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WO2020257189A1 - Macrocycles for treating disease - Google Patents

Macrocycles for treating disease Download PDF

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Publication number
WO2020257189A1
WO2020257189A1 PCT/US2020/037917 US2020037917W WO2020257189A1 WO 2020257189 A1 WO2020257189 A1 WO 2020257189A1 US 2020037917 W US2020037917 W US 2020037917W WO 2020257189 A1 WO2020257189 A1 WO 2020257189A1
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WIPO (PCT)
Prior art keywords
alkyl
compound
pharmaceutically acceptable
acceptable salt
deuterium
Prior art date
Application number
PCT/US2020/037917
Other languages
French (fr)
Inventor
Jingrong Jean Cui
Evan W. ROGERS
Dayong Zhai
Jane Ung
Vivian NGUYEN
Original Assignee
Turning Point Therapeutics, Inc.
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Publication of WO2020257189A1 publication Critical patent/WO2020257189A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

Definitions

  • the present disclosure relates to certain macrocyclic derivatives, pharmaceutical compositions containing them, and methods of using them to treat disease, such as cancer.
  • RET is a receptor tyrosine kinase that was initially discovered in 1985 through transfection of NIH3T3 cells with human lymphoma DNA
  • RET is expressed with its highest levels in early embryogenesis (during which it has diverse roles in different tissues) and decreases to relatively low levels in normal adult tissues (Pachnis, V., et al. Development 1993, 119, 1005-1017). RET plays a critical role in the development of enteric nervous system and kidneys during embryogenesis (Schuchardt, A. et al. Nature 1994, 367:380-383). RET activation regulates the downstream signalling pathways (RAS/MAPK/ERK, PI3K/AKT, and JAK-STAT etc.), leading to cellular proliferation, migration, and differentiation (Mulligan, LM. Nat Rev Cancer. 2014, 14(3): 173-86).
  • Gain-of-function mutations of RET with constitutive activation have been found in heritable and sporadic tumors including activating point mutations within the full-length RET protein or genomic rearrangements that produce chimeric RET oncoproteins in the cytosol.
  • the heritable oncogenic RET mutations are found in multiple endocrine neoplasia type 2 (MEN2) including medullary thyroid cancer (MTC) and familial MTC with more than 80 pathogenic variants spanning RET exons 5-16 reported (Mulligan, LM. Nat Rev Cancer. 2014, 14(3): 173- 86).
  • RET M918T and RET A883F are found in 40-65% of sporadic MTC.
  • RET fusion oncoproteins have been identified in sporadic tumors.
  • the RET rearrangements are originally reported in papillary thyroid cancers (PTCs) (Grieco, M. et al. Cell. 1990, 23; 60 (4):557-63.).
  • PTCs papillary thyroid cancers
  • the resulting fusion transcripts composed of the 3’ end of RET kinase domain and the 5’ end of separate partner genes (CCDC6, NCOA4, TRIM24, TRIM33, PRKAR1A, GOLGA5, KTN1, ERC1, MBD1, and TRIM27 etc.).
  • RET fusions are identified in approximately 20% 40% of PTCs, and CCDC6-RET and NCOA4-RET are the most commonly identified RET fusions in PTCs (Drilon A, et al. Nat Rev Clin Oncol. 2017 Nov 14. doi: 10.1038/nrclinonc.2017.175). RET gene fusions are also found in approximately l%-2% of non-small cell lung cancer (NSCLC) (Gainor JF, Shaw AT. Oncologist. 2013, 18(7):865-75), and over 50% of RET fusions in NSCLC is KIF5B-RET, representing the most frequent RET fusion form.
  • NSCLC non-small cell lung cancer
  • the RET inhibitors have relatively low response rates and short treatment duration in the treatment of NSCLC patients with KIF5B-RET fusion gene in multiple clinical trials (Drilon, A. Nat Rev Clin Oncol. 2017 Nov 14. doi: 10.1038/nrclinonc. 2017.175). It was reported that the kinesin and kinase domains of KIF5B-RET act together to establish an emergent microtubule and RAB -vesicle-dependent RET-SRC-EGFR-FGFR signaling hub (Das TK and Cagan RL Cell Rep. 2017, 20(10):2368-2383).
  • SRC kinase The inhibition of SRC kinase will have the potential to stop the recruitment of multiple RTKs via the N terminus of the KIF5B-RET fusion protein and the oncogenic signaling to increase the therapeutic efficiency of RET inhibitors.
  • Src family tyrosine kinases regulate MTC cellular proliferation in vitro and mediate growth signals by increasing DNA synthesis and decreasing apoptosis (Liu Z, et al. J. Clin. Endocrinol. Metab. 2004, 89, 3503-3509). Therefore, a dual inhibitor of RET and SRC represents a highly desired therapeutic intervention to maximally target abnormal RET signaling in cancers.
  • Endochondral ossification is a process that results in both the replacement of the embryonic cartilaginous skeleton during organogenesis and the growth of long bones until adult height is achieved.
  • Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling plays a vital role in the development and maintenance of growth plates in endochondral ossification process
  • FGFR1 in chondrocytes causes joint fusion. Deletion of both FGFR1 and FGFR2 in mice caused a decreased length of the growth plate with a reduced number of proliferating chondrocytes (Karuppaiah K 2016). Therefore, the selectivity over FGFRs is an important parameter for better safety profile, especially for pediatric population.
  • the disclosure relates to a compound of the formula I
  • each R 1 and R 2 is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, mono- or bicyclic heteroaryl, -OR a , -OC(O)R a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O) 2 NR a R b , -OS(O) 2 NR a R b , -OS
  • heterocycloalkyl C 6 -Cio aryl, and mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, Ci-Ce haloalkyl, -OR e , -OC(O)R e ,
  • R 6 is H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, -OR e , -SR e , or -NR e R f ;
  • each R 7 is independently hydrogen or deuterium
  • each R a , R b , R c , R d , R e , and R f is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 7- membered heteroaryl; [015] m is 1 or 2; and
  • n is i, 2, or 3;
  • the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula II
  • the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula III
  • the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula IV
  • the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula V
  • the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula VI
  • each R 1 and R 2 is independently H, deuterium, halogen, Ci- , alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, mono- or bicyclic heteroaryl, -OR a , -OC(O)R a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O) 2 NR a R b , -OS(O) 2 NR a R b , -OS(
  • heterocycloalkyl C 6 -Cio aryl, and mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, Ci-Ce haloalkyl, -OR e , -OC(O)R e ,
  • each R 3 is independently H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in
  • R 6 is H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, -OR e , -SR e , or -NR e R f ;
  • each R 7 is independently hydrogen or deuterium
  • each R a , R b , R c , R d , R e , and R f is independently selected from the group consisting of H, deuterium, C ⁇ -Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 7- membered heteroaryl;
  • m is 1 or 2;
  • n is i, 2, or 3;
  • [066] 26 A pharmaceutical composition comprising a compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, and optionally at least one diluent, carrier or excipient.
  • 27 A method of treating cancer comprising administering to a subject in need of such treatment an effective amount of at least one compound of any one of clauses 1 to 25, or a pharmaceutically acceptable salt thereof.
  • a method of inhibiting RET or SRC comprising contacting a cell comprising one or more of such kinases with an effective amount of at least one compound of any one of clauses 1 to 25, or a pharmaceutically acceptable salt thereof, and/or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.
  • yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently.
  • alkyl includes a chain of carbon atoms, which is optionally branched and contains from 1 to 20 carbon atoms. It is to be further understood that in certain embodiments, alkyl may be advantageously of limited length, including C1-C12, C1-C10, C1-C 9 , C 1 -C 8 , C 1 -C 7 , C 1 -C 6 , and C 1 -C 4 , Illustratively, such particularly limited length alkyl groups, including Ci-Cs, Ci-C 7 , Ci-C 6 , and C 1 -C 4 , and the like may be referred to as“lower alkyl.” Illustrative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-p
  • Alkyl may be substituted or unsubstituted.
  • “alkyl” may be combined with other groups, such as those provided above, to form a functionalized alkyl.
  • the combination of an“alkyl” group, as described herein, with a “carboxy” group may be referred to as a“carboxyalkyl” group.
  • Other non-limiting examples include hydroxyalkyl, aminoalkyl, and the like.
  • Alkenyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • Illustrative alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.
  • alkynyl includes a chain of carbon atoms, which is optionally branched, and contains from 2 to 20 carbon atoms, and also includes at least one carbon-carbon triple bond (i.e., CoC). It will be understood that in certain embodiments, alkynyl may each be advantageously of limited length, including C 2 -C 12 , C 2 -C 9 , C 2 -C 8 , C 2 -C 7 , C 2 -C 6 , and C 2 -C 4 .
  • alkynyl groups including C 2 -C 8 , C 2 -C 7 , C 2 -O,, and C 2 -C 4 may be referred to as lower alkynyl.
  • Alkynyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • Illustrative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.
  • the term“aryl” refers to an all-carbon monocyclic or fused-ring polycyclic groups of 6 to 12 carbon atoms having a completely conjugated pi-electron system.
  • aryl may be advantageously of limited size such as C6-C10 aryl.
  • Illustrative aryl groups include, but are not limited to, phenyl, naphthylenyl and anthracenyl. The aryl group may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • cycloalkyl refers to a 3 to 15 member all-carbon monocyclic ring, including an all-carbon 5-member/6-member or 6-member/6-member fused bicyclic ring, or a multicyclic fused ring (a“fused” ring system means that each ring in the system shares an adjacent pair of carbon atoms with each other ring in the system) group, or a carbocyclic ring that is fused to another group such as a heterocyclic, such as ring 5- or 6-membered cycloalkyl fused to a 5- to 7- membered heterocyclic ring, where one or more of the rings may contain one or more double bonds but the cycloalkyl does not contain a completely conjugated pi-electron system.
  • cycloalkyl may be advantageously of limited size such as C3-C13, C3-C9, C3-C6 and C4-C6.
  • Cycloalkyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • Illustrative cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, norbornyl, norbornenyl, 9//-lluoren-9-yl, and the like.
  • Illustrative examples of cycloalkyl groups shown in graphical representations include the following entities, in the form of properly bonded moieties: . a . O . 0 . 0. 0 . o . 0 . 0 . 0 0 0
  • heterocycloalkyl refers to a monocyclic or fused ring group having in the ring(s) from 3 to 12 ring atoms, in which at least one ring atom is a heteroatom, such as nitrogen, oxygen or sulfur, the remaining ring atoms being carbon atoms.
  • Heterocycloalkyl may optionally contain 1, 2, 3 or 4 heteroatoms.
  • a heterocycloalkyl group may be fused to another group such as another heterocycloalkyl, or a heteroaryl group.
  • heterocycloalkyl may be advantageously of limited size such as 3- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, 3-, 4-, 5- or 6-membered heterocycloalkyl, and the like.
  • Heterocycloalkyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • Illustrative heterocycloalkyl groups include, but are not limited to, oxiranyl, thianaryl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4- dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, oxepanyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1, 2, 3, 4-tetrahydropyridinyl, and the like.
  • Illustrative examples of heterocycloalkyl groups shown in graphical representations include the following entities, in the form of properly bonded moieties:
  • heteroaryl refers to a monocyclic or fused ring group of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur, the remaining ring atoms being carbon atoms, and also having a completely conjugated pi-electron system. It will be understood that in certain embodiments, heteroaryl may be advantageously of limited size such as 3- to 7-membered heteroaryl, 5- to 7-membered heteroaryl, and the like. Heteroaryl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, tetrazolyl, triazinyl, pyrazinyl, tetrazinyl, quinazolinyl, quinoxalinyl, thienyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl and carbazoloyl, and the like.
  • Illustrative examples of heteroaryl groups shown in graphical representations include the following entities, in the form of properly bonded
  • “hydroxy” or“hydroxyl” refers to an -OH group.
  • alkoxy refers to both an -O-(alkyl) or an -O- (unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • aryloxy refers to an -O-aryl or an -O-heteroaryl group. Representative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and the like.
  • mercapto refers to an -SH group.
  • alkylthio refers to an -S-(alkyl) or an -S-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.
  • arylthio refers to an -S-aryl or an -S-heteroaryl group. Representative examples include, but are not limited to, phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio, and the like.
  • halo or“halogen” refers to fluorine, chlorine, bromine or iodine.
  • cyano refers to a -CN group.
  • oxo represents a carbonyl oxygen.
  • a cyclopentyl substituted with oxo is cyclopentanone.
  • substituted means that the specified group or moiety bears one or more substituents.
  • unsubstituted means that the specified group bears no substituents.
  • substitution is meant to occur at any valency-allowed position on the system.
  • “substituted” means that the specified group or moiety bears one, two, or three substituents.
  • “substituted” means that the specified group or moiety bears one or two substituents.
