WO2024149214A1 - Composés bifonctionnels pour dégrader kras-12d par l'intermédiaire de la voie ubiquitine-protéasome - Google Patents

Composés bifonctionnels pour dégrader kras-12d par l'intermédiaire de la voie ubiquitine-protéasome Download PDF

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WO2024149214A1
WO2024149214A1 PCT/CN2024/071245 CN2024071245W WO2024149214A1 WO 2024149214 A1 WO2024149214 A1 WO 2024149214A1 CN 2024071245 W CN2024071245 W CN 2024071245W WO 2024149214 A1 WO2024149214 A1 WO 2024149214A1
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compound
hydrogen
pharmaceutically acceptable
alkylene
acceptable salt
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PCT/CN2024/071245
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Jiping Fu
Yongfeng SUN
Haiqiang ZENG
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Nikang Therapeutics, Inc.
Shanghai Blueray Biopharma Co., Ltd.
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Publication of WO2024149214A1 publication Critical patent/WO2024149214A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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
    • C07D498/22—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 four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure provides certain bifunctional compounds that cause degradation of K-ras G12D via ubiquitin proteasome pathway and are therefore useful for the treatment of diseases mediated by K-ras G12D. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
  • Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRAS) gene is a prevalent oncogene that encodes a small GTPase transductor protein called K-Ras.
  • K-Ras can serve as a molecular switch by cyling between active GTP-bound and inactive GDP-bound forms (see Science 2001; 294: 1299–304. ) .
  • K-Ras signaling is activated by RAS guanine nucleotide exchange factors (GEFs) , e.g., Son of Sevenless homologue (SOS) protein, that facilitate the GDP to GTP exchange of K-Ras (see Curr Biol 2005; 15: 563–74. ) .
  • GEFs RAS guanine nucleotide exchange factors
  • SOS Son of Sevenless homologue
  • GAPs GTPase-activating proteins
  • K-Ras plays a crucial role in the regulation of cell proliferation, differentiation and survival by signaling through several major downstream pathways, including the MAPK, the PI3K and the Ral-GEFs pathways (see Lung Cancer 2018; 124: 53–64) , among them the MAPK pathway is the best characterized (see Mol. Cell Biol. 1995; 15: 6443–6453. ) .
  • K-Ras-GTP binds to and activates RAF kinases, which phosphorylates MEK and subsequently phosphorylates ERK. Phospho-ERK can further activate downstream cytosolic proteins and which then translocate to the nucleus to drive the expression of diverse genes, propagating the growth signal.
  • PI3K pathway is also involved in RAS-mediated tumorigenesis (see Cell 2007; 129: 957–968. ) .
  • PI3K phosphorylates PIP2 to form PIP3, activates PDK1 and then phosphorylates AKT.
  • pAKT yields phosphorylation of several physiological substrates, e.g., mTOR, FOXO and NF- ⁇ B that promote metabolism, cell-cycle progression, resistance to apoptosis, cell survival and migration.
  • the Ral-GEFs signaling pathway plays a key role in RAS-mediated oncogenesis as well (see Proc. Natl. Acad. Sci. U.S.A.
  • RALGDS The K-Ras effector, RALGDS, stimulates the RAS family RAL-A/B small GTPases for the subsequent signaling cascades. RALGDS can also promote the JNK pathway to stimulate transcription of pro-survival and cell-cycle progression genes for cell proliferation and survival.
  • KRAS gene is the most frequently mutated oncogene in human cancer. KRAS mutations are associated with poor clinical outcome and found at high frequency in pancreatic cancer ( ⁇ 90%) , colorectal cancer ( ⁇ 44%) and non-small-cell lung cancer (NSCLC) ( ⁇ 29%) (see Cancer Discov. 2021; 11: 1–16) . KRAS mutations are also present in breast cancer, liver cancer, biliary tract malignancies, endometrial cancer, cervical cancer, bladder cancer and myeloid leukemia.
  • K-Ras G12C offers special opportunity, because it harbors a non-native cysteine residue, which can act as nucleophile and therefore can be targeted by covelent attachment.
  • AMG510 which is an approved drug for treating K-Ras G12C driven cancers
  • K-Ras G12C covelent inhibitors including MRTX849, JNJ-74699157 and LY349944631, are in clinical trials for treating cancer patients with KRAS G12C mutation (see ACS Cent. Sci. 2020; 6: 1753-1761) .
  • K-Ras G12D mutant Compared to K-ras G12C mutant, since K-Ras G12D mutant, does not contain non-native cysteine residue and cycle through inactive state at extremely low rate, thus making K-Ras G12D mutant specific drug discovery more challenging.
  • K-Ras G12D protein As an alternative to inhibition, removal of K-Ras G12D protein would eliminate K-Ras G12D activity as well as any protein interaction or scaffolding function of K-Ras G12D. Accordingly, there is a need for bifunctional molecules that could recruit K-Ras G12D to a ubiquitin ligase and thereby causing ubiquitylation and proteasomal degradation of K-Ras G12D.
  • the present disclosure fulfills this and related needs.
  • X is N or CH
  • Z is CH 2 , O or NH
  • one of m and n is 1 or 2, and the other of m and n is 1, 2, or 3;
  • p is 1, 2 or 3 when Z is O or NH; and p is 0, 1, or 2, when Z is CH 2 ;
  • q 0, 1, 2, 3;
  • R 1 is independently hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxylalkyl, alkoxyalkyl, cyano, or cyanomethyl, provided R 1 is not attached to the ring -NH-;
  • R 1a is independently hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxylalkyl, or alkoxyalkyl, provided R 1a is not attached to the ring -NH-; or
  • R 1b is hydrogen, deuterium, alkyl, alkylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, cyanomethyl, cyanoethyl, or 2-cyanovinyl, provided R 1b is not attached to the ring -NH-;
  • R 1c is hydrogen or alkyl, provided R 1c is not attached to the ring -NH-; or
  • R 1b and R 1c when attached to the same carbon of the ring, they can combine to form cycloalkylene optionally substituted with alkyl, halo, alkoxy, or hydroxy;
  • R 2 is hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, or cyano;
  • R 3 is hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, cycloalkyl, cycloalkyloxy, hydroxy, or cyano;
  • R 4 is -Q 2 -R 6 where Q 2 is a bond, O, NH, N (alkyl) , S, or a bond to L; and R 6 is absent when Q 2 is a bond to L, heterocyclylalkyl, fused heterocyclylalkyl, bicyclic heterocyclyl, or bicyclic heterocyclylalkyl, wherein:
  • R 7 and R 9 are independently hydrogen, deuterium, alkyl, halo, or haloalkyl
  • R 8 and R 10 are independently a bond to L, cyano, cycloalkyl, cycloalkylalkyl, heterocyclyl, phenyl, or heteroaryl; or independently of each other, R 7 and R 8 and R 9 and R 10 together with the carbon atom to which they are attached form cycloalkylene optionally substituted with alkyl, halo, alkoxy, or hydroxy;
  • R b and R e are independently a bond to L, hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, or – (Q 1 ) n1 -OC (O) NR 11 R 12 , wherein n1 is 0 or 1; Q 1 is alkylene, R 11 is hydrogen, deuterium, alkyl, deuterioalkyl, haloalkyl, haloalkoxyalkyl, or alkoxyalkyl, and R 12 is hydrogen, alkyl, deuterioalkyl, cycloalkyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, or heterocyclyl substituted with R g and R h independently selected from hydrogen, alkyl, halo, alkoxy, haloalkyl, and haloalkoxy; or R 11 and R 12 together with the
  • R c and R f are independently hydrogen, deuterium, alkyl, halo, alkoxy, alkoxyalkyl, or hydroxy;
  • R c1 and R f1 are independently selected from hydrogen, deuterium, alkyl, and halo;
  • Degron is an E3 ubiquitin ligase ligand selected from:
  • W a is bond, O, S, or alkylene
  • Y a is CH or N
  • Z a is a bond, -CH 2 -, -NH-, O, or -NHC (O) -where NH of -NHC (O) -is attached to Y a ;
  • ring A in the group of formula (i) is a ring of formula (a) , (b) , or (c) :
  • R aa , R bb , R cc , and R dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano;
  • R 24 is hydrogen or alkyl
  • ring B is phenylene, cyclylaminylene, a 5-or 6-membered monocyclic heteroarylene, or a 9-or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains one to three nitrogen ring atoms and further wherein the phenylene, cyclylaminylene, and heteroarylene are independently substituted with R jj and R kk independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; and
  • each R 15 is alkyl, hydroxyalkyl, cycloalkyl or heterocyclyl (wherein cycloalkyl and heterocyclyl are substituted with R mm selected from hydrogen, alkyl, halo, haloalkyl, alkoxyl, haloalkoxyl, cyano, alkylcarbonyl, alkylcarbonylamino) , or -COR 25 (where R 25 is alkyl, hydroxalkyl, cycloalkyl or heterocyclyl wherein cycloalkyl and heterocyclyl are substituted with R nn selected from hydrogen, alkyl, halo, haloalkyl, alkoxyl, haloalkoxyl, cyano, alkylcarbonyl, and alkylcarbonylamino) ;
  • each R 16a is hydrogen or alkyl
  • each R 16b is hydrogen, alkyl, haloalkyl, cycloalkyl (optionally substituted with alkyl, halo, or hydroxy) , or hydroxyalkyl;
  • R 17 is heteroaryl optionally substituted with alkyl, haloalkyl, alkoxyalkyl, or cyano;
  • R 17a is hydrogen, alkyl, or halo
  • R 18 and R 18a are independently hydrogen or alkyl; or R 18 and R 18a together with the carbon can form a cycloalkylene;
  • R 19 is alkyl, cycloalkyl, heteroaryl, or heterocyclyl (wherein cycloalkyl, heteroaryl, and heterocyclyl are substituted with R oo selected from hydrogen, alkyl, halo, haloalkyl, alkoxyl, oxo, and cyano) or fused heterocyclyl; and
  • each R 16 and R 20 is hydrogen, alkyl, haloalkyl, or cycloalkyl wherein cycloalkyl can be substituted with alkyl, or halo;
  • R 21 , R 21a , R 21b , R 21c , R 21d , R 21e , and R 21f are hydrogen or alkyl
  • L is -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -where:
  • Z 1 is a bond, alkylene, -NR”-, -O-, - (alkylene-O) -, -C (O) -, -OC (O) -, - (alkylene-OC (O) -) , -S (O) 2 -, -NR’ (CO) -, -C (O) NR-, - (alkylene) -cycloalkylene--cycloalkylene- (alkylene) -, or heterocyclylene;
  • Z 2 is a bond, alkylene, -NR”-, -O-, -C (O) -, -S (O) 2 -, -NR’ (CO) -, -C (O) NR-, phenylene, monocyclic heteroarylene, or heterocyclylene, - (alkylene) -heterocyclylene-, -heterocyclylene- (alkylene) -, where each ring is substituted with R pp and R qq independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy;
  • Z 3 is a bond, alkylene, alkynylene, - (alkylene-NR”) -, - (NR”-alkylene) -, -O-, -C (O) -, -OC (O) -, -S (O) 2 -, -NR”-, - (O-alkylene) d -, - (alkylene-O) d -, cycloalkylene, spiro cyclolalkylene, phenylene, heteroarylene, heterocyclylene, fused heterocyclylene, bridged heterocyclylene, bicyclic heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R rr and R ss independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;
  • Z 4 is a bond, alkylene, alkynylene, -O-, -NR”-, -C (O) -, -S (O) 2 -, -C (O) NR-, -NR’ (CO) -, -S (O) 2 NR-, -NR’S (O) 2 -, - (O-alkylene) c -, - (alkylene-O) c -, cycloalkylene, spiro cyclolalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, spiro heterocyclylene, - (alkylene) -phenylene-, -phenylene- (alkylene) -, - (alkylene) -heteroarylene-, -heteroarylylene- (alkylene) -, - (alkylene)
  • Z 5 is a bond, alkylene, alkynylene, -O-, -NR”-, -C (O) -, -C (O) NR’-, -NR’ (CO) -, - (O-alkylene) b -, - (alkylene-O) b -, -O (CH 2 ) 7 -, -O (CH 2 ) 8 -, cycloalkylene, -phenylene- (alkylene) -, - (alkylene) -phenylene-, or heterocyclylene, where each ring is substituted with R vv and R ww independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy;
  • Z 6 is a bond, alkylene, -NR”-, -C (O) NR-, -NR’ (CO) -, -S (O) 2 NR-, -NR’S (O) 2 -, - (O-alkylene) a -, - (alkylene-O) a -, phenylene, monocyclic heteroarylene, or heterocyclylene, where each ring is substituted with R xx and R yy independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; and
  • each alkylene of -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 - is independently one to twelve carbon atoms
  • each R, R’ and R” is independently hydrogen or alkyl
  • each a, b, c, and d is independently an integer selected from 1 to 6, and each alkylene of -Z 1 -, -Z 2 -, -Z 3 -, -Z 4 -, -Z 5 -and -Z 6 -is substituted with R zz and R zz1
  • R zz is hydrogen or deuterium and R zz1 is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy,
  • a pharmaceutical composition comprising a compound of Formula (I) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • a method of inhibiting K-Ras in particular K-Ras G12D, in a cell, comprising contacting the cell with a compound of Formula (I) (or any of the embodiments thereof described herein) .
