WO2020132014A1 - Substituted 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions thereof, and methods of treatment therewith - Google Patents

Substituted 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions thereof, and methods of treatment therewith Download PDF

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WO2020132014A1
WO2020132014A1 PCT/US2019/067088 US2019067088W WO2020132014A1 WO 2020132014 A1 WO2020132014 A1 WO 2020132014A1 US 2019067088 W US2019067088 W US 2019067088W WO 2020132014 A1 WO2020132014 A1 WO 2020132014A1
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compound
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substituted
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French (fr)
Inventor
Massimo AMMIRANTE
Sogoie BAHMANYAR
Matthew D. CORREA
Virginia GRANT
Joshua Hansen
Evan J. HORN
Timothy S. Kercher
Christopher Mayne
Mark A. Nagy
Rama Krishna Narla
Surendra NAYAK
Stephen Norris
Patrick Papa
Veronique Plantevin-Krenitsky
John J. Sapienza
Brandon W. WHITEFIELD
Shuichan SU
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Celgene Corp
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Celgene Corp
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Priority to SI201930889T priority patent/SI3897636T1/sl
Priority to HRP20250095TT priority patent/HRP20250095T1/hr
Priority to FIEP19901383.0T priority patent/FI3897636T3/fi
Priority to CN201980092358.2A priority patent/CN113453681B/zh
Priority to KR1020217019479A priority patent/KR102866144B1/ko
Priority to MYPI2021003454A priority patent/MY205718A/en
Priority to SG11202106507RA priority patent/SG11202106507RA/en
Priority to NZ777281A priority patent/NZ777281B2/en
Priority to RS20250148A priority patent/RS66556B1/sr
Priority to PE2021000924A priority patent/PE20212247A1/es
Priority to EA202191712A priority patent/EA202191712A1/ru
Priority to SM20250111T priority patent/SMT202500111T1/it
Priority to EP19901383.0A priority patent/EP3897636B1/en
Priority to CA3124130A priority patent/CA3124130A1/en
Priority to KR1020257032139A priority patent/KR20250144505A/ko
Application filed by Celgene Corp filed Critical Celgene Corp
Priority to PL19901383.0T priority patent/PL3897636T3/pl
Priority to IL284223A priority patent/IL284223B2/en
Priority to MX2021007473A priority patent/MX2021007473A/es
Priority to ES19901383T priority patent/ES3009308T3/es
Priority to CN202411325996.3A priority patent/CN119219606A/zh
Priority to BR112021011968-0A priority patent/BR112021011968A2/pt
Priority to AU2019403207A priority patent/AU2019403207B2/en
Priority to LTEPPCT/US2019/067088T priority patent/LT3897636T/lt
Publication of WO2020132014A1 publication Critical patent/WO2020132014A1/en
Priority to ZA2021/04200A priority patent/ZA202104200B/en
Priority to CONC2021/0007973A priority patent/CO2021007973A2/es
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/94—Oxygen atom, e.g. piperidine N-oxide
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D233/30—Oxygen or sulfur atoms
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds are certain 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions comprising an effective amount of such compounds, and methods for treating or preventing androgen receptor mediated diseases, comprising administering an effective amount of such 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds to a subject in need thereof.
  • compounds and compositions for use in these methods are also provided herein.
  • Androgen receptor signaling is known to play a crucial role in the pathogenesis of prostate cancer and is involved in the development of other androgen receptor positive cancers (Chen Y et ah, Lancet Oncol, 2009, 10:981-91; Mills I G, Nat Rev Cancer, 2014, 14: 187-98; Taplin M E, Nat Clin Pract Oncol , 2007, 4:236-44; Wirth M P et al, Eur Urol , 2007, 51(2):306- 13).
  • the inhibition of androgen receptor signaling with anti-androgens that antagonize the androgen receptor has been used or proposed for the treatment of prostate cancer.
  • the androgen receptor normally resides in the cytoplasm bound to chaperones such as HSP90 (Brinkmann A O et al, J Steroid Biochem Mol Biol , 1999, 69:307-13).
  • DHT dihydrotestosterone
  • the androgen receptor changes its conformation and translocates to the nucleus, where it binds androgen responsive elements (AREs) driving the transcription of canonical targets such as KLK3 (also known as prostate specific antigen PSA), TMPRSS2 and KLK2 (Tran C et al, Science , 2009, 324:787-90; Murtha P et al, Biochemistry (Mosc.), 1993, 32:6459-64).
  • KLK3 also known as prostate specific antigen PSA
  • TMPRSS2 TMPRSS2
  • KLK2 Tran C et al, Science , 2009, 324:787-90; Murtha P et al, Biochemistry (Mosc.), 1993, 32:6459
  • PCa Prostate cancer
  • ADT Androgen-deprivation therapy
  • PCa castration-resistant prostate cancer
  • R N , R 1 , R 2 , R 3 , R 4 , X, L, V, m and n are as defined herein.
  • a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof (each being referred to herein as a“Piperidine Dione Compound”) is useful for treating or preventing androgen receptor mediated diseases in a subject.
  • Piperidine Dione Compounds as described in the instant disclosure such as, for example, in Table 1.
  • compositions comprising an effective amount of a compound as described herein, and a pharmaceutically acceptable carrier, excipient or vehicle.
  • pharmaceutical compositions comprising an effective amount of a Piperidine Dione Compound as described herein, and a pharmaceutically acceptable carrier, excipient or vehicle.
  • the pharmaceutical composition is suitable for oral, parenteral, mucosal, transdermal or topical administration.
  • kits for treating or preventing androgen receptor mediated diseases in a subject comprising administering to a subject in need thereof an effective amount of a compound as described herein; and a
  • provided herein are methods for treating or preventing androgen receptor mediated diseases in a subject, comprising administering to a subject in need thereof an effective amount of a Piperidine Dione Compound as described herein; and a pharmaceutically acceptable carrier, excipient or vehicle.
  • a Piperidine Dione Compound as described herein comprising administering to a subject in need thereof an effective amount of a Piperidine Dione Compound as described herein; and a pharmaceutically acceptable carrier, excipient or vehicle.
  • compounds for use in methods of treatment of androgen receptor mediated diseases comprising administering to a subject in need thereof an effective amount of a Piperidine Dione Compound as described herein; and a pharmaceutically acceptable carrier, excipient or vehicle.
  • compounds for use in methods of treatment of androgen receptor mediated diseases comprising an effective amount of a Piperidine Dione Compound as described herein; and a pharmaceutically acceptable carrier, excipient or vehicle.
  • the term“or” is to be interpreted as an inclusive“or” meaning any one or any combination. Therefore,“A, B or C” means any of the following:“A; B; C; A and B; A and C; B and C; A, B and C”. An exception to this definition will occur only when a combination of elements, functions, steps or acts are in some way inherently mutually exclusive.
  • An“alkyl” group is a saturated, partially saturated, or unsaturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms, typically from 1 to 8 carbons or, in some embodiments, from 1 to 6, 1 to 4, or 2 to 6 carbon atoms. In some embodiments, the alkyl group is a saturated alkyl group.
  • saturated alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl; while saturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl and the like.
  • the alkyl group is an unsaturated alkyl group, also termed an alkenyl or alkynyl group.
  • An“alkenyl” group is an alkyl group that contains one or more carbon-carbon double bonds.
  • An“alkynyl” group is an alkyl group that contains one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl,
  • An alkyl group can be substituted or unsubstituted.
  • alkyl groups described herein when they are said to be“substituted,” they may be substituted with any substituent or substituents as those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine;
  • A“cycloalkyl” group is a saturated, or partially saturated cyclic alkyl group of from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed or bridged rings which can be optionally substituted.
  • the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7.
  • the cycloalkyl groups are saturated cycloalkyl groups.
  • Such saturated cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple or bridged ring structures such as l-bicyclo[l.l. l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl and the like.
  • the cycloalkyl groups are unsaturated cycloalkyl groups.
  • unsaturared cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, among others.
  • a cycloalkyl group can be substituted or unsubstituted. Such substituted cycloalkyl groups include, by way of example, cyclohexanol and the like.
  • An“aryl” group is an aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring ( e.g ., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl).
  • aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6 to 10 carbon atoms in the ring portions of the groups.
  • Particular aryls include phenyl, biphenyl, naphthyl and the like.
  • An aryl group can be substituted or unsubstituted.
  • the phrase“aryl groups” also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).
  • A“heteroaryl” group is an aromatic ring system having one to four heteroatoms as ring atoms in a heteroaromatic ring system, wherein the remainder of the atoms are carbon atoms.
  • heteroaryl groups contain 3 to 6 ring atoms, and in others from 6 to 9 or even 6 to 10 atoms in the ring portions of the groups. Suitable heteroatoms include oxygen, sulfur and nitrogen.
  • the heteroaryl ring system is monocyclic or bicyclic.
  • Non-limiting examples include but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl
  • imidazopyridyl e.g., azabenzimidazolyl
  • lH-imidazo[4,5-b]pyridyl pyrazolopyridyl, triazolopyridyl, benzotriazolyl (e.g., lH-benzo[d][l,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin-l(2H)-onyl), tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.
  • a heteroaryl group can be substituted or unsubstituted.
  • A“heterocyclyl” is an aromatic (also referred to as heteroaryl) or non-aromatic cycloalkyl in which one to four of the ring carbon atoms are independently replaced with a heteroatom from the group consisting of O, S and N.
  • heterocyclyl groups include 3 tolO ring members, whereas other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members.
  • Heterocyclyls can also be bonded to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocyclic ring).
  • a heterocycloalkyl group can be substituted or unsubstituted.
  • Heterocyclyl groups encompass unsaturated, partially saturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl (e.g., imidazolidin-4- one or imidazolidin-2,4-dionyl) groups.
  • the phrase heterocyclyl includes fused ring species, including those comprising fused aromatic and non-aromatic groups, such as, for example,
  • benzotriazolyl e.g., lH-benzo[d][l,2,3]triazolyl
  • benzimidazolyl e.g., lH-benzo[d]imidazolyl
  • 2,3-dihydrobenzo[l,4]dioxinyl 2,3-dihydrobenzo[l,4]dioxinyl
  • benzo[l,3]dioxolyl also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl.
  • Representative examples of a heterocyclyl group include, but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidyl, imidazolidinyl
  • tetrahydrothiophenyl tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathiany
  • benzimidazolyl e.g., lH-benzo[d]imidazolyl or lH-benzo[d]imidazol-2(3H)-onyl
  • benzofuranyl benzothiophenyl, benzothiazolyl
  • benzoxadiazolyl benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl (i.e., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo[l,3]dioxolyl, pyrazolopyridyl (for example, lH-pyrazolo[3,4-b]pyridyl, lH-pyrazolo[4,3-b]pyridyl), imidazopyridyl
  • azabenzimidazolyl or lH-imidazo[4,5-b]pyridyl triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl (e.g., 3,4-dihydroisoquinolin- l(2H)-onyl), quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimi
  • non-aromatic heterocyclyl groups do not include fused ring species that comprise a fused aromatic group.
  • non-aromatic heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4- onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl,
  • tetrahydrofuranyl piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, l,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidin-2(lH)-one.
  • piperazinyl e.g., piperazin-2-onyl
  • morpholinyl thiomorpholinyl
  • tetrahydropyranyl e.g., tetrahydro-2H-pyranyl
  • tetrahydrothiopyranyl tetrahydrothiopyranyl
  • oxathianyl dithi
  • substituted heterocyclyl groups may be mono- substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed below.
  • a“cycloalkylalkyl” group is a radical of the formula: -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined above.
  • Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl, or both the alkyl and the cycloalkyl portions of the group.
  • Representative cycloalkylalkyl groups include but are not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
  • an“aralkyl” group is a radical of the formula: -alkyl-aryl, wherein alkyl and aryl are defined above. Substituted aralkyl groups may be substituted at the alkyl, the aryl, or both the alkyl and the aryl portions of the group.