  • “substituted” means the specified group or moiety bears one substituent.
  • “optional” or“optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • “wherein each hydrogen atom in C ⁇ -Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-to 7- membered heterocycloalkyl, C 6 -C 10 aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by C 1 -C 6 alkyl” means that an alkyl may be but need not be present on any of the C 1 -C 6 alkyl, CF-Ce alkenyl, C 2 -O, alkynyl, C 3 -C 6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C 6 -C 10 aryl, or mono- or bicyclic heteroaryl by replacement of
  • “independently” means that the subsequently described event or circumstance is to be read on its own relative to other similar events or circumstances.
  • the use of“independently optionally” means that each instance of a hydrogen atom on the group may be substituted by another group, where the groups replacing each of the hydrogen atoms may be the same or different.
  • the use of “independently” means that each of the groups can be selected from the set of possibilities separate from any other group, and the groups selected in the circumstance may be the same or different.
  • the phrase“R 8 and R 9 combine to form a C 3 -C 7 cycloalkyl, a 5- to 8- membered heterocycloalkyl, C6-C10 aryl, or 5- to 7-membered heteroaryl” also means that R 8 and R 9 are taken together with the carbon atoms to which they are attached to form a a C 3 -C 7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl.
  • “R 8 and R 9 combine to form a C 3 -C 7 cycloalkyl” used in connection with the embodiments described herein includes fragments represented by the following:
  • the term“pharmaceutically acceptable salt” refers to those salts which counter ions which may be used in pharmaceuticals. See, generally, S.M. Berge, et ak, “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19.
  • Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response.
  • a compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Such salts include:
  • acid addition salts which can be obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methane sulfonic acid,
  • inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like
  • organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methane sulfonic acid
  • ethanesulfonic acid p-toluenesulfonic acid
  • salicylic acid tartaric acid, citric acid, succinic acid or malonic acid and the like
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • organic base such as ethanolamine, diethanolamine, triethanolamine, trimethamine, N-methylglucamine, and the like.
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne- 1,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates,
  • a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as man
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulf
  • the disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of
  • prodrug means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula I, II, III, IV, V, or VI).
  • A“pharmaceutically acceptable prodrug” is a prodrug that is non- toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in“Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
  • the present disclosure also relates to pharmaceutically active metabolites of compounds of Formula I, II, III, IV, V, or VI, and uses of such metabolites in the methods of the disclosure.
  • A“pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula I, II, III, IV, V, or VI, or salt thereof.
  • Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).
  • any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms.
  • a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof.
  • any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof.
  • compounds depicted by a structural formula containing the symbol“ n/nl - G ” include both stereoisomers for the carbon atom to which the symbol“ iLLL '” is attached, specifically both the bonds“ ” and . 111 111” are encompassed by the meaning of“/vw p or example, in some exemplary embodiments, certain compounds provided herein can be described by the formula
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, n C, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, 36 C1, and 125 I, respectively.
  • Such isotopically labelled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed.
  • compounds described herein comprise a moiety of the formula
  • compounds described herein comprise a moiety of the formula
  • compounds described herein comprise a moiety of the formula wherein Y is otherwise defined as described herein. In still other embodiments, compounds described herein comprise a moiety of the formula
  • compounds described herein comprise a moiety of the formula
  • compounds described herein comprise a moiety of the formula In still other embodiments, compounds described herein comprise a moiety of the formula
  • each R 1 and R 2 is independently H, deuterium, halogen, C 1 -C 6 , alkyl, C 2 -C 6 alkenyl, Ci-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, mono- or bicyclic heteroaryl, -OR a , -OC(O)R a , -OC(O)R a , -OC(O)NR a R b ,
  • R 1 is H or D.
  • R 2 is H or deuterium.
  • each R 3 when present, is H or C1-C6 alkyl.
  • R 4 is H or deuterium.
  • R 5 is F.
  • R 6 is H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, -OR e , -SR e , or -NR e R f . In some embodiments R 6 is H.
  • each R 7 is independently hydrogen or deuterium. In some embodiments, R 7 is H.
  • R 8 and R 9 together with the carbons which they are attached combine to form a C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to
  • R 8 and R 9 combine to form a cyclobutane ring, cyclopentane ring, or
  • R 8 and R 9 combine to form a 3-, 4-, 5- or 6-membered heterocycloalkyl, wherein each hydrogen atom in the 3-, 4-, 5- or 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH 2 ,
  • Ci-C 6 alkyl -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) 2 , -NHC(O)Ci-C 6 alkyl, -N(CI-C 6 alkyl)C(O)Ci-C 6 alkyl, -NHC(O)NH 2 , -NHC(O)NH(Ci-C 6 alkyl), -N(CI-C 6 alkyl)C(O)NH 2 ,
  • each R a , R b , R c , R d , R e , and R f is independently selected from the group consisting of H, deuterium, C 1 -C 6 alkyl, C 2 -Ce alkenyl, C 2 -Ce alkynyl, C 3 -C 6 cycloalkyl,
  • n is 1 or 2. In some embodiments, m is 1.
  • n is 1, 2, or 3. In some embodiments, n is 1 or 2.
  • compositions comprising the compounds described herein may further comprise one or more pharmaceutically-acceptable excipients.
  • a pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, anti oxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents.
  • pharmaceutical compositions according to the invention are sterile compositions. Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art.
  • compositions are also contemplated by the invention, including compositions that are in accord with national and local regulations governing such compositions.
  • compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms.
  • Pharmaceutical compositions of the invention may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation.
  • the compositions are formulated for intravenous or oral administration.
  • the compounds the invention may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension.
  • the compounds of the invention may be formulated to yield a dosage of, e.g., from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily.
  • Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents.
  • Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.
  • Exemplary liquid oral excipients include ethanol, glycerol, water, and the like.
  • Starch polyvinyl -pyrrolidone (PVP), sodium starch glycolate,
  • microcrystalline cellulose, and alginic acid are exemplary disintegrating agents.
  • Binding agents may include starch and gelatin.
  • the lubricating agent if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
  • Capsules for oral administration include hard and soft gelatin capsules.
  • active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent.
  • Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may optionally contain:
  • suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like
  • non-aqueous vehicles e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water
  • preservatives for example, methyl or propyl p-hydroxybenzoate or sorbic acid
  • wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
  • the agents of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation.
  • Illustrative infusion doses range from about 1 to 1000 pg/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
  • inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable carrier.
  • inventive compositions may be formulated for rectal administration as a suppository.
  • the compounds of the present invention are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration ⁇
  • the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
  • Another mode of administering the agents of the invention may utilize a patch formulation to effect transdermal delivery.
  • “treat” or“treatment” encompass both“preventative” and “curative” treatment.“Preventative” treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition.
  • treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.
  • subject refers to a mammalian patient in need of such treatment, such as a human.
  • Exemplary diseases include cancer, pain, neurological diseases, autoimmune diseases, and inflammation.
  • Cancer includes, for example, lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophago-gastric cancers, glioblastoma, head and neck cancers, inflammatory myofibroblastic tumors, and anaplastic large cell lymphoma.
  • Pain includes, for example, pain from any source or etiology, including cancer pain, pain from chemotherapeutic treatment, nerve pain, pain from injury, or other sources.
  • Autoimmune diseases include, for example, rheumatoid arthritis, Sjogren syndrome, Type I diabetes, and lupus.
  • Exemplary neurological diseases include Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic lateral sclerosis, and Huntington’s disease.
  • Exemplary inflammatory diseases include atherosclerosis, allergy, and inflammation from infection or injury.
  • the compounds and pharmaceutical compositions of the invention specifically target receptor tyrosine kinases, in particular RET.
  • the compounds and pharmaceutical compositions of the invention specifically target non-receptor tyrosine kinases, in particular SRC.
  • the compounds and pharmaceutical compositions of the invention specifically target receptor tyrosine kinases and non-receptor tyrosine kinases, such as RET and SRC, respectively.
  • compositions can be used to prevent, reverse, slow, or inhibit the activity of one or more of these kinases.
  • methods of treatment target cancer In preferred embodiments, methods are for treating lung cancer or non-small cell lung cancer.
  • an“effective amount” means an amount sufficient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays.
  • the cell is preferably a cancer cell with abnormal signaling due to upregulation of RET and/or SRC.
  • an“effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment.
  • Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject’s health status, condition, and weight, and the judgment of the treating physician.
  • An exemplary dose is in the range of about from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily.
  • the total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).
  • the dose may be adjusted for preventative or maintenance treatment.
  • the dosage or the frequency of administration, or both may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained.
  • treatment may cease.
  • Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.
  • inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein.
  • Further additional active ingredients include other therapeutics or agents that mitigate adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound.
  • the additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present invention or may be included with a compound of the present invention in a single pharmaceutical composition.
  • the additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present invention.
  • Combination agents include additional active ingredients are those that are known or discovered to be effective in treating the diseases and disorders described herein, including those active against another target associated with the disease.
  • compositions and formulations of the invention, as well as methods of treatment can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for the target diseases or related symptoms or conditions.
  • additional such agents include, but are not limited to, kinase inhibitors, such as EGFR inhibitors (e.g., erlotinib, gefitinib), Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib), ALK inhibitors (e.g., crizotinib) standard chemotherapy agents such as alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormone therapies, or corticosteroids.
  • suitable combination agents include anti-inflammatories such as NSAIDs.
  • the pharmaceutical compositions of the invention may additionally comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents.
  • Step 3 To a solution of A-4 (865 mg, 3.11 mmol, 1.0 eq.) in ethanol (16.0 mL), THF (6.00 mL) and water (11.0 mL) was added zinc powder (1.02 g, 15.6 mmol, 5.0 eq.) and ammonium chloride (700 mg, 13.1 mmol, 4.21 eq.) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. The mixture was filtered and the filtrate was dilute with water (50.0 mL).
  • Step 4 To a solution of (15,2 ⁇ )-2-aminocyclopentanol (262 mg, 1.90 mmol, 1.00 eq. HC1, available from e.g.
  • Step 5 To a solution of A-6 (520 mg, 1.69 mmol, 1.00 eq.) in DML (8.00 mL) was added cesium carbonate (1.66 g, 5.11 mmol, 3.03 eq.). The mixture was stirred at 130 °C for 5 hrs. The mixture was quenched by water (20.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The organic layer was washed by brine (50.0 mL) and dried over anhydrous sodium. The residue was purified by Prep-HPLC to give A (100 mg, 336 pmol, 20 % yield, 97.1% purity) as a yellow solid.
  • Step 1 To a solution of 1-1 (374.47 mg, 2 mmol, tert-butyl ((lr,3r)-3- hydroxycyclobutyl)carbamate, available from e.g. Enamine Ltd.), 1-2 (408.33 mg, 2.40 mmol, methyl 5-fluoro-2-hydroxybenzoate, available from e.g. Sigma- Aldrich), and PPI13 (786.86 mg, 3.00 mmol) in anhydrous DCM (2.23 mL) at 0 °C was added DIAD (647.07 mg, 3.20 mmol, 628.22 pL) with stirring. The mixture was stirred for 3 hr as it warmed to ambient temperature. The mixture was purified by flash column chromatography (ISCO, 12 g silica, 0-60% ethyl acetate in hexanes) twice to afford 1-3 (602 mg, 1.77 mmol, 88.70% yield).
  • DIAD 647.07 mg, 3.
  • Step 2. 1-3 (300 mg, 884.02 pmol) was dissolved in anhydrous methanol (4.42 mL) and the mixture was cooled to 0 °C in ice bath. NaBPU (334.45 mg, 8.84 mmol) was added slowly over 8 hrs and the mixture was stirred as temperature increases to ambient. The reaction was quenched with cold water (10 mL) and stirred vigorously. The reaction was worked up with DCM (20 mL) and more water (20 mL total) with 5mL of 2N NaOH. Layers were partitioned, and the aqueous layer was extracted 2x with DCM (10 mL). The combined organic layer was washed with brine and dried over sodium sulfate. Llash column chromatography (ISCO, 12 g silica, 0-50% EtOAc in hexanes) provided 1-4 (173.3 mg, 556.61 pmol, 62.96% yield).
  • Step 3 To 1-4 (100 mg, 321.18 pmol) in DCM (1.53 mL) was added Hunig's base (207.55 mg, 1.61 mmol, 279.72 pL). The mixture was cooled to 0 °C and mesyl chloride (73.58 mg, 642.37 pmol, 49.72 pL) was added. The reaction was stirred as temperature increase to ambient over 18 hrs. The reaction was quenched with 2M HC1 (aq) (5mL) at 0 °C. The reaction was diluted with water and DCM (1 OmL each), layers partitioned, and the aqueous layer extracted 2x with DCM (5mL).