  • the contacting is in vitro.
  • the contacting is in vivo.
  • a method of inhibiting cell proliferation in vitro or in vivo comprising contacting a cell with a compound of Formula (I) (or any of the embodiments thereof described herein) or a pharmaceutical composition thereof as disclosed herein.
  • the contacting is in vitro.
  • the contacting is in vivo.
  • a method of treating cancer in a patient preferably the patient is in need of such treatment, which method comprises administering to the patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a a pharmaceutical composition thereof as disclosed herein.
  • a method of treating cancer associated with K-Ras, in particular K-Ras G12D, in a patient, preferably the patient is in need of such treatment comprises administering to the patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a a pharmaceutical composition thereof as disclosed herein.
  • a compound of Formula (I) (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use as a medicament.
  • the medicament is useful for the treatment of cancer.
  • a compound of Formula (I) (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use as a therapy.
  • a compound of Formula (I) (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use in the treatment of cancer.
  • a compound of Formula (I) (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use in the treatment of cancers associated with KRas, in particular cancers associated with K-Ras G12D.
  • a compound of Formula (I) (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use in inhibiting K-Ras, in particular K-Ras G12D.
  • any of the aforementioned aspects involving the treatment of cancer are further embodiments comprising administering the compound of Formula (I) (or any embodiments thereof disclosed herein) , or a pharmaceutically acceptable salt thereof in combination with at least one additional anticancer agent.
  • the agents can be administered simultaneously or sequentially.
  • Alkyl means a linear or branched saturated monovalent hydrocarbon radical of one to six carbon atomsunless stated otherwise, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like.
  • Alkylene means a linear or branched saturated divalent hydrocarbon radical of one to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
  • Alkenyl means a linear or branced monovalent hydrocarbon radical of two to six carbon atoms containing a double bond e.g., ethenyl, propenyl, 2-propenyl, butenyl, pentenyl, and the like.
  • Alkynyl means a linear or branched monovalent hydrocarbon radical of two to six carbon atoms containing a triple bond e.g., ethynyl, propynyl, 2-propynyl, butynyl, and the like.
  • Alkynylene means a linear or branched unsaturated divalent hydrocarbon radical of two to six carbon atoms containing a triple bond, e.g., and the like.
  • Alkylamino means a –NHR radical where R is alkyl as defined above, e.g., methylamino, ethylamino, and the like.
  • Alkylthio means a -SR radical where R is alkyl as defined above, e.g., methylthio, ethylthio, and the like.
  • Alkylsulfonyl means a -SO 2 R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.
  • Alkoxy means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.
  • Alkoxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group, such as one or two alkoxy groups, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.
  • the alkylidene group, methylidenyl is enclosed by the box which is indicated by the arrow.
  • alkoxyalkylidenyl group methoxethylidenyl
  • box which is indicated by the arrow.
  • Alkylcarbonyl means a –C (O) R radical where R is alkyl as defined above e.g., -C (O) CH 3 , and the like.
  • Alkoxycarbonyl means a –C (O) OR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.
  • Amino means a —NH 2 radical.
  • Aryl means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl.
  • Alkyl means a – (alkylene) -R radical where R is aryl as defined above. Examples include, but are not limited to, benzyl, phenethyl, and the like.
  • Bicyclic heterocyclyl means a saturated monovalent fused bicyclic ring of 8 to 12 ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S (O) n , where n is an integer from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a –CO-group. More specifically the term bicyclic heterocyclyl includes, but is not limited to, hexahydro-1H-pyrrolizinyl, and the like.
  • Bicyclic heterocyclylalkyl means a – (alkylene) -R radical where R is bicyclic heterocyclyl as defined above. Examples include, but are not limited to, hexahydro-1H-pyrrolizinylmethyl, hexahydro-1H-pyrrolizinylethyl, and the like.
  • Bicyclic heterocyclylene means a saturated or unsaturated divalent fused bicyclic group of 9 to 12 ring atoms in which one, two, or three ring atoms are heteroatoms independently selected from N, O, and S (O) n , where n is an integer selected from 0 to 2 inclusive, the remaining ring atoms being carbon, unless stated otherwise. Additionally, one or two ring carbon atoms of the bicyclic heterocyclylene ring can optionally be replaced by a –CO-group. More specifically the term bicyclic heterocyclylene includes, but is not limited to, hexahydrofuro [3, 2-b] furan-3, 6-diyl, and the like.
  • the heterocyclylene ring When the heterocyclylene ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic.
  • the bicyclic heterocyclylene When the bicyclic heterocyclylene contains at least one nitrogen atom, the bicyclic heterocyclylene may be referred to herein as bicyclic cyclylaminylene.
  • “Bridged heterocyclyl” means a saturated bicyclic ring having 5 to 9 ring atoms in which two non-adjacent ring atoms are linked by a (CRR’) n group where n is 1 to 3 and R and R’ are independently H or methyl (also may be referred to herein as “bridging” group) and further wherein one or two ring atoms, including the atoms of the bridging group, are heteroatoms independently selected from N, O, and S (O) n , where n is an integer from 0 to 2. Examples include, but are not limited to, 6-oxa-3-azabicyclo [3.1.1] heptane-3-yl8-oxa-3-azabicyclo [3.2.1] octane-3-yl, and the like.
  • “Bridged heterocyclylene” means a saturated divalent bicyclic ring having 5 to 8 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CRR z ’) n group where n is an integer selected from 1 to 3 inclusive and R and R z ’ are independently H or methyl (also may be referred to herein as “bridging” group) and further wherein one or two ring carbon atoms, including an atom in the bridging group, is replaced by a heteroatom selected from N, O, and S (O) n , where n is an integer selected from 0 to 2 inclusive.
  • Bridged heterocyclylene is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano unless stated otherwise.
  • the bicyclic heterocyclylene may be referred to herein as bridged cyclylaminylene. Examples include, but are not limited to, 3, 8-diazabicyclo [3.2.1] octa-3, 8-diyl, and the like.
  • Cycloalkyl means a monocyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • Cycloalkylene means a monocyclic saturated divalent hydrocarbon radical of three to ten carbon atoms. Examples include, but are not limited to, 1, 1-cyclopropylene, 1, 1-cyclobutylene, 1, 1-cyclopentylene, and the like.
  • Cycloalkylalkyl means a – (alkylene) -R radical where R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyl cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.
  • Cycloalkyloxy or “cycloalkoxy” means a -OR radical where R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Cyanoalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with cyano e.g., cyanomethyl, cyanoethyl, and the like.
  • Cyanoalkynyl means an alkynyl radical as defined above where one of the hydrogen atom in the alkynyl chain is replace by a cyano. Examples include, but are not limited to, -C ⁇ C (CN) , -CH 2 C ⁇ C (CN) , and the like.
  • Cyclylaminylene means a saturated divalent monocyclic ring of 4 to 8 ring atoms in which one ring atom is nitrogen, the remaining ring atoms being C. More specifically, the term cyclylaminyl includes, but is not limited to, pyrrolidinylene, piperidinylene, homopiperidinylene, and the like.
  • Deuterioalkyl means alkyl as defined above that is substituted with one or two deuterium, e.g., CD 2 , CHD, and the like.
  • the alkylidene group, methylidenyl-d 2 is enclosed by the box which is indicated by the arrow.
  • Dialkylamino means a –NRR’ radical where R and R’ are independently alkyl as defined above, e.g., dimethylamino, methylethylamino, and the like.
  • fused cycloalkyl as used herein, means cycloalkyl as defined above where two adjacent ring atoms of the cycloalkyl ring are fused to two adjacent ring atoms of phenyl or a five or six membered heteroaryl, each as defined herein, unless stated otherwise.
  • the fused cycloalkyl can be attached at any atom of the ring.
  • Non limiting examples of the fused cycloalkyl include bicyclo [4.1.0] hepta-1, 3, 5-triene, bicyclo [4.2.0] octa-1, 3, 5-triene, and the like.
  • “Fused spirocycloalkyl” means spirocycloalkyl as defined herein where two adjacent ring atoms of the spiro cycloalkyl are fused to two adjacent ring atoms of a phenyl or a five or six membered heteroaryl, each as defined herein.
  • “Fused heterocyclyl” means a saturated monovalent monocyclic ring of 4 to 7 ring atoms having from one to three heteroatoms independently selected from N, O, and S (O) n where n is 0, one ring atoms can be -CO-, and the remaining ring atoms being carbon, and further wherein two adjacent ring atoms of the monocyclic ring are fused to two adjacent ring atoms of a cycloalkyl, phenyl or a five or six membered heteroaryl, each as defined herein, unless stated otherwise.
  • the nitrogen atom (s) are optionally oxidized optionally quaternized and one or two carbon atoms of the fused ring atoms in the saturated monocyclic ring includes the two common ring vertices shared with the fused phenyl or five or six membered heteroaryl.
  • the fused heterocyclyl can be attached at any atom of the ring.
  • Non limiting examples of the fused heterocycloalkyl include 2, 3-dihydrobenzo [b] [1, 4] -dioxinyl, 2-oxabicyclo [3.1.0] hexanyl, indolin-2-one-1-yl, indolinyl, and the like.
  • “Fused heterocyclylalkyl” as used herein, means a – (alkylene) -R radical where R is fused heterocyclyl, as defined herein.
  • “Fused heterocyclylene” as used herein refers to a divalent bicyclic ring in which two adjacent ring atoms of a saturated monocyclic ring of 4 to 7 ring atoms having one or two heteroatoms independently selected from N, O, and S (O) n (where n is 0, 1, or 2) and the remaining ring atoms being carbon, are fused to two adjacent ring members of a phenyl or a five or six membered heteroaryl, each as defined herein, unless stated otherwise.
  • the nitrogen atom is optionally oxidized or quaternized.
  • the fused heterocyclylene can be attached at any two atoms of the ring.
  • fused heterocyclylene When the 4 to 7 membered saturated monocyclic ring contains at least one nitrogen atom, the fused heterocyclylene may be referred to herein as fused cyclylaminylene.
  • Representative examples include, but are not limited to, 1, 2, 3, 4-tetrahydroquinolin-1, 4-diyl, 3, 4-dihydro-2H-benzo [b] [1, 4] oxazin-5, 8-diyl, and the like.
  • “Fused heteroaryl” means fused bicyclic heteroaryl, as defined herein, where two adjacent ring atoms of the heteroaryl ring are fused to two adjacent ring atoms of phenyl.
  • Halo means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.
  • Haloalkyl means alkyl radical as defined above, which is substituted with one or more halogen atoms, e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH 2 Cl, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -CF (CH 3 ) 2 , and the like.
  • halogen atoms e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH 2 Cl, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -CF (CH 3 ) 2 , and the like.
  • fluoroalkyl When the alkyl is substituted with only fluoro, it can be referred to in this Application
  • the group pointed to by the arrow is the haloalkylidenyl group, difluoromethylidenyl.
  • Haloalkoxy means a –OR radical where R is haloalkyl as defined above e.g., -OCF 3 , -OCHF 2 , and the like.
  • R is haloalkyl where the alkyl is substituted with only fluoro, it is referred to in this Application as fluoroalkoxy.
  • Haloalkoxyalkyl means a – (alkylene) OR radical where R is haloalkyl as defined above, e.g., trifluoromethoxymethyl, difluoromethoxymethyl, and the like.
  • Haloalkylcarbonyl means a –C (O) R radical where R is haloalkyl as defined above e.g., -C (O) CF 3 , -C (O) CHF 2 , and the like.
  • Hydroalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2, 3-dihydroxypropyl, 1- (hydroxymethyl) -2-hydroxyethyl, 2, 3-dihydroxybutyl, 3, 4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl, preferably 2-hydroxyethyl, 2, 3-dihydroxypropyl, and 1- (hydroxymethyl) -2-hydroxyethyl.