  • aralkyl groups include but are not limited to benzyl and phenethyl groups and aralkyl groups wherein the aryl group is fused to a cycloalkyl group such as indan-4-yl ethyl.
  • a“heterocyclylalkyl” group is a radical of the formula: -alkyl-heterocyclyl, wherein alkyl and heterocyclyl are defined above.
  • a “heteroarylalkyl” group is a radical of the formula: -alkyl-heteroaryl, wherein alkyl and heteroaryl are defined above.
  • A“heterocycloalkylalkyl” group is a radical of the formula:
  • heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl, or both the alkyl and the heterocyclyl portions of the group.
  • Representative heterocylylalkyl groups include but are not limited to morpholin-4-yl ethyl, morpholin-4-yl propyl, furan-2-yl methyl, furan-3-yl methyl, pyri din-3 -yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
  • A“halogen” is fluorine, chlorine, bromine or iodine.
  • A“hydroxyalkyl” group is an alkyl group as described above substituted with one or more hydroxy groups.
  • An“alkoxy” group is -O-(alkyl), wherein alkyl is defined above.
  • An“alkoxyalkyl” group is -(alkyl)-O-(alkyl), wherein alkyl is defined above.
  • An“amino” group is a radical of the formula: -NIL ⁇ , -NH(R # ), or -N(R # )2, wherein each R # is independently an alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl (e.g., heteroaryl or heterocycloalkyl), or heterocyclylalkyl (e.g., heteroarylalkyl or
  • heterocycloalkylalkyl group defined above, each of which is independently substituted or unsubstituted.
  • an“amino” group is an“alkylamino” group, which is a radical of the formula: -NH-alkyl or -N(alkyl)2, wherein each alkyl is independently defined above.
  • heterocycloalkyl or the like, respectively.
  • A“carboxy” group is a radical of the formula: -C(0)OH.
  • an“acyl” group is a radical of the formula: -C(0)(R # ) or -C(0)H, wherein R # is defined above.
  • A“formyl” group is a radical of the formula: -C(0)H.
  • an“amido” group is a radical of the formula: -C(0)-NH 2 , -C(0)-NH(R # ), -C(0)-N(R # ) 2 , -NH-C(0)H, -NH-C(0)-(R # ),
  • each R # is independently defined above.
  • an“amido” group is an“aminocarbonyl” group, which is a radical of the formula: -C(0)-NH 2 , -C(0)-NH(R # ), -C(0)-N(R # ) 2 , wherein each R # is
  • an“amido” group is an“acylamino” group, which is a radical of the formula: -NH-C(0)H, -NH-C(0)-(R # ), -N(R # )-C(0)H, or -N(R # )-C(0)-(R # ), wherein each R # is independently defined above.
  • A“sulfonylamino” group is a radical of the formula: -NHS0 2 (R # )
  • A“urea” group is a radical of the formula: -N(alkyl)C(0)N(R # ) 2 ,
  • monocyclic or fused or non-fused polycyclic aryl or heteroaryl e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy.
  • aryl or heteroaryl e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiopheny
  • the term“Piperidine Dione Compound” refers to compounds of formula (I) as well as to further embodiments provided herein.
  • an “Piperidine Dione Compound” is a compound set forth in Table 1.
  • the term“Piperidine Dione Compound” includes pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers of the compounds provided herein.
  • the term“pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base.
  • Suitable pharmaceutically acceptable base addition salts of the compounds of formula (I) include, but are not limited to metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N’-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,
  • non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,
  • stereoisomerically pure means one stereoisomer of a Piperidine Dione Compound that is substantially free of other stereoisomers of that compound.
  • a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
  • a stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • a typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
  • the Piperidine Dione Compounds can have chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof.
  • Piperidine Dione Compounds can include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof.
  • the Piperidine Dione Compounds are isolated as either the E or Z isomer.
  • the Piperidine Dione Compounds are a mixture of the E and Z isomers.
  • Tautomers refers to isomeric forms of a compound that are in equilibrium with each other.
  • concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution.
  • pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:
  • Piperidine Dione Compounds can contain unnatural proportions of atomic isotopes at one or more of the atoms.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), sulfur-35 ( 35 S), or carbon-14 ( 14 C), or may be isotopically enriched, such as with deuterium ( 2 H), carbon-13 ( 13 C), or nitrogen-15 ( 15 N).
  • an“isotopologue” is an isotopically enriched compound.
  • the term“isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom.
  • “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.
  • the term“isotopic composition” refers to the amount of each isotope present for a given atom.
  • Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the Piperidine Dione Compounds as described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein.
  • isotopologues of the Piperidine Dione Compounds are deuterium, carbon-13, and/or nitrogen-15 enriched Piperidine Dione Compounds.
  • “deuterated” means a compound wherein at least one hydrogen (H) has been replaced by deuterium (indicated by D or 2 H), that is, the compound is enriched in deuterium in at least one position.
  • each Piperidine Dione Compound referred to herein can be provided in the form of any of the pharmaceutically acceptable salts discussed herein. Equally, it is understood that the isotopic composition may vary independently from the stereoisomerical composition of each Piperidine Dione Compound referred to herein. Further, the isotopic composition, while being restricted to those elements present in the respective Piperidine Dione Compound or salt thereof, may otherwise vary independently from the selection of the pharmaceutically acceptable salt of the respective Piperidine Dione Compound.
  • Treating means an alleviation, in whole or in part, of a disorder, disease or condition, or one or more of the symptoms associated with a disorder, disease, or condition, or slowing or halting of further progression or worsening of those symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
  • the disorder is an androgen receptor mediated disease, as
  • Preventing means a method of delaying and/or precluding the onset, recurrence or spread, in whole or in part, of a disorder, disease or condition;
  • the disorder is an androgen receptor mediated disease, as described herein, or symptoms thereof.
  • Compound means an amount capable of treating or preventing a disorder, disease or
  • a subject is a human having or at risk for having an androgen receptor mediated disease, or a symptom thereof.
  • androgen receptor refers to a nuclear hormone receptor activated by binding of the androgenic hormones, including testosterone or dihydrotestosterone.
  • androgen receptor may refer to the nucleotide sequence or protein sequence of human androgen receptor (e.g., Entrez 367, Uniprot P10275, RefSeq NM_000044, or RefSeq NP_000035).
  • AR-full length refers to AR protein that contains all four functional domains, including the N-terminal transactivation domain (NTD, exon 1), the DNA-binding domain (DBD, exons 2-3), the hinge domain (exon 4), and the C-terminal ligand binding domain (LBD, exons 4-8).
  • CRPC castration resistant prostate cancer
  • CRPC castration resistant prostate cancer
  • Castration resistant prostate cancer is defined as prostate cancer that continues to progress or worsen or adversely affect the health of the patient despite prior surgical castration, continued treatment with gonadotropin releasing hormone agonists (e.g., leuprolide) or antagonists (e.g., degarelix or abarelix), antiandrogens (e.g., bicalutamide, flutamide, enzalutamide, ketoconazole, aminoglutethamide), chemotherapeutic agents (e.g., docetaxel, paclitaxel, cabazitaxel, adriamycin, mitoxantrone, estramustine, cyclophosphamide), kinase inhibitors (imatinib (Gleevec®) or gefitinib (Iressa®), cabozantinib (Cometriq®, also known as XL184)) or other prostate cancer therapies (e.g., vaccines (sipuleucel-T
  • R N is H
  • each R 1 is independently selected from halogen, CN, and C1-3 alkyl;
  • R 2 and R 3 are each independently selected from H, and C1- 3 alkyl, or R 2 and R 3 and the carbon to which they are attached form a substituted or unsubstituted C3- 6 cycloalkyl;
  • each R 4 is independently substituted or unsubstituted C1-3 alkyl, or two R 4 groups, together with the same carbon atom or adjacent carbon atoms to which they are attached, form a substituted or unsubstituted C3-6 cycloalkyl, or two R 4 groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7-membered heterocyclyl;
  • X is N
  • L is -0(Ci- 6 alkyl)- or -(C1-9 alkyl)-;
  • n 0-4;
  • A is N, CH, or CR A ;
  • B is N, CH, or CR B ;
  • each R A is independently selected from halogen, substituted or unsubstituted Ci- 6 alkyl, and substituted or unsubstituted C3-6 cycloalkyl;
  • each R B is independently selected from halogen, and substituted or unsubstituted
  • R c is halogen or CF3
  • R 5 and R 6 are C1-3 alkyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a substituted or unsubstituted C3- 6 cycloalkyl or a 3-6 membered heterocyclyl;
  • a 0-3;
  • b is 0-2.
  • R N is H
  • each R 1 is independently selected from halogen, CN, and C1-3 alkyl
  • R 2 and R 3 are each independently selected from H, and C1-3 alkyl, or R 2 and R 3 and the carbon to which they are attached form a substituted or unsubstituted C3- 6 cycloalkyl
  • each R 4 is independently substituted or unsubstituted C1-3 alkyl, or two R 4 groups, together with the same carbon atom or adjacent carbon atoms to which they are attached, form a substituted or unsubstituted C3-6 cycloalkyl, or two R 4 groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7-membered heterocyclyl;
  • X is N
  • L is -0(CH 2 )p- or -(CH 2 ) P -;
  • n 0-4;
  • n 0-8;
  • p 1-3;
  • A is N, CH, or CR A ;
  • B is N, CH, or CR B ;
  • each R A is independently selected from halogen, substituted or unsubstituted Ci- 6 alkyl, and substituted or unsubstituted C3-6 cycloalkyl;
  • each R B is independently selected from halogen, and substituted or unsubstituted
  • R c is halogen or CF3
  • R 5 and R 6 are C1- 3 alkyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a substituted or unsubstituted C 3 -5 cycloalkyl or a 3-5 membered heterocyclyl;
  • a 0-3;
  • b is 0-2.
  • each R 1 is independently selected from halogen, and C1-3 alkyl. In some embodiments of compounds of formula (I), (Ila) and (lib), each R 1 is independently selected from Cl, F, Br, CN, -CFb,
  • each R 1 is independently selected from Cl, F, CN, and -CFb. In some other embodiments, each R 1 is independently selected from Cl, F, and CN.
  • n is 0. In other embodiments, n is 1 or 2.
  • the compound is a compound of formula (III), (IV) or (V), wherein each R 1 is independently selected from Cl, F, CN, and CFb. In some such
  • the compound is a compound of formula (III), (IV) or (V), wherein R 1 is F or Cl. In some embodiments of compounds of formula (III), R 1 is F, Cl, or CN. In some embodiments of compounds of formula (IV), R 1 is F.
  • R 2 and R 3 are each independently selected from H, substituted or unsubstituted methyl, and ethyl, or R 2 and R 3 and the carbon to which they are attached form a substituted or unsubstituted cyclopropyl, cyclobutyl or cyclopentyl.
  • R 2 and R 3 are each independently selected from H and methyl, or R 2 and R 3 and the carbon to which they are attached form an unsubstituted cyclopropyl.
  • R 2 and R 3 are both H or methyl, or R 2 and R 3 and the carbon to which they are attached form an unsubstituted cyclopropyl.
  • R 2 and R 3 are H.
  • each R 4 is independently selected from substituted or unsubstituted methyl and ethyl, or two R 4 groups, together with the same carbon atom to which they are attached, form a substituted or unsubstituted cyclopropyl or cyclobutyl. In some embodiments, each R 4 is independently substituted or unsubstituted methyl, or two R 4 groups, together with the same carbon atom to which they are attached, form an unsubstituted cyclopropyl.
  • each R 4 is independently selected from methyl, CF3, and CH2OH, or two R 4 groups, together with the same carbon atom to which they are attached, form an unsubstituted cyclopropyl.
  • R 4 is methyl.