  • Step 4 To 1-5 (19.07 mg, 57.81 pmol) in DML (.5 mL), CS2CO3 (56.51 mg, 173.43 pmol) followed by A (20 mg, 69.37 pmol) was added. The mixture was stirred at 23 °C for 4 hrs after which the reaction was diluted with DCM (5 mL) then syringe filtered. The filtrate was concentrated under reduced pressure. Llash column chromatography (ISCO, 12 g silica, 0- 80% ethyl acetate in hexanes) to afford 1-6 (41.8 mg, 71.87 pmol, assumed quantitative with a minor impurity).
  • Step 5 To 1-6 (41.8 mg, 71.87 pmol) in MeOH (0.5 mL) and THE (2 mL), 2M aqueous
  • [0160] 2-2 (5.08 g, 27.58 mmol) was dissolved in methanol (137.92 mL) and cooled to 0 °C in ice bath.
  • NaBH4 (2.09 g, 55.17 mmol) was added slowly under argon and the mixture was stirred as temperature increases over 5 hr. Quenched with water (20mL) and volatiles were removed under reduced pressure to ⁇ 1/3 of its volume. Diluted with water (50mL) and EA (lOOmL) and the layers were partitioned in a separatory funnel. Aqueous layer was extracted twice more with EA (2x50mL). The combined organic layer was washed with brine and dried over sodium sulfate.
  • a (796.97 mg, 2.76 mmol) and CS2CO3 (2.39 g, 7.33 mmol) were combined in DMF (12.22 mL) and 2-4 (0.5 g, 2.44 mmol) was added. Stirred at ambient temperature for 1.5 hr. Diluted with DCM (200mL) and cooled in -20 °C freezer for a half hour, then filtered through a celite pad. Filtrate was transferred to a separatory funnel and 200mL of water added. Layers were partitioned and aqueous layer was extracted twice more with DCM (2xl00mL).
  • Human medulla thyroid carcinoma cell line TT (containing RET C634W mutation) and acute myelogenous cell line KG-1 with FGFR10P2-FGFR1 fusion FGFR 1 gene were purchased from ATCC.
  • Human colon cancer cell line KM12 (containing TPM3-TRKA) was obtained from NCI.
  • the EMF4-AFK gene (variant 1) was synthesized at GenScript and cloned into pCDH- CMV-MCS-EFl-Puro plasmid (System Biosciences, Inc).
  • Ba/F3-EMF4-AFK wild type were generated by transducing Ba/F3 cells with lenti virus containing EMF4-AFK wild type. Stable cell lines were selected by puromycin treatment, followed by IF-3 withdrawal. Briefly, 5 x 10 6 Ba/F3 cells were transduced with lentivirus supernatant in the presence of 8 pg/mF protamine sulfate.
  • the transduced cells were subsequently selected with 1 pg/mF puromycin in the presence of IF3 -containing medium RPMI1640, plus 10% FBS. After 10-12 days of selection, the surviving cells were further selected for IF3 independent growth. [0173]
  • the KIF5B-RET gene was synthesized at GenScript and cloned into pCDH-CMV- MCS-EFl-Puro plasmid (System Biosciences, Inc). KIF5B-RET point mutation V804M and G810R were generated at GenScript by PCR and confirmed by sequencing.
  • Ba/F3 KIF5B-RET wild type and mutants were generated by transducing Ba/F3 cells with lenti virus containing KIF5B-RET wild type or mutants. Stable cell lines were selected by puromycin treatment, followed by IL-3 withdrawal. Briefly, 5 x 10 6 Ba/F3 cells were transduced with lentivirus supernatant in the presence of 8 pg/mL protamine sulfate. The transduced cells were subsequently selected with 1 pg/mL puromycin in the presence of IL3 -containing medium RPMI1640, plus 10% FBS. After 10-12 days of selection, the surviving cells were further selected for IL3 independent growth.

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Abstract

The present disclosure relates to certain macrocyclic derivatives, pharmaceutical compositions containing them, and methods of using them to treat disease, such as cancer. Also provided are methods of inhibiting receptor tyrosine kinases such as RET or SRC using the macrocyclic derivatives. The macrocyclic compounds have a tetracyclic heterocyclic core moiety, such as, cylopenta[5,6][1,4]oxazino[3,4-j] pyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotetradecin-15-one.

Description

MACROCYCLES FOR TREATING DISEASE
CROSS-REFERENCE TO RELATED APPLICATIONS
[001] This application claim priority under 35 U.S.C. § 119(e) to U.S. Provisional
Application Serial No. 62/863,496 filed on June 19, 2019, the entire disclosure of which is incorporated herein by reference.
TECHNICAL FIELD
[002] The present disclosure relates to certain macrocyclic derivatives, pharmaceutical compositions containing them, and methods of using them to treat disease, such as cancer.
BACKGROUND
[003] Protein kinases regulate various functions in the cell including cell growth, proliferation and survival. Dysregulation of protein kinases is often the cause of many solid malignancies (Manning G. et al. Science. 2002, 298, 1912-1934). The use of protein kinase inhibitors has led to substantial clinical benefit in patients harboring oncogenic aberrations. More than thirty protein kinase inhibitors have been approved for clinical treatment of cancer (Berndt N. et al. Curr. Opin. Chem. Biol. 2017, 39:126-132). RET is a receptor tyrosine kinase that was initially discovered in 1985 through transfection of NIH3T3 cells with human lymphoma DNA
(Takahashi, M. et al. Cell. 1985, 42:581-588.). RET is expressed with its highest levels in early embryogenesis (during which it has diverse roles in different tissues) and decreases to relatively low levels in normal adult tissues (Pachnis, V., et al. Development 1993, 119, 1005-1017). RET plays a critical role in the development of enteric nervous system and kidneys during embryogenesis (Schuchardt, A. et al. Nature 1994, 367:380-383). RET activation regulates the downstream signalling pathways (RAS/MAPK/ERK, PI3K/AKT, and JAK-STAT etc.), leading to cellular proliferation, migration, and differentiation (Mulligan, LM. Nat Rev Cancer. 2014, 14(3): 173-86).
[004] Gain-of-function mutations of RET with constitutive activation have been found in heritable and sporadic tumors including activating point mutations within the full-length RET protein or genomic rearrangements that produce chimeric RET oncoproteins in the cytosol. The heritable oncogenic RET mutations are found in multiple endocrine neoplasia type 2 (MEN2) including medullary thyroid cancer (MTC) and familial MTC with more than 80 pathogenic variants spanning RET exons 5-16 reported (Mulligan, LM. Nat Rev Cancer. 2014, 14(3): 173- 86). Among them, RET M918T and RET A883F are found in 40-65% of sporadic MTC. The somatic mutation, chimeric RET fusion oncoproteins have been identified in sporadic tumors. The RET rearrangements are originally reported in papillary thyroid cancers (PTCs) (Grieco, M. et al. Cell. 1990, 23; 60 (4):557-63.). The resulting fusion transcripts composed of the 3’ end of RET kinase domain and the 5’ end of separate partner genes (CCDC6, NCOA4, TRIM24, TRIM33, PRKAR1A, GOLGA5, KTN1, ERC1, MBD1, and TRIM27 etc.). RET fusions are identified in approximately 20% 40% of PTCs, and CCDC6-RET and NCOA4-RET are the most commonly identified RET fusions in PTCs (Drilon A, et al. Nat Rev Clin Oncol. 2017 Nov 14. doi: 10.1038/nrclinonc.2017.175). RET gene fusions are also found in approximately l%-2% of non-small cell lung cancer (NSCLC) (Gainor JF, Shaw AT. Oncologist. 2013, 18(7):865-75), and over 50% of RET fusions in NSCLC is KIF5B-RET, representing the most frequent RET fusion form. However, the RET inhibitors have relatively low response rates and short treatment duration in the treatment of NSCLC patients with KIF5B-RET fusion gene in multiple clinical trials (Drilon, A. Nat Rev Clin Oncol. 2017 Nov 14. doi: 10.1038/nrclinonc. 2017.175). It was reported that the kinesin and kinase domains of KIF5B-RET act together to establish an emergent microtubule and RAB -vesicle-dependent RET-SRC-EGFR-FGFR signaling hub (Das TK and Cagan RL Cell Rep. 2017, 20(10):2368-2383). The inhibition of SRC kinase will have the potential to stop the recruitment of multiple RTKs via the N terminus of the KIF5B-RET fusion protein and the oncogenic signaling to increase the therapeutic efficiency of RET inhibitors. In addition, Src family tyrosine kinases regulate MTC cellular proliferation in vitro and mediate growth signals by increasing DNA synthesis and decreasing apoptosis (Liu Z, et al. J. Clin. Endocrinol. Metab. 2004, 89, 3503-3509). Therefore, a dual inhibitor of RET and SRC represents a highly desired therapeutic intervention to maximally target abnormal RET signaling in cancers.
[005] Endochondral ossification is a process that results in both the replacement of the embryonic cartilaginous skeleton during organogenesis and the growth of long bones until adult height is achieved. Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling plays a vital role in the development and maintenance of growth plates in endochondral ossification process
(Xie Y 2014). Missense mutations in FGFs and FGFRs can cause multiple genetic skeletal diseases with disordered endochondral ossification. Activating mutations in FGFR3 cause achondroplasia, the most common form of dwarfism among live births (Samsa WE 2017). The growth plates of humans with FGFR3 mutations show disrupted chondrocyte columns and reduced numbers of hypertrophic chondrocytes. FGFR1 and FGFR2 play many essential and mostly redundant roles during development, including growth plate formation. FGFR2- deficient embryos fail to form limb buds (Omitz DM 2015). In addition, Overexpression of
FGFR1 in chondrocytes causes joint fusion. Deletion of both FGFR1 and FGFR2 in mice caused a decreased length of the growth plate with a reduced number of proliferating chondrocytes (Karuppaiah K 2016). Therefore, the selectivity over FGFRs is an important parameter for better safety profile, especially for pediatric population.
SUMMARY
[006] In one aspect, the disclosure relates to a compound of the formula I
Figure imgf000004_0001
I
[007] wherein
[008] each R1 and R2 is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Cio aryl, mono- or bicyclic heteroaryl, -ORa, -OC(O)Ra, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)20Ra, -CN, or -NO2, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered
heterocycloalkyl, C6-Cio aryl, and mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, Ci-Ce haloalkyl, -ORe, -OC(O)Re,
-OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf,
-NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -N02;
[009] each R3 is independently H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)0Rf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)0Re, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf,
-P(O)NReRf, -P(O)2NReRf, -P(O)0Re, -P(O)20Re, -CN, or -N02;
[010] each R4 and R5 is independently hydrogen, deuterium, halogen, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -NRcC(O)0Rd,
-NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd,
-NRcS(O)2NRcRd, -C(O)Rc, -C(O)0Rc, -C(O)NRcRd, -C(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)0Rc, -P(O)20Rc, -CN, -N02, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Cio aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, mono- or bicyclic heteroaryl, C5-C8 cycloalkyl, or 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, Ci-Ce haloalkyl, -ORe, -OC(O)Re,
-OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)0Rf,
-NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)0Re, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)0Re, -P(O)20Re, -CN, or -N02;
[Oil] R6 is H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, -ORe, -SRe, or -NReRf;
[012] each R7 is independently hydrogen or deuterium,
[013] R8 and R9 together with the carbons which they are attached combine to form a C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-Cio aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 7-membered heteroaryl is independently optionally substituted by deuterium, halogen, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re,
-OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf,
-P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -N02;
[014] each Ra, Rb, Rc, Rd, Re, and Rf is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 7- membered heteroaryl; [015] m is 1 or 2; and
[016] n is i, 2, or 3;
[017] or a pharmaceutically acceptable salt thereof.
[018] In another aspect, the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula II
Figure imgf000006_0001
[019] In another aspect, the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula III
Figure imgf000006_0002
III.
[020] In another aspect, the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula IV
Figure imgf000007_0001
IV.
[021] In another aspect, the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula V
Figure imgf000007_0002
[022] In another aspect, the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula VI
Figure imgf000007_0003
VI. [023] Additional embodiments, features, and advantages of the disclosure will be apparent from the following detailed description and through practice of the disclosure. The compounds of the present disclosure can be described as embodiments in any of the following enumerated clauses. It will be understood that any of the embodiments described herein can be used in connection with any other embodiments described herein to the extent that the embodiments do not contradict one another.