  • Heteroalkyl mean alkyl radical as defined above wherein one or two carbon atoms are replaced by O, NR (R is H or alkyl) , or S, provided the heteroalkyl group is attached to the remainder of the molecule via a carbon atom, e.g., methoxymethyl, methylethylaminoethyl, and the like.
  • Heteroaryl means a monovalent monocyclic or fused bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more, (in one embodiment, one, two, or three) , ring atoms are heteroatom selected from N, O, and S, the remaining ring atoms being carbon.
  • Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.
  • the terms “heteroaryl” and “aryl” are mutually exclusive.
  • heteroaryl ring contains 5-or 6 ring atoms it is also referred to herein as 5-or 6-membered heteroaryl.
  • heteroaryl ring is fused bicyclic aromatic radical 9-or 10 ring atoms it is also referred to herein as fused bicyclic heteroaryl.
  • Heteroaralkyl means a - (alkylene) -R radical where R is heteroaryl as defined above, e.g., pyridinylmethyl, and the like.
  • R is heteroaryl as defined above, e.g., pyridinylmethyl, and the like.
  • heteroaryl ring in heteroaralkyl contains 5-or 6 ring atoms it is also referred to herein as 5-or 6-membered heteroaralkyl.
  • Heteroarylene means a divalent heteroaryl radical as defined above, unless stated otherwise. Representative examples include, but are not limited to, benzimidazoldiyl e.g., benzimidazole-1, 5-diyl, and the like.
  • the heteroarylene ring contains 5 or 6 ring atoms and is a monocyclic ring it is also referred to herein as monocyclic heteroarylene or as 5-or 6-membered monocyclic heteroarylene e.g., pyrazolyl-1.4-diyl.
  • the heteroarylene ring contains 9 or 10 ring atoms and is a fused bicyclic ring, it is also referred to herein as 9-or 10-membered fused bicyclic heteroarylene.
  • Heterocyclyl means a saturated monovalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S (O) n , where n is an integer from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a –CO-group.
  • heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydro-pyranyl, thiomorpholino, and the like.
  • heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocycloamino and is a subset of the heterocyclyl group.
  • Heterocyclylalkyl or “heterocycloalkyl” means a – (alkylene) -R radical where R is heterocyclyl ring as defined above e.g., tetraydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.
  • Heterocyclylene means a saturated divalent monocyclic group of 4 to 6 ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S (O) n , where n is an integer selected from 0 to 2 inclusive, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclylene ring can optionally be replaced by a –CO-group. More specifically, the term heterocyclylene includes, but is not limited to, piperidin-1, 4-diyl, azetidin-1, 3-diyl, and the like.
  • Optionally substituted aryl means aryl as defined above, that is optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, alkylsulfonyl, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, and cyano.
  • substituents independently selected from alkyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, alkylsulfonyl, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, and cyano.
  • aryl is phenyl
  • optionally substituted aryl is referred to herein as optionally substituted phenyl.
  • Optionally substituted heteroaryl means heteroaryl as defined above that is optionally substituted with one, two, or three substituents independently selected from alkyl, alkylsulfonyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, and cyano.
  • Optionally substituted heterocyclyl means heterocyclyl as defined above that is optionally substituted with one, two, or three substituents independently selected from alkyl, alkylsulfonyl, alkylcarbonyl, hydroxyl, cycloalkyl, cycloalkylalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, cyanoalkyl, halo, haloalkyl, haloalkoxy, and cyano, unless stated otherwise.
  • Optionally substituted heterocyclylalkyl means — (alkylene) -R where R is optionally substituted heterocyclyl as defined above.
  • “Spirocycloalkyl” means a saturated bicyclic monovalent ring having 5 to 10 ring atoms in in which the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon ( "spiro carbon” ) .
  • spiro cycloalkyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano. Examples include, but are not limited to, Representative examples include, but are not limited to, spiro [3.3] heptane, spiro [3.4] octane, spiro [3.5] -nonane, and the like.
  • “Spiro cycloalkylene” means a saturated bicyclic divalent hydrocarbon ring having 6 to 12 ring atoms wherein the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon ( “spiro carbon” ) .
  • Spiro cycloalkylene is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano, unless stated otherwise. Representative examples include, but are not limited to, spiro [3, 5] nonandiyl e.g., spiro [3.5] nonane-2, 7-diyl, and the like.
  • “Spiro heterocyclyl” means a saturated monovalent bicyclic ring having 6 to 10 ring atoms in which one, two, or three ring atoms are heteroatom selected from N, O, and S (O) n, where n is an integer selected from 0 to 2, the remaining ring atoms being C and the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon ( “spiro carbon” ) .
  • Representative examples include, but are not limited to, 2, 6-diazaspiro- [3.3] heptanyl, 2, 2-dioxido-2-thiaspiro [3.3] heptan-6-yl, 2, 6-diazaspiro [3.4] octanyl, 2-azaspiro [3.4] octanyl, 2-azaspiro [3.5] -nonanyl, 2, 7-diazaspiro [4.4] nonanyl, and the like.
  • “Spiro heterocyclylene” means a saturated bicyclic divalent ring having 6 to 10 ring atoms in which one, two, or three ring atoms are heteroatom selected from N, O, and S (O) n , where n is an integer selected from 0 to 2 inclusive, the remaining ring atoms being C and the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon ( “spiro carbon” ) .
  • the bicyclic heterocyclylene may be referred to herein as spiro cyclylaminylene.
  • the present disclosure also includes protected derivatives of compounds of Formula (I) .
  • compounds of Formula (I) when compounds of Formula (I) contain groups such as hydroxy, carboxy, or any group containing a nitrogen atom (s) , these groups can be protected with suitable protecting groups.
  • suitable protecting groups A comprehensive list of suitable protective groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, 5 th Ed., John Wiley &Sons, Inc. (2014) , the disclosure of which is incorporated herein by reference in its entirety.
  • the protected derivatives of compounds of the present disclosure can be prepared by methods well known in the art.
  • the present disclosure also includes polymorphic forms and deuterated forms of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • prodrug refers to a compound that is made more active in vivo.
  • Certain compounds Formula (I) may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003) .
  • Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the active compound. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodrug” ) , but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.
  • a “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include:
  • acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic
  • the compounds of Formula (I) may have asymmetric centers.
  • Compounds of Formula (I) containing an asymmetrically substituted atom may be isolated in optically active or racemic forms.
  • Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. All chiral, diastereomeric, all mixtures of chiral or diastereomeric forms, and racemic forms are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically indicated. It will also be understood by a person of ordinary skill in the art that when a compound is denoted as (R) stereoisomer, it may contain the corresponding (S) stereoisomer as an impurity and vice versa.
  • Certain compounds of Formula (I) can exist as tautomers and/or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this disclosure. Additionally, as used herein the term alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth. Furthermore, when the cyclic groups such as aryl is substituted, it includes all the positional isomers albeit only a few examples are set forth. Furthermore, all hydrates of a compound of Formula (I) are within the scope of this disclosure.
  • the compounds of Formula (I) may also contain unnatural amounts of isotopes at one or more of the atoms that constitute such compounds.
  • Unnatural amounts of an isotope may be defined as ranging from the amount found in nature to an amount 100%of the atom in question. that differ only in the presence of one or more isotopically enriched atoms.
  • Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 1, respectively.
  • Isotopically labeled compounds e.g., those labeled with 3 H and 14 C
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) .
  • substituents such as deuterium (i.e., 2 H)
  • one or more hydrogen atoms are replaced by 2 H or 3 H, or one or more carbon atoms are replaced by 13 C-or 14 C-enriched carbon.
  • Positron emitting isotopes such as 15 O, 13 N, 11 C, and 15 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • a “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a pharmaceutically acceptable carrier/excipient includes both one and more than one such excipient.
  • aryl substituted with alkyl is intended to cover aryl that is unsubstituted and aryl that is substituted with alkyl.
  • alkylene optionally substituted with one or two fluoro in the definition of X 1 , X 2 , X 3, and X 4 in Formula (I) is intended to cover alkylene that is unsubstituted and alkylene that is substituted one or two fluoro.
  • R 2 and R 3 groups are floating substituents and can replace any unsubstitued carbon atom of the portion of the depicted ring, including when X is CH recited in the structure of Formula (I) (and any embodinments thereof defined herein) , valency permitting.
  • R 1b and R 1c groups are floating substituents and can replace any unsubstitued carbon atom of rings designed as “A” and “B” in Formula (I) , including when Z is CH 2 or NH, unless the bond of R 1b and/or R 1c is through ring “A” or “B” .
  • R 1b and R 1c groups are floating substituents and can replace any unsubstitued carbon atom of rings designed as “A” and “B” in Formula (I) , including when Z is CH 2 or NH, unless the bond of R 1b and/or R 1c is through ring “A” or “B” .
  • R aa substituent of R aa , R bb and X 1 , and similarly the R bb and X 1 substituents can replace hydrogen of any CH that is part of the benzo portion of the bicyclic ring that is not already substituted with R bb and/or X 1 , and similarly R aa and/or X 1 , and R aa and/or R bb substituents with respect to R bb and X 1 , respectively.
  • the left bond of the divalent group is attached to the group which is to its left in the remainder of the molecule
  • the right bond of the divalent group is attached to the group which is to its right in the remainder of the molecule.
  • L i.e, -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -
  • Z 1 the left side in L (i.e., Z 1 ) is attached to an atom of an R 4 group as denoted in this Application and Z 6 is attached to X 1 , X 2 , X 3 , or X 4 .
  • L is a group of formula:
  • Degron is a group of formula (a) , i.e., the left bond of L (i.e., the nitrogen atom of the piperidine ring ) is attached to R 4 and the right hand bond of L (i.e., -NH-) is attached to an X 2 group as denoted in this Application.
  • disease as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder, ” “syndrome, ” and “condition” (as in medical condition) , in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
  • combination therapy means the administration of two or more therapeutic agents to treat a disease or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • patient is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.
  • Treating” or “treatment” of a disease includes:
  • treating or treatment of a disease includes inhibiting the disease, i.e., delaying, arresting or reducing the development or severity of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • a “therapeutically effective amount” means the amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof that, when administered to a patient for treating a disease, is sufficient to affect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • the therapeutically effective amount of a K-ras inhibitor disclosed herein can be administered to the patient in a single dosage form or multiples thereof. For example, 600 mg dose of a K-ras inhibitor can be administered in a single 600 mg tablet or two 300 mg tablets.
  • the term “degrading” and “degrade, ” or any variation of these terms in relation of Kras G12D means any measurable decrease in the concentration of G12D, in a sample over time. For example, there may be a decrease of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, in G12D concentration in a sample containing G12D, and a compound disclosed herein in the Summary and Embodiments as compared to an equivalent sample comprising G12D, in the absence of said compound.
  • the %degradation can be determined as described in Biological Example 2 below.
  • the decrease in the concentration of G12D is ⁇ 40%. In some embodiments, the decrease in the concentration of G12D is ⁇ 50%. In some embodiments, the decrease in the concentration of G12D is ⁇ 60%. In some embodiments, the decrease in the concentration of G12D is ⁇ 70%. In some embodiments, the decrease in the concentration of G12D is ⁇ 80%.
  • Embodiment A is a diagrammatic representation of Embodiment A.
  • the present disclosure includes:
  • the compound of embodiment 1, or a pharmaceutically acceptable salt thereof is wherein the compound of Formula (I) is according to structure (Ia) :
  • the compound of embodiment 1, or a pharmaceutically acceptable salt thereof is wherein the compound of Formula (I) is according to structure (Ib) :
  • the compound of embodiment 1, or a pharmaceutically acceptable salt thereof is wherein the compound of Formula (I) is according to structure (Ic) :
  • the compound of any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, is wherein Q 2 is a bond.
  • the compound of any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, is wherein Q 2 is O.
  • the compound of any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, is wherein Q 2 is NH.
  • the compound of any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, is wherein Q 2 is N (alkyl) .
  • the compound of any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, is wherein Q 2 is S.
  • the compound of any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, is wherein Q 2 is a bond to L.
  • the compound of any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof is wherein R 6 is fused heterocyclylalkyl where fused heterocyclyl of fused heterocyclylalkyl is substituted with R a , R b , R c and R c1 as defined in the Summary.
  • the compound of any one of embodiments 1 to 12 and 14, or a pharmaceutically acceptable salt thereof is wherein the fused heterocyclyl of fused heterocyclylalkyl of R 6 is isoindolinyl substituted with R a , R b , R c and R c1 as defined therein.