  • R 4 is ethyl.
  • m is 0, 1, 2, 3 or 4. In some embodiments, m is 0, 1, or 2.
  • two R 4 groups together with the non-adjacent carbon atoms to which they are attached form an unsubstituted 4-7-membered heterocyclyl. In some such embodiments, the compound is
  • the compound 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
  • the compound 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
  • exemplary L groups include, but are not limited to, -0(CH 2 )(CH 2 )-, -0(CH 2 )(CH(CH 3 ))-, -0(CH 2 )(C(CH 3 ) 2 )-, -0(CH(CH 3 ))(CH 2 )-,
  • L is -0(CH 2 )(CH 2 )-
  • L is -0(CH 2 )(CH 2 )-, -(CH 2 )-, -(CH 2 )(CH 2 )-, or -(CH 2 )(CH 2 )(CH 2 )-. In other embodiments, L is -0(CH 2 )(CH 2 )-, or -(CH 2 )(CH 2 )(CH 2 )-. In still other embodiments, L is -0(CH 2 )(CH 2 )-. In some embodiments of compounds of formula (I),
  • L is -0(CH 2 )(CH 2 )-, -0(CH 2 )(CH(CH 3 ))-, -0(CH(CH 3 ))(CH 2 )-, or -(CH 2 )(CH 2 )(CH 2 )-.
  • A is CH. In some other embodiments of compounds of formula (I), B is CH. In some other embodiments, B is N.
  • a is 0, 1 or 2.
  • each R A is independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, CH 2 CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH(CH 3 ) 2 , CF 3 , CF(CH 3 ) 2 , CF 2 CH 3 , CH 2 CH 2 F,
  • each R A is independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, CF3, CF2CH3, CH2CH2F, CH2CHF2, CH2OH, CH(CH3)OH, cyclopropyl, cyclobutyl, and cyclopentyl.
  • each R A is independently selected from Cl, Br, F, methyl, ethyl, n— propyl, isopropyl, isobutyl, sec-butyl, CF3, CF2CH3, CH2CH2F, CH2CHF2, cyclopropyl, cyclobutyl, and cyclopentyl.
  • each R A is independently selected from Cl, F, methyl, ethyl, n-propyl, isopropyl, sec-butyl, CF2CH3, CH2CH2F, CH2CHF2, CH2OH, CH(CH3)OH, cyclopropyl, and cyclobutyl.
  • each R A is independently selected from ethyl, isopropyl and cyclopropyl.
  • b is 0 or 1.
  • R B is methyl.
  • R c is CF3 or Cl.
  • R 5 and R 6 are methyl, or
  • R 5 and R 6 together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, tetrahydrofuranyl, or tetrahydropyranyl.
  • R 5 and R 6 are methyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a cyclobutyl, or tetrahydrofuranyl.
  • R 5 and R 6 are methyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a cyclobutyl, cyclopentyl, cyclohexyl, or tetrahydrofuranyl.
  • each R 1 is independently selected from Cl, F, CN, and CFb, and R 2 and R 3 are H. In some such
  • each R 4 is independently selected from methyl, CF3, and CH2OH, or two
  • R 4 groups together with the same carbon atom to which they are attached, form an unsubstituted cyclopropyl.
  • R 4 is methyl.
  • R 4 is ethyl.
  • L is -0(CH2)(CH2)-, or -(CH2XCH2XCH2)-.
  • L is -0(CH2)(CH(CH3))-, -0(0 ⁇ (03 ⁇ 4))(03 ⁇ 4)-.
  • A is CH.
  • B is CH, and each R A is independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, CF3, CF2CH3, CH2CH2F, CH2CHF2, cyclopropyl, cyclobutyl, and cyclopentyl.
  • B is N, and each R A is independently selected from Cl, F, methyl, ethyl, n-propyl, isopropyl, sec-butyl, CF2CH3, CH2CH2F, CH2CHF2, CH2OH, CH(CH 3 )OH, and cyclopropyl.
  • each R A is ethyl, isopropyl or cyclopropyl.
  • R 5 and R 6 are methyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a cyclobutyl, or tetrahydrofuranyl.
  • R 5 and R 6 are methyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a cyclobutyl, cyclopentyl, cyclohexyl, or tetrahydrofuranyl.
  • R N is H
  • each R 1 is independently selected from Cl, F, Br, CN, -CFb, -CH2CH3, and isopropyl;
  • R 2 and R 3 are each independently selected from H, substituted or unsubstituted methyl and ethyl, or R 2 and R 3 and the carbon to which they are attached form a substituted or unsubstituted cyclopropyl, cyclobutyl or cyclopentyl;
  • each R 4 is independently selected from substituted or unsubstituted methyl or ethyl, or two R 4 groups, together with the same carbon atom or adjacent carbon atoms to which they are attached, form a substituted or unsubstituted cyclopropyl or cyclobutyl, or two R 4 groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7-membered heterocyclyl;
  • X is N
  • L is -0(Ci-5 alkyl)- or -(C1-5 alkyl)-;
  • n 0-4;
  • n 0-2;
  • A is N, CH, or CR A
  • B is N, CH, or CR B ;
  • each R A is independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, CFhCFhCH ⁇ CFb
  • each R B is independently selected from halogen, and methyl
  • R c is halogen or CF 3 ;
  • R 5 and R 6 are methyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a substituted or unsubstituted cyclobutyl, cyclopentyl, cyclohexyl, or tetrahy drofuranyl ;
  • a 0-3;
  • b is 0-2.
  • R N is H
  • each R 1 is independently selected from Cl, F, Br, CN, -CFb, -CH2CH3, and isopropyl;
  • R 2 and R 3 are each independently selected from H, substituted or unsubstituted methyl and ethyl, or R 2 and R 3 and the carbon to which they are attached form a substituted or unsubstituted cyclopropyl, cyclobutyl or cyclopentyl;
  • each R 4 is independently selected from substituted or unsubstituted methyl or ethyl, or two R 4 groups, together with the same carbon atom or adjacent carbon atoms to which they are attached, form a substituted or unsubstituted cyclopropyl or cyclobutyl, or two R 4 groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7-membered heterocyclyl;
  • X is N
  • L is -0(CH 2 )p- or -(CH 2 ) P -;
  • n 0-4;
  • n 0-2;
  • A is N, CH, or CR A ;
  • B is N, CH, or CR B ;
  • each R A is independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, CH2CH2CH(CH3)2,
  • each R B is independently selected from halogen, and methyl
  • R c is halogen or CF 3 ;
  • R 5 and R 6 are methyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a substituted or unsubstituted cyclobutyl, or tetrahydrofuranyl;
  • a 0-3;
  • b is 0-2.
  • R N is H
  • each R 1 is independently selected from Cl, F, Br, CN, -CH 3 , -CH2CH 3 , and isopropyl;
  • R 2 and R 3 are each independently selected from H, substituted or unsubstituted methyl and ethyl, or R 2 and R 3 and the carbon to which they are attached form a substituted or unsubstituted cyclopropyl, cyclobutyl or cyclopentyl;
  • each R 4 is independently selected from substituted or unsubstituted methyl or ethyl, or two R 4 groups, together with the same carbon atom or adjacent carbon atoms to which they are attached, form a substituted or unsubstituted cyclopropyl or cyclobutyl, or two R 4 groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7-membered heterocyclyl;
  • X is N;
  • L is -0(Ci-5 alkyl)- or -(C1-5 alkyl)-;
  • n 0-4;
  • n 0, 1 or 2;
  • A is N, CH, or CR A ;
  • B is N, CH, or CR B ;
  • each R A is independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, CH2CH2CH(CH3)2,
  • each R B is independently selected from halogen, and methyl
  • R c is halogen or CF 3 ;
  • R 5 and R 6 are methyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a substituted or unsubstituted cyclobutyl, cyclopentyl, cyclohexyl, or tetrahy drofuranyl ;
  • a 0-3;
  • b is 0-2.
  • R N is H
  • each R 1 is independently selected from Cl, F, Br, CN, -CH 3 , -CH2CH 3 , and isopropyl;
  • R 2 and R 3 are each independently selected from H, substituted or unsubstituted methyl and ethyl, or R 2 and R 3 and the carbon to which they are attached form a substituted or unsubstituted cyclopropyl, cyclobutyl or cyclopentyl; each R 4 is independently selected from substituted or unsubstituted methyl or ethyl, or two R 4 groups, together with the same carbon atom or adjacent carbon atoms to which they are attached, form a substituted or unsubstituted cyclopropyl or cyclobutyl, or two R 4 groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7-membered heterocycle;
  • X is N
  • L is -0(CH 2 )p- or -(CH 2 ) P -;
  • n 0-4;
  • n 0, 1 or 2;
  • p 1-3;
  • A is N, CH, or CR A ;
  • B is N, CH, or CR B ;
  • each R A is independently selected from Cl, Br, F, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, CH 2 CH 2 CH(CH3) 2 ,
  • each R B is independently selected from halogen, and methyl
  • R c is halogen or CF 3 ;
  • R 5 and R 6 are methyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a substituted or unsubstituted cyclobutyl, or tetrahydrofuranyl;
  • a 0-3;
  • b is 0-2.
  • the Piperidine Dione Compound is a compound as described herein, wherein the compound at a concentration of 1 mM leads to degradation of AR protein, by at least about 50% or more.
  • Piperidine Dione Compounds described herein can be made using conventional organic syntheses and commercially available starting materials, or the
  • -0(Ci-6 alkyl)- can be prepared starting by reacting the phenol (A is CH or CR A ) or pyridinone (A is N) derivative V-OH with the appropriately derivatized and N-protected piperazinyl (for example, wherein P N is Boc and the leaving group LG 1 is Br, Cl, OTs, or OMs), in the presence of a base, in a solvent (for example, CsCCb in DMF, or K2CO3 in acetonitrile), at elevated temperature (for example, between about 40 °C and about 70 °C) to provide intermediate a.
  • a solvent for example, CsCCb in DMF, or K2CO3 in acetonitrile
  • V-OH when LG 1 is -OH, V-OH is treated under Mitsunobu conditions (for example, with PPh3 and DIAD or DEAD, in a solvent such as THF, at room temperature) to provide intermediate a.
  • V-OH can first be reacted with LG 2 -L-Hal, wherein Hal is Cl, Br, OMs or OTs, and wherein LG 2 is Br, Cl, OH, and, when LG 2 is Br or Cl, the reaction is performed in the presence of a base, such as CsC03 or K2CO3, in a solvent, such as DMF or NMP, at elevated temperature, for example, between about 40 °C and about 70 °C; or when LG 2 is OH, a Mitsunobu reaction is performed (using PPI13 and DIAD or DEAD, in a solvent, such as THF, at room temperature) to generate V-L-Hal, which is reacted with the appropriately protected piperazinyl (in the presence of a base, such as
  • intermediate c is prepared by reaction of V-L-Hal (wherein Hal is Cl, Br, OMs, or OTs) with the appropriately derivatized 2-(piperazin-l-yl)acetate (wherein R is Ci-4 alkyl, for example, methyl, ethyl, or t-butyl) in the presence of a base, such as DIEA, TEA, or DBU, in a solvent, such as DMF or NMP, at room temperature.
  • a base such as DIEA, TEA, or DBU
  • intermediate e The nitro group in intermediate e is reduced (by treatment with a reducing agent, for example H2, in the presence of a catalyst, such as Pd/C, in a solvent, such as EtOH or MeOH; or Fe and NH4CI, in a solvent such as EtOH and H2O) to provide the mono-protected derivatized dianiline intermediate f.