[024] 1. A compound of the formula I
Figure imgf000008_0001
I
[025] wherein
[026] each R1 and R2 is independently H, deuterium, halogen, Ci- , alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Cio aryl, mono- or bicyclic heteroaryl, -ORa, -OC(O)Ra, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -N02, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered
heterocycloalkyl, C6-Cio aryl, and mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, Ci-Ce haloalkyl, -ORe, -OC(O)Re,
-OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf,
-NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -N02;
[027] each R3 is independently H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in
C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re,
-OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)0Rf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)0Re, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf,
-P(O)NReRf, -P(O)2NReRf, -P(O)0Re, -P(O)20Re, -CN, or -N02;
[028] each R4 and R5 is independently hydrogen, deuterium, halogen, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -NRcC(O)0Rd,
-NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd,
-NRcS(O)2NRcRd, -C(O)Rc, -C(O)0Rc, -C(O)NRcRd, -C(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)0Rc, -P(O)20Rc, -CN, -N02, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Cio aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, mono- or bicyclic heteroaryl, Cs-Cs cycloalkyl, or 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re,
-OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)0Rf,
-NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)0Re, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)0Re, -P(O)20Re, -CN, or -N02;
[029] R6 is H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, -ORe, -SRe, or -NReRf;
[030] each R7 is independently hydrogen or deuterium,
[031] R8 and R9 together with the carbons which they are attached combine to form a C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-Cio aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 7-membered heteroaryl is independently optionally substituted by deuterium, halogen, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re,
-OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf,
-P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -N02; [032] each Ra, Rb, Rc, Rd, Re, and Rf is independently selected from the group consisting of H, deuterium, C\-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 7- membered heteroaryl;
[033] m is 1 or 2; and
[034] n is i, 2, or 3;
[035] or a pharmaceutically acceptable salt thereof.
[036] 2. The compound of clause 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1.
[037] 3. The compound of clause 1 or 2, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.
[038] 4. The compound of clause 1, having the formula II
Figure imgf000010_0001
II
[039] or a pharmaceutically acceptable salt thereof.
[040] 5. The compound of any one of the preceding clauses, having the formula III
Figure imgf000010_0002
III
[041] or a pharmaceutically acceptable salt thereof.
[042] 6. The compound of any one of the preceding clauses, having the formula IV
Figure imgf000011_0001
IV
[043] or a pharmaceutically acceptable salt thereof.
[044] 7. The compound of any one of clauses 1 to 3, having the formula V
Figure imgf000011_0002
[045] or a pharmaceutically acceptable salt thereof.
[046] 8. The compound of any one of clauses 1 to 3 or 7, having the formula VI
Figure imgf000011_0003
[047] or a pharmaceutically acceptable salt thereof.
[048] 9. The compound of clause 1, or a pharmaceutically acceptable salt thereof, selected
Figure imgf000012_0001
[049] 10. The compound of clause 1, or a pharmaceutically acceptable salt thereof, selected form the group consisting of
Figure imgf000013_0001
[050] 11. The compound of clause 1, or a pharmaceutically acceptable salt thereof, selected form the group consisting of
Figure imgf000013_0002
[052] 12. The compound of clause 1, or a pharmaceutically acceptable salt thereof, selected form the group consisting of
Figure imgf000014_0001
[053] 13. The compound of clause 1, or a pharmaceutically acceptable salt thereof, selected form the group consisting of
Figure imgf000015_0001
[054] 14. The compound of clause 1, or a pharmaceutically acceptable salt thereof, selected form the group consisting of
Figure imgf000015_0002
[055] 15. The compound of any one of clauses 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R8 and R9 combine to form a 4-, 5- or 6-membered cycloalkyl, wherein each hydrogen atom in the 5- or 6-membered cycloalkyl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -OC(O)Ci-C6 alkyl, -OC(O)N(CI-C6 alkyl)2, -OC(O)NH(Ci-C6 alkyl), -OC(O)NH2, -OC(=N)N(CI-C6 alkyl)2, -OC(=N)NH(CI-C6 alkyl), -OC(=N)NH2, -OS(O)Ci-C6 alkyl, -OS(O)2Ci-C6 alkyl, -NH(CI-C6 alkyl), -N(CI-C6 alkyl)2, -NHC(O)Ci-C6 alkyl, -N(CI-C6 alkyl)C(O)Ci-C6 alkyl, -NHC(O)NH2,
-NHC(O)NH(CI-C6 alkyl), -N(CI-C6 alkyl)C(O)NH2, -N(Ci-Ce alkyl)C(O)NH(Ci-C6 alkyl), -NHC(O)N(CI-C6 alkyl)2, -N(CI-C6 alkyl)C(O)N(Ci-C6 alkyl)2, -NHC(O)OCi-C6 alkyl, -N(Ci-Ce alkyl)C(O)OCi-C6 alkyl, -NHC(O)0H, -N(CI-C6 alkyl)C(O)0H, -NHS(O)Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(Ci-Ce alkyl)S(O)Ci-C6 alkyl, -N(Ci-Ce a]kyl)S(O)2Ci-C6 alkyl, -NHS(O)NH2, -NHS(O)2NH2, -N(CI-C6 alkyl)S(O)NH2, -N(Ci-Ce alkyl)S(O)2NH2,
-NHS(O)NH(CI-C6 alkyl), -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)N(Ci-C6 alkyl)2,
-NHS(O)2N(CI-C6 alkyl)2, -N(Ci-Ce alkyl)S(O)NH(Ci-C6 alkyl), -N(Ci-Ce
alkyl)S(O)2NH(Ci-C6 alkyl), -N(CI-C6 alkyl)S(O)N(Ci-C6 alkyl)2, -N(CI-C6
alkyl)S(O)2N(Ci-C6 alkyl)2, -C(O)Ci-C6 alkyl, -C02H, -C(O)OCi-C6 alkyl, -C(O)NH2, -C(O)NH(CI-C6 alkyl), -C(O)N(Ci-Ce alkyl)2, -SCi-Ce alkyl, -S(O)Ci-C6 alkyl, -S(O)2Ci-C6 alkyl, -S(O)NH(Ci-C6 alkyl), -S(O)2NH(Ci-C6 alkyl), -S(O)N(Ci-Ce alkyl)2, -S(O)2N(Ci-C6 alkyl)2, -S(O)NH2, -S(O)2NH2, -OS(O)N(Ci-C6 alkyl)2, -OS(O)2N(Ci-C6 alkyl)2,
-OS(O)NH(CI-C6 alkyl), -OS(O)2NH(Ci-C6 alkyl), -OS(O)NH2, -OS(O)2NH2, -P(Ci-C6 alkyl)2, -P(O)(Ci-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl.
[056] 16. The compound of any one of clauses 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R8 and R9 combine to form a cyclobutane ring, cyclopentane ring, or cyclohexane ring.
[057] 17. The compound of any one of clauses 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R8 and R9 combine to form a 3-, 4-, 5- or 6-membered heterocycloalkyl, wherein each hydrogen atom in the 3-, 4-, 5- or 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -OC(O)Ci-Ce alkyl, -OC(O)N(CI-C6 alkyl)2, -OC(O)NH(CI-C6 alkyl), -OC(O)NH2, -OC(=N)N(CI-C6 alkyl)2,
-OC(=N)NH(CI-C6 alkyl), -OC(=N)NH2, -OS(O)Ci-C6 alkyl, -OS(O)2Ci-C6 alkyl, -NH(CI-C6 alkyl), -N(Ci-Ce alkyl)2, -NHC(O)Ci-C6 alkyl, -N(Ci-Ce alkyl)C(O)Ci-C6 alkyl, -NHC(O)NH2,
-NHC(O)NH(CI-C6 alkyl), -N(Ci-Ce alkyl)C(O)NH2, -N(Ci-Ce alkyl)C(O)NH(Ci-C6 alkyl),
-NHC(O)N(CI-C6 alkyl)2, -N(Ci-Ce alkyl)C(O)N(Ci-C6 alkyl)2, -NHC(O)OCI-C6 alkyl,
-N(Ci-Ce alkyl)C(O)OCi-C6 alkyl, -NHC(O)OH, -N(CI-C6 alkyl)C(O)OH, -NHS(O)Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(Ci-Ce alkyl)S(O)Ci-C6 alkyl, -N(Ci-Ce a]kyl)S(O)2Ci-C6 alkyl, -NHS(O)NH2, -NHS(O)2NH2, -N(CI-C6 alkyl)S(O)NH2, -N(Ci-Ce alkyl)S(O)2NH2,
-NHS(O)NH(CI-C6 alkyl), -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)N(Ci-C6 alkyl)2,
-NHS(O)2N(CI-C6 alkyl)2, -N(Ci-Ce alkyl)S(O)NH(Ci-C6 alkyl), -N(Ci-Ce
alkyl)S(O)2NH(C i -C6 alkyl), -N(Ci-Ce alkyl)S(O)N(Ci-C6 alkyl)2, -N(Ci-Ce
alkyl)S(O)2N(Ci-C6 alkyl)2, -C(O)Ci-C6 alkyl, -C02H, -C(O)OCi-C6 alkyl, -C(O)NH2, -C(O)NH(CI-C6 alkyl), -C(O)N(Ci-Ce alkyl)2, -SCi-C6 alkyl, -S(O)Ci-C6 alkyl, -S(O)2Ci-C6 alkyl, -S(O)NH(Ci-C6 alkyl), -S(O)2NH(Ci-C6 alkyl), -S(O)N(Ci-Ce alkyl)2, -S(O)2N(Ci-C6 alkyl)2, -S(O)NH2, -S(O)2NH2, -OS(O)N(Ci-C6 alkyl)2, -OS(O)2N(Ci-C6 alkyl)2,
-OS(O)NH(CI-C6 alkyl), -OS(O)2NH(Ci-C6 alkyl), -OS(O)NH2, -OS(O)2NH2, -P(Ci-C6 alkyl)2, -P(O)(Ci-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl.
[058] 18. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each R3, when present, is H or C1-C6 alkyl.
[059] 19. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each R4 is H or deuterium.
[060] 20. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each R1 is H or D.
[061] 21. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each R2 is H.
[062] 22. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each R7 is H.
[063] 23. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R5 is F.
[064] 24. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R6 is H.
[065] 25. The compound of clause 1, or a pharmaceutically acceptable salt thereof, selected
from the group consisting
Figure imgf000017_0001
[066] 26. A pharmaceutical composition comprising a compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, and optionally at least one diluent, carrier or excipient. [067] 27. A method of treating cancer comprising administering to a subject in need of such treatment an effective amount of at least one compound of any one of clauses 1 to 25, or a pharmaceutically acceptable salt thereof.
[068] 28. Use of a compound of any one of clauses 1 to 25, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of cancer.
[069] 29. Use of a compound of any one of clauses 1 to 25, or a pharmaceutically acceptable salt thereof, for treating cancer.
[070] 30. A method of inhibiting RET or SRC, comprising contacting a cell comprising one or more of such kinases with an effective amount of at least one compound of any one of clauses 1 to 25, or a pharmaceutically acceptable salt thereof, and/or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.
[071] 31. A compound of any one of clauses 1 to 25 for use in treating cancer in a patient
DETAILED DESCRIPTION
[072] Before the present disclosure is further described, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.
[073] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication that is herein incorporated by reference, the definition set forth in this section prevails over the definition incorporated herein by reference.
[074] As used herein and in the appended claims, the singular forms“a,”“an,” and“the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as“solely,”“only” and the like in connection with the recitation of claim elements, or use of a“negative” limitation.
[075] As used herein, the terms“including,”“containing,” and“comprising” are used in their open, non-limiting sense. [076] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term“about.” It is understood that, whether the term“about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and/or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently.
[077] Except as otherwise noted, the methods and techniques of the present embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001.
[078] Chemical nomenclature for compounds described herein has generally been derived using the commercially-available ACD/Name 2014 (ACD/Labs) or ChemBioDraw pLtra 13.0 (Perkin Elmer).
[079] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present disclosure and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein. Definitions
[080] As used herein, the term“alkyl” includes a chain of carbon atoms, which is optionally branched and contains from 1 to 20 carbon atoms. It is to be further understood that in certain embodiments, alkyl may be advantageously of limited length, including C1-C12, C1-C10, C1-C9, C1-C8, C1-C7, C1-C6, and C1-C4, Illustratively, such particularly limited length alkyl groups, including Ci-Cs, Ci-C7, Ci-C6, and C1-C4, and the like may be referred to as“lower alkyl.” Illustrative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl, octyl, and the like. Alkyl may be substituted or unsubstituted. Typical substituent groups include cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, oxo, (=0), thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, nitro, and amino, or as described in the various embodiments provided herein. It will be understood that“alkyl” may be combined with other groups, such as those provided above, to form a functionalized alkyl. By way of example, the combination of an“alkyl” group, as described herein, with a “carboxy” group may be referred to as a“carboxyalkyl” group. Other non-limiting examples include hydroxyalkyl, aminoalkyl, and the like.
[081] As used herein, the term“alkenyl” includes a chain of carbon atoms, which is optionally branched, and contains from 2 to 20 carbon atoms, and also includes at least one carbon-carbon double bond (i.e., C=C). It will be understood that in certain embodiments, alkenyl may be advantageously of limited length, including C2-C12, C2-C9, C2-C8, C2-C7, C2-C6, and C2-C4. Illustratively, such particularly limited length alkenyl groups, including C2-C8, C2-C7, C2-C6, and C2-C4 may be referred to as lower alkenyl. Alkenyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.