  • the compound of any one of embodiments 1 to 12 and 14-15, or a pharmaceutically acceptable salt thereof, is wherein the fused heterocyclylalkyl of R 6 is a ring of formula:
  • R a , R b and R c are as defined therein and R c1 is hydrogen.
  • the compound of any one of embodiments 1 to 12, or a pharmaceutically acceptable salt thereof is wherein R 6 is heterocyclylalkyl, bicyclic heterocyclyl, or bicyclic heterocylalkylalkyl, where heterocyclyl of heterocyclylalkyl and bicyclic heterocyclyl, by itself or as part of bicyclic heterocyclylalkyl are substituted with R d , R e , R f , and R f1 as defined in the Summary.
  • the compound of any one of embodiments 1 to 12 and 17, or a pharmaceutically acceptable salt thereof is wherein R 6 is heterocyclylalkyl where heterocyclyl of heterocyclylalkyl of R 6 is substituted with R d , R e , R f , and R f1 as defined therein.
  • the compound of any one of embodiments 1 to 12, 17 and 18, or a pharmaceutically acceptable salt thereof is wherein the heterocyclylalkyl of R 6 is pyrrolidin-2-ylmethyl, piperidin-2-ylmethyl, or piperidin-3-ylmethyl, preferably pyrrolidin-2-ylmethyl substituted with R d , R e , R f , and R f1 as defined therein.
  • the compound of any one of embodiments 1 to 12, 17, 18, and 19, or a pharmaceutically acceptable salt thereof is wherein the heterocyclylalkyl of R 6 is pyrrolidin-2-ylmethyl of structure substituted with R e , R f , and R f1 where R f1 is hydrogen.
  • the compound of any one of embodiments 1 to 12 and 17, or a pharmaceutically acceptable salt thereof is wherein R 6 is bicyclic heterocyclalkylalkyl substituted with R d , R e , R f , and R f1 as defined therein.
  • the compound of any one of embodiments 1 to 12, 17, and 21, or a pharmaceutically acceptable salt thereof is wherein the bicyclic heterocyclylalkyl of R 6 is hexahydro-1H-pyrrolizin-7a-ylalkyl, preferably, hexahydro-1H-pyrrolizin-7a-ylmethyl, where hexahydro-1H-pyrrolizin-7a-yl is substituted with R d , R e , R f , and R f1 as defined therein.
  • the compound of any one of embodiments 1 to 12, 17, 21, and 22, or a pharmaceutically acceptable salt thereof is wherein the bicyclic heterocyclylalkyl is a ring of formula:
  • R e , R f , and R f1 are substituted with R e , R f , and R f1 as defined therein, preferably is where R d , R e , R f , and R f1 are as defined therein.
  • the compound of any one of embodiments 1 to 12, 17, 21, 22, and 23, or a pharmaceutically acceptable salt thereof is wherein the bicyclic heterocyclylalkyl of R 6 is a ring of formula: where R d , R e , R f , are as defined therein and R f1 is hydrogen.
  • the compound of any one of embodiments 1 to 12, 17, 21, 22, 23, and 24, or a pharmaceutically acceptable salt thereof is wherein the bicyclic heterocyclylalkyl of R 6 is a ring of formula:
  • R d , R e , and R f are as defined therein.
  • the compound of any one of embodiments 1 to 12 14 to 25, or a pharmaceutically acceptable salt thereof is wherein R a and R d are independently alkylidenyl, deuterioalkylidenyl, haloalkylidenyl, or alkoxyalkylidenyl.
  • the compound of any one of embodiments 1 to 12, 17 to 25, and 28, or a pharmaceutically acceptable salt thereof is wherein R d is hydrogen, alkyl, alkoxy, halo, haloalkyl, or haloalkoxy.
  • the compound of any one of embodiments 1 to 12 and 14 to 26, or a pharmaceutically acceptable salt thereof is wherein R a and R d are alkylidenyl.
  • the compound of any one of embodiments 1 to 12 and 14 to 26, and 29, or a pharmaceutically acceptable salt thereof, is wherein R a and R d are methylidenyl.
  • the compound of any one of embodiments 1 to 12 and 14 to 26, or a pharmaceutically acceptable salt thereof is wherein R a and R d are haloalkylidenyl.
  • the compound of any one of embodiments 1 to 12, and 14 to 26, or a pharmaceutically acceptable salt thereof is wherein R a and R d , are alkoxyalkylidenyl.
  • the compound of any one of embodiments 1 to 12 and 14 to 26, or a pharmaceutically acceptable salt thereof is wherein R a and R d are deuterioalkylidenyl.
  • the compound of any one of embodiments 1 to 12, 14 to 25, and 37, or a pharmaceutically acceptable salt thereof is wherein R 7 and R 9 are fluoro.
  • the compound of any one of embodiments 1 to 12, 14 to 25, and 37, or a pharmaceutically acceptable salt thereof is wherein R 7 and R 9 are alkyl.
  • the compound of any one of embodiments 1 to 12, 14 to 25, 37, and 40, or a pharmaceutically acceptable salt thereof is wherein R 7 and R 9 are independently methyl, ethyl, or propyl.
  • the compound of any one of embodiments 1 to 12, 14 to 25, 37, and 40, or a pharmaceutically acceptable salt thereof, is wherein R 7 and R 9 are independently a bond to L.
  • the compound of any one of embodiments 1 to 12, 14 to 25, and 37 to 41a, or a pharmaceutically acceptable salt thereof is wherein R 8 and R 10 are independently cyano, cycloalkyl, or cycloalkylalkyl.
  • the compound of any one of embodiments 1 to 12, 14 to 25, and 37 to 42, or a pharmaceutically acceptable salt thereof is wherein R 8 and R 10 are independently cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, cyclobutylethyl, or cyclopentylethyl.
  • the compound of any one of embodiments 1 to 12, 14 to 25, and 37 to 43, or a pharmaceutically acceptable salt thereof, is wherein R 8 and R 10 are cyano.
  • the compound of any one of embodiments 1 to 12, 14 to 25, and 37 to 41a, or a pharmaceutically acceptable salt thereof is wherein R 8 and R 10 are independently heterocyclyl, phenyl, or heteroaryl.
  • the compound of any one of embodiments 1 to 12, 14 to 25, 37 to 41a, and 45, or a pharmaceutically acceptable salt thereof is wherein R 8 and R 10 are independently phenyl, pyrrolidinyl, furanyl, pyranyl, piperidinyl, morpholinyl, or 5-or 6-membered heteroaryl.
  • the compound of any one of embodiments 1 to 12, 14 to 25, and 37, or a pharmaceutically acceptable salt thereof is wherein R 7 and R 8 , and R 9 and R 10 of R a and R d respectively, together with the carbon atom to which they are attached form cycloalkylene optionally substituted with alkyl, halo, alkoxy, or hydroxy.
  • the compound of any one of embodiments 1 to 12, 14 to 25, 37, and 47, or a pharmaceutically acceptable salt thereof is wherein R 7 and R 8 , and R 9 and R 10 of R a and R d respectively, together with the carbon atom to which they are attached form cyclopropyl, cyclobutylene, or cyclopentylene, each ring optionally substituted with methyl, fluoro, or methoxy.
  • the compound of any one of embodiments 1 to 12 and 17 to 25, or a pharmaceutically acceptable salt thereof is wherein R a and R d are independently hydrogen, alkyl, alkoxy, halo, haloalkyl, or haloalkoxy.
  • the compound of any one of embodiments 1 to 12, 14 to 25 and 49, or a pharmaceutically acceptable salt thereof is wherein R a and R d are independently hydrogen or fluoro.
  • the compound of any one of embodiments 1 to 12 and 14 to 50, or a pharmaceutically acceptable salt thereof is wherein R b and R e are independently hydrogen, alkyl, halo, alkoxy, alkoxyalkyl, hydroxy, or hydroxyalkyl.
  • the compound of any one of embodiments 1 to 12 and 14 to 51, or a pharmaceutically acceptable salt thereof is wherein R b and R e are independently hydrogen, methyl, fluoro, methoxy, ethoxy, or methoxymethyl.
  • the compound of any one of embodiments 1 to 12 and 14 to 52, or a pharmaceutically acceptable salt thereof, is wherein R b and R e are fluoro.
  • the compound of any one of embodiments 1 to 12 and 14 to 52, or a pharmaceutically acceptable salt thereof, is wherein R b and R e are hydrogen.
  • the compound of any one of embodiments 1 to 50, or a pharmaceutically acceptable salt thereof is wherein R b and R e are independently – (Q 1 ) n1 -OC (O) NR 11 R 12 .
  • the compound of any one of embodiments 1 to 12, 14 to 50 and 55, or a pharmaceutically acceptable salt thereof, is wherein Q 1 is alkylene.
  • the compound of any one of embodiments 1 to 12, 14 to 50 and 55, or a pharmaceutically acceptable salt thereof, is wherein Q 1 is deuterioalkyl.
  • the compound of any one of embodiments 1 to 12, 14 to 50 and 55 to 57, or a pharmaceutically acceptable salt thereof is wherein Q 1 is methylene, ethylene, -CH (CH 3 ) -, -C (CH 3 ) 2 -, or -CD 2 -.
  • the compound of any one of embodiments 1 to 12, 14 to 50, 55, 56, and 58, or a pharmaceutically acceptable salt thereof is wherein Q 1 is methylene, ethylene, -CH (CH 3 ) -, -C (CH 3 ) 2 , preferably methylene.
  • the compound of any one of embodiments 1 to 12, 14 to 50, 57, and 58, or a pharmaceutically acceptable salt thereof, is wherein Q 1 is -CD 2 -.
  • the compound of any one of embodiments 1 to 12, 14 to 50 and 55 to 60, or a pharmaceutically acceptable salt thereof is wherein R 11 is hydrogen, deuterium, alkyl, deuterioalkyl, haloalkyl, haloalkoxyalkyl, or alkoxyalkyl and R 12 is hydrogen, alkyl, deuterioalkyl, cycloalkyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, or heterocyclyl substituted with R j and R k .
  • the compound of any one of embodiments 1 to 12, 14 to 50 and 55 to 61, or a pharmaceutically acceptable salt thereof, is wherein R 11 is hydrogen or deuterium.
  • the compound of any one of embodiments 1 to 12, 14 to 50 and 55 to 61, or a pharmaceutically acceptable salt thereof, is wherein R 11 is alkyl.
  • the compound of any one of embodiments 1 to 12, 14 to 50 and 55 to 61, or a pharmaceutically acceptable salt thereof, is wherein R 11 is haloalkyl.
  • the compound of any one of embodiments 1 to 12, 14 to 50 and 55 to 61, or a pharmaceutically acceptable salt thereof, is wherein R 11 is haloalkoxyalkyl.
  • the compound of any one of embodiments 1 to 12, 14 to 50 and 55 to 61, or a pharmaceutically acceptable salt thereof, is wherein R 11 is alkoxyalkyl.
  • the compound of any one of embodiments 1 to 12, 14 to 50 and 55 to 61, or a pharmaceutically acceptable salt thereof, is wherein R 11 is deuterioalkyl.
  • the compound of any one of embodiments 1 to 12, 14 to 50 and 55 to 67, or a pharmaceutically acceptable salt thereof, is wherein R 12 is alkoxy.
  • the compound of any one of embodiments 1 to 12, 14 to 50 and 55 to 67, or a pharmaceutically acceptable salt thereof, is wherein R 12 is alkoxyalkyl.
  • the compound of any one of embodiments 1 to 12, 14 to 50 and 55 to 67, or a pharmaceutically acceptable salt thereof, is wherein R 12 is haloalkyl.
  • the compound of any one of embodiments 1 to 12, 14 to 50 and 55 to 67, or a pharmaceutically acceptable salt thereof, is wherein R 12 is haloalkoxyalkyl.
  • the compound of any one of embodiments 1 to 12, 14 to 50 and 55 to 67, or a pharmaceutically acceptable salt thereof, is wherein R 12 is cycloalkyl.
  • the compound of any one of embodiments 1 to 12, 14 to 50 and 55 to 67, or a pharmaceutically acceptable salt thereof, is wherein R 12 is deuterioalkyl.
  • the compound of any one of embodiments 1 to 12, 14 to 50 and 55 to 67, or a pharmaceutically acceptable salt thereof, is wherein R 12 is heterocyclyl substituted with R g and R h .
  • the compound of any one of embodiments 1 to 12, 14 to 50 and 55 to 74, or a pharmaceutically acceptable salt thereof is wherein R 11 is hydrogen, methyl, methyl-d3, methoxyethyl, ethoxyethyl, or propoxyethyl; and R 12 is methyl-d3, cyclopropyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl, 2, 2-difluoroethoxymethyl, 2, 2, 2-trifluoroethoxymethyl, methoxyethyl, ethoxyethyl, oxetan-3-yl, tetrahydrofuranyl, or tetrahydropyranyl.