  • a reducing agent for example H2
  • a catalyst such as Pd/C
  • solvent such as EtOH or MeOH
  • Fe and NH4CI in a solvent such as EtOH and H2O
  • a solvent for example, NaHC03, CsC0 3 or K2CO3, in DMF or NMP, at elevated temperature, for example between about 50 °C and about 80 °C; or DIEA in DMF or NMP, at elevated temperature, for example, about 150 °C
  • P N for example, when P N is Boc, treatment with an acid in a solvent, such as T
  • intermediate h is obtained via iron-catalyzed reductive coupling of intermediate e and 3-bromopiperidine-2,6-dione (for example, by reaction in the presence of Zn, TMSC1, FeCk FhO, in a solvent, such as NMP, at elevated temperature, for example between about 80 °C to about 100 °C), followed by removal of the protecting group P N (for example, when P N is Boc, treatment with an acid in a solvent, such as TFA in DCM; or treatment with HC1 in dioxane or EtOAc).
  • a solvent such as NMP
  • Coupling of intermediate d with intermediate h for example in the presence of a coupling agent, such as HATU, HBTU, or EDC or DCC, optionally in combination with HOBt, in the presence of a base, such as DIEA, NMM, or TEA, in a solvent, such as DCM, DMF, or NMP, or mixtures thereof, provides compounds of formula (I), wherein L is -0(Ci- 6 alkyl)-.
  • a coupling agent such as HATU, HBTU, or EDC or DCC
  • a base such as DIEA, NMM, or TEA
  • a solvent such as DCM, DMF, or NMP, or mixtures thereof
  • the common intermediate h is reacted with Hal 2 -C(R 2 )(R 3 )COY (wherein Hal 2 is Cl or Br), in the presence of, when Y is OH, a coupling agent (for example HATU, HBTU, or EDC or DCC, optionally in combination with HOBt), and a base (for example DIEA, TEA, or NMM), in a solvent (for example, DCM, DMF, NMP or mixtures thereof); or in the presence of, when Y is Cl, a base, such as TEA or DIEA, in a solvent, such as DMF or NMP, at a temperature between about 0 °C and about 25 °C, to provide intermediate i.
  • a coupling agent for example HATU, HBTU, or EDC or DCC, optionally in combination with HOBt
  • a base for example DIEA, TEA, or NMM
  • a solvent for example, DCM, DMF, NMP or mixtures thereof
  • intermediate i Treatment of intermediate i with intermediate b, in the presence of a base, such as DIEA, TEA, or NMM, in a solvent, such as DMF or NMP, at elevated temperature, for example, between about 40 °C and about 60 °C, optionally in the presence of Nal or KI, provides the target compounds of formula (I).
  • a base such as DIEA, TEA, or NMM
  • a solvent such as DMF or NMP
  • intermediate h is coupled with an N-protected, appropriately derivatized 2-(piperazin-l-yl)acetic acid (wherein P N is, for example, Boc), by reaction in the presence of a coupling agent (for example, HATU, HBTU, or EDC or DCC, optionally in combination with HOBt), and a base (for example, DIEA, TEA or NMM), in a solvent (for example DCM, DMF, NMP or mixtures thereof) to provide intermediate j.
  • a coupling agent for example, HATU, HBTU, or EDC or DCC, optionally in combination with HOBt
  • a base for example, DIEA, TEA or NMM
  • solvent for example DCM, DMF, NMP or mixtures thereof
  • intermediate j is prepared by reaction of intermediate i with an appropriately derivatized protected piperazine (wherein P N is, for example, Boc), in the presence of a base, such as DIEA, TEA, or NMM, in a solvent, such as DMF or NMP, at elevated temperature, for example, between about 40 °C and about 80 °C, optionally in the presence of Nal or KI.
  • P N is, for example, Boc
  • a base such as DIEA, TEA, or NMM
  • a solvent such as DMF or NMP
  • intermediate j is prepared starting by reacting intermediate ae (wherein P N is, for example, Cbz) with Hal-C(R 2 )(R 3 )COY (wherein Hal is Cl or Br), in the presence of, when Y is OH, a coupling agent (for example HATU, HBTU, or EDC or DCC, optionally in combination with HOBt), and a base (for example, DIEA, TEA, or NMM), in a solvent (for example, DCM, DMF, NMP, or mixtures thereof), to provide intermediate af.
  • a coupling agent for example HATU, HBTU, or EDC or DCC, optionally in combination with HOBt
  • a base for example, DIEA, TEA, or NMM
  • solvent for example, DCM, DMF, NMP, or mixtures thereof
  • intermediate af Treatment of intermediate af with an N-protected, appropriately functionalized piperazine (wherein P N is, for example, Boc), in the presence of a base, such as DIEA or TEA, in a solvent, such as DMF or NMP, at elevated temperature, for example, between about 60 °C and about 90 °C, optionally in the presence of Nal or KI, provides intermediate ag.
  • Intermediate ag is deprotected, for example with a reducing agent, such as 3 ⁇ 4, when P N is Cbz, in the presence of a catalyst (for example, Pd/C, Pt/C, or Pd(OH)2), in a solvent, such as MeOH or EtOAc, to give intermediate ah.
  • a reducing agent such as 3 ⁇ 4
  • a catalyst for example, Pd/C, Pt/C, or Pd(OH)2
  • Reaction of intermediate 0 with ROOC-C(R 5 )(R 6 )Hal (wherein Hal is Br or Cl and R’ is C1-3 alkyl) in the presence of a base (for example DIEA or TEA) at elevated temperature (for example, between 110 °C and about 130 °C) provides intermediate p.
  • a base for example DIEA or TEA
  • elevated temperature for example, between 110 °C and about 130 °C
  • 5-isothiocyanatopicolinonitrile in the presence of a base, such as TEA, in a solvent, such as EtOAc, at elevated temperature, for example, between about 70 °C and about 90 °C, provides intermediates a, which can be further reacted to provide compounds of formula (I), wherein L is -0(Ci- 6 alkyl)-, as described in the schemes above.
  • a base such as TEA
  • EtOAc a solvent
  • reaction of intermediate 0 with CN-C(R 5 )(R 6 )OH in the presence of MgSCE, at elevated temperature, for example between about 50 °C to about 70 °C, provides intermediate q.
  • Intermediates r wherein P° is a phenol protecting group, for example acetyl or benzyl, can be treated with R A -Zn-Br, in the presence of a catalyst and a ligand, for example, CPhosPdG3 and CPhos in a solvent, for example, toluene, at lower temperature for example, between about 0 °C and about 25 °C to generate intermediates s.
  • a catalyst and a ligand for example, CPhosPdG3 and CPhos in a solvent, for example, toluene
  • intermediates s wherein A is CH or CR A
  • A is CH or CR A
  • an alkylating agent such as bromomethylbenzene
  • a solvent such as acetonitrile
  • K2CO3 a base
  • elevated temperature such as about 80 °C
  • intermediate aw Treatment of intermediate aw with R A -B(OH)2, in the presence of a catalyst and a base, for example Pd(dppf)2Ck and CS2CO3, in a solvent, such as a toluene and water mixture, at elevated temperature, such as about 100 °C, provides intermediate ax.
  • a catalyst and a base for example Pd(dppf)2Ck and CS2CO3
  • a solvent such as a toluene and water mixture
  • elevated temperature such as about 100 °C
  • R A can be incorporated by reaction of intermediate t with R A -Zn-Br, in the presence of a catalyst and a ligand, for example,
  • CPhosPdG3 and CPhos in a solvent for example, toluene, at lower temperature for example, between about 0 °C and about 25 °C to generate intermediates u, wherein R A is substituted or unsubstituted Ci- 6 alkyl, or substituted or unsubstituted C3-6 cycloalkyl and which can be used similarly to intermediate a in the schemes above.
  • LG 3 is -OH
  • 2-bromo-4-nitrophenol or 3-bromo-5-nitropyridin-2-ol is treated under Mitsunobu conditions (for example, with PPh3 and DIAD or DEAD, in a solvent such as THF, at room temperature) to provide intermediate v.
  • 2-bromo-4-nitrophenol or 3-bromo-5-nitropyridin-2-ol is reacted with Hal-L-Hal, wherein Hal is Br, in the presence of a base (such as K2CO3 or CSCO3), in a solvent (such as acetonitrile or DMF), at elevated temperature, for example between about 80 °C and about 100 °C, followed by coupling with the appropriately derivatized and protected piperazinyl, in the presence of a base, for example DIEA or TEA, in a solvent, for example DMF or NMP, at elevated temperature, for example at between about 50 °C and about 70 °C, to provide intermediate v.
  • a base such as K2CO3 or CSCO3
  • a solvent such as acetonitrile or DMF
  • R A is achieved by reaction of intermediate v with a boronate R A [B(OR + )2]2, (wherein R A is substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted C5-6 cycloalkenyl, and R + together with the boron atom and the atoms to which they are attached, forms a cyclic boronate, for example, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane), in the presence of a palladium catalyst (for example Pd(dppf)Cl2) and a base (such as K3PO4) in a solvent (such as a 1,4-dioxane/water mixtures), providing intermediate w, wherein R A is substituted or unsubstituted C2-6 alkenyl, substituted or
  • intermediate v is treated with R A BF 3 K + , wherein R A is substituted or unsubstituted Ci- 6 alkyl, in the presence of a catalyst and a ligand (for example, cataCXium® A Palladacycle Gen. 3 and butyldi-l-adamantylphosphine), in the presence of a base, such as CS2CO3 or K2CO3, in a solvent, such as a toluene/water mixtures, at elevated temperature, for example, between about 90 °C and about 110 °C, to provide intermediate y, wherein R A is substituted or unsubstituted Ci- 6 alkyl.
  • a catalyst and a ligand for example, cataCXium® A Palladacycle Gen. 3 and butyldi-l-adamantylphosphine
  • a base such as CS2CO3 or K2CO3
  • solvent such as a toluene/water mixtures
  • intermediate ac is oxidized using an oxidizing agent (for example Dess-Martin periodinane (l,l,l-triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)-one), in a solvent, such as DCM, at lower temperature, for example, about 0 °C), then coupled to the N-protected appropriately derivatized piperazinyl via reductive amination, using a reducing agent, for example, sodium triacetoxyborohydride, in a solvent, for example, MeOH, to provide
  • an oxidizing agent for example Dess-Martin periodinane (l,l,l-triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)-one
  • intermediate ad which can be used as described in Schemes 1 and 2 for intermediate a, to provide compounds of formula (I), wherein L is -(C2-9 alkyl)-.
  • Intermediates c wherein L is -0(Ci- 6 alkyl)- or -(C1-9 alkyl)-, can also be prepared as shown in Scheme 8.
  • an appropriately derivatized intermediate ai is reacted with an alkylating agent, such as an O-protected LG 4 -L-Hal (for example, wherein the
  • O-protecting group P° is benzyl, LG 4 is O, and Hal is Br or Cl), in the presence of a base in a solvent (for example, CsCCb in DMF, or K2CO3 in acetonitrile), at elevated temperature (for example, between about 40 °C and about 70 °C) to provide intermediate aj.
  • a solvent for example, CsCCb in DMF, or K2CO3 in acetonitrile
  • Reaction of intermediate aj with Hal-C(R 2 )(R 3 )COOR (wherein R is Ci-4 alkyl, for example, methyl, ethyl, or t-butyl, and Hal is Cl or Br), in the presence of a base, such as TEA, DBU, or DIEA, in a solvent, such as THF, NMP, or DMF, optionally at elevated temperature (for example, a temperature between about 20 °C and about 80 °C), optionally in the presence of Nal or KI, provides intermediate ak.
  • a base such as TEA, DBU, or DIEA
  • solvent such as THF, NMP, or DMF
  • elevated temperature for example, a temperature between about 20 °C and about 80 °C
  • Nal or KI optionally in the presence of Nal or KI
  • P N is an N-protecting group, such as Boc, and Hal is Br or Cl), in the presence of a base, such as TEA, DBU, or DIEA, in a solvent, such as THF, NMP, or DMF, optionally at elevated temperature (for example, a temperature between about 20 °C and about 80 °C), optionally in the presence ofNal or KI, provides intermediate am.