[082] As used herein, the term“alkynyl” includes a chain of carbon atoms, which is optionally branched, and contains from 2 to 20 carbon atoms, and also includes at least one carbon-carbon triple bond (i.e., CºC). It will be understood that in certain embodiments, alkynyl may each be advantageously of limited length, including C2-C12, C2-C9, C2-C8, C2-C7, C2-C6, and C2-C4. Illustratively, such particularly limited length alkynyl groups, including C2-C8, C2-C7, C2-O,, and C2-C4 may be referred to as lower alkynyl. Alkynyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. [083] As used herein, the term“aryl” refers to an all-carbon monocyclic or fused-ring polycyclic groups of 6 to 12 carbon atoms having a completely conjugated pi-electron system.
It will be understood that in certain embodiments, aryl may be advantageously of limited size such as C6-C10 aryl. Illustrative aryl groups include, but are not limited to, phenyl, naphthylenyl and anthracenyl. The aryl group may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
[084] As used herein, the term“cycloalkyl” refers to a 3 to 15 member all-carbon monocyclic ring, including an all-carbon 5-member/6-member or 6-member/6-member fused bicyclic ring, or a multicyclic fused ring (a“fused” ring system means that each ring in the system shares an adjacent pair of carbon atoms with each other ring in the system) group, or a carbocyclic ring that is fused to another group such as a heterocyclic, such as ring 5- or 6-membered cycloalkyl fused to a 5- to 7- membered heterocyclic ring, where one or more of the rings may contain one or more double bonds but the cycloalkyl does not contain a completely conjugated pi-electron system. It will be understood that in certain embodiments, cycloalkyl may be advantageously of limited size such as C3-C13, C3-C9, C3-C6 and C4-C6. Cycloalkyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, norbornyl, norbornenyl, 9//-lluoren-9-yl, and the like. Illustrative examples of cycloalkyl groups shown in graphical representations include the following entities, in the form of properly bonded moieties: . a . O . 0 . 0. 0 . o . 0 . 0 . 0
Figure imgf000021_0001
[085] As used herein, the term“heterocycloalkyl” refers to a monocyclic or fused ring group having in the ring(s) from 3 to 12 ring atoms, in which at least one ring atom is a heteroatom, such as nitrogen, oxygen or sulfur, the remaining ring atoms being carbon atoms.
Heterocycloalkyl may optionally contain 1, 2, 3 or 4 heteroatoms. A heterocycloalkyl group may be fused to another group such as another heterocycloalkyl, or a heteroaryl group. Heterocycloalkyl may also have one of more double bonds, including double bonds to nitrogen (e.g., C=N or N=N) but does not contain a completely conjugated pi-electron system. It will be understood that in certain embodiments, heterocycloalkyl may be advantageously of limited size such as 3- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, 3-, 4-, 5- or 6-membered heterocycloalkyl, and the like. Heterocycloalkyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative heterocycloalkyl groups include, but are not limited to, oxiranyl, thianaryl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4- dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, oxepanyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1, 2, 3, 4-tetrahydropyridinyl, and the like. Illustrative examples of heterocycloalkyl groups shown in graphical representations include the following entities, in the form of properly bonded moieties:
Figure imgf000022_0001
[086] As used herein, the term“heteroaryl” refers to a monocyclic or fused ring group of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur, the remaining ring atoms being carbon atoms, and also having a completely conjugated pi-electron system. It will be understood that in certain embodiments, heteroaryl may be advantageously of limited size such as 3- to 7-membered heteroaryl, 5- to 7-membered heteroaryl, and the like. Heteroaryl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein. Illustrative heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, tetrazolyl, triazinyl, pyrazinyl, tetrazinyl, quinazolinyl, quinoxalinyl, thienyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl and carbazoloyl, and the like. Illustrative examples of heteroaryl groups shown in graphical representations, include the following entities, in the form of properly bonded moieties:
Figure imgf000023_0001
[087] As used herein,“hydroxy” or“hydroxyl” refers to an -OH group.
[088] As used herein,“alkoxy” refers to both an -O-(alkyl) or an -O- (unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
[089] As used herein,“aryloxy” refers to an -O-aryl or an -O-heteroaryl group. Representative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and the like.
[090] As used herein,“mercapto” refers to an -SH group.
[091] As used herein,“alkylthio” refers to an -S-(alkyl) or an -S-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.
[092] As used herein,“arylthio” refers to an -S-aryl or an -S-heteroaryl group. Representative examples include, but are not limited to, phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio, and the like. [093] As used herein,“halo” or“halogen” refers to fluorine, chlorine, bromine or iodine.
[094] As used herein,“cyano” refers to a -CN group.
[095] The term“oxo” represents a carbonyl oxygen. For example, a cyclopentyl substituted with oxo is cyclopentanone.
[096] As used herein,“bond” refers to a covalent bond.
[097] The term“substituted” means that the specified group or moiety bears one or more substituents. The term“unsubstituted” means that the specified group bears no substituents. Where the term“substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In some embodiments,“substituted” means that the specified group or moiety bears one, two, or three substituents. In other embodiments,“substituted” means that the specified group or moiety bears one or two substituents. In still other embodiments,“substituted” means the specified group or moiety bears one substituent.
[098] As used herein,“optional” or“optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example,“wherein each hydrogen atom in C\-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-to 7- membered heterocycloalkyl, C6-C10 aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by C1-C6 alkyl” means that an alkyl may be but need not be present on any of the C1-C6 alkyl, CF-Ce alkenyl, C2-O, alkynyl, C3-C6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C6-C10 aryl, or mono- or bicyclic heteroaryl by replacement of a hydrogen atom for each alkyl group, and the description includes situations where the C1-C6 alkyl, CF-Ce alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C6-C10 aryl, or mono- or bicyclic heteroaryl is substituted with an alkyl group and situations where the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-to 7-membered heterocycloalkyl, Ce- C10 aryl, or mono- or bicyclic heteroaryl is not substituted with the alkyl group.
[099] As used herein,“independently” means that the subsequently described event or circumstance is to be read on its own relative to other similar events or circumstances. For example, in a circumstance where several equivalent hydrogen groups are optionally substituted by another group described in the circumstance, the use of“independently optionally” means that each instance of a hydrogen atom on the group may be substituted by another group, where the groups replacing each of the hydrogen atoms may be the same or different. Or for example, where multiple groups exist all of which can be selected from a set of possibilities, the use of “independently” means that each of the groups can be selected from the set of possibilities separate from any other group, and the groups selected in the circumstance may be the same or different.
[0100] As used herein, the phrase“R8 and R9 combine to form a C3-C7 cycloalkyl, a 5- to 8- membered heterocycloalkyl, C6-C10 aryl, or 5- to 7-membered heteroaryl” also means that R8 and R9 are taken together with the carbon atoms to which they are attached to form a a C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-Cio aryl, or 5- to 7-membered heteroaryl. In particular,“R8 and R9 combine to form a C3-C7 cycloalkyl” used in connection with the embodiments described herein includes fragments represented by the following:
Figure imgf000025_0001
[0101] where the above fused rings can be optionally substituted as defined in a given embodiment. One of skill in the art will appreciate that all stereochemical arragnements are included within the structures provided above, such as with respect to the five-carbon ring formed by R8 and R9 as provided in the following fragments:
Figure imgf000025_0002
[0102] As used herein, the term“pharmaceutically acceptable salt” refers to those salts which counter ions which may be used in pharmaceuticals. See, generally, S.M. Berge, et ak, “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response. A compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
Such salts include:
[0103] (1) acid addition salts, which can be obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methane sulfonic acid,
ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid and the like; or
[0104] (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, trimethamine, N-methylglucamine, and the like.
[0105] Pharmaceutically acceptable salts are well known to those skilled in the art, and any such pharmaceutically acceptable salt may be contemplated in connection with the
embodiments described herein. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne- 1,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates,
dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,
methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene- 1 -sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, g-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable
pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.
[0106] For a compound of Formula I, II, III, IV, V, or VI that contains a basic nitrogen, a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p- toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid, or any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.
[0107] The disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of
Formula I, II, III, IV, V, or VI and treatment methods employing such pharmaceutically acceptable prodrugs. The term“prodrug” means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula I, II, III, IV, V, or VI). A“pharmaceutically acceptable prodrug” is a prodrug that is non- toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in“Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
[0108] The present disclosure also relates to pharmaceutically active metabolites of compounds of Formula I, II, III, IV, V, or VI, and uses of such metabolites in the methods of the disclosure. A“pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula I, II, III, IV, V, or VI, or salt thereof.
Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).
[0109] Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms. For example, a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof. Additionally, any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof. For example, it will be appreciated that compounds depicted by a structural formula containing the symbol“ n/nl-G ” include both stereoisomers for the carbon atom to which the symbol“ iLLL'” is attached, specifically both the bonds“
Figure imgf000027_0001
” and .111111” are encompassed by the meaning of“/vw por example, in some exemplary embodiments, certain compounds provided herein can be described by the formula
Figure imgf000028_0001
[0110] which formula will be understood to encompass compounds having both stereochemical configurations at the relevant carbon atom, specifically in this example
Figure imgf000028_0002
and other stereochemical combinations.
[0111] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H, 3H, nC, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, 36C1, and 125I, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
[0112] Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed. For example, reference to disubstituent -A-B-, where A ¹ B, refers herein to such disubstituent with A attached to a first substituted member and B attached to a second substituted member, and it also refers to such disubstituent with A attached to the second substituted member and B attached to the first substituted member.
REPRESENTATIVE EMBODIMENTS
[0113] In some embodiments, compounds described herein comprise a moiety of the formula
[0114] In still other embodiments, compounds described herein comprise a moiety of the formula
Figure imgf000029_0001
wherein Y is otherwise defined as described herein, and the substituents on the non-aromatic ring marked by a bond and ~ correspond to R7 and R8 as described herein. In still other embodiments, compounds described herein comprise a moiety of the formula
Figure imgf000030_0001
wherein Y is otherwise defined as described herein. In still other embodiments, compounds described herein comprise a moiety of the formula
Figure imgf000030_0002
Figure imgf000030_0003
still other embodiments, compounds described herein comprise a moiety of the formula
Figure imgf000030_0004
Figure imgf000030_0005
In still other embodiments, compounds described herein comprise a moiety of the formula
Figure imgf000031_0001
In still other embodiments, compounds described herein comprise a moiety of the formula
Figure imgf000031_0002
[0115] In some embodiments, each R1 and R2 is independently H, deuterium, halogen, C1 -C6, alkyl, C2-C6 alkenyl, Ci-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, mono- or bicyclic heteroaryl, -ORa, -OC(O)Ra, -OC(O)Ra, -OC(O)NRaRb,
-OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)0Rb, -NRaC(O)NRaRb, -NRaS(O)Rb,
-NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)0Ra, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)0Ra, -P(O)2ORa, -CN, or -NO2, wherein each hydrogen atom in C1-C6 alkyl, C2-Ce alkenyl, C2-C>, alkynyl, C3-C6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C6-C10 aryl, and mono- or bicyclic heteroaryl is
independently optionally substituted by deuterium, halogen, C1-C6 alkyl, Ci-Cehaloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf,
-OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)0Rf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf,
-NReS(O)2NReRf, -C(O)Re, -C(O)0Re, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf,
-P(O)NReRf, -P(O)2NReRf, -P(O)0Re, -P(O)2ORe, -CN, or -NO2. In some embodiments, R1 is H or D. In some embodiments, R2 is H or deuterium.
[0116] In some embodiments, each R3 is independently H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Cehaloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)0Rf, -NReC(O)NReRf, -NReS(O)Rf,
-NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)0Re, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)0Re, -P(O)20Re, -CN, or -N02. In some embodiments, each R3, when present, is H or C1-C6 alkyl.
[0117] In some embodiments, each R4 and R5 is independently hydrogen, deuterium, halogen, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -NRcC(O)0Rd, -NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd,
-NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)Rc, -C(O)0Rc, -C(O)NRcRd, -C(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)0Rc, -P(O)20Rc, -CN, -N02, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Cio aryl, mono- or bicyclic heteroaryl, Cs-Cs cycloalkyl, or 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, Ci-Cehaloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf,
-OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)0Rf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf,
-NReS(O)2NReRf, -C(O)Re, -C(O)0Re, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf,
-P(O)NReRf, -P(O)2NReRf, -P(O)0Re, -P(O)20Re, -CN, or -N02. In some embodiments, R4 is H or deuterium. In some embodiments, R5 is F.
[0118] In some embodiments, R6 is H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, -ORe, -SRe, or -NReRf. In some embodiments R6 is H.
