 1998-04-21 3-Dimensional Pharmaceuticals, Inc. Arylsulfonylaminobenzene derivatives and the use thereof as factor Xa inhibitors
JP3906935B2 (en) 1995-12-18 2007-04-18 杏林製薬株式会社 N-substituted dioxothiazolidylbenzamide derivative and process for producing the same
JP2002525352A (en) 1998-09-30 2002-08-13 ザ、プロクター、エンド、ギャンブル、カンパニー 2-substituted ketoamide
UA71587C2 (en) 1998-11-10 2004-12-15 Шерінг Акцієнгезелльшафт Anthranilic acid amides and use thereof as medicaments
US6710058B2 (en) 2000-11-06 2004-03-23 Bristol-Myers Squibb Pharma Company Monocyclic or bicyclic carbocycles and heterocycles as factor Xa inhibitors
BR0116539A (en) 2000-12-28 2003-09-23 Shionogi & Co Pyridone derivatives having a cannabinoid receptor 2 binding activity
WO2002060492A1 (en) 2001-01-30 2002-08-08 Cytopia Pty Ltd Methods of inhibiting kinases
US7700293B2 (en) 2001-08-02 2010-04-20 The Regents Of The University Of Michigan Expression profile of prostate cancer
WO2003059884A1 (en) 2001-12-21 2003-07-24 X-Ceptor Therapeutics, Inc. Modulators of lxr
AU2003211442A1 (en) 2002-02-19 2003-09-09 Shionogi And Co., Ltd. Antipruritics
TW200306155A (en) 2002-03-19 2003-11-16 Du Pont Benzamides and advantageous compositions thereof for use as fungicides
TWI336254B (en) 2002-12-27 2011-01-21 Sucampo Ag Pharmaceutical composition for treating abdominal discomfort
US7405295B2 (en) 2003-06-04 2008-07-29 Cgi Pharmaceuticals, Inc. Certain imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of Bruton's tyrosine kinase by such compounds
US7442685B2 (en) 2003-06-13 2008-10-28 The University Of North Carolina At Chapel Hill DOT1 histone methyltransferases as a target for identifying therapeutic agents for leukemia
JP4869068B2 (en) 2003-06-19 2012-02-01 スミスクライン ビーチャム コーポレーション Compound
ME00294B (en) 2003-07-23 2011-05-10 Bayer Pharmaceuticals Corp Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
DE602004026321D1 (en) 2003-08-26 2010-05-12 Merck Hdac Res Llc Use of SAHA for the treatment of mesothelioma
US20050059682A1 (en) 2003-09-12 2005-03-17 Supergen, Inc., A Delaware Corporation Compositions and methods for treatment of cancer
DE602005021770D1 (en) * 2004-03-11 2010-07-22 Actelion Pharmaceuticals Ltd INDOLE-1-YL-ACETIC DERIVATIVES
CN1286973C (en) 2004-04-12 2006-11-29 上海第二医科大学附属瑞金医院 Histone methyl transferase and its preparing method
EP1765994B1 (en) 2004-06-01 2009-11-18 The University of North Carolina at Chapel Hill Reconstituted histone methyltransferase complex and methods of identifying modulators thereof
JO2787B1 (en) 2005-04-27 2014-03-15 امجين إنك, Substituted Amid derivatives & methods of use
DE602006019423D1 (en) 2005-06-02 2011-02-17 Univ North Carolina CLEANING, CHARACTERIZATION AND RECONSTITUTION OF A UBIQUITINE E3 LIGASE
FR2889526B1 (en) 2005-08-04 2012-02-17 Aventis Pharma Sa SUBSTITUTED 7-AZA-INDAZOLES, COMPOSITIONS CONTAINING SAME, PROCESS FOR PRODUCTION AND USE