  • a base such as TEA, DBU, or DIEA
  • a solvent such as THF, NMP, or DMF
  • elevated temperature for example, a temperature between about 20 °C and about 80 °C
  • Nal or KI optionally in the presence ofNal or KI
  • Hal is Br or Cl
  • a base for example DIEA, TEA or NMM
  • a solvent for example DMF or NMP
  • LG 4 is -OH
  • the reaction is performed under Mitsunobu conditions (for example, in the presence of PPh3 and DIAD or DEAD, in a solvent such as THF, at room temperature) to provide intermediate c.
  • the leaving group LG 4 in intermediate ao is Br, Cl, OTs, or OMs (prepared from the corresponding alcohol)
  • the reaction with V-OH is performed in the presence of a base, in a solvent (for example, CsC03 in DMF, or K2CO3 in acetonitrile), at elevated temperature (for example, between about 40 °C and about 70 °C) to provide intermediate c.
  • 5-nitropyridin-2-ol (wherein LG 5 is OH, and A is N) (intermediate ar), in the presence of a base (for example, NaOtBu, CsC0 3 or K2CO3), in a solvent (for example, acetonitrile, DMF or NMP), at elevated temperature (for example, between about 0 °C and about 90 °C), to provide intermediate as.
  • a base for example, NaOtBu, CsC0 3 or K2CO3
  • a solvent for example, acetonitrile, DMF or NMP
  • intermediate ao wherein LG 4 is OH
  • is reacted with intermediate ar wherein LG 5 is OH under Mitsunobu conditions (by reaction in the presence of PPh3 and DIAD or DEAD, in a solvent, such as THF, at room temperature) to provide intermediate as.
  • intermediate ao wherein LG 4 is OH is reacted with an appropriately derivatized 2-halo-5-nitropyridine (wherein LG 5 is F or Cl, and A is N), or l-halo-4-nitrobenzene (wherein LG 5 is F or Cl and A is CH or CR A ) in the presence of a base, such as NaOtBu, CsC03 or K2CO3, in a solvent, such as acetonitrile, DMF, THF, or NMP, at elevated temperature, for example between about 0 °C and about 70 °C, to provide
  • a base such as NaOtBu, CsC03 or K2CO3
  • a solvent such as acetonitrile, DMF, THF, or NMP
  • an appropriately derivatized 4-nitrophenol (wherein A is CH or CR A ) or 5-nitropyridin-2-ol (wherein A is N) (intermediate ap) can be reacted with LG 6 -L-Hal (wherein LG 6 is Br or Cl, and Hal is Cl or Br), in the presence of a base (for example, NaOtBu, CsC0 3 or K2CO3), in a solvent (for example acetonitrile, DMF or NMP), at elevated temperature (for example between about 0 °C and about 90 °C), to provide intermediate aq.
  • a base for example, NaOtBu, CsC0 3 or K2CO3
  • a solvent for example acetonitrile, DMF or NMP
  • Intermediate ap can also be reacted with LG 6 -L-Hal, wherein LG 6 is OH, under Mitsunobu conditions (using PPI13 and DIAD or DEAD, in a solvent, such as THF, at room temperature) to provide intermediate aq.
  • Intermediate aq can then be used to alkylate intermediate an, in the presence of a base, such as NaOtBu, CsC0 3 or K2CO3, in a solvent, such as acetonitrile, DMF, THF, or NMP, at elevated temperature, for example between about 0 °C and about 70 °C, to provide intermediate as.
  • a base such as NaOtBu, CsC0 3 or K2CO3
  • a solvent such as acetonitrile, DMF, THF, or NMP
  • reaction of intermediate at with CN-C(R 5 )(R 6 )OH in the presence of MgSCE, at elevated temperature, for example between about 50 °C and about 70 °C, provides intermediate au.
  • Intermediate as (when R A is Br) can also be used to obtain intermediate as wherein R A is substituted or unsubstituted C2-6 alkyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C5-6 cycloalkyl, by reaction of intermediate as (when R A is Br) with a boronate R A '[B(OR + )2]2, (wherein R A' is substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted C5-6 cycloalkenyl, and R + together with the boron atom and the atoms to which they are attached, forms a cyclic boronate, for example, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane), in the presence of a pal
  • R N is H
  • each R 1 is independently selected from halogen, CN, and C1-3 alkyl;
  • R 2 and R 3 are each independently selected from H, and C1- 3 alkyl or R 2 and R 3 and the carbon to which they are attached form a substituted or unsubstituted C3- 6 cycloalkyl;
  • each R 4 is independently substituted or unsubstituted C1-3 alkyl, or two R 4 groups, together with the same carbon atom or adjacent carbon atoms to which they are attached, form a substituted or unsubstituted C3-6 cycloalkyl, or two R 4 groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7-membered heterocyclyl;
  • X is N
  • L is -0(Ci-6 alkyl)- or -(C1-9 alkyl)-;
  • n 0-4;
  • n 0-8;
  • A is N, CH, or CR A ;
  • B is N, CH, or CR B ;
  • each R A is independently selected from halogen, substituted or unsubstituted Ci- 6 alkyl, or substituted and unsubstituted C3-6 cycloalkyl;
  • each R B is independently selected from halogen, and substituted or unsubstituted
  • R c is halogen or CF3
  • R 5 and R 6 are C1- 3 alkyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a substituted or unsubstituted C 3 - 6 cycloalkyl or a 3-6 membered heterocyclyl;
  • a 0-3;
  • b is 0-2.
  • the coupling agent is HATU, HBTU, EDC, or DCC, optionally in combination with HOBt.
  • the coupling agent is HATU.
  • the base is DIEA, NMM or TEA.
  • the base is DIEA.
  • the solvent is DCM, DMF, NMP, or mixtures thereof. In one embodiment the solvent is DMF.
  • R b , R c , L, V, A, B, n, m, p, a, and b are as defined herein, unless otherwise specified.
  • the methods additionally comprise preparing a compound of formula (h)
  • P N is a Boc group.
  • the deprotecting is performed by treatment with an acid, in a solvent.
  • acid is TFA and the solvent is DCM.
  • the acid is HC1, and the solvent is dioxane or EtOAc.
  • the methods additionally comprise preparing a compound of formula (g)
  • the base is NaHCCb, CsCCb or K2CO3 and the solvent is DMF or NMP.
  • base is NaHCCb
  • the solvent is DMF.
  • the contacting is performed at a temperature of between about 50 °C and about 80 °C.
  • the base is DIEA.
  • the solvent is DMF or NMP.
  • the contacting is performed at a temperature of about 150 °C.
  • the methods additionally comprise preparing a
  • the reducing agent is H2, and the catalyst is Pd/C.
  • the solvent is EtOH or MeOH.
  • the reducing agent is Fe and NH4CI.
  • the solvent is EtOH and H2O.
  • the methods additionally comprise preparing a
  • amine protecting group P N is Boc and the protecting agent is B0C2O.
  • the base is TEA, DIEA or DBU.
  • the base is TEA.
  • the solvent is THF, NMP or DMF.
  • the solvent is THF.
  • the methods additionally comprise preparing a compound of formula (g)
  • the solvent is NMP.
  • the temperature is between about 80 °C to about 100 °C.
  • the methods additionally comprise preparing a compound of formula (d)
  • R is Ci-4 alkyl, under conditions suitable to provide a compound of formula (d).
  • the deprotecting is performed by treatment with a base, in a solvent.
  • the base is LiOH or NaOH.
  • the solvent is THF/H2O mixtures or dioxane/H20 mixtures.
  • the deprotecting is performed by treatment with an acid in a solvent.
  • the acid is HC1 and the solvent is dioxane/DCM mixtures.
  • the acid is TFA and the solvent is DCM.
  • the methods additionally comprise preparing a compound of formula (c)
  • V-L-Hal wherein Hal is Cl, Br, OMs, or OTs, in the presence of a base, in a solvent under conditions suitable to provide a compound of formula (c).
  • the base is DIEA, TEA, or DBU. In some embodiments, the base is DIEA, TEA, or DBU. In some
  • the base is DIEA.
  • the solvent is DMF or NMP.
  • the solvent is DMF.
  • the contacting is at room temperature.
  • Hal is Cl or Br.
  • the methods additionally comprise preparing a compound of formula (c)
  • the base is TEA, DBU, or DIEA. In some embodiments, the base is TEA, DBU, or DIEA. In some
  • the base is TEA.
  • the solvent is THF, NMP, or DMF.
  • the solvent is THF.
  • the contacting is at elevated temperature, for example, a temperature between about 20 °C and about 80 °C. In some embodiments, the contacting is in the presence of Nal or KI. [00132] In some embodiments, the methods additionally comprise preparing a compound of formula (b)
  • P N is an amine protecting group, under conditions suitable to provide a compound of formula (b).
  • the P N is Boc.
  • the deprotecting is performed by treatment with an acid in a solvent.
  • the acid is HC1 and the solvent is dioxane or EtOAc.
  • the acid is
  • the methods additionally comprise preparing a compound of formula (a)
  • the base is CsCCb or K2CO3.
  • the base is CsCCb.
  • the solvent is DMF or NMP. In some such embodiments, the solvent is DMF.
  • the contacting is performed at elevated temperature, for example, a temperature between about 40 °C and about 70 °C.
  • Hal is Cl or Br.
  • the methods additionally comprise preparing a compound V-L-Hal, wherein L is -0(Ci- 6 alkyl)-, the methods comprising contacting a compound V-OH with LG 2 -L-Hal, wherein LG 2 is a leaving group selected from Br, Cl, and OH, under conditions suitable to provide a compound V-L-Hal.
  • the contacting is performed in the presence of a base, in a solvent.
  • the base is CsC03 or
  • the base is CsC0 3.
  • the solvent is DMF or NMP.
  • the solvent is DMF.
  • the contacting is performed at elevated temperature, for example, a
  • LG 2 is OH
  • the contacting is performed in the presence of PPI13 and DIAD or DEAD, in a solvent.
  • the solvent is THF.
  • the contacting is performed at room temperature.
  • the methods additionally comprise preparing a compound of formula (a)
  • LG 1 is a leaving group selected from OH, Br, Cl, OTs, and OMs, under conditions suitable to provide a compound of formula (a).
  • LG 1 is Br, Cl, OTs, or OMs
  • the contacting is performed in the presence of a base, in a solvent.
  • the base is CsCCb and the solvent is DMF.
  • the base is K2CO3 and the solvent is acetonitrile.
  • the contacting is performed at elevated temperature.
  • the temperature is between about 40 °C and about 70 °C.
  • LG 1 is -OH
  • the contacting is performed in the presence of PPh3 and DIAD or DEAD, in a solvent.
  • the solvent is
  • the contacting is performed at room temperature.
  • R N is H
  • each R 1 is independently selected from halogen, CN, and C1-3 alkyl;
  • R 2 and R 3 are each independently selected from H, and C1- 3 alkyl or R 2 and R 3 and the carbon to which they are attached form a substituted or unsubstituted C 3 - 6 cycloalkyl;
  • each R 4 is independently substituted or unsubstituted C1-3 alkyl, or two R 4 groups, together with the same carbon atom or adjacent carbon atoms to which they are attached, form a substituted or unsubstituted C3-6 cycloalkyl, or two R 4 groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7-membered heterocyclyl;
  • X is N
  • L is -0(Ci-6 alkyl)- or -(C1-9 alkyl)-;
  • n 0-4;
  • n 0-8;
  • A is N, CH, or CR A ;
  • B is N, CH, or CR B ;
  • each R A is independently selected from halogen, substituted or unsubstituted Ci- 6 alkyl, or substituted or unsubstituted C3-6 cycloalkyl;
  • each R B is independently selected from halogen, or substituted or unsubstituted
  • R c is halogen or CF3
  • R 5 and R 6 are C1- 3 alkyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a substituted or unsubstituted C 3 - 6 cycloalkyl or a 3-6 membered heterocyclyl;
  • a 0-3;
  • b is 0-2.