[0119] In some embodiments, each R7 is independently hydrogen or deuterium. In some embodiments, R7 is H.
[0120] In some embodiments, R8 and R9 together with the carbons which they are attached combine to form a C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to
7-membered heteroaryl; wherein each hydrogen atom in C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 7-membered heteroaryl is independently optionally substituted by deuterium, halogen, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re,
-OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf,
-NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)0Re, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)0Re, -P(O)20Re, -CN, or -N02.
[0121] In some embodiments, R8 and R9 combine to form a 4-, 5- or 6-membered cycloalkyl, wherein each hydrogen atom in the 5- or 6-membered cycloalkyl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -OC(O)Ci-C6 alkyl, -OC(O)N(CI-C6 alkyl)2, -OC(O)NH(Ci-C6 alkyl), -OC(O)NH2, -OC(=N)N(CI-C6 alkyl)2, -OC(=N)NH(CI-C6 alkyl), -OC(=N)NH2, -OS(O)Ci-C6 alkyl, -OS(O)2Ci-C6 alkyl, -NH(CI-C6 alkyl), -N(Ci-Ce alkyl)2, -NHC(O)Ci-C6 alkyl, -N(Ci-Ce alkyl)C(O)Ci-C6 alkyl, -NHC(O)NH2, -NHC(O)NH(CI-C6 alkyl), -N(CI-C6 alkyl)C(O)NH2, -N(Ci-Ce alkyl)C(O)NH(Ci-C6 alkyl), -NHC(O)N(CI-C6 alkyl)2, -N(CI-C6 alkyl)C(O)N(Ci-C6 alkyl)2, -NHC(O)OCi-C6 alkyl, -N(Ci-Ce alkyl)C(O)OCi-C6 alkyl, -NHC(O)0H, -N(CI-C6 alkyl)C(O)0H, -NHS(O)Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(Ci-Ce alkyl)S(O)Ci-C6 alkyl, -N(Ci-Ce alkyl)S(O)2Ci-C6 alkyl, -NHS(O)NH2, -NHS(O)2NH2, -N(CI-C6 alkyl)S(O)NH2, -N(Ci-Ce alkyl)S(O)2NH2,
-NHS(O)NH(CI-C6 alkyl), -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)N(Ci-C6 alkyl)2,
-NHS(O)2N(CI-C6 alkyl)2, -N(CI-C6 alkyl)S(O)NH(Ci-C6 alkyl), -N(Ci-Ce
alkyl)S(O)2NH(Ci-C6 alkyl), -N(CI-C6 alkyl)S(O)N(Ci-C6 alkyl)2, -N(CI-C6
alkyl)S(O)2N(Ci-C6 alkyl)2, -C(O)Ci-Ce alkyl, -C02H, -C(O)OCi-Ce alkyl, -C(O)NH2, -C(O)NH(CI-C6 alkyl), -C(O)N(Ci-Ce alkyl)2, -SCi-Ce alkyl, -S(O)Ci-Ce alkyl, -S(O)2Ci-Ce alkyl, -S(O)NH(Ci-C6 alkyl), -S(O)2NH(Ci-C6 alkyl), -S(O)N(Ci-Ce alkyl)2, -S(O)2N(Ci-C6 alkyl)2, -S(O)NH2, -S(O)2NH2, -OS(O)N(Ci-C6 alkyl)2, -OS(O)2N(Ci-C6 alkyl)2,
-OS(O)NH(CI-C6 alkyl), -OS(O)2NH(Ci-C6 alkyl), -OS(O)NH2, -OS(O)2NH2, -P(Ci-C6 alkyl)2, -P(O)(Ci-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl. In some embodiments, R8 and R9 combine to form a cyclobutane ring, cyclopentane ring, or
cyclohexane ring.
[0122] In some embodiments, R8 and R9 combine to form a 3-, 4-, 5- or 6-membered heterocycloalkyl, wherein each hydrogen atom in the 3-, 4-, 5- or 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2,
-OC(O)Ci-C6 alkyl, -OC(O)N(Ci-Ce alkyl)2, -OC(O)NH(Ci-C6 alkyl), -OC(O)NH2,
-OC(=N)N(Ci-Ce alkyl)2, -OC(=N)NH(CI-C6 alkyl), -OC(=N)NH2, -OS(O)Ci-C6 alkyl,
-OS(O)2Ci-C6 alkyl, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, -NHC(O)Ci-C6 alkyl, -N(CI-C6 alkyl)C(O)Ci-C6 alkyl, -NHC(O)NH2, -NHC(O)NH(Ci-C6 alkyl), -N(CI-C6 alkyl)C(O)NH2,
-N(Ci-Ce alkyl)C(O)NH(Ci-C6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -N(Ci-Ce alkyl)C(O)N(Ci-Ce alkyl)2, -NHC(O)OCi-C6 alkyl, -N(Ci-Ce alkyl)C(O)OCi-C6 alkyl, -NHC(O)0H, -N(Ci-Ce alkyl)C(O)0H, -NHS(O)Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(Ci-Ce alkyl)S(O)Ci-C6 alkyl,
-N(Ci-Ce alkyl)S(O)2Ci-C6 alkyl, -NHS(O)NH2, -NHS(O)2NH2, -N(CI-C6 alkyl)S(O)NH2, -N(Ci-Ce alkyl)S(O)2NH2, -NHS(O)NH(Ci-C6 alkyl), -NHS(O)2NH(Ci-C6 alkyl),
-NHS(O)N(CI-C6 alkyl)2, -NHS(O)2N(Ci-C6 alkyl)2, -N(Ci-Ce alkyl)S(O)NH(Ci-C6 alkyl), -N(Ci-Ce alkyl)S(O)2NH(Ci-C6 alkyl), -N(Ci-Ce alkyl) S(O)N(Ci-Ce alkyl)2, -N(Ci-Ce alkyl)S(O)2N(Ci-C6 alkyl)2, -C(O)Ci-C6 alkyl, -C02H, -C(O)OCi-C6 alkyl, -C(O)NH2, -C(O)NH(CI-C6 alkyl), -C(O)N(Ci-Ce alkyl)2, -SCi-Ce alkyl, -S(O)Ci-C6 alkyl, -S(O)2Ci-C6 alkyl, -S(O)NH(Ci-C6 alkyl), -S(O)2NH(Ci-C6 alkyl), -S(O)N(Ci-Ce alkyl)2, -S(O)2N(Ci-C6 alkyl)2, -S(O)NH2, -S(O)2NH2, -OS(O)N(Ci-C6 alkyl)2, -OS(O)2N(Ci-C6 alkyl)2,
-OS(O)NH(CI-C6 alkyl), -OS(O)2NH(Ci-C6 alkyl), -OS(O)NH2, -OS(O)2NH2, -P(Ci-C6 alkyl)2, -P(O)(Ci-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl.
[0123] In some embodiments, each Ra, Rb, Rc, Rd, Re, and Rf is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl,
3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 7- membered heteroaryl.
[0124] In some embodiments, m is 1 or 2. In some embodiments, m is 1.
[0125] In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2.
[0126] The following represent illustrative embodiments of compounds of the formula I, II, III, IV, V, and VI:
Figure imgf000034_0001
Figure imgf000035_0001
[0127] Those skilled in the art will recognize that the species listed or illustrated herein are not exhaustive, and that additional species within the scope of these defined terms may also be selected.
[0128] These and other embodiments described herein can bemade and used according to the processes and methods described in International PCT Publication No. WO2019/126121, corresponding to International PCT Application No. PCT/US2018/066158, filed December 18, 2018, which is incorporated herein by reference.
PHARMACEUTICAL COMPOSITIONS
[0129] For treatment purposes, pharmaceutical compositions comprising the compounds described herein may further comprise one or more pharmaceutically-acceptable excipients. A pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, anti oxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents. In preferred embodiments, pharmaceutical compositions according to the invention are sterile compositions. Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art.
[0130] Sterile compositions are also contemplated by the invention, including compositions that are in accord with national and local regulations governing such compositions.
[0131] The pharmaceutical compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms. Pharmaceutical compositions of the invention may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration.
[0132] For oral administration, the compounds the invention may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds of the invention may be formulated to yield a dosage of, e.g., from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl -pyrrolidone (PVP), sodium starch glycolate,
microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
[0133] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
[0134] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain:
pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
[0135] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 pg/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
[0136] For nasal, inhaled, or oral administration, the inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable carrier. The inventive compositions may be formulated for rectal administration as a suppository.
[0137] For topical applications, the compounds of the present invention are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration· For topical administration, the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the agents of the invention may utilize a patch formulation to effect transdermal delivery.
[0138] As used herein, the terms“treat” or“treatment” encompass both“preventative” and “curative” treatment.“Preventative” treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition. Thus, treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.
[0139] The term“subject” refers to a mammalian patient in need of such treatment, such as a human.
[0140] Exemplary diseases include cancer, pain, neurological diseases, autoimmune diseases, and inflammation. Cancer includes, for example, lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophago-gastric cancers, glioblastoma, head and neck cancers, inflammatory myofibroblastic tumors, and anaplastic large cell lymphoma. Pain includes, for example, pain from any source or etiology, including cancer pain, pain from chemotherapeutic treatment, nerve pain, pain from injury, or other sources. Autoimmune diseases include, for example, rheumatoid arthritis, Sjogren syndrome, Type I diabetes, and lupus. Exemplary neurological diseases include Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic lateral sclerosis, and Huntington’s disease.
Exemplary inflammatory diseases include atherosclerosis, allergy, and inflammation from infection or injury.
[0141] In one aspect, the compounds and pharmaceutical compositions of the invention specifically target receptor tyrosine kinases, in particular RET. In another aspect, the compounds and pharmaceutical compositions of the invention specifically target non-receptor tyrosine kinases, in particular SRC. In yet another aspect, the compounds and pharmaceutical compositions of the invention specifically target receptor tyrosine kinases and non-receptor tyrosine kinases, such as RET and SRC, respectively. Thus, these compounds and
pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit the activity of one or more of these kinases. In preferred embodiments, methods of treatment target cancer. In other embodiments, methods are for treating lung cancer or non-small cell lung cancer.
[0142] In the inhibitory methods of the invention, an“effective amount” means an amount sufficient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays. In such methods, the cell is preferably a cancer cell with abnormal signaling due to upregulation of RET and/or SRC.
[0143] In treatment methods according to the invention, an“effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment. Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject’s health status, condition, and weight, and the judgment of the treating physician. An exemplary dose is in the range of about from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. The total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).
[0144] Once improvement of the patient’s disease has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis. DRUG COMBINATIONS
[0145] The inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein. Further additional active ingredients include other therapeutics or agents that mitigate adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound. The additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present invention or may be included with a compound of the present invention in a single pharmaceutical composition. The additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present invention.
[0146] Combination agents include additional active ingredients are those that are known or discovered to be effective in treating the diseases and disorders described herein, including those active against another target associated with the disease. For example, compositions and formulations of the invention, as well as methods of treatment, can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for the target diseases or related symptoms or conditions. For cancer indications, additional such agents include, but are not limited to, kinase inhibitors, such as EGFR inhibitors (e.g., erlotinib, gefitinib), Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib), ALK inhibitors (e.g., crizotinib) standard chemotherapy agents such as alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormone therapies, or corticosteroids. For pain indications, suitable combination agents include anti-inflammatories such as NSAIDs. The pharmaceutical compositions of the invention may additionally comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents.
CHEMICAL SYNTHESIS
[0147] Exemplary chemical entities useful in methods of the description will now be described by reference to illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the pLtimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the pLtimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups.
[0148] Abbreviations: The examples described herein use materials, including but not limited to, those described by the following abbreviations known to those skilled in the art:
Figure imgf000040_0001
General Method A
Preparation of (5a/?,8aS)-ethyl 5, 5a, 6,7,8,8a- hexahydrocyclopenta[6]pyrazolo[ l',5' : 1 ,2]pyrimido[4,5-e][ 1 ,4]oxazine-3-carboxylate (A)
Figure imgf000041_0002
Figure imgf000041_0001
[0149] Step 1: To a solution of A-2 (2.50 g, 16.1 mmol, 1.00 eq., ethyl 3-amino- lH-pyrazole-4- carboxylate, available from e.g. Sigma-Aldrich) in methanol (20.0 mL) was added sodium methoxide (4.00 g, 74.0 mmol, 4.60 eq.) and A-l (3.75 g, 25.0 mmol, 1.55 eq., dimethyl 2- fluoromalonate, available from e.g. Sigma-Aldrich). The mixture was stirred at 80 °C for 5 hrs. The mixture was concentrated and residue was dissolved in water (50 mL). The mixture was adjusted to pH = 3 with HC1 (2.00 M, 2.00 mL) and lyophilized to give A-3 (2.5 g, 10.4 mmol, 64.3% yield) as a white solid.