  • the compound of any one of embodiments 1 to 12, 14 to 50 and 55 to 60, or a pharmaceutically acceptable salt thereof is wherein R 11 and R 12 together with the nitrogen atom to which they are attached form heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl wherein (a) heterocyclyl is substituted with R m , R n , R o , and R p and (b) bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiroheterocyclyl are independently substituted with R q , R r , and R s .
  • the compound of any one of embodiments 1 to 12, 14 to 50, 55 to 60, and 76, or a pharmaceutically acceptable salt thereof is wherein R 11 and R 12 together with the nitrogen atom to which they are attached form heterocyclyl substituted with R i , R j , R k , and R m .
  • the compound of any one of embodiments 1 to 12, 14 to 50, 55 to 60, and 76, or a pharmaceutically acceptable salt thereof is wherein R 11 and R 12 together with the nitrogen atom to which they are attached form bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, each ring independently substituted with R n , R o , and R p .
  • the compound of any one of embodiments 1 to 12, 14 to 50, 55 to 60, 76, and 77, or a pharmaceutically acceptable salt thereof is wherein R 11 and R 12 together with the nitrogen atom to which they are attached form heterocyclyl selected from azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-1-yl, and homomorpholin-1-yl, each ring substituted with R i , R j , R k , and R m .
  • the compound of any one of embodiments 1 to 12, 14 to 50, 55 to 60, 76, 77, and 79, or a pharmaceutically acceptable salt thereof is wherein R 11 and R 12 together with the nitrogen atom to which they are attached form heterocyclyl selected from azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-1-yl, and homomorpholin-1-yl, each ring substituted with R i , R j , R k , and R m where R i and R j are independently selected from hydrogen, deuterium, methyl, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyano, or methoxy, R k is hydrogen, deuterium, methoxymethyl, or fluoro, and R m is hydrogen, deuterium, or fluoro.
  • the compound of any one of embodiments 1 to 12, 14 to 50, 55 to 60, 76, 77, 79, and 80, or a pharmaceutically acceptable salt thereof is wherein R i , R j , R k , and R m are hydrogen.
  • the compound of any one of embodiments 1 to 12, 14 to 50, 55 to 60, 76, 77, 79, and 80, or a pharmaceutically acceptable salt thereof is wherein R 11 and R 12 together with the nitrogen atom to which they are attached form heterocyclyl selected from 3-methoxymethylazetidin-1-yl, 2-methoxymethyl-piperidin-1-yl, 3, 3, 4, 4-tetrafluoropyrrolidin-1-yl, morpholin-1-yl.
  • the compound of any one of embodiments 1 to 12, 14 to 50, 55 to 60, 76, 77, and 79 to 82, or a pharmaceutically acceptable salt thereof is wherein R 11 and R 12 together with the nitrogen atom to which they are attached form heterocyclyl selected from morpholin-1-yl. 2, 6-dimethylmorpholin-4-yl, 2, 2-dimethylmorpholin-4-yl, 2- (trifluoromethyl) morpholin-4-yl, 2, 2- difluoromorpholin-4-yl, 2-methylmorpholin-4-yl, 3-methylmorpholin-4-yl, and 2- (difluoromethyl) morpholin-4-yl.
  • the compound of any one of embodiments 1 to 12, 14 to 50, 55 to 60, 76, and 78, or a pharmaceutically acceptable salt thereof is wherein R 11 and R 12 together with the nitrogen atom to which they are attached form bicyclic heterocyclyl substituted with R n , R o , and R p
  • the compound of any one of embodiments 1 to 12, 14 to 50, 55 to 60, 76, and 78, or a pharmaceutically acceptable salt thereof is wherein R 11 and R 12 together with the nitrogen atom to which they are attached form bridged heterocyclyl substituted with R n , R o , and R p .
  • the compound of any one of embodiments 1 to 12, 14 to 50, 55 to 60, 76, and 78, or a pharmaceutically acceptable salt thereof is wherein R 11 and R 12 together with the nitrogen atom to which they are attached form fused heterocyclyl substituted with R n , R o , and R p .
  • the compound of any one of embodiments 1 to 12, 14 to 50, 55 to 60, 76, and 78, or a pharmaceutically acceptable salt thereof is wherein R 11 and R 12 together with the nitrogen atom to which they are attached form spiroheterocyclyl substituted with R n , R o , and R p .
  • the compound of any one of embodiments 1 to 12, 14 to 50, 55 to 60, 76, and 84 to 87, or a pharmaceutically acceptable salt thereof is wherein R 11 and R 12 together with the nitrogen atom to which they are attached form a ring selected from:
  • each ring substituted with R q , R r , and R s .
  • the compound of any one of embodiments 1 to 12, 14 to 50, 55 to 60, 76, and 84 to 88, or a pharmaceutically acceptable salt thereof, is wherein R p is hydrogen.
  • the compound of any one of embodiments 1 to 12, 14 to 50, 55 to 60, 76, and 84 to 88, or a pharmaceutically acceptable salt thereof, is wherein R o and R p are hydrogen.
  • the compound of any one of embodiments 1 to 12, 14 to 50, 55 to 60, 76, and 84 to 90, or a pharmaceutically acceptable salt thereof is wherein R n , R o , and R p (where applicable) are independently selected from hydrogen, methyl, methoxy, or fluoro.
  • the compound of any one of embodiments 1 to 12 and 14 to 91, or a pharmaceutically acceptable salt thereof is wherein R c and R f are independently hydrogen, deuterium, methyl, ethyl, methoxy, ethoxy, methyloxy, ethyloxy, chloro, or fluoro.
  • the compound of any one of embodiments 1 to 12 and 14 to 92, or a pharmaceutically acceptable salt thereof, is wherein R c and R f are hydrogen.
  • the compound of any one of embodiments 1 to 12 and 14 to 92, or a pharmaceutically acceptable salt thereof, is wherein R c and R f are deuterium.
  • the compound of any one of embodiments 1 to 12 and 14 to 92, or a pharmaceutically acceptable salt thereof is wherein R c and R f are independently methyl, methoxy, methyloxy, chloro, or fluoro.
  • the compound of any one of embodiments 1 to 12 and 14 to 92, or a pharmaceutically acceptable salt thereof is wherein R c and R f are independently chloro or fluoro, preferably, R c , R f are fluoro.
  • the compound of any one of embodiments 1 to 12 and 14 to 96, or a pharmaceutically acceptable salt thereof is wherein R c1 and R f1 are independently selected from hydrogen, deuterium, or fluoro.
  • the compound of any one of embodiments 1 to 12 and 14 to 97, or a pharmaceutically acceptable salt thereof, is wherein R c1 and R f1 are hydrogen.
  • the compound of any one of embodiments 1 to 12 and 14 to 97, or a pharmaceutically acceptable salt thereof is wherein R c1 and R f1 are deuterium.
  • the compound of any one of embodiments 1 to 12 and 14 to 97, or a pharmaceutically acceptable salt thereof, is wherein R c1 and R f1 are fluoro.
  • the compound of any one of embodiments 1 to 50 and 92 to 100, or a pharmaceutically acceptable salt thereof, is wherein R b and R e are a bond to L.
  • the compound of any one of embodiments 1 to 12, and 14 to 100a, or a pharmaceutically acceptable salt thereof is wherein Q 2 is O.
  • the compound of any one of embodiments 1 to 101a, or a pharmaceutically acceptable salt thereof, is wherein q is 0.
  • the compound of any one of embodiments 1 to 101a, or a pharmaceutically acceptable salt thereof, is wherein q is 1.
  • the compound of any one of embodiments 1 to 101a, or a pharmaceutically acceptable salt thereof, is wherein q is 2.
  • the compound of any one of embodiments 1 to 104, or a pharmaceutically acceptable salt thereof, is wherein p is 1.
  • the compound of any one of embodiments 1 to 104, or a pharmaceutically acceptable salt thereof, is wherein p is 2.
  • the compound of any one of embodiments 1 to 3 and 6 to 104, or a pharmaceutically acceptable salt thereof, is wherein p is 3.
  • the compound of any one of embodiments 1, 4, 5 and 8 to 104, or a pharmaceutically acceptable salt thereof, is wherein p is 0.
  • the compound of any one of embodiments 1 to 108, or a pharmaceutically acceptable salt thereof is wherein m and n are each 1, or one of m and n is 1 and the other of m and n is 2.
  • the compound of any one of embodiments 1 to 108, or a pharmaceutically acceptable salt thereof is wherein m and n are each 1, or one of m and n is 1.
  • the compound of any one of embodiments 1 to 108, or a pharmaceutically acceptable salt thereof is wherein one of m and n is 1 and the other of m and n is 2.
  • the compound of any one of embodiments 1 to 108, or a pharmaceutically acceptable salt thereof, is wherein m and n are each 1.
  • the compound of any one of embodiments 1 to 108, or a pharmaceutically acceptable salt thereof is wherein m is 1 and n is 3.
  • the compound of any one of embodiments 1 to 113, or a pharmaceutically acceptable salt thereof is wherein R 1 and R 1a are independently selected from hydrogen, methyl, and ethyl, and R 1b and R 1c are hydrogen.
  • the compound of any one of embodiments 1 to 113, or a pharmaceutically acceptable salt thereof is wherein R 1 is cyanomethyl and R 1a is hydrogen, methyl, or ethyl, preferably R 1a is hydrogen, and R 1b and R 1c are hydrogen.
  • the compound of any one of embodiments 1 to 113, or a pharmaceutically acceptable salt thereof is wherein R 1 and R 1a are attached to the carbon atoms of the ring that are opposite or diagonal to each other and combine to form – (CH 2 ) z -where z is 1, 2, or 3, preferably z is 2, and R 1b and R 1c are independently hydrogen or alkyl, preferably methyl.
  • the compound of any one of embodiments 1 to 113, or a pharmaceutically acceptable salt thereof is wherein R 1 and R 1a are attached to the carbon atoms of the ring that are opposite or diagonal to each other and combine to form – (CH 2 ) z -where z is 1, 2, or 3, preferably 2, R 1c is hydrogen and R 1b is hydrogen.
  • the compound of any one of embodiments 1 and 8 to 120 or a pharmaceutically acceptable salt thereof, is wherein Z is O.
  • the compound of any one of embodiments 1 and 8 to 120 or a pharmaceutically acceptable salt thereof, is wherein Z is CH.
  • the compound of any one of embodiments 1 and 8 to 120 or a pharmaceutically acceptable salt thereof, is wherein X is N.
  • the compound of any one of embodiments 1 and 8 to 120 or a pharmaceutically acceptable salt thereof, is wherein X is CH.
  • the compound of any one of embodiments 1 to 124, or a pharmaceutically acceptable salt thereof is wherein R 5 is -Q-R 14 where Q is bond and R 14 is cycloalkyl, fused cycloalkyl, fused spirocycloalkyl, aryl, heteroaryl, or fused heteroaryl, wherein aryl, heteroaryl, and fused heteroaryl are substituted with R q , R r , R s and R t wherein R q and R r are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R s is hydrogen, alkenyl, alkynyl, cyanoalkenyl, cyanoalkynyl, or halo, and R t is hydrogen, alkyl, cycloalkyl
  • the compound of any one of embodiments 1 to 124, or a pharmaceutically acceptable salt thereof is wherein R 5 is -Q-R 14 where Q is alkylene and R 14 is cycloalkyl, aryl, or fused heteroaryl, wherein aryl, fused heteroaryl, and heteroaryl are substituted with R q , R r , R s and R t wherein R q and R r are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R s is hydrogen, alkynyl, or halo, and R t is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted
  • the compound of any one of embodiments 1 to 124, or a pharmaceutically acceptable salt thereof is wherein R 5 is -Q-R 14 where Q is -C (O) -and R 14 is cycloalkyl, aryl, fused heteroaryl, or heteroaryl, wherein aryl, fused heteroaryl and heteroaryl are substituted with R q , R r , R s and R t wherein R q and R r are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R s is hydrogen, alkynyl, or halo, and R t is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R s is
  • the compound of any one of embodiments 1 to 127, or a pharmaceutically acceptable salt thereof is wherein R 14 is cycloalkyl, fused cycloalkyl, aryl, or heteroaryl wherein aryl, and heteroaryl are substituted with R q , R r , R s and R t wherein R q and R r are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R s is hydrogen, alkenyl, alkynyl, cyanoalkenyl, cyanoalkynyl, or halo, and R t is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano,
  • the compound of any one of embodiments 1 to 128, or a pharmaceutically acceptable salt thereof is wherein R 5 is -Q-R 14 where Q is bond and R 14 is phenyl or naphthyl substituted with R q , R r , R s and R t .