PT1940821E (en) 2005-10-19 2013-05-29 Gruenenthal Gmbh Novel vanilloid receptor ligands and their use for producing medicaments
EP1951672B1 (en) 2005-10-21 2011-05-25 Merck Sharp & Dohme Corp. Potassium channel inhibitors
US20090203057A1 (en) 2005-10-28 2009-08-13 Yi Zhang Protein demethylases comprising a jmjc domain
WO2007072225A2 (en) 2005-12-01 2007-06-28 Medical Prognosis Institute Methods and devices for identifying biomarkers of treatment response and use thereof to predict treatment efficacy
JP2009519966A (en) 2005-12-14 2009-05-21 ブリストル−マイヤーズ スクイブ カンパニー 6-membered heterocycles useful as serine protease inhibitors
CA2623271A1 (en) 2006-01-20 2007-08-02 The University Of North Carolina At Chapel Hill Interaction between dot1l polypeptide and calm-af10 fusion protein as a therapeutic target for leukemia
UA93548C2 (en) * 2006-05-05 2011-02-25 Айерем Елелсі Compounds and compositions as hedgehog pathway modulators
JP2009537521A (en) 2006-05-15 2009-10-29 アイアールエム・リミテッド・ライアビリティ・カンパニー Terephthalamate compounds and compositions and their use as HIV integrase inhibitors
WO2007136592A2 (en) 2006-05-18 2007-11-29 Amphora Discovery Corporation 2-0x0-l,2-dihydr0quin0line derivatives, compositions, and uses thereof as antiproliferative agents
JP2010505958A (en) 2006-10-10 2010-02-25 バーンハム インスティトゥート フォー メディカル リサーチ Neuroprotective compositions and methods
EP2114898A2 (en) 2007-02-16 2009-11-11 Amgen Inc. Nitrogen-containing heterocyclyl ketones and their use as c-met inhibitors
EP2137158A4 (en) 2007-02-28 2012-04-18 Methylgene Inc Small molecule inhibitors of protein arginine methyltransferases (prmts)
WO2008109534A1 (en) 2007-03-02 2008-09-12 Mdrna, Inc. Nucleic acid compounds for inhibiting ezh2 gene expression and uses thereof
WO2008113006A1 (en) 2007-03-14 2008-09-18 Xenon Pharmaceuticals Inc. Methods of using quinolinone compounds in treating sodium channel-mediated diseases or conditions
DE102007017884A1 (en) 2007-04-13 2008-10-16 Grünethal GmbH Novel vanilloid receptor ligands and their use in the preparation of medicines
WO2009006577A2 (en) 2007-07-03 2009-01-08 The Regents Of The University Of Michigan Compositions and methods for inhibiting ezh2
JP5364875B2 (en) 2007-07-16 2013-12-11 アッヴィ・インコーポレイテッド Indazoles, benzisoxazoles and benzisothiazoles as protein kinase inhibitors
AU2008319308B2 (en) 2007-10-31 2013-01-31 Merck Sharp & Dohme Corp. P2X3, receptor antagonists for treatment of pain
WO2009077766A1 (en) 2007-12-19 2009-06-25 Cancer Research Technology Limited Pyrido[2,3-b]pyrazine-8-substituted compounds and their use
ES2531396T3 (en) 2008-01-23 2015-03-13 Bristol Myers Squibb Co Process to prepare pyridinone compounds