[0150] Step 2: To a solution of A-3 (2.0 g, 8.29 mmol, 1 eq.) in phosphorus oxychloride (64.9 g, 423 mmol, 39.3 mL, 51 eq.). The mixture was stirred at 100 °C for 12 hrs. The mixture was concentrated to give crude product. The residue was purified by Prep-TLC (S1O2, petroleum ether: ethyl acetate = 2:1) to give A-4 (1.0 g, 3.60 mmol, 43.4% yield) as a white solid.
[0151] Step 3: To a solution of A-4 (865 mg, 3.11 mmol, 1.0 eq.) in ethanol (16.0 mL), THF (6.00 mL) and water (11.0 mL) was added zinc powder (1.02 g, 15.6 mmol, 5.0 eq.) and ammonium chloride (700 mg, 13.1 mmol, 4.21 eq.) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. The mixture was filtered and the filtrate was dilute with water (50.0 mL). The mixture was extracted with ethyl acetate (30.0 mL x 3) and the organic layer was washed with brine (50.0 mL), dried over anhydrous sodium sulfate, concentrated to give a residue. The residue was purified by Prep-TLC (S1O2, petroleum ether: ethyl acetate = 3: 1) to give A-5 (465 mg, 1.91 mmol, 61.4% yield) as a white solid. [0152] Step 4: To a solution of (15,2^)-2-aminocyclopentanol (262 mg, 1.90 mmol, 1.00 eq. HC1, available from e.g. Sigma- Aldrich) in n-BuOH (6.00 mL) was added DIEA (1.14 g, 8.85 mmol, 1.54 mL, 4.65 eq.) and A-5 (463 mg, 1.90 mmol, 1.00 eq.). The mixture was stirred at 100 °C for 5 hrs. The mixture was quenched by water (20.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The organic layer was washed by brine (50.0 mL) and dried over anhydrous sodium sulfate. The residue was purified by Prep-TLC (S1O2, petroleum ether: ethyl acetate = 1:1) to give A-6 (570 mg, 1.79 mmol, 93.8% yield, 96.6% purity) as a white solid.
[0153] Step 5: To a solution of A-6 (520 mg, 1.69 mmol, 1.00 eq.) in DML (8.00 mL) was added cesium carbonate (1.66 g, 5.11 mmol, 3.03 eq.). The mixture was stirred at 130 °C for 5 hrs. The mixture was quenched by water (20.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The organic layer was washed by brine (50.0 mL) and dried over anhydrous sodium. The residue was purified by Prep-HPLC to give A (100 mg, 336 pmol, 20 % yield, 97.1% purity) as a yellow solid.
Figure imgf000042_0001
[0154] Step 1. To a solution of 1-1 (374.47 mg, 2 mmol, tert-butyl ((lr,3r)-3- hydroxycyclobutyl)carbamate, available from e.g. Enamine Ltd.), 1-2 (408.33 mg, 2.40 mmol, methyl 5-fluoro-2-hydroxybenzoate, available from e.g. Sigma- Aldrich), and PPI13 (786.86 mg, 3.00 mmol) in anhydrous DCM (2.23 mL) at 0 °C was added DIAD (647.07 mg, 3.20 mmol, 628.22 pL) with stirring. The mixture was stirred for 3 hr as it warmed to ambient temperature. The mixture was purified by flash column chromatography (ISCO, 12 g silica, 0-60% ethyl acetate in hexanes) twice to afford 1-3 (602 mg, 1.77 mmol, 88.70% yield).
[0155] Step 2. 1-3 (300 mg, 884.02 pmol) was dissolved in anhydrous methanol (4.42 mL) and the mixture was cooled to 0 °C in ice bath. NaBPU (334.45 mg, 8.84 mmol) was added slowly over 8 hrs and the mixture was stirred as temperature increases to ambient. The reaction was quenched with cold water (10 mL) and stirred vigorously. The reaction was worked up with DCM (20 mL) and more water (20 mL total) with 5mL of 2N NaOH. Layers were partitioned, and the aqueous layer was extracted 2x with DCM (10 mL). The combined organic layer was washed with brine and dried over sodium sulfate. Llash column chromatography (ISCO, 12 g silica, 0-50% EtOAc in hexanes) provided 1-4 (173.3 mg, 556.61 pmol, 62.96% yield).
[0156] Step 3. To 1-4 (100 mg, 321.18 pmol) in DCM (1.53 mL) was added Hunig's base (207.55 mg, 1.61 mmol, 279.72 pL). The mixture was cooled to 0 °C and mesyl chloride (73.58 mg, 642.37 pmol, 49.72 pL) was added. The reaction was stirred as temperature increase to ambient over 18 hrs. The reaction was quenched with 2M HC1 (aq) (5mL) at 0 °C. The reaction was diluted with water and DCM (1 OmL each), layers partitioned, and the aqueous layer extracted 2x with DCM (5mL). The combined organic layer was washed with brine and dried over sodium sulfate. Llash column chromatography (ISCO, 12 g silica, 0-40% EA in Hex) to afford 1-5 (80.2 mg, 243.18 pmol, 75.71% yield) as the chloride.
[0157] Step 4. To 1-5 (19.07 mg, 57.81 pmol) in DML (.5 mL), CS2CO3 (56.51 mg, 173.43 pmol) followed by A (20 mg, 69.37 pmol) was added. The mixture was stirred at 23 °C for 4 hrs after which the reaction was diluted with DCM (5 mL) then syringe filtered. The filtrate was concentrated under reduced pressure. Llash column chromatography (ISCO, 12 g silica, 0- 80% ethyl acetate in hexanes) to afford 1-6 (41.8 mg, 71.87 pmol, assumed quantitative with a minor impurity).
[0158] Step 5. To 1-6 (41.8 mg, 71.87 pmol) in MeOH (0.5 mL) and THE (2 mL), 2M aqueous
LiOH (1.72 mg, 71.87 pmol, 4 mL) was added. The mixture was stirred at 70 °C for 24 hrs.
The reaction was cooled and diluted with DCM (5 mL) then cooled to -20°C. The mixture was quenched with 2M HC1 solution (4.1 mL) until slightly acidic by pH paper and the layers were partitioned. The aqueous layer was extracted again with DCM (2 x 5 mL). The combined organic layer was washed with brine, dried over Na2SC>4, then concentrated under reduced pressure. The obtained crude was dissolved in DCM (3 mL) and 4M HC1 in 1, 4-dioxane (2.62 mg, 71.86 pmol, 2 mL) was added and reaction was stirred at 22 °C for 1.5 hr. The reaction was concentrated to dryness under reduced pressure. The residue was dissolved in anhydrous DCM (7.06 mL) and Hunig's base (92.89 mg, 718.69 pmol, 125.18 pL) was added followed by FDPP (41.42 mg, 107.80 pmol) in one portion and stirred at 22 °C for 2.5 hr. The reaction was quenched with 2M Na2CC>3 solution (5 mL) and stirred vigorously for 5 minutes. The layers were separated, and the aqueous layer was extracted again with DCM (2 x 10 mL). The combined organic layer was washed with brine, dried over Na2SC>4, then concentrated under reduced pressure. Flash column chromatography (ISCO, 12 g silica, 0-10% methanol in DCM) to afford compound 1 (14.5 mg, 33.30 pmol, 46.33% yield).
General Method C
Preparation of (3aR,llS,13S,21aS)-7-Fluoro-13-methyl-2,3,3a,ll,12,13,14,21a-octahydro- lH,5H,15H-ll,13-methano-18,20-(metheno)cyclopenta[5,6][l,4]oxazino[3,4- j]pyrazolo[4,3-g][l,5,9,ll]benzoxatriazacyclotetradecin-15-one (2)
Figure imgf000044_0001
[0159] To 2-1 (5 g, 35.69 mmol) in THF (100 mL) was added Hunig's base (18.45 g, 142.74 mmol, 24.86 mL). Cooled to -78 °C and MOM chloride (5.75 g, 71.37 mmol, 5.42 mL) was added. Stirred as temperature increase from -78 to 22 °C over 60 hr. Diluted with aqueous NaHC03 solution (1:1 water: saturated NaHC03, lOOmL) and DCM (lOOmL), layers were partitioned and the aqueous layer extracted 2x with DCM (30mL). Combined organic layers was washed with brine and dried over sodium sulfate. Flash column chromatography (ISCO, 24g, 0-25% EA in Hex) to afford 2-2 (5.08 g, 27.58 mmol, 77.30% yield).
[0160] 2-2 (5.08 g, 27.58 mmol) was dissolved in methanol (137.92 mL) and cooled to 0 °C in ice bath. NaBH4 (2.09 g, 55.17 mmol) was added slowly under argon and the mixture was stirred as temperature increases over 5 hr. Quenched with water (20mL) and volatiles were removed under reduced pressure to ~ 1/3 of its volume. Diluted with water (50mL) and EA (lOOmL) and the layers were partitioned in a separatory funnel. Aqueous layer was extracted twice more with EA (2x50mL). The combined organic layer was washed with brine and dried over sodium sulfate. Purified by flash column chromatography (ISCO, 120g, 0-60% EA in Hexanes) to afford 2-3 (4.77 g, 25.62 mmol, 92.88% yield) [0161] To 2-3 (4.77 g, 25.62 mmol) in DCM (121.66 mL) was added Hunig's base (13.25 g, 102.48 mmol, 17.85 mL). Cooled to 0 °C and mesyl chloride (3.23 g, 28.18 mmol, 2.18 mL) was added. Stirred as temperature increase to 0 to 22 °C over 18 hr. Quenched with 2M HCl(aq) (5mL) at 0 °C. Diluted with water and DCM (lOmL), layers partitioned, and the aqueous layer extracted 2x with DCM (5mL). Combined organic layers was washed with brine and dried over sodium sulfate. Flash column chromatography (120g, ISCO, 0-50% EA in Hex) to afford 2-4 (4.33 g, 21.16 mmol, 82.59% yield)
Figure imgf000045_0001
[0162] A (796.97 mg, 2.76 mmol) and CS2CO3 (2.39 g, 7.33 mmol) were combined in DMF (12.22 mL) and 2-4 (0.5 g, 2.44 mmol) was added. Stirred at ambient temperature for 1.5 hr. Diluted with DCM (200mL) and cooled in -20 °C freezer for a half hour, then filtered through a celite pad. Filtrate was transferred to a separatory funnel and 200mL of water added. Layers were partitioned and aqueous layer was extracted twice more with DCM (2xl00mL). The combined organic layer was back washed with water (150mL) and brine (lOOmL), then dried over sodium sulfate. Flash column chromatography (ISCO, 80g silica, 0-70% EA in Hexanes) to afford 2-5 (1.04 g, 2.28 mmol, 93.24% yield).
[0163] To a solution of 2-5 (1.04 g, 2.28 mmol) in anhydrous DCM (25 mL) was added HCl/4 M DIOXANE (4 M, 5.70 mL). Stirred for 16 hr at 22 °C, then concentrated to dryness under reduced pressure followed by high vacuum treatment. The obtained crude was purified by flash column chromatography (24g, ISCO, Gold, 20-80% EA in Hexanes) to afford 2-6 (939.63 mg, 2.28 mmol, 100.00% yield).
[0164] 2-6 (100 mg, 242.48 umol) was dissolved in DMF (1.21 mL) at room
temperature. CS2CO3 (237.01 mg, 727.43 umol) was added followed by 2-7 (103.42 mg, 290.97 umol). The mixture stirred at 60 °C for 18 hr. Reaction was diluted with dcm and the solution was filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography (ISCO, 12g, 10-50% ethyl acetate in hexanes) to afford 2-8 (110 mg, 184.67 umol, 76.16% yield). [0165] Compound 2 (37.6 mg, 83.65 umol, 45.32% yield) was prepared from 2-8 using General Method B, Step 5.
Figure imgf000046_0001
[0166] Biologic assays
[0167] In-Vitro Assays
[0168] Materials and Methods
[0169] Cell lines and cell culture:
[0170] Human medulla thyroid carcinoma cell line TT (containing RET C634W mutation) and acute myelogenous cell line KG-1 with FGFR10P2-FGFR1 fusion FGFR 1 gene were purchased from ATCC. Human colon cancer cell line KM12 (containing TPM3-TRKA) was obtained from NCI.