  • the compound of any one of embodiments 1 to 129, or a pharmaceutically acceptable salt thereof is wherein R q and R r are independently selected from hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, difluoromethyl, trifluoromethoxy, hydroxy, methyl, ethoxy, cyclopropyl, amino, cyano, and hydroxymethyl, R s is hydrogen, ethynyl, 2-cyanovinyl, 2-cyanoethyn-1-yl, or fluoro, and R r is hydrogen, methyl, fluoro, amino, or cyclopropyl.
  • the compound of any one of embodiments 1 to 128, or a pharmaceutically acceptable salt thereof is wherein R 5 is -Q-R 14 where Q is bond and R 14 is heteroaryl or fused heteroaryl substituted with R q , R r , R s and R t .
  • the compound of any one of embodiments 1 to 128 and 131, or a pharmaceutically acceptable salt thereof is wherein R 5 is -Q-R 14 where Q is bond and R 14 is a monocyclic heteroaryl (e.g., pyridyl, pyrimidinyl, benzothiazolyl) substituted with R q , R r , R s and R t .
  • R 5 is -Q-R 14 where Q is bond and R 14 is a monocyclic heteroaryl (e.g., pyridyl, pyrimidinyl, benzothiazolyl) substituted with R q , R r , R s and R t .
  • the compound of any one of embodiments 1 to 128 and 131, or a pharmaceutically acceptable salt thereof is wherein R 5 is -Q-R 14 where Q is bond and R 14 is bicyclic heteroaryl (e, g, quinolinyl, isoquinolinyl, or indazolyl) , substituted with R q , R r , R s and R t .
  • R 5 is -Q-R 14 where Q is bond and R 14 is bicyclic heteroaryl (e, g, quinolinyl, isoquinolinyl, or indazolyl) , substituted with R q , R r , R s and R t .
  • the compound of any one of embodiments 1 to 128 and 131 to 133, or a pharmaceutically acceptable salt thereof is wherein the heteroaryl is substituted with R q , R r , R s and R t wherein R q and R r independently selected from hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, amino, cyano, and hydroxyalkyl and R t is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.
  • the compound of any one of embodiments 1 to 128 and 131 to 134, or a pharmaceutically acceptable salt thereof is wherein R q and R r are independently selected from hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, difluoromethyl, trifluoromethoxy, hydroxy, ethoxy, cyclopropyl, amino, cyano, and hydroxymethyl, R s is hydrogen or fluoro, and R t is hydrogen, methyl, fluoro, amino, or cyclopropyl.
  • the compound of any one of embodiments 1 to 135, or a pharmaceutically acceptable salt thereof is wherein R q , R r , and R t are independently hydrogen or halo, and R s is alkynyl.
  • the compound of any one of embodiments 1 to 135, or a pharmaceutically acceptable salt thereof is wherein R s is hydrogen and R q , R r , and R t are independently hydrogen, alkyl, haloalkyl or amino.
  • the compound of any one of embodiments 1 to 133, or a pharmaceutically acceptable salt thereof is wherein R 5 is -Q-R 14 where Q is bond and R 14 is:
  • R q , R r , and R t substituted with R q , R r , and R t , wherein R q , R r are independently hydrogen or halo, and R s is alkynyl.
  • the compound of any one of embodiments 1 to 132, or a pharmaceutically acceptable salt thereof is wherein R 5 is -Q-R 14 where Q is bond and R 14 is pyridyl substituted with R q , R r , R s and R t , wherein R s is hydrogen and R q , R r , and R t are independently hydrogen, alkyl, haloalkyl or amino.
  • the compound of any one of embodiments 1 to 139, or a pharmaceutically acceptable salt thereof, is wherein R t is hydrogen.
  • the compound of any one of embodiments 1 to 134 and 138, or a pharmaceutically acceptable salt thereof, is wherein R t is halo.
  • the compound of any one of embodiments 1 to 132, or a pharmaceutically acceptable salt thereof is wherein R 5 is -Q-R 14 where Q is bond and R 14 is:
  • the compound of any one of embodiments 1 to 132, and 142, or a pharmaceutically acceptable salt thereof is wherein R 5 is -Q-R 14 where Q is bond and R 14 is:
  • the compound of any one of embodiments 1 to 132, 142, and 143, or a pharmaceutically acceptable salt thereof is wherein R 5 is -Q-R 14 where Q is bond and R 14 is:
  • the compound of any one of embodiments 1 to 132, 134, 135, and 139, or a pharmaceutically acceptable salt thereof is wherein R 5 is -Q-R 14 where Q is bond and R 14 is:
  • the compound of any one of embodiments 1 to 145, or a pharmaceutically acceptable salt thereof, is wherein R 2 is hydrogen.
  • the compound of any one of embodiments 1 to 145, or a pharmaceutically acceptable salt thereof, is wherein R 3 is halo.
  • the compound of any one of embodiments 1 to 146, or a pharmaceutically acceptable salt thereof is wherein R 2 is hydrogen, halo, or alkyl, and R 3 is hydrogen, halo, cycloalkyl, cycloalkyloxy, or alkyl.
  • the compound of any one of embodiments 1 to 146, or a pharmaceutically acceptable salt thereof is wherein R 2 and R 3 are each hydrogen.
  • the compound of any one of embodiments 1 to 146, or a pharmaceutically acceptable salt thereof is wherein R 2 is hydrogen or chloro and R 3 is hydrogen, fluoro, cyclopropyl, or cyclopropyloxy.
  • the compound of any one of embodiments 1 to 146 or a pharmaceutically acceptable salt thereof is wherein R 2 is hydrogen and R 3 is fluoro or cyclopropyl.
  • the compound of any one of embodiments 1 to 146, 149, and 150, or a pharmaceutically acceptable salt thereof is wherein R 2 is hydrogen and R 3 is fluoro or cyclopropyl and R 3 is attached to carbon meta to X.
  • the compound of any one of embodiments 1 to 152, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ubiquitin ligase ligand of formula (i) :
  • the compound of any one of embodiments 1 to 153, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (a) :
  • the compound of any one of embodiments 1 to 154, or a pharmaceutically acceptable salt thereof is wherein R 22 and R 23 are independently hydrogen or alkyl.
  • the compound of any one of embodiments 1 to 155, or a pharmaceutically acceptable salt thereof, is wherein R 22 and R 23 are hydrogen.
  • the compound of any one of embodiments 1 to 155, or a pharmaceutically acceptable salt thereof is wherein R 22 is hydrogen and R 23 is methyl.
  • the compound of any one of embodiments 1 to 153, or a pharmaceutically acceptable salt thereof is wherein the ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (b) :
  • the compound of any one of embodiments 1 to 153 and 159, or a pharmaceutically acceptable salt thereof, is wherein R 24 is hydrogen.
  • embodiment 161 the compound of any one of embodiments 1 to 153 and 159, or a pharmaceutically acceptable salt thereof, wherein R 24 is alkyl, preferably methyl.
  • the compound of any one of embodiments 1 to 161, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is:
  • the compound of any one of embodiments 1 to 162, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is:
  • the compound of any one of embodiments 1 to 163, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is:
  • the compound of any one of embodiments 1 to 154, 158, and 162 to 164, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ligase ubiquitin ligand of formula (i) is:
  • the compound of any one of embodiments 1 to 154 and 162 to 164, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is:
  • the compound of any one of embodiments 1 to 154 and 162 to 164, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is:
  • the compound of any one of embodiments 1 to 154 and 162 to 164, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is:
  • the compound of any one of embodiments 1 to 164, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is:
  • the compound of any one of embodiments 1 to 159 and 161 to 164, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is:
  • the compound of any one of embodiments 1 to 153, or a pharmaceutically acceptable salt thereof is wherein ring A of the E3 ubiquitin ligase ligand of formula (i) is a group of formula (c) :
  • the compound of any one of embodiments 1 to 167 and 170a, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy.
  • the compound of any one of embodiments 1 to 167 and 170a, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and cyano.
  • the compound of any one of embodiments 1 to 167, 170a, and 171, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen, methyl, methoxy, ethoxy, fluoro, trifluoromethyl, difluoromethyl, and trifluoromethoxy.
  • the compound of any one of embodiments 1 to 167, 170a, and 171 to 173, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen and methyl.
  • the compound of any one of embodiments 1 to 167, 170a, and 171 to 173, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen and methoxy.
  • the compound of any one of embodiments 1 to 167, 170a, and 171 to 173, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen and fluoro.
  • the compound of any one of embodiments 1 to 167, 170a, and 171 to 173, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are hydrogen.
  • the compound of any one of embodiments 1 to 167, 170a, and 171 to 173, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen, trifluoromethyl, and difluoromethyl.
  • the compound of any one of embodiments 1 to 167, 170a, and 171 to 173, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen and trifluoromethoxy.
  • the compound of any one of embodiments 1 to 167, 170a, and 171 to 173, or a pharmaceutically acceptable salt thereof is wherein R aa , R bb , R cc , and R dd are independently selected from hydrogen, fluoro, and trifluoromethyl.
  • the compound of any one of embodiments 1 to 152, or a pharmaceutically acceptable salt thereof is wherein the Degron is an E3 ubiquitin ligand of formula (ii) :
  • the compound of any one of embodiments 1 to 152 and 181, or a pharmaceutically acceptable salt thereof is wherein Y a is CH.
  • the compound of any one of embodiments 1 to 152 and 181, or a pharmaceutically acceptable salt thereof, is wherein Y a is N.
  • the compound of any one of embodiments 1 to 152, and 181 to 183, or a pharmaceutically acceptable salt thereof is wherein Z a is a bond, -NH-, O, or -NHC (O) -.
  • the compound of any one of embodiments 1 to 152, and 181 to 184, or a pharmaceutically acceptable salt thereof is wherein Z a is a bond, -NH-, or -NHC (O) -.
  • the compound of any one of embodiments 1 to 152, and 181 to 184, or a pharmaceutically acceptable salt thereof, is wherein Z a is a bond.
  • the compound of any one of embodiments 1 to 152, and 181 to 184, or a pharmaceutically acceptable salt thereof is wherein Z a is -NH-, or -NHC (O) -.
  • the compound of any one of embodiments 1 to 152, and 181-, or a pharmaceutically acceptable salt thereof is wherein Z a is -NH-.
  • the compound of any one of embodiments 1 to 152, and 181 to 184, or a pharmaceutically acceptable salt thereof, is wherein Z a is -NHC (O) -.
  • the compound of any one of embodiments 1 to 152, and 181 to 189, or a pharmaceutically acceptable salt thereof, is wherein ring B is phenylene substituted with R jj and R kk .
  • the compound of any one of embodiments 1 to 152, and 181 to 189, or a pharmaceutically acceptable salt thereof is wherein ring B is cyclylaminylene substituted with R jj and R kk .
  • the compound of any one of embodiments 1 to 152, and 181 to 189, or a pharmaceutically acceptable salt thereof is wherein ring B is 5-or 6-membered monocyclic heteroarylene or a 9-or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains one to three nitrogen ring atoms and each ring is substituted with R jj and R kk .
  • the compound of any one of embodiments 1 to 152, 181 to 189, and 192, or a pharmaceutically acceptable salt thereof is wherein ring B is 5-or 6-membered monocyclic heteroarylene containing one or two nitrogen ring atoms substituted with R jj and R kk .
  • the compound of any one of embodiments 1 to 152, 181 to 189, and 192, or a pharmaceutically acceptable salt thereof is wherein ring B is a 9-or 10-membered fused bicyclic heteroarylene containing one to three nitrogen ring atoms and substituted with R jj and R kk .
  • the compound of any one of embodiments 1 to 152, 181 to 189, and 192, or a pharmaceutically acceptable salt thereof is wherein ring B is a 9-membered fused bicyclic heteroarylene containing one to three nitrogen ring atoms and substituted with R jj and R kk .
  • the compound of any one of embodiments 1 to 152, 181 to 189 and 192, or a pharmaceutically acceptable salt thereof is wherein ring B is a 10-membered fused bicyclic heteroarylene containing two nitrogen ring atoms and substituted with R jj and R kk .