WO2009124137A2 (en) 2008-04-01 2009-10-08 Mount Sinai School Of Medicine Of New York University Method of suppressing gene transcription through histone lysine methylation
US20100113415A1 (en) 2008-05-29 2010-05-06 Rajapakse Hemaka A Epha4 rtk inhibitors for treatment of neurological and neurodegenerative disorders and cancer
UY31982A (en) 2008-07-16 2010-02-26 Boehringer Ingelheim Int DERIVATIVES OF 1,2-DIHYDROPIRIDIN-3-CARBOXAMIDS N-SUBSTITUTED
JP5548197B2 (en) 2008-08-08 2014-07-16 ニューヨーク ブラッド センター， インコーポレイテッド Small molecule inhibitors of retrovirus assembly and maturation
FR2934995B1 (en) 2008-08-14 2010-08-27 Sanofi Aventis POLYSUBSTITUTED AZETIDINE COMPOUNDS, PREPARATION THEREOF AND THERAPEUTIC USE THEREOF
RU2011142791A (en) 2009-03-24 2013-04-27 Санофи 9H-PYRROLO DERIVATIVES [2,3-B: 5,4-C ′] DIPYRIDINE-AZACARBOLINES, METHOD FOR PRODUCING THEM AND USE IN THERAPY
WO2010111653A2 (en) 2009-03-27 2010-09-30 The Uab Research Foundation Modulating ires-mediated translation
US20110021362A1 (en) 2009-07-20 2011-01-27 Constellation Pharmaceuticals Agents for stimulating activity of methyl modifying enzymes and methods of use thereof
US8329149B2 (en) 2009-12-30 2012-12-11 Avon Products, Inc. Topical lightening composition and uses thereof
EP2566328B1 (en) 2010-05-07 2015-03-04 GlaxoSmithKline LLC Indazoles
US8637509B2 (en) 2010-05-07 2014-01-28 Glaxosmithkline Llc Azaindazoles
HUE034787T2 (en) 2010-05-07 2018-02-28 Glaxosmithkline Llc Indoles
CA2841142C (en) 2010-06-23 2020-12-15 Ryan D. Morin Biomarkers for non-hodgkin lymphomas and uses thereof
HUE028977T2 (en) 2010-09-10 2017-02-28 Epizyme Inc Method for determining the suitability of inhibitors of human ezh2 in treatment
US20130310379A1 (en) 2010-11-19 2013-11-21 Constellation Pharmaceuticals Modulators of methyl modifying enzymes, compositions and uses thereof
US8765792B2 (en) 2010-12-01 2014-07-01 Glaxosmithkline Llc Indoles
US9145438B2 (en) 2010-12-03 2015-09-29 Epizyme, Inc. 7-deazapurine modulators of histone methyltransferase, and methods of use thereof
US8791782B2 (en) * 2011-01-28 2014-07-29 Uses, Inc. AC power conditioning circuit
WO2012118812A2 (en) 2011-02-28 2012-09-07 Epizyme, Inc. Substituted 6,5-fused bicyclic heteroaryl compounds
WO2013049770A2 (en) 2011-09-30 2013-04-04 Glaxosmithkline Llc Methods of treating cancer
TR201904660T4 (en) 2012-03-12 2019-05-21 Epizyme Inc Human EZH2 inhibitors and methods of use.
JP6255382B2 (en) * 2012-04-13 2017-12-27 エピザイム，インコーポレイティド Salt form of human histone methyltransferase EZH2 inhibitor
CA2870010C (en) * 2012-04-13 2023-02-21 Epizyme, Inc. Combination therapy for treating cancer
WO2013173441A2 (en) 2012-05-16 2013-11-21 Glaxosmithkline Llc Enhancer of zeste homolog 2 inhibitors
RU2662436C2 (en) * 2012-10-15 2018-07-26 Эпизайм, Инк. Substituted benzene compounds
CN105142642B (en) * 2012-10-15 2019-10-18 Epizyme股份有限公司 Cancer treatment method