[0171] Cloning and Ba/F3 stable cell lines creation
[0172] The EMF4-AFK gene (variant 1) was synthesized at GenScript and cloned into pCDH- CMV-MCS-EFl-Puro plasmid (System Biosciences, Inc). Ba/F3-EMF4-AFK wild type were generated by transducing Ba/F3 cells with lenti virus containing EMF4-AFK wild type. Stable cell lines were selected by puromycin treatment, followed by IF-3 withdrawal. Briefly, 5 x 106 Ba/F3 cells were transduced with lentivirus supernatant in the presence of 8 pg/mF protamine sulfate. The transduced cells were subsequently selected with 1 pg/mF puromycin in the presence of IF3 -containing medium RPMI1640, plus 10% FBS. After 10-12 days of selection, the surviving cells were further selected for IF3 independent growth. [0173] The KIF5B-RET gene was synthesized at GenScript and cloned into pCDH-CMV- MCS-EFl-Puro plasmid (System Biosciences, Inc). KIF5B-RET point mutation V804M and G810R were generated at GenScript by PCR and confirmed by sequencing. Ba/F3 KIF5B-RET wild type and mutants were generated by transducing Ba/F3 cells with lenti virus containing KIF5B-RET wild type or mutants. Stable cell lines were selected by puromycin treatment, followed by IL-3 withdrawal. Briefly, 5 x 106Ba/F3 cells were transduced with lentivirus supernatant in the presence of 8 pg/mL protamine sulfate. The transduced cells were subsequently selected with 1 pg/mL puromycin in the presence of IL3 -containing medium RPMI1640, plus 10% FBS. After 10-12 days of selection, the surviving cells were further selected for IL3 independent growth.
[0174] Cell proliferation assays:
[0175] Two thousand cells per well were seeded in 384 well white plate for 24 hrs, and then treated with compounds for 72 hours (37 °C, 5% CO2). Cell proliferation was measured using CellTiter-Glo luciferase-based ATP detection assay (Promega) following the manufactures’s protocol. IC50 determinations were performed using GraphPad Prism software (GraphPad, Inc., San Diego, CA).
[0176] Data and Results:
[0177] Anti-cell proliferation activity
Figure imgf000047_0001

Claims

WHAT IS CLAIMED IS:
1. A compound of the formula I
Figure imgf000048_0001
wherein
each R1 and R2 is independently H, deuterium, halogen, C1-C6 alkyl, Ci-Ce alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Cio aryl, mono- or bicyclic heteroaryl, -ORa, -OC(O)Ra, -OC(O)Ra, -OC(O)NRaRb, -OS(O)Ra, -OS(O)2Ra, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -OS(O)NRaRb, -OS(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)0Rb, -NRaC(O)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)0Ra, -C(O)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)0Ra, -P(O)20Ra, -CN, or -N02, wherein each hydrogen atom in C1-C6 alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered
heterocycloalkyl, C6-Cio aryl, and mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, Ci-Ce haloalkyl, -ORe, -OC(O)Re,
-OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)0Rf,
-NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)0Re, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)0Re, -P(O)20Re, -CN, or -N02;
each R3 is independently H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re,
-OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)0Rf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)0Re, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf,
-P(O)NReRf, -P(O)2NReRf, -P(O)0Re, -P(O)20Re, -CN, or -N02;
each R4 and R5 is independently hydrogen, deuterium, halogen, -ORc, -OC(O)Rc, -OC(O)NRcRd, -OC(=N)NRcRd, -OS(O)Rc, -OS(O)2Rc, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)Rc, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -NRcC(O)0Rd,
-NRcC(O)NRcRd, -NRcC(=N)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd,
-NRcS(O)2NRcRd, -C(O)Rc, -C(O)0Rc, -C(O)NRcRd, -C(=N)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)0Rc, -P(O)20Rc, -CN, -N02, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-Cio aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, mono- or bicyclic heteroaryl, Cs-Cs cycloalkyl, or 5- to 8-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, Ci-Ce haloalkyl, -ORe, -OC(O)Re,
-OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)0Rf,
-NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)0Re, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)0Re, -P(O)20Re, -CN, or -N02;
R6 is H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, -ORe, -SRe, or -NReRf;
each R7 is independently hydrogen or deuterium,
R8 and R9 together with the carbons which they are attached combine to form a C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-Cio aryl, or 5- to 7-membered heteroaryl; wherein each hydrogen atom in C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 7-membered heteroaryl is independently optionally substituted by deuterium, halogen, -ORe, -OC(O)Re, -OC(O)NReRf, -OC(=N)NReRf, -OS(O)Re, -OS(O)2Re,
-OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Re, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)0Rf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)0Re, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf,
-P(O)NReRf, -P(O)2NReRf, -P(O)0Re, -P(O)20Re, -CN, or -N02;
each Ra, Rb, Rc, Rd, Re, and Rf is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 7- membered heteroaryl;
m is 1 or 2; and
n is 1, 2, or 3; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.
4. The compound of claim 1 , having the formula II
Figure imgf000050_0001
or a pharmaceutically acceptable salt thereof.
5. The compound of any one of the preceding claims, having the formula III
Figure imgf000050_0002
III
or a pharmaceutically acceptable salt thereof.
6. The compound of any one of the preceding claims, having the formula IV
Figure imgf000051_0001
IV
or a pharmaceutically acceptable salt thereof.
7. The compound of any one of claims 1 to 3, having the formula V
Figure imgf000051_0002
or a pharmaceutically acceptable salt thereof.
8. The compound of any one of claims 1 to 3 or 7, having the formula VI
Figure imgf000052_0001
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected form the group consisting of
Figure imgf000052_0002
10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected form the group consisting of
Figure imgf000053_0001
11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected form the group consisting of
Figure imgf000054_0001
12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected form the group consisting of
Figure imgf000055_0001
13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected form the group consisting of
Figure imgf000056_0001
14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected form the group consisting of
Figure imgf000057_0001
15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R8 and R9 combine to form a 4-, 5- or 6-membered cycloalkyl, wherein each hydrogen atom in the 5- or 6-membered cycloalkyl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OCi-C6 alkyl, -NH2, -OC(O)Ci-C6 alkyl, -OC(O)N(Ci-Ce alkyl)2, - OC(O)NH(CI-C6 alkyl), -OC(O)NH2, -OC(=N)N(Ci-Ce alkyl)2, -OC(=N)NH(CI-C6 alkyl), - OC(=N)NH2, -OS(O)Ci-Ce alkyl, -OS(O)2Ci-C6 alkyl, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, -NHC(O)CI-C6 alkyl, -N(Ci-Ce alkyl)C(O)Ci-C6 alkyl, -NHC(O)NH2, -NHC(O)NH(Ci-C6 alkyl), -N(Ci-Ce alkyl)C(O)NH2, -N(Ci-Ce alkyl)C(O)NH(Ci-C6 alkyl), -NHC(O)N(Ci-C6 alkyl)2, -N(Ci-Ce alkyl)C(O)N(Ci-C6 alkyl)2, -NHC(O)OCi-C6 alkyl, -N(Ci-Ce alkyl)C(O)OCi- C6 alkyl, -NHC(O)0H, -N(CI-C6 alkyl)C(O)0H, -NHS(O)Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, - N(Ci-Ce alkyl)S(O)Ci-C6 alkyl, -N(CI-C6 alkyl)S(O)2Ci-C6 alkyl, -NHS(O)NH2,
-NHS(O)2NH2, -N(CI-C6 alkyl)S(O)NH2, -N(CI-C6 alkyl)S(O)2NH2, -NHS(O)NH(Ci-C6 alkyl), -NHS(O)2NH(CI-C6 alkyl), -NHS(O)N(Ci-C6 alkyl)2, -NHS(O)2N(Ci-C6 alkyl)2, -N(Ci-Ce alkyl)S(O)NH(Ci-C6 alkyl), -N(Ci-Ce alkyl)S(O)2NH(Ci-C6 alkyl), -N(Ci-Ce alkyl)S(O)N(Ci- C6 alkyl)2, -N(Ci-Ce alkyl)S(O)2N(Ci-C6 alkyl)2, -C(O)Ci-C6 alkyl, -C02H, -C(O)OCi-C6 alkyl, -C(O)NH2, -C(O)NH(CI-C6 alkyl), -C(O)N(Ci-C6 alkyl)2, -SCi-Ce alkyl, -S(O)Ci-C6 alkyl, -S(O)2Ci-C6 alkyl, -S(O)NH(Ci-C6 alkyl), -S(O)2NH(Ci-C6 alkyl), -S(O)N(Ci-Ce alkyl)2, -S(O)2N(CI-C6 alkyl)2, -S(O)NH2, -S(O)2NH2, -OS(O)N(Ci-C6 alkyl)2, -OS(O)2N(Ci-C6 alkyl)2, -OS(O)NH(Ci-C6 alkyl), -OS(O)2NH(Ci-C6 alkyl), -OS(O)NH2, -OS(O)2NH2, -P(Ci-C6 alkyl)2, -P(O)(Ci-C6 alkyl)2, C3-C6 cycloalkyl, or 3- to 7-membered heterocycloalkyl.
16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R8 and R9 combine to form a cyclobutane ring, cyclopentane ring, or cyclohexane ring.
17. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R8 and R9 combine to form a 3-, 4-, 5- or 6-membered heterocycloalkyl, wherein each hydrogen atom in the 3-, 4-, 5- or 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH2, -OC(O)Ci-C6 alkyl, -OC(O)N(CI-C6 alkyl)2, -OC(O)NH(Ci-C6 alkyl), -OC(O)NH2, -OC(=N)N(CI-C6 alkyl)2, -OC(=N)NH(CI-C6 alkyl), -OC(=N)NH2, -OS(O)Ci-C6 alkyl, -OS(O)2Ci-C6 alkyl, -NH(CI-C6 alkyl), -N(Ci-Ce alkyl)2, -NHC(O)Ci-C6 alkyl, -N(Ci-Ce alkyl)C(O)Ci-C6 alkyl, -NHC(O)NH2, -NHC(O)NH(CI-C6 alkyl), -N(CI-C6 alkyl)C(O)NH2, -N(Ci-Ce alkyl)C(O)NH(Ci-C6 alkyl), -NHC(O)N(CI-C6 alkyl)2, -N(Ci-Ce alkyl)C(O)N(Ci-C6 alkyl)2, -NHC(O)OCi-C6 alkyl, -N(Ci-Ce alkyl)C(O)OCi-Ce alkyl, -NHC(O)0H, -N(Ci-Ce alkyl)C(O)0H, -NHS(O)Ci-C6 alkyl, -NHS(O)2Ci-C6 alkyl, -N(Ci-Ce alkyl)S(O)Ci-C6 alkyl, -N(Ci-Ce alkyl)S(O)2Ci-C6 alkyl, -NHS(O)NH2, -NHS(O)2NH2, -N(CI-C6 alkyl)S(O)NH2, -N(Ci-Ce alkyl)S(O)2NH2,
-NHS(O)NH(CI-C6 alkyl), -NHS(O)2NH(Ci-C6 alkyl), -NHS(O)N(Ci-C6 alkyl)2,
-NHS(O)2N(CI-C6 alkyl)2, -N(CI-C6 alkyl)S(O)NH(Ci-C6 alkyl), -N(Ci-Ce alkyl)S(O)2NH(Ci- C6 alkyl), -N(Ci-Ce alkyl)S(O)N(Ci-C6 alkyl)2, -N(Ci-Ce alkyl)S(O)2N(Ci-C6 alkyl)2, -C(O)Ci- C6 alkyl, -C02H, -C(O)OCi-C6 alkyl, -C(O)NH2, -C(O)NH(Ci-C6 alkyl), -C(O)N(Ci-Ce alkyl)2, -SCi-Ce alkyl, -S(O)Ci-C6 alkyl, -S(O)2Ci-C6 alkyl, -S(O)NH(Ci-Ce alkyl), -S(O)2NH(Ci-C6 alkyl), -S(O)N(CI-C6 alkyl)2, -S(O)2N(Ci-C6 alkyl)2, -S(O)NH2, -S(O)2NH2, -OS(O)N(Ci-C6 alkyl)2, -OS(O)2N(Ci-C6 alkyl)2, -OS(O)NH(Ci-C6 alkyl), -OS(O)2NH(Ci-C6 alkyl),
-OS(O)NH2, -OS(O)2NH2, -P(CI-C6 alkyl)2, -P(O)(Ci-C6 alkyl)2, C -C6 cycloalkyl, or 3- to 7- membered heterocycloalkyl.
18. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R3, when present, is H or C1-C6 alkyl.
19. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R4 is H or deuterium.
20. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R1 is H or deuterium.
21. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R2 is H.
22. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R7 is H.
23. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R5 is F.
24. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6 is H.
25. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the
Figure imgf000059_0001
26. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and optionally at least one diluent, carrier or excipient.
27. A method of treating cancer comprising administering to a subject in need of such treatment an effective amount of at least one compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof.
28. Use of a compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of cancer.
29. Use of a compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, for treating cancer.
30. A method of inhibiting RET or SRC, comprising contacting a cell comprising one or more of such kinases with an effective amount of at least one compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, and/or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.
31. A compound of any one of claims 1 to 25 for use in treating cancer in a patient.
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