  • the base is DIEA, TEA or NMM. In one embodiment, the base is DIEA. In another embodiment, the solvent is DMF or NMP. In one embodiment, the contacting is performed at elevated temperature. In one such embodiment, the temperature is between about 50 °C and about 70 °C. In one embodiment, Hal is Br or Cl. [00142] In some embodiments, the methods additionally comprise preparing a compound of formula (k)
  • P N is a Boc group.
  • the deprotecting is performed by treatment with an acid, in a solvent. In some such
  • the acid is TFA and the solvent is DCM.
  • the acid is HC1, and the solvent is dioxane/DCM or EtOAc.
  • the methods additionally comprise preparing a compound of formula (j)
  • the coupling agent is HATU, HBTU, EDC or DCC, optionally in combination with HOBt.
  • the coupling agent is HATU.
  • the base is DIEA, NMM or TEA.
  • the base is DIEA.
  • the solvent is DCM, DMF, NMP, or mixtures thereof. In one embodiment, the solvent is DMF.
  • Hal 2 is Br or Cl, in the presence of a base, in a solvent, under conditions suitable to provide a compound of formula (I); wherein
  • R N is H; each R 1 is independently selected from halogen, CN, and C1-3 alkyl;
  • R 2 and R 3 are each independently selected from H, and C1- 3 alkyl, or R 2 and R 3 and the carbon to which they are attached form a substituted or unsubstituted C3- 6 cycloalkyl;
  • each R 4 is independently substituted or unsubstituted C1-3 alkyl, or two R 4 groups, together with the same carbon atom or adjacent carbon atoms to which they are attached, form a substituted or unsubstituted C3-6 cycloalkyl, or two R 4 groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7-membered heterocyclyl;
  • X is N
  • L is -0(Ci-6 alkyl)- or (C1-9 alkyl)-;
  • n 0-4;
  • n 0-8;
  • A is N, CH, or CR A ;
  • B is N, CH, or CR B ;
  • each R A is independently selected from halogen, substituted or unsubstituted Ci- 6 alkyl, and substituted or unsubstituted C3-6 cycloalkyl;
  • each R B is independently selected from halogen, or substituted and unsubstituted
  • R c is halogen or CF3
  • R 5 and R 6 are C1- 3 alkyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a substituted or unsubstituted C 3 - 6 cycloalkyl or a 3-6 membered heterocyclyl;
  • a 0-3;
  • the base is DIEA, TEA or NMM. In one embodiment, the base is DIEA. In another embodiment, the solvent is DMF or NMP. In one embodiment, the contacting is performed at elevated temperature. In one such embodiment, the temperature is between about 40 °C and about 60 °C. In one embodiment, the contacting is performed in the presence of Nal or KI.
  • the methods additionally comprise preparing a compound of formula (i)
  • the contacting is performed in the presence of a coupling agent, and a base, in a solvent.
  • the coupling agent is HATU, HBTU, EDC or DCC, optionally in combination with HOBt.
  • the coupling agent is HATU.
  • the base is DIEA, TEA, or NMM.
  • the base is DIEA.
  • the solvent is
  • the solvent is DMF.
  • the contacting is performed in the presence of a base, in a solvent.
  • the base is TEA or DIEA.
  • the solvent is DMF or NMP.
  • the contacting is performed at a
  • the methods additionally comprise preparing a compound of formula (j)
  • P N is Boc group.
  • the base is DIEA, NMM or TEA. In one embodiment, the base is DIEA. In another embodiment, the solvent is DMF, NMP, or a mixture thereof. In one such embodiment, the contacting is performed at a temperature between about 40 °C and about 80 °C. In one embodiment, the contacting is performed in the presence of Nal or KI.
  • the methods provided herein comprise preparing a compound of formula (j)
  • P N is Boc group.
  • the base is NaHCCb, CsCCb or K2CO3.
  • the solvent is DMF, NMP, or a mixture thereof.
  • the contacting is performed at a temperature between about 50 °C and about 80 °C.
  • the base is NaHCCb, CsCCb or K2CO3, the solvent is DMF or NMP, and the contacting is performed at a temperature between about 50 °C and about 80 °C.
  • the base is DIEA.
  • the solvent is DMF, NMP, or a mixture thereof.
  • the contacting is performed at a temperature of about 150 °C.
  • the base is DIEA, the solvent is DMF or NMP, and the contacting is performed at a temperature of about 150 °C.
  • the methods provided herein comprise preparing a compound of formula (j)
  • the methods provided herein comprise preparing a compound of formula (ah)
  • the reducing agent is H2.
  • PN’ is Cbz
  • the deprotecting is conducted in presence of a catalyst Pd/C, Pt/C, or Pd(OH)2, in a solvent.
  • the solvent is MeOH or EtOAc.
  • the methods provided herein comprise preparing a compound of formula (ag)
  • P N is a protecting group, in the presence of a base in a solvent, under conditions suitable to provide a compound of formula (ag).
  • P N is Boc group.
  • the base is DIEA or TEA.
  • the solvent is DMF or NMP.
  • the contacting is performed at a temperature between about 60 °C and about 90 °C. In one embodiment, the contacting is performed in the presence of Nal or KI.
  • the methods provided herein comprise preparing a compound of formula (af),
  • the contacting is performed in the presence of a coupling agent, and a base, in a solvent.
  • the coupling agent is HATU, HBTU, EDC or DCC, optionally in combination with HOBt.
  • the base is DIEA, TEA, or NMM.
  • the solvent is DCM, DMF, NMP or a mixture thereof.
  • the contacting is performed in the presence of a base, in a solvent.
  • the base is TEA or DIEA.
  • the solvent is DMF or NMP.
  • the contacting is performed at a temperature between about 0 °C and about 25 °C.
  • the methods additionally comprise preparing a compound of formula (a)
  • the first solvent is DMF or DMA. In some embodiments, the first solvent is DMF or DMA.
  • the acid is HC1.
  • the second solvent is MeOH or EtOH.
  • the contacting with the acid is performed at elevated temperature. In some such embodiments, the temperature is between about 70 °C and about 80 °C.
  • the methods additionally comprise preparing a compound of formula (q)
  • the drying agent is MgSC>4.
  • the contacting is performed at elevated temperature. In some such embodiments, the temperature is between about 50 °C and about 70 °C.
  • the methods additionally comprise preparing a compound of formula (a)
  • R’ is C1-3 alkyl, in the presence of a base, in a solvent, under conditions suitable to provide a compound of formula (a), wherein L is -0(Ci- 6 alkyl)-.
  • the base is TEA.
  • the solvent is EtOAc.
  • the contacting is performed at elevated temperature. In some such embodiments, the temperature is between about 70 °C and about 90 °C.
  • the methods additionally comprise preparing a compound of formula (p)
  • Hal is Br.
  • the base is DIEA or TEA.
  • the contacting is performed at elevated temperature. In some such embodiments, the temperature is between about 110 °C and about 130 °C.
  • the methods additionally comprise preparing a compound of formula (o)
  • the reducing agent is H2. In some such embodiments, the contacting is performed in the presence of a catalyst. In some embodiments the catalyst is Pd/C. In some such embodiments, the solvent is EtOH. In other embodiments, the reducing agent is Fe and NFECl. In some such embodiments, the solvent is EtOH and H2O. In some such embodiments, the contacting is performed at elevated temperature. In some embodiments, the temperature is about 80 °C.
  • the methods additionally comprise preparing a
  • A is N, in the presence of a base, in a solvent, under conditions suitable to provide a compound of formula (n), wherein A is N.
  • the base is CsCCb or K2CO3. In some embodiments, the base is fGCCb. In some embodiments, the solvent is acetonitrile, DMF, THF, or NMP. In some embodiments, the solvent is acetonitrile. In some embodiments, the contacting is performed at elevated temperature. In some such embodiments, the temperature is between about 50 °C and about 70 °C.
  • the methods additionally comprise preparing a compound of formula (n)
  • LG 2 is Br, Cl or OH, under conditions suitable to provide a compound of formula (n), wherein A is N.
  • LG 2 is Br or Cl
  • the contacting is performed in the presence of a base, in a solvent.
  • the base is CsC03 or K2CO3.
  • the base is CsCCb.
  • the solvent is acetonitrile, DMF or NMP.
  • the solvent is acetonitrile.
  • the contacting is performed at elevated temperature. In some embodiments the temperature is between about 50 °C and about 80 °C.
  • Hal is Br
  • the base is CsCCh
  • the solvent is DMF and the temperature is about 70 °C.
  • Hal is Cl
  • the base is K2CO3
  • the solvent is acetonitrile
  • the temperature is about 60 °C.
  • LG 2 is OH
  • the contacting is performed in the presence of PPI13 and DIAD or DEAD, in a solvent.
  • the solvent is THF. In some embodiments the contacting is performed at room temperature.
  • the methods additionally comprise preparing a compound of formula V-OH
  • R A is substituted or unsubstituted Ci-6 alkyl, or substituted or unsubstituted C3-6 cycloalkyl and P° is a phenol protecting group, under conditions suitable to provide a compound of formula V-OH.
  • P° is acetyl, and the deprotecting is performed by treatment with a base, in a solvent.
  • the base is such as K2CO3.
  • the solvent is MeOH or EtOH.
  • P° is benzyl, and the deprotecting is performed by treatment with a reducing agent in a solvent.
  • the reducing agent is Eh, and the contacting is performed in the presence of a catalyst.
  • the catalyst is Pd/C.
  • the solvent is EtOH or MeOH.
  • the methods additionally comprise preparing a compound of formula (s)
  • R A -Zn-Br wherein R A is substituted or unsubstituted Ci- 6 alkyl, or substituted or unsubstituted C3-6 cycloalkyl, in the presence of a catalyst and a ligand, in a solvent, under conditions suitable to provide a compound of formula (s).
  • the catalyst and the ligand are CPhosPdG3 and CPhos.
  • the solvent is toluene.
  • the contacting is performed at lower temperature. In some such embodiments, the temperature is between about 0 °C and about 25 °C.
  • the methods additionally comprise preparing a
  • A is CH or CR A and P° is a phenol protecting group
  • B is CH, CR B or N, in a solvent, followed by treatment with an acid in a solvent, under conditions suitable to provide a compound of formula (s).
  • P° is benzyl group.
  • the solvent is DMF or DMA.
  • the acid is HC1.
  • the acid is in a solvent, such as MeOH or EtOH.
  • the contacting is performed at a temperature between about 70 °C and about 80 °C.
  • the contacting is performed at a temperature between about 50 °C and about 70 °C.
  • a method for preparing compound (ay) is provided herein.
  • the reducing agent is iron.
  • the Lewis acid is ammonium chloride.
  • the solvent is an EtOH and water mixture. In one embodiment, the contacting is performed at a temperature of about 60 °C.
  • the catalyst is Pd(dppf)2Cl2.
  • the base is CS2CO3.
  • the solvent is a toluene and water mixture.
  • the contacting is performed at a temperature of about 100 °C.
  • the alkylating agent is bromomethylbenzene.
  • the solvent is acetonitrile.
  • the base is K2CO3.
  • the contacting is performed at a temperature of about 80 °C.
  • the methods additionally comprise preparing a compound of formula (u)
  • R A -Zn-Br wherein R A is substituted or unsubstituted Ci- 6 alkyl or substituted or unsubstituted C3-6 cycloalkyl, in the presence of a catalyst and a ligand, in a solvent, under conditions suitable to provide a compound of formula (u).
  • the catalyst and the ligand are CPhosPdG3 and CPhos.
  • the solvent is toluene.
  • the contacting is performed at lower temperature. In some such embodiments, the temperature is between about 0 °C and about 25 °C.