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4522811A (en) 1982-07-08 1985-06-11 Syntex (U.S.A.) Inc. Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides
US5763263A (en) 1995-11-27 1998-06-09 Dehlinger; Peter J. Method and apparatus for producing position addressable combinatorial libraries
US20130040906A1 (en) 2010-09-10 2013-02-14 Kevin W. Kuntz Inhibitors of Human EZH2, and Methods of Use Thereof
WO2012142513A1 (en) 2011-04-13 2012-10-18 Epizyme, Inc. Substituted benzene compounds
WO2012142504A1 (en) 2011-04-13 2012-10-18 Epizyme, Inc. Aryl-or heteroaryl-substituted benzene compounds

Non-Patent Citations (21)

* Cited by examiner, † Cited by third party
Title
"Encyclopedia of Reagents for Organic Synthesis", 1995, JOHN WILEY AND SONS
"Remington: the Science and Practice of Pharmacy", 1995, MACK PUBLISHING CO.
"Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING CO.
AUSUBEL ET AL.: "Current Protocols in Molecular Biology", 2005, JOHN WILEY AND SONS, INC.
CAHN ET AL., ANGEW. CHEM. INTER. EDIT., vol. 5, 1966, pages 385
CAHN ET AL., ANGEW. CHEM., vol. 78, 1966, pages 413
CAHN ET AL., EXPERIENTIA, vol. 12, 1956, pages 81
CAHN, J. CHEM. EDUC., vol. 41, 1964, pages 116
CAHN; INGOLD, J. CHEM. SOC., 1951, pages 612
COLIGAN ET AL.: "Current Protocols in Immunology", JOHN WILEY & SONS
DEVLIN: "High Throughput Screening", 1998, MARCEL DEKKER
ENNA ET AL.: "Current Protocols in Pharmacology", JOHN WILEY & SONS
FINGL ET AL.: "The Pharmacological Basis of Therapeutics", 1975
GREENE, T.W.; WUTS, P.G. M.: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY & SONS
L. FIESER; M. FIESER: "Fieser and Fieser's Reagents for Organic Synthesis", 1994, JOHN WILEY AND SONS
PATANI; LAVOIE, CHEM. REV., vol. 96, 1996, pages 3147 - 3176
R. LAROCK: "Comprehensive Organic Transformations", 1989, VCH PUBLISHERS
SAMBROOK ET AL.: "Molecular Cloning, A Laboratory Manual", 2000, COLD SPRING HARBOR PRESS
See also references of EP2906537A4
SMITH, M. B.; MARCH, J.: "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 2001, JOHN WILEY & SONS
SNEERINGER ET AL., PROC NATL ACAD SCI USA, vol. 107, no. 49, 2010, pages 20980 - 5