  • the compound of any one of embodiments 1 to 152 and 181 to 196, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligand of formula (ii) is:
  • the compound of any one of embodiments 1 to 152 and 181 to 197, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula (ii) is:
  • ring B is cyclylaminylene
  • the compound of any one of embodiments 1 to 152 and 181 to 198, or a pharmaceutically acceptable salt thereof, is wherein the E3 ubiquitin ligase ligand of formula (ii) is:
  • the compound of any one of embodiments 1 to 152 and 181 to 199, or a pharmaceutically acceptable salt thereof is wherein each R jj and R kk are independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and haloalkoxy.
  • the compound of any one of embodiments 1 to 152 and 181 to 199, or a pharmaceutically acceptable salt thereof is wherein R jj and R kk are independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and cyano.
  • the compound of any one of embodiments 1 to 152 and 181 to 200, or a pharmaceutically acceptable salt thereof is wherein R jj and R kk are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, 2, 2, 2-trifluoroethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, or cyano.
  • the compound of any one of embodiments 1 to 152 and 181 to 201, or a pharmaceutically acceptable salt thereof, is wherein R jj and R kk are independently selected from hydrogen, methyl, ethyl, or isopropyl.
  • the compound of any one of embodiments 1 to 152 and 181 to 201, or a pharmaceutically acceptable salt thereof, is wherein R jj and R kk are alkyl.
  • the compound of any one of embodiments 1 to 152 and 181 to 201, or a pharmaceutically acceptable salt thereof, is wherein R jj and R kk are methyl.
  • the compound of any one of embodiments 1 to 152 and 181 to 201, or a pharmaceutically acceptable salt thereof, is wherein R jj and R kk are independently selected from hydrogen and methoxy.
  • the compound of any one of embodiments 1 to 152, and 181 to 201, or a pharmaceutically acceptable salt thereof is wherein R jj and R kk are independently selected from hydrogen, methyl, ethyl, isopropyl, chloro, and fluoro.
  • the compound of any one of embodiments 1 to 152 and 181 to 201, or a pharmaceutically acceptable salt thereof is wherein one of R jj and R kk is hydrogen or fluoro and the other of R jj and R kk is selected from hydrogen, trifluoromethyl, 2, 2, 2-trifluoroethyl, and difluoromethyl.
  • the compound of any one of embodiments 1 to 152 and 181 to 201, or a pharmaceutically acceptable salt thereof, is wherein R jj and R kk are independently selected from hydrogen, difluoromethoxy, and trifluoromethoxy.
  • the compound of any one of embodiments 1 to 152 and 181 to 201 or a pharmaceutically acceptable salt thereof is wherein R jj and R kk are independently selected from hydrogen, chloro, fluoro, and trifluoromethyl.
  • the compound of any one of embodiments 1 to 152 and 181 to 201, or a pharmaceutically acceptable salt thereof, is wherein R jj and R kk are each hydrogen.
  • the compound of any one of embodiments 1 to 152 and 181 to 201, or a pharmaceutically acceptable salt thereof is wherein R jj and R kk are each chloro or one of R jj and R kk is hydrogen and the other of R jj and R kk is chloro.
  • the compound of any one of embodiments 1 to 153 and 181 to 201, or a pharmaceutically acceptable salt thereof, is wherein R jj and R kk are each fluoro or one of R jj and R kk is hydrogen and the other of R jj and R kk is fluoro.
  • the compound of any one of embodiments 1 to 152 and 181 to 201, or a pharmaceutically acceptable salt thereof is wherein R jj and R kk are independently trifluoromethyl or 2, 2, 2-trifluoroethyl or one of R jj and R kk is hydrogen and the other of R jj and R kk is trifluoromethyl.
  • the compound of any one of embodiments 1 to 214, or a pharmaceutically acceptable salt thereof is wherein X 1 , X 2 , X 3 , and X 4 are each a bond.
  • the compound of any one of embodiments 1 to 214, or a pharmaceutically acceptable salt thereof is wherein X 1 , X 2 , X 3 , and X 4 are each alkylene, preferably methylene.
  • the compound of any one of embodiments 1 to 214, or a pharmaceutically acceptable salt thereof is wherein X 1 , X 2 , X 3 , and X 4 are each -O-.
  • the compound of any one of embodiments 1 to 214, or a pharmaceutically acceptable salt thereof is wherein X 1 , X 2 , X 3 , and X 4 are each - (O-alkylene) -.
  • the compound of any one of embodiments 1 to 214, or a pharmaceutically acceptable salt thereof is wherein X 1 , X 2 , X 3 , and X 4 are each - (alkylene-O) -.
  • the compound of any one of embodiments 1 to 214, or a pharmaceutically acceptable salt thereof is wherein X 1 , X 2 , X 3 , and X 4 are each - (NR ee -alkylene) -.
  • the compound of any one of embodiments 1 to 214, or a pharmaceutically acceptable salt thereof is wherein X 1 , X 2 , X 3 , and X 4 are each - (alkylene-NR ff ) -.
  • the compound of any one of embodiments 1 to 214, or a pharmaceutically acceptable salt thereof is wherein X 1 , X 2 , X 3 , and X 4 are each
  • the compound of any one of embodiments 1 to 214, or a pharmaceutically acceptable salt thereof is wherein X 1 , X 2 , X 3 , and X 4 are each-NH-.
  • the compound of any one of embodiments 1 to 214, or a pharmaceutically acceptable salt thereof is wherein X 1 , X 2 , X 3 , and X 4 are each -N (alkyl) -.
  • the compound of any one of embodiments 1 to 214, 220, 221, 226, and 227, or a pharmaceutically acceptable salt thereof is wherein R ee , R ff , R gg , and R hh are independently hydrogen or alkyl.
  • the compound of any one of embodiments 1 to 152, or a pharmaceutically acceptable salt thereof is wherein the Degron is an E3 ubiquitin ligase ligand of formula (iii) , (iv) , (v) , (vi) , (vii) , (viii) , or (ix) .
  • the compound of any one of embodiments 1 to 152 and 229, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ubiquitin ligase ligand of formula (iii) .
  • the compound of any one of embodiments 1 to 152 and 229, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ubiquitin ligase ligand of formula (iv) .
  • the compound of any one of embodiments 1 to 152 and 229, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ubiquitin ligase ligand of formula (v) .
  • the compound of any one of embodiments 1 to 152 and 229, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ubiquitin ligase ligand of formula (vi) .
  • the compound of embodiment 234, or a pharmaceutically acceptable salt thereof is wherein R 16 is alkyl; R 16a and R 16b are independently selected from hydrogen and alkyl, R 17a is hydrogen, and R 17 is heteroaryl substituted with alkyl.
  • the compound of any one of embodiments 1 to 152 and 229, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ubiquitin ligase ligand of formula (vii) .
  • the compound of any one of embodiments 1 to 152 and 229, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ubiquitin ligase ligand of formula (viii) .
  • the compound of any one of embodiments 229 to 237, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ubiquitin ligase is a ligand of formula (v) according to structure
  • the compound of any one of embodiments 1 to 240, or a pharmaceutically acceptable salt thereof, is wherein Z 6 is a bond.
  • the compound of any one of embodiments 1 to 240, or a pharmaceutically acceptable salt thereof, is wherein Z 6 is -NR” .
  • the compound of any one of embodiments 1 to 243, or a pharmaceutically acceptable salt thereof is wherein Z 1 is -OC (O) -or -alkylene-OC (O) -where O of -OC (O) -and alkylene -alkylene-OC (O) -are attached to R 4 .
  • the compound of any one of embodiments 1 to 244, or a pharmaceutically acceptable salt thereof is wherein Z 1 is -OC (O) -.
  • the compound of any one of embodiments 1 to 244, or a pharmaceutically acceptable salt thereof is wherein Z 1 is -alkylene-OC (O) -.
  • the compound of any one of embodiments 1 to 244 and 246, or a pharmaceutically acceptable salt thereof is wherein Z 1 is -CH 2 -OC (O) -.
  • the compound of any one of embodiments 1 to 244, or a pharmaceutically acceptable salt thereof is wherein Z 1 is - (alkylene) -cycloalkylene) -.
  • the compound of any one of embodiments 1 to 249, or a pharmaceutically acceptable salt thereof, is wherein Z 2 is a bond.
  • the compound of any one of embodiments 1 to 249, or a pharmaceutically acceptable salt thereof is wherein Z 2 is NR” where R” is H or methyl.
  • the compound of any one of embodiments 1 to 249, or a pharmaceutically acceptable salt thereof, is wherein Z 2 is a heterocyclylene.
  • the compound of any one of embodiments 1 to 249, and 252, or a pharmaceutically acceptable salt thereof, is wherein when Z 2 is heterocyclylene, the heterocyclylene is selected from:
  • the compound of any one of embodiments 1 to 255, or a pharmaceutically acceptable salt thereof is wherein Z 3 is a bond, - (alkylene-O) d -, - (alkylene-NR”) -, alkylene, alkynylene, cycloalkylene, heteroarylene, -C (O) -, -OC (O) -, -O-, heterocyclylene, or spiro heterocyclylene.
  • the compound of any one of embodiments 1 to 256, or a pharmaceutically acceptable salt thereof is wherein Z 3 is a bond, - (alkylene-O) d -, alkylene, alkynylene, cycloalkylene, heteroarylene, -C (O) -, -O-, phenylene, spiro heterocyclylene, bridged heterocyclylene, bicyclic heterocyclylene, or fused heterocyclylene.
  • the compound of any one of embodiments 1 to 259, or a pharmaceutically acceptable salt thereof is wherein Z 4 is a bond, alkynylene, -NR’ (CO) -, -C (O) NR-, -S (O) 2 NR-, -O-, -C (O) -, -S (O) 2 -, - (alkylene-O) c -, alkylene, cyclolalkylene, heterocyclylene, phenylene, or monocyclic heteroarylene.
  • the compound of embodiment 256 to 258 and 260, or a pharmaceutically acceptable salt thereof is wherein Z 4 is a bond, -C (O) NR-, -S (O) 2 NR-, -O-, -C (O) -, -S (O) 2 -, alkylene, cyclolalkylene, or heterocyclylene.
  • the compound of embodiment 259 and 260, or a pharmaceutically acceptable salt thereof is wherein Z 4 is a bond, alkynylene, -NR’ (CO) -, -O-, - (alkylene-O) c -, alkylene, phenylene, heterocyclylene, or monocyclic heteroarylene.
  • the compound of of any one of embodiments 1 to 259, or a pharmaceutically acceptable salt thereof is wherein Z 4 is a bond, -S (O) 2 -, heterocyclylene, or phenylene.
  • the compound of embodiment 256, 261, and 264, or a pharmaceutically acceptable salt thereof is wherein Z 5 is a bond, -O-, -C (O) NR-, -NR”-, heterocyclylene, cycloalkylene, or -phenylene- (alkylene) -.
  • the compound of any one of embodiments 1 to 263, or a pharmaceutically acceptable salt thereof is wherein Z 5 is a bond, -O-, -C (O) -or -phenylene- (alkylene) .
  • the compound of any one of embodiments 1 to 263, or a pharmaceutically acceptable salt thereof, is wherein Z 5 is a bond.
  • the compound of embodiment 259 and 262 to 264, or a pharmaceutically acceptable salt thereof is wherein Z 5 is a bond, -O-, -C (O) -, , -C (O) NR-, -NR”-, alkylene, heterocyclylene, cycloalkylene, -phenylene- (alkylene) -or - (alkylene) -phenylene.
  • the compound of any one of embodiments 256, 261 and 265, or a pharmaceutically acceptable salt thereof, is wherein Z 6 is a bond, -NR”-, or heterocyclylene.
  • the compound of any one of embodiments 257, 262, 263, and 264, or a pharmaceutically acceptable salt thereof, is wherein Z 6 is a bond or heterocyclylene.
  • Z 2 is a bond, NH, or heterocyclylene
  • Z 3 is a bond, - (alkylene-O) d -, - (alkylene-NR”) -, alkylene, alkynylene, cycloalkylene,
  • heteroarylene -C (O) -, -O-, heterocyclylene, or spiro heterocyclylene
  • Z 4 is a bond, -C (O) NR-, -S (O) 2 NR-, -O-, -C (O) -, -S (O) 2 -, alkylene, cyclolalkylene, or heterocyclylene,
  • Z 5 is a bond, -O-, -C (O) NR-, -NR”-, heterocyclylene, cycloalkylene, or -phenylene- (alkylene) -;
  • Z 6 is a bond, -NR”-, or heterocyclylene, provided that at least one of Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 is other than a bond.