  • the methods additionally comprise preparing a compound of formula (x)
  • the reducing agent is H2, in the presence of a catalyst.
  • the catalyst is Pd/C.
  • the solvent is MeOH or EtOH.
  • the contacting is performed at a temperature between about 20 °C and about 30 °C.
  • the methods additionally comprise preparing a compound of formula (y)
  • R A BF3 K + wherein R A is substituted or unsubstituted Ci- 6 alkyl, in the presence of a catalyst and a ligand, in the presence of a base, in a solvent, under conditions suitable to provide a compound of formula (y).
  • the catalyst and the ligand are cataCXium® A Palladacycle Gen. 3 and butyldi-l-adamantylphosphine.
  • the base is CS2CO3 or K2CO3.
  • the base is CS2CO3.
  • the solvent is a toluene/water mixture.
  • the contacting is performed at elevated temperature. In some embodiments, the temperature is between about 90 °C and about 110 °C.
  • the methods additionally comprise preparing a compound of formula (x)
  • L is -0(Ci- 6 alkyl)-
  • R A is substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted cyclopropyl, or substituted or
  • the reducing agent is H2, in the presence of a catalyst.
  • the catalyst is Pd/C.
  • the solvent is MeOH or EtOH.
  • the contacting is performed at a temperature between about 20 °C and about 30 °C.
  • the methods additionally comprise preparing a compound of formula (w)
  • R A is substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted C5-6 cycloalkenyl, and R + together with the boron atom and the atoms to which they are attached, forms a cyclic boronate, for example, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane, in the presence of a catalyst and a base, in a solvent, under conditions suitable to provide a compound of formula (w).
  • the catalyst is Pd(dppf)Cl2.
  • the base is K3PO4.
  • the solvent is a 1,4-dioxane/water mixture.
  • the methods additionally comprise preparing a compound of formula (v)
  • Hal is Br, in the presence of a base, in a solvent, under conditions suitable to provide a compound of formula (v).
  • the base is DIEA or TEA.
  • the solvent is DMF or NMP.
  • the contacting is performed at elevated temperature. In some embodiments, the temperature is between about 50 °C and about 70 °C.
  • the methods additionally comprise preparing a compound of formula
  • Hal-L-Hal wherein Hal is Br, in the presence of a base, in a solvent, under conditions suitable to provide a compound of formula
  • the base is K2CO3 or CsCCb.
  • the solvent is acetonitrile or DMF.
  • the contacting is performed at elevated temperature. In some embodiments, the temperature is between about 80 °C and about 100 °C. [00205] In some embodiments, the methods additionally comprise preparing a compound of formula (v)
  • LG 3 is OH, Br, Cl, OTs, or OMs, under conditions suitable to provide a compound of formula (v).
  • LG 3 is Br, Cl, OTs, or OMs
  • the contacting is performed in the presence of a base, in a solvent.
  • the base CsCCb or K2CO3.
  • the solvent is DMF, NMP, or acetonitrile.
  • the contacting is performed at elevated temperature. In some embodiments, the temperature is between about 40 °C and about 70 °C. In other embodiments, LG 3 is -OH, and the contacting is performed in the presence of PPI13 and DIAD or DEAD, in a solvent. In some embodiments, the solvent is THF. In some embodiments, the contacting is performed at room temperature.
  • the methods additionally comprise preparing a compound of formula (ad)
  • the reducing agent is sodium triacetoxyborohydride.
  • the solvent is MeOH.
  • the oxidizing agent is Dess-Martin periodinane
  • the solvent is DCM.
  • the contacting is performed at lower temperature. In one embodiment, the temperature is about 0 °C.
  • the methods additionally comprise preparing a compound of formula (ac)
  • the deprotection is performed by treatment with and acid in a solvent.
  • the acid is TsOH.
  • the solvent is a DCM/EtOH mixture.
  • the methods additionally comprise preparing a compound of formula (ab)
  • the catalyst and a ligand are CPhosPdG3 and CPhos.
  • the solvent is toluene.
  • the contacting is performed at lower temperature. In some embodiments, the temperature is about 0 °C.
  • the methods additionally comprise preparing a compound of formula (aa)
  • the base is DIEA or TEA.
  • the solvent is DCM.
  • the contacting of compound (ak) with a reducing agent in the presence of a catalyst is in a solvent at a temperature between about 20 °C and about 30 °C under increased pressure.
  • P° is benzyl group.
  • the reducing agent is Hz.
  • the catalyst is Pd/C or Pd(OH)2.
  • the solvent is MeOH or EtOAc.
  • the pressure is increased to about 15 psi.
  • the methods provided herein comprise preparing a compound of formula (ak),
  • R is alkyl and Hal is Cl or Br, under conditions suitable to provide a compound of formula (ak).
  • R is C1-4 alkyl. In one embodiment, R is methyl, ethyl, or t-butyl. In some embodiments, the contacting is performed in the presence of a base in a solvent. In some embodiments, the base is TEA, DBU or DIEA. In one embodiment, the solvent is THF, NMP, or DMF. In one embodiment, the contacting is conducted at a temperature between about 20 °C and about 80 °C. In one embodiment, the contacting is conducted in the presence of Nal or KI.
  • the methods provided herein comprise preparing a compound of formula (aj),
  • P° is benzyl group
  • LG 4 is O
  • Hal is Br or Cl.
  • the contacting is performed in the presence of a base in a solvent.
  • the contacting is performed in the presence of CsCCb in DMF, or K2CO3 in acetonitrile.
  • the contacting is conducted at an elevated temperature. In one embodiment, the temperature is between about 40 °C and about 70 °C.
  • LG 4 -L-Hal wherein LG 4 is Br, Cl or OH, and Hal is Br or Cl, in the presence of a base in a solvent under conditions suitable to provide a compound of formula (ao).
  • the base is DIEA, TEA or NMM.
  • the solvent is DMF or NMP.
  • the contacting is conducted at a temperature between about 50 °C and about 70 °C.
  • the acid is TFA or HC1.
  • the solvent is DCM, dioxane, MeOH or EtOH.
  • the acid and solvent is TFA in DCM, or HC1 in dioxane/DCM, MeOH or EtOAc.
  • the methods provided herein comprise preparing a compound of formula (am),
  • P N is an N-protecting group
  • R is alkyl and Hal is Cl or Br, under conditions suitable to provide a compound of formula (am).
  • P N is Boc group.
  • R is Ci-4 alkyl.
  • R is methyl, ethyl, or t-butyl.
  • the contacting is performed in the presence of a base in a solvent.
  • the base is TEA, DBU or DIEA.
  • the solvent is THF, NMP, or DMF.
  • the contacting is conducted at a temperature between about 20 °C and about 80 °C. In one embodiment, the contacting is conducted in the presence of Nal or KI.
  • the methods provided herein comprise preparing a compound of formula (c),
  • LG 4 is -OH
  • the contacting of (ao) with V-OH is conducted under Mitsunobu conditions, for example, in the presence of PPh3 and DIAD or DEAD, in a solvent such as THF, at room temperature.
  • the leaving group LG 4 in compound (ao) is Br, Cl, OTs, or OMs
  • the reaction with V-OH is performed in the presence of a base, in a solvent.
  • the base is CsC03 and the solvent is DMF.
  • the base is K2CO3 and the solvent is acetonitrile.
  • the reaction is conducted at an elevated temperature. In one embodiment, the reaction is conducted at a temperature between about 40 °C and about 70 °C.
  • the methods provided herein comprise preparing a compound of formula (as),
  • LG 4 is Br, Cl or OH
  • LG 5 is OH
  • A is CH or CR A or N, under conditions suitable to provide a compound of formula (as).
  • LG 4 in compound (ao) is OH, and the reaction is performed in the presence of a base in a solvent.
  • the base is NaOtBu, CsC03 or K2CO3.
  • the solvent is acetonitrile, DMF or NMP.
  • the reaction is conducted at a temperature between about 0 °C and about 70 °C.
  • LG 4 in compound (ao) is OH, and the contacting of compound (ao) and compound (ar) is conducted under Mitsunobu conditions, for example, in the presence of PPI13 and DIAD or DEAD, in a solvent such as THF, at room temperature to obtain compound (as).
  • LG 4 is OH; in compound (ar), LG 5 is F or Cl, and A is N; and the contacting of compound (ao) and compound (ar) is conducted in the presence of a base, in a solvent at a temperature between about 0 °C and about 70 °C to provide compound (as).
  • the base is NaOtBu, CsC0 3 or K2CO3.
  • the solvent is acetonitrile, DMF, THF or NMP.
  • LG 4 is OH; in compound (ar), LG 5 is F or Cl, and A is CH or CR A ; and the contacting of compound (ao) and compound (ar) is conducted in the presence of a base in a solvent at a temperature between about 0 °C and about 70 °C to provide compound (as).
  • the base is NaOtBu, CsC0 3 or K2CO3.
  • the solvent is acetonitrile, DMF, THF or NMP.
  • the methods provided herein comprise preparing a compound of formula (as),
  • the base is NaOtBu, CsCCb or K2CO3.
  • the solvent is acetonitrile, DMF, THF or NMP.
  • the contacting is performed at a temperature between about 0 °C and about 70 °C.
  • the methods provided herein comprise preparing a compound of formula (aq),
  • A is CH, CR A or N;
  • LG 6 is Br or Cl
  • Hal is Cl or Br
  • the contacting is performed in the presence of a base.
  • the base is NaOtBu, CsCCb or K2CO3.
  • the solvent is acetonitrile, DMF, THF or NMP.
  • the contacting is performed at a temperature between about 0 °C and about 90 °C.
  • LG 6 is OH
  • the contacting is performed in the presence of PPh3 and DIAD or DEAD.
  • the solvent is THF.
  • the contacting is performed at room temperature.
  • the methods provided herein comprise preparing a compound of formula (c)
  • L is -0(Ci- 6 alkyl)-
  • B is CH, CR B or N, with base in a solvent, under conditions suitable to provide a compound of formula (c).
  • the solvent is EtOAc.
  • the base is TEA.
  • the contacting is performed at a temperature between about 60 °C and about
  • the methods provided herein comprise preparing a compound of formula (av)
  • the base is NaHCCb, DIEA or TEA.
  • the contacting is conducted at a temperature of between about 90 °C and about 130 °C.
  • the methods provided herein comprise preparing a compound of formula (at)
  • the reducing agent is H2 in MeOH or EtOH.
  • the catalyst is Pd/C.
  • the pressure is about 50 psi.
  • the contacting is performed at a temperature of about 80 °C.
  • the methods provided herein comprise preparing a compound of formula (c)
  • L is -0(Ci- 6 alkyl)-
  • B is CH, CR B or N, in a solvent, followed by treatment with an acid in a solvent, under conditions suitable to provide a compound of formula (c).
  • the solvent is DMF or DMA.
  • the acid is HC1.
  • the acid is in a solvent, such as MeOH or EtOH.
  • the contacting is performed at a temperature between about 70 °C and about 80 °C.
  • the methods provided herein comprise preparing a compound of formula (at)
  • R A is substituted or unsubstituted C2-6 alkyl, substituted or unsubstituted cyclopropyl or substituted or unsubstituted C5-6 cycloalkyl, and L is
  • the reducing agent is Eh in MeOH or EtOH.
  • the catalyst is Pd/C.
  • the contacting is performed at a temperature between about 20 °C and about 30 °C.
  • the methods provided herein comprise preparing a compound of formula (as)
  • R A is substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted C5-6 cycloalkenyl;
  • R A' is substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted C5-6 cycloalkenyl, and R + together with the boron atom and the atoms to which they are attached, forms a cyclic boronate, in the presence of a palladium catalyst and a base in a solvent, under conditions suitable to provide a compound of formula (as), wherein R A is substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted cyclopropyl, or substituted or unsubstituted C5-6 cycloalkenyl.