Cited By (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9522152B2 (en) 2011-04-13 2016-12-20 Epizyme, Inc. Aryl- or heteroaryl-substituted benzene compounds
US10420775B2 (en) 2011-04-13 2019-09-24 Epizyme, Inc. Aryl-or heteroaryl-substituted benzene compounds
US11052093B2 (en) 2011-04-13 2021-07-06 Epizyme, Inc. Aryl-or heteroaryl-substituted benzene compounds
US9090562B2 (en) 2011-04-13 2015-07-28 Epizyme, Inc. Aryl- or heteroaryl-substituted benzene compounds
US10155002B2 (en) 2011-04-13 2018-12-18 Epizyme, Inc. Aryl- or heteroaryl-substituted benzene compounds
US9376422B2 (en) 2011-04-13 2016-06-28 Epizyme, Inc. Dihidropyridin-2-one benzamine compounds
US9855275B2 (en) 2011-04-13 2018-01-02 Epizyme, Inc. Aryl-or heteroaryl-substituted benzene compounds
US9549931B2 (en) 2011-04-13 2017-01-24 Epizyme, Inc. Aryl- or heteroaryl-substituted benzene compounds
US10016405B2 (en) 2012-02-10 2018-07-10 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US9980952B2 (en) 2012-02-10 2018-05-29 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US9469646B2 (en) 2012-02-10 2016-10-18 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
JP2015506985A (en) * 2012-02-10 2015-03-05 コンステレーション・ファーマシューティカルズ・インコーポレイテッドＣｏｎｓｔｅｌｌａｔｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． Methyl group-modifying enzyme regulator, composition and use thereof
USRE47428E1 (en) 2012-02-10 2019-06-11 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US10092572B2 (en) 2012-10-15 2018-10-09 Epizyme, Inc. Substituted benzene compounds
US9532992B2 (en) 2012-10-15 2017-01-03 Epizyme, Inc. Substituted benzene compounds
US10098888B2 (en) 2012-10-15 2018-10-16 Epizyme, Inc. Substituted benzene compounds
US11642348B2 (en) 2012-10-15 2023-05-09 Epizyme, Inc. Substituted benzene compounds
US9089575B2 (en) 2012-10-15 2015-07-28 Epizyme, Inc. Substituted benzene compounds
US9006242B2 (en) 2012-10-15 2015-04-14 Epizyme, Inc. Substituted benzene compounds
US9745305B2 (en) 2013-03-15 2017-08-29 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
US9969716B2 (en) 2013-08-15 2018-05-15 Constellation Pharmaceuticals, Inc. Indole derivatives as modulators of methyl modifying enzymes, compositions and uses thereof
US10710987B2 (en) 2013-10-16 2020-07-14 Epizyme, Inc. Hydrochloride salt form for EZH2 inhibition
US10463671B2 (en) 2013-12-06 2019-11-05 Epizyme, Inc. Combination therapy for treating cancer
US11642347B2 (en) 2014-06-17 2023-05-09 Epizyme, Inc. EZH2 inhibitors for treating lymphoma
US10946024B2 (en) 2014-10-16 2021-03-16 Epizyme, Inc. Method for treating cancer
JP2017532338A (en) * 2014-10-16 2017-11-02 エピザイム，インコーポレイティド How to treat cancer
WO2016061507A1 (en) * 2014-10-16 2016-04-21 Epizyme, Inc. Method for treating cancer
AU2021200995B2 (en) * 2014-10-16 2022-06-02 Epizyme, Inc. Method for treating cancer
US9889138B2 (en) 2014-10-16 2018-02-13 Epizyme, Inc. Method for treating cancer
IL276545A (en) * 2014-10-16 2020-09-30 Epizyme Inc Method for treating cancer
JP2020097615A (en) * 2014-10-16 2020-06-25 エピザイム，インコーポレイティド Method for treating cancer
US10369155B2 (en) 2014-10-16 2019-08-06 Epizyme, Inc. Method for treating cancer
US10786511B2 (en) 2014-11-17 2020-09-29 Epizyme, Inc. Method for treating cancer
WO2016101956A2 (en) 2014-12-23 2016-06-30 University Of Copenhagen Treatment of cancer by inhibiting ezh2 activity
US11026949B2 (en) 2015-04-20 2021-06-08 Epizyme, Inc. Combination therapy for treating cancer
US10456407B2 (en) 2015-04-20 2019-10-29 Epizyme, Inc. Combination therapy for treating cancer
US11202781B2 (en) 2015-06-10 2021-12-21 Epizyme, Inc. EZH2 inhibitors for treating lymphoma
US11951109B2 (en) 2015-06-10 2024-04-09 Epizyme, Inc. EZH2 inhibitors for treating lymphoma
US10493076B2 (en) 2015-08-24 2019-12-03 Epizyme, Inc. Method for treating cancer
US11642349B2 (en) 2015-08-24 2023-05-09 Epizyme, Inc. Method for treating cancer
US10898490B2 (en) 2015-08-24 2021-01-26 Epizyme, Inc. Method for treating cancer
US10577350B2 (en) 2015-08-28 2020-03-03 Constellation Pharmaceuticals, Inc. Crystalline forms of (R)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide
US11951108B2 (en) 2016-01-29 2024-04-09 Epizyme, Inc. Combination therapy for treating cancer
US11786533B2 (en) 2016-06-01 2023-10-17 Epizyme, Inc. Use of EZH2 inhibitors for treating cancer
US11147819B2 (en) 2016-06-17 2021-10-19 Epizyme, Inc. EZH2 inhibitors for treating cancer
US10457640B2 (en) 2016-10-19 2019-10-29 Constellation Pharmaceuticals, Inc. Synthesis of inhibitors of EZH2
US11642346B2 (en) 2017-03-31 2023-05-09 Epizyme, Inc. Combination therapy for treating cancer
US11602529B2 (en) 2017-06-02 2023-03-14 Epizyme, Inc. Use of EZH2 inhibitors for treating cancer
US11452727B2 (en) 2017-09-05 2022-09-27 Epizyme, Inc. Combination therapy for treating cancer
WO2020011607A1 (en) 2018-07-09 2020-01-16 Fondation Asile Des Aveugles Inhibition of prc2 subunits to treat eye disorders