  • Z 2 is a bond, NH, or heterocyclylene
  • Z 3 is a bond, - (alkylene-O) d -, alkylene, alkynylene, cycloalkylene, -C (O) -, -O-, phenylene, heterocyclylene, spiro heterocyclylene, bridged heterocyclylene, bicyclic heterocyclylene, fused heterocyclylene;
  • Z 4 is a bond, alkynylene, -NR’ (CO) -, -O-, - (alkylene-O) c -, alkylene, cyclolalkylene, heterocyclylene, phenylene, monocyclic heteroarylene;
  • Z 5 is a bond, -O-, -C (O) -, -NR’ (CO) -, alkylene, - (alkylene) -phenylene-, or -phenylene- (alkylene) -; and
  • Z 6 is a bond, heterocyclylene provided that at least one of Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 is other than a bond.
  • the compound of embodiment 273 or 274, or a pharmaceutically acceptable salt thereof is wherein two of Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 are each a bond.
  • the compound of embodiment 273 or 274, or a pharmaceutically acceptable salt thereof is wherein three of Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 are each a bond.
  • the compound of embodiment 273 or 274, or a pharmaceutically acceptable salt thereof is wherein four of Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 are each a bond and the remaining of
  • Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 is NH or heterocyclylene, spiro heterocyclylene, bridged heterocyclylene, bicyclic heterocyclylene, or fused heterocyclylene wherein the heterocyclylene, spiro heterocyclylene, bridged heterocyclylene, bicyclic heterocyclylene, and fused heterocyclylene contains at one or two nitrogen ring atoms and optionally an oxygen ring atom and the NH and one of of the nitrogen ring atoms is attached to Z 1 .
  • L is -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -where -Z 1 -of L is -OC (O) -or -CH 2 OC (O) -and -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -of L is selected from the group consisting of:
  • L is -Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -where -Z 1 -of L is -OC (O) -or -CH 2 OC (O) -and -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -of L together with the Degron is selected from the group consisting of:
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis. ) , Bachem (Torrance, Calif. ) , or Sigma (St. Louis, Mo.
  • the reactions described herein take place at atmospheric pressure over a temperature range from about –78 °C to about 150 °C, such as from about 0 °C to about 125 °C and further such as at about room (or ambient) temperature, e.g., about 20 °C.
  • the sulfide in compound 1-d can be oxidized with an oxidation reagent such as m-CPBA, followed by displacement of the resulting sulfone or sulfoxide with an alcohol of formula 1-g provides a compound of formula 1-e. Removal of amino protecting group PG 1 in 1-e under standard reaction condition provides a compound of Formula (I) .
  • Treatment of a compound of formula 2-c where X a and X b are halogen, and R 2 and R 3 are as defined in the Summary under standard amide coupling conditions such as HATU, NH 4 Cl and DIPEA can provide an amide compound of formula 2-d.
  • Compound 2-d can undergo cyclization to provide a compound of formula 2-e by treating with NH 4 SCN and thionylchloride.
  • Methylation of thiol in compound 2-e by reacting with methyl iodide and a suitable base such as NaOH can provide compound 1-h.
  • Compound of formula 3-a where R 1 and R 1a are as defined in the Summary can be deprotonated with a base such s-BuLi, followed by trapping the resulting anion with methyl chloroformate can provide compound of formula 3-b.
  • the ester group in 3-b can be reduced with a suitable reducing reagent such as LiAlH 4 to provide alcohol 3-c, which can be converted to cyclic carbamate 3-d by treating with a base such as NaH.
  • the benzyl group in 3-d can be cleaved understand hydrogenation condition such as Pd/carbon as catalyst in hydrogen atmosphere.
  • Amine 3-e can be protected as t-butyl carbamate by reacting with Boc 2 O in the presence a base such as DIPEA.
  • the cyclic carbamate can be hydrolyzed by treating with a base such as NaOH in EtOH/water solvent to provide alcohol 1-f.
  • Compound of formula 3-a where R 1 and R 1a are as defined in the Summary can be deprotonated with a base such s-BuLi, followed by trapping the resulting anion with allylhalide such allylbromide can provide compound of formula 3-h.
  • Oxidative cleavage of the olefin in 3-h with an oxidation reagent such as K 2 OsO 4 and NaIO 4 can provide aldehyde 3-i, which can be reduced with a suitable reducing reagent such as NaBH 4 to provide compound of formula 3-j.
  • Compound 3-j can be converted to compound 1-f by the method described for the synthesis of 1-f where p is 1 from 3-c.
  • the present disclosure provides treatment of cancer mediated by K-ras, in particular with K-ras G12D mutants.
  • the cancer is pancreatic cancer, colorectal cancer, lung cancer, gall bladder cancer, thyroid cancer, and bile duct cancer.
  • the lung cancer is a non-small cell lung carcinoma (NSCLC) , for example adenocarcinoma, squamous-cell lung carcinoma or large-cell lung carcinoma.
  • the lung cancer is a small cell lung carcinoma.
  • Other lung cancers treatable with the disclosed compounds include, but are not limited to, glandular tumors, carcinoid tumors and undifferentiated carcinomas.
  • K-ras G12D mutations are observed in hematological malignancies that affect blood, bone marrow, and/or lymph nodes.
  • the compounds of Formula (I) or a pharmaceutically acceptable salt thereof can be used for the treatment of acute lymphoblastic leukemia (ALL) , acute myelogenous leukemia (AML) , chronic lymphocytic leukemia (CLL) , small lymphocytic lymphoma (SLL) , chronic myelogenous leukemia (CML) , acute monocytic leukemia (AMoL) and/or other leukemias, lymphomas such as all subtypes of Hodgkins lymphoma or non-Hodgkins lymphoma, plasma cell malignancies such as multiple myeloma, mantle cell lymphoma, and Waldenstrom’s macroglubunemia.
  • ALL acute lymphoblastic leukemia
  • AML acute myelogenous leukemia
  • CLL chronic lymphocy
  • the compounds of Formula (I) can be used for the treatment of a hyperproliferative disorder or metastasis in human who suffers from a cancer such as acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS related cancers (e.g.
  • Lymphoma and Kaposi's Sarcoma anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL) , chronic myelogenous leukemia (CML) , chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS) , embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthe
  • the compounds of Formula (I) , or a pharmaceutically acceptable salt thereof can also be used for the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis) , restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH) ) .
  • a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis) , restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH) ) .
  • the K-Ras G12D activity of the compounds of Formula (I) , or a pharmaceutically acceptable salt thereof can be tested using the in vitro assay described in Biological Examples 1 below.
  • the compounds Formula (I) (unless stated otherwise, reference to compound/compounds of Formula (I) herein includes any embodiments thereof described herein or a pharmaceutically acceptable salt thereof) will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • Therapeutically effective amounts of compounds Formula (I) may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses.
  • a suitable dosage level may be from about 0.1 to about 250 mg/kg per day; about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day.
  • the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day.
  • the compositions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient.
  • the actual amount of the compound Formula (I) i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors.
  • compounds Formula (I) will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository) , or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • routes oral, systemic (e.g., transdermal, intranasal or by suppository) , or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • parenteral e.g., intramuscular, intravenous or subcutaneous
  • compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • formulations in the form of tablets, pills or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred.
  • compositions are comprised of in general, a compound of Formula (I) in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are generally non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (I) .
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • the compounds of Formula (I) may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the compounds of Formula (I) may also be formulated as a depot preparation.
  • Such long -acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
  • Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
  • the compounds of Formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
  • Certain compounds of Formula (I) may be administered topically, that is by non-systemic administration. This includes the application of a compound of Formula (I) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient for topical administration may comprise, for example, from 0.001%to 10%w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10%w/w. In other embodiments, it may comprise less than 5%w/w. In certain embodiments, the active ingredient may comprise from 2%w/w to 5%w/w. In other embodiments, it may comprise from 0.1%to 1%w/w of the formulation.
  • compounds of Formula (I) may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds of Formula (I) may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E.W. Martin (Mack Publishing Company, 20th ed., 2000) .
  • the compounds of Formula (I) or a pharmaceutically acceptable salt thereof may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of Formula (I) or the other drugs may have utility.
  • Such other drug (s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula (I) or a pharmaceutically acceptable salt thereof can be used.
  • the pharmaceutical compositions of the present disclosure also include those that contain one or more other drugs, in addition to a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the combination therapy may also include therapies in which the compound of Formula (I) or a pharmaceutically acceptable salt thereof and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of Formula (I) and the other active ingredients may be used in lower doses than when each is used singly.
  • the weight ratio of the compound of this disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • the patient can be treated with a compound of Formula (I) or a pharmaceutically acceptable salt thereof in any combination with one or more other anti-cancer agents including but not limited to:
  • MAP kinase pathway (RAS/RAF/MEK/ERK) inhibitors including but not limited to: Vemurafanib (PLX4032, CAS No. 918504-65-1) , Dabrafenib (CAS No. 1195765-45-7) , Encorafenib (LGX818 CAS No. 1269440-17-6) , TQ-B3233, XL-518 (Cas No. 1029872-29-4, available from ACC Corp) ; trametinib (CAS No. 871700-17-3) , selumetinib (AZD6244 CAS No. 606143-52-6) , TQ-B3234, PD184352 (CAS No.
  • SHP2 inhibitors including but not limited to: SHP099 (CAS No. 2200214-93-1) , TNO155 (CAS No. 1801765-04-7) , RMC4630, JAB-3312, JAB-3068 and ERAS-601;
  • SOS1 inhibitors including but not limited to BI1701963 and BAY-293;
  • CSF1R inhibitors PLX3397, LY3022855,
  • CSF1R antibodies IMC-054, RG7l55
  • TGF beta receptor kinase inhibitor such as LY2157299
  • BTK inhibitor such as ibrutinib; BCR-ABL inhibitors: Imatinib (CAS No. 152459-95-5) ; Inilotinib hydrochloride; Nilotinib (CAS No. 923288-95-3) ; Dasatinib (BMS-345825 CAS No. 302962-49-8) ; Bosutinib (SKI-606 CAS No. 380843-75-4) ; Ponatinib (AP24534 CAS No. 943319-70-8) ; Bafetinib (INNO406 CAS No. 859212-16-1) ; Danusertib (PHA-739358 CAS No.
  • ALK inhibitors PF-2341066 ( crizotinib) ; 5-chloro-N4- (2- (isopropyl-sulfonyl) phenyl) -N2- (2-methoxy-4- (4- (4-methylpiperazin-l-yl) piperidin-l-yl) phenyl) pyrimidine-2, 4-diamine; GSK1838705A (CAS No. 1116235-97-2) ; CH5424802 (CAS No. 1256580-46-7) ; Ceritinib (ZYKADIA CAS No. 1032900-25-6) ; TQ-B3139, and TQ-B3101;
  • PI3K inhibitors 4- [2- (1H-indazol-4-yl) -6- [ [4- (methylsulfonyl) -piperazin-l-yl] methyl] thieno [3, 2-d] pyrimidin-4-yl] morpholine (also known as GDC 0941 and described in PCT Publication Nos. WO 09/036082 and WO 09/055730) , BEZ235 or NVP-BEZ235 (CAS No. 915019-65-7) , disclosed in PCT Publication No. WO 06/122806) ;
  • VEGF receptor inhibitors Bevacizumab (sold under the trademark by Genentech/Roche) , axitinib, (N-methyl-2- [ [3- [ (E) -2-pyridin-2-ylethenyl] -lH-indazol-6-yl] sulfanyl] benzamide, also known as AG013736, and described in PCT Publication No.
  • pasireotide also known as SOM230, and described in PCT Publication No. WO 02/010192
  • sorafenib sold under the tradename CAS No. 284461-73-0
  • AL-2846 AL-2846
  • MET inhibitor such as foretinib (CAS No. 849217-64-7) , cabozantinib (CAS No. 1140909-48-3) , capmatinib (CAS No. 1029712-80-8) , tepotinib (CAS No. 1100598-32-0) , savolitinib (CAS No. 1313725-88-0, or crizotinib (CAS No. 877399-52-5) ;
  • FLT3 inhibitors -sunitinib malate (CAS No. 341031-54-7, sold under the tradename by Pfizer) ; PKC412 (CAS No. 120685-11-2, midostaurin) ; tandutinib (CAS No. 387867-13-2) , sorafenib (CAS No. 284461-73-0) , lestaurtinib (CAS No.: 111358-88-4) , KW-2449 (CAS No. 1000669-72-6) , quizartinib (AC220, CAS No. 950769-58-1) , or crenolanib (CAS No. 670220-88-9) ;
  • Epidermal growth factor receptor (EGFR) inhibitors Gefitnib (sold under the tradename ) , N- [4- [ (3-chloro-4-fluorophenyl) amino] -