  • the cyclic boronate is 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2-dioxaborolane).
  • the catalyst is Pd(dppf)2Cl2.
  • the base is K3PO4.
  • the solvent is a 1,4-dioxane/water mixture.
  • A is N, CH, or CR A ;
  • B is N, CH, or CR B ;
  • each R A is independently selected from halogen, substituted or unsubstituted Ci- 6 alkyl, and substituted or unsubstituted C3-6 cycloalkyl;
  • each R B is independently selected from halogen, and substituted or unsubstituted
  • R c is halogen or CF3
  • R 5 and R 6 are C1-3 alkyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a substituted or unsubstituted C3-6 cycloalkyl or a 3-6 membered heterocyclyl;
  • a 0-3;
  • L is -0(C i-6 alkyl)- or -(C 1-9 alkyl)-;
  • Hal is Cl, Br, OMs or OTs
  • A is N, CH, or CR A ;
  • B is N, CH, or CR B ;
  • each R A is independently selected from halogen, substituted or unsubstituted Ci- 6 alkyl, and substituted or unsubstituted C3-6 cycloalkyl;
  • each R B is independently selected from halogen, and substituted or unsubstituted
  • R c is halogen or CF3
  • R 5 and R 6 are C1- 3 alkyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a substituted or unsubstituted C 3 - 6 cycloalkyl or a 3-6 membered heterocyclyl;
  • a 0-3;
  • X is N
  • L is -0(Ci-6 alkyl)- or -(C1-9 alkyl)-;
  • each R 4 is independently substituted or unsubstituted C1-3 alkyl, or two R 4 groups, together with the same carbon atom or adjacent carbon atoms to which they are attached, form a substituted or unsubstituted C3-6 cycloalkyl, or two R 4 groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7-membered heterocyclyl; m is 0-8; and
  • P N is an amine protecting group
  • P N is tert-butyloxycarbonyl or carboxybenzyl.
  • A is N, CH, or CR A ;
  • B is N, CH, or CR B ;
  • each R A is independently selected from halogen, substituted or unsubstituted Ci- 6 alkyl, and substituted or unsubstituted C3-6 cycloalkyl;
  • each R B is independently selected from halogen, and substituted or unsubstituted
  • R c is halogen or CF3
  • R 5 and R 6 are C1- 3 alkyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a substituted or unsubstituted C 3 - 6 cycloalkyl or a 3-6 membered heterocyclyl;
  • a 0-3;
  • X is N
  • L is -0(Ci- 6 alkyl)- or -(C1-9 alkyl)-; each R 4 is independently substituted or unsubstituted C1-3 alkyl, or two R 4 groups, together with the same carbon atom or adjacent carbon atoms to which they are attached, form a substituted or unsubstituted C3-6 cycloalkyl, or two R 4 groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7-membered heterocyclyl;
  • n 0-8;
  • R x is Ci-4 alkyl.
  • A is N, CH, or CR A ;
  • B is N, CH, or CR B ;
  • each R A is independently selected from halogen, substituted or unsubstituted Ci- 6 alkyl, and substituted or unsubstituted C3-6 cycloalkyl;
  • each R B is independently selected from halogen, and substituted or unsubstituted
  • R c is halogen or CF3
  • R 5 and R 6 are C1-3 alkyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a substituted or unsubstituted C3-6 cycloalkyl or a 3-6 membered heterocyclyl;
  • a 0-3;
  • X is N;
  • L is -0(Ci-6 alkyl)- or -(C1-9 alkyl)-;
  • each R 4 is independently substituted or unsubstituted C1-3 alkyl, or two R 4 groups, together with the same carbon atom or adjacent carbon atoms to which they are attached, form a substituted or unsubstituted C3-6 cycloalkyl, or two R 4 groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7-membered heterocyclyl;
  • n 0-8.
  • A is N, CH, or CR A ;
  • B is N, CH, or CR B ;
  • each R A is independently selected from halogen, substituted or unsubstituted Ci- 6 alkyl, and substituted or unsubstituted C3-6 cycloalkyl;
  • each R B is independently selected from halogen, and substituted or unsubstituted
  • R c is halogen or CF3
  • R 5 and R 6 are C1-3 alkyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a substituted or unsubstituted C3-6 cycloalkyl or a 3-6 membered heterocyclyl;
  • a 0-3;
  • X is N;
  • L is -0(Ci-6 alkyl)- or -(C1-9 alkyl)-;
  • each R 4 is independently substituted or unsubstituted C1-3 alkyl, or two R 4 groups, together with the same carbon atom or adjacent carbon atoms to which they are attached, form a substituted or unsubstituted C3-6 cycloalkyl, or two R 4 groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7-membered heterocyclyl;
  • n 0-8;
  • R 2 and R 3 are each independently selected from H, and C1-3 alkyl, or R 2 and R 3 and the carbon to which they are attached form a substituted or unsubstituted
  • R is Ci-4 alkyl.
  • A is N, CH, or CR A ;
  • B is N, CH, or CR B ;
  • each R A is independently selected from halogen, substituted or unsubstituted Ci- 6 alkyl, and substituted or unsubstituted C3-6 cycloalkyl;
  • each R B is independently selected from halogen, and substituted or unsubstituted
  • R c is halogen or CF3;
  • R 5 and R 6 are C1-3 alkyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a substituted or unsubstituted C3- 6 cycloalkyl or a 3-6 membered heterocyclyl;
  • a 0-3;
  • X is N
  • L is -0(Ci-6 alkyl)- or -(C1-9 alkyl)-;
  • each R 4 is independently substituted or unsubstituted C1-3 alkyl, or two R 4 groups, together with the same carbon atom or adjacent carbon atoms to which they are attached, form a substituted or unsubstituted C3-6 cycloalkyl, or two R 4 groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7-membered heterocyclyl;
  • n 0-8;
  • R 2 and R 3 are each independently selected from H, and C1-3 alkyl, or R 2 and R 3 and the carbon to which they are attached form a substituted or unsubstituted
  • A is N, CH, or CR A ;
  • B is N, CH, or CR B ;
  • each R B is independently selected from halogen, and substituted or unsubstituted
  • Ci-6 alkyl is halogen or CF3;
  • R 5 and R 6 are C1- 3 alkyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a substituted or unsubstituted C 3 - 6 cycloalkyl or a 3-6 membered heterocyclyl;
  • X is N
  • L is -0(Ci-6 alkyl)- or -(C1-9 alkyl)-;
  • each R 4 is independently substituted or unsubstituted C1-3 alkyl, or two R 4 groups, together with the same carbon atom or adjacent carbon atoms to which they are attached, form a substituted or unsubstituted C3-6 cycloalkyl, or two R 4 groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7-membered heterocyclyl;
  • n 0-8;
  • P N is an amine protecting group
  • P N is tert-butyloxycarbonyl or carboxybenzyl.

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PCT/US2019/067088 2018-12-19 2019-12-18 Substituted 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions thereof, and methods of treatment therewith Ceased WO2020132014A1 (en)

Priority Applications (29)

Application Number Priority Date Filing Date Title
CA3124130A CA3124130A1 (en) 2018-12-19 2019-12-18 Substituted 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions thereof, and methods of treatment therewith
EP24218737.5A EP4494711A3 (en) 2018-12-19 2019-12-18 Substituted 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions thereof, and methods of treatment therewith
SI201930889T SI3897636T1 (sl) 2018-12-19 2019-12-18 Substituirane 3-((3-aminofenil)amino)piperidin-2,6-dionske spojine, sestavki iz le-teh in postopki zdravljenja z njimi
HRP20250095TT HRP20250095T1 (hr) 2018-12-19 2019-12-18 Supstituirani spojevi 3-((3-aminofenil)amino)piperidin-2,6-diona, njihovi pripravci, i postupci za liječenje s njima
FIEP19901383.0T FI3897636T3 (fi) 2018-12-19 2019-12-18 Substituoituja 3-((3-aminofenyyli)amino)piperidiini-2,6-dioniyhdisteitä, niiden koostumuksia ja menetelmiä niillä annettavia hoitoja varten
CN201980092358.2A CN113453681B (zh) 2018-12-19 2019-12-18 经取代的3-((3-氨基苯基)氨基)哌啶-2，6-二酮化合物、其组合物及使用它们的治疗方法
KR1020217019479A KR102866144B1 (ko) 2018-12-19 2019-12-18 치환된 3-((3-아미노페닐)아미노)피페리딘-2,6-디온 화합물, 이의 조성물, 및 이를 사용한 치료 방법
MYPI2021003454A MY205718A (en) 2018-12-19 2019-12-18 Substituted 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions thereof, and methods of treatment therewith
SG11202106507RA SG11202106507RA (en) 2018-12-19 2019-12-18 Substituted 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions thereof, and methods of treatment therewith
NZ777281A NZ777281B2 (en) 2019-12-18 Substituted 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions thereof, and methods of treatment therewith
RS20250148A RS66556B1 (sr) 2018-12-19 2019-12-18 Supstituisana 3-((3-aminofenil)amino)piperidin-2,6-dion jedinjenja, njihove kompozicije i postupci lečenja koji ih koriste
PE2021000924A PE20212247A1 (es) 2018-12-19 2019-12-18 Compuestos de 3-((3-aminofenil)amino)piperidina-2,6-diona sustituida, composiciones de estos y metodos de tratamiento con estos
EA202191712A EA202191712A1 (ru) 2019-07-29 2019-12-18 Соединения замещенного 3-((3-аминофенил)амино)пиперидин-2,6-диона, их композиции и способы лечения с их помощью
SM20250111T SMT202500111T1 (it) 2018-12-19 2019-12-18 Composti di 3-((3-amminofenil)ammino)piperidin-2,6-dione sostituiti, loro composizioni e metodi di trattamento con gli stessi
EP19901383.0A EP3897636B1 (en) 2018-12-19 2019-12-18 Substituted 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions thereof, and methods of treatment therewith
JP2021535539A JP7494181B2 (ja) 2018-12-19 2019-12-18 置換３－（（３－アミノフェニル）アミノ）ピペリジン－２，６－ジオン化合物、その組成物、及びそれを用いた治療方法
DK19901383.0T DK3897636T3 (da) 2018-12-19 2019-12-18 Substituerede 3-((3-aminophenyl)amino)piperidin-2,6-dionforbindelser, sammensætninger heraf og fremgangsmåde til behandling hermed
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PL19901383.0T PL3897636T3 (pl) 2018-12-19 2019-12-18 Podstawione związki 3-((3-aminofenylo)amino)piperydyno-2,6-dionu, ich kompozycje i sposoby leczenia nimi
IL284223A IL284223B2 (en) 2018-12-19 2019-12-18 Substituted 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions thereof, and methods of treatment therewith
MX2021007473A MX2021007473A (es) 2018-12-19 2019-12-18 Compuestos de 3-((3-aminofenil)amino)piperidina-2,6-diona sustituida, composiciones de estos y metodos de tratamiento con estos.
ES19901383T ES3009308T3 (en) 2018-12-19 2019-12-18 Substituted 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions thereof, and methods of treatment therewith
CN202411325996.3A CN119219606A (zh) 2018-12-19 2019-12-18 经取代的3-((3-氨基苯基)氨基)哌啶-2，6-二酮化合物、其组合物及使用它们的治疗方法
BR112021011968-0A BR112021011968A2 (pt) 2018-12-19 2019-12-18 Compostos de 3-((3-aminofenil)amino)piperidina-2,6-diona substituídos, composições dos mesmos e métodos de tratamento com os mesmos
AU2019403207A AU2019403207B2 (en) 2018-12-19 2019-12-18 Substituted 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions thereof, and methods of treatment therewith
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JP2024511342A (ja) * 2021-03-17 2024-03-13 メッドシャイン ディスカバリー インコーポレイテッド フラン縮合環置換グルタルイミド系化合物
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