Also Published As

Publication number Publication date
US9089575B2 (en) 2015-07-28
KR102057365B1 (en) 2019-12-18
US20190060322A1 (en) 2019-02-28
RU2015118145A (en) 2016-12-10
SG11201502803VA (en) 2015-05-28
AR093244A1 (en) 2015-05-27
PH12015500800B1 (en) 2015-06-08
HK1213552A1 (en) 2016-07-08
MX2015004722A (en) 2016-01-25
ZA201502526B (en) 2016-06-29
IL238135B (en) 2018-10-31
SG10201705989YA (en) 2017-08-30
PH12015500825B1 (en) 2015-06-22
MX2015004721A (en) 2016-01-25
CN105102432B (en) 2019-01-04
US20150174136A1 (en) 2015-06-25
AU2013331381A1 (en) 2015-04-30
RU2662436C2 (en) 2018-07-26
CN110041250A (en) 2019-07-23
TW201427950A (en) 2014-07-16
SG11201502820YA (en) 2015-05-28
PH12015500800A1 (en) 2015-06-08
JP6461802B2 (en) 2019-01-30
EP2906537B1 (en) 2020-03-11
UA115074C2 (en) 2017-09-11
US9006242B2 (en) 2015-04-14
EP3725314A1 (en) 2020-10-21
US20170290837A1 (en) 2017-10-12
US10092572B2 (en) 2018-10-09
ZA201502560B (en) 2019-08-28
US20210060027A1 (en) 2021-03-04
KR20150067370A (en) 2015-06-17
RU2015118135A (en) 2016-12-10
JP2015533177A (en) 2015-11-19
PE20150887A1 (en) 2015-06-04
AU2013331380A1 (en) 2015-04-30
CN105102432A (en) 2015-11-25
NZ706738A (en) 2018-10-26
HK1213264A1 (en) 2016-06-30
PH12015500825A1 (en) 2015-06-22
US20150284370A1 (en) 2015-10-08
CA2887562C (en) 2021-01-12
EP2906537A2 (en) 2015-08-19
IL261964B (en) 2019-09-26
WO2014062732A1 (en) 2014-04-24
US11642348B2 (en) 2023-05-09
EP2906538A1 (en) 2015-08-19
JP2018087239A (en) 2018-06-07
KR20150069011A (en) 2015-06-22
AU2013331381B2 (en) 2018-04-05
US20150352119A1 (en) 2015-12-10
US10098888B2 (en) 2018-10-16
IL261964A (en) 2018-10-31
AU2013331380B2 (en) 2018-03-22
CL2015000944A1 (en) 2016-01-04
NZ706739A (en) 2018-11-30
BR112015008487B1 (en) 2022-05-31
CL2015000942A1 (en) 2016-01-04
PE20150886A1 (en) 2015-06-04
EP3628662A1 (en) 2020-04-01
MX353929B (en) 2018-02-02
BR112015008480A2 (en) 2017-07-04
JP2015533176A (en) 2015-11-19
JP6461803B2 (en) 2019-01-30
MY180311A (en) 2020-11-28
CA2888021A1 (en) 2014-04-24
CN105102431B (en) 2018-03-02
CA2887562A1 (en) 2014-04-24
IL238197A0 (en) 2015-05-31
JP6559275B2 (en) 2019-08-14
IL265437A (en) 2019-05-30
EP2906538A4 (en) 2016-05-11
RU2658919C2 (en) 2018-06-26
US20140107122A1 (en) 2014-04-17
UA119136C2 (en) 2019-05-10
BR112015008487A2 (en) 2017-07-04
KR102057366B1 (en) 2019-12-18
US9532992B2 (en) 2017-01-03
TWI588131B (en) 2017-06-21
JP2018087238A (en) 2018-06-07
TW201803851A (en) 2018-02-01
EP2906537A4 (en) 2016-06-08
TWI651303B (en) 2019-02-21
CN105102431A (en) 2015-11-25
WO2014062733A3 (en) 2014-06-12

Similar Documents

Publication Publication Date Title
US11642348B2 (en) Substituted benzene compounds
EP2935214B1 (en) 1,4-pyridone compounds
US10150759B2 (en) 1,4-pyridone bicycic heteroaryl compounds
US20200361914A1 (en) Substituted benzene and 6,5-fused bicyclic heteroaryl compounds
US10150764B2 (en) Substituted benzene compounds
JP2023011933A (en) Aryl- or heteroaryl-substituted benzene compounds
US9624205B2 (en) Substituted 6,5-fused bicyclic heteroaryl compounds
AU2013361060A1 (en) 1,4-pyridone compounds
AU2013361079A1 (en) 1,4-pyridone bicyclic heteroaryl compounds
RU2785567C2 (en) Aryl- or heteroaryl-substituted benzene compounds

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201380065683.2

Country of ref document: CN

ENP Entry into the national phase

Ref document number: 2888021

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 238197

Country of ref document: IL

ENP Entry into the national phase

Ref document number: 2015537019

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 14435704

Country of ref document: US

Ref document number: 000488-2015

Country of ref document: PE

Ref document number: MX/A/2015/004722

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 12015500825

Country of ref document: PH

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112015008480

Country of ref document: BR

WWE Wipo information: entry into national phase

Ref document number: 2013846696

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2013331381

Country of ref document: AU

Date of ref document: 20131015

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20157012673

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2015118145

Country of ref document: RU

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: IDP00201502913

Country of ref document: ID

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

Ref document number: 13846696

Country of ref document: EP

Kind code of ref document: A2

ENP Entry into the national phase

Ref document number: 112015008480

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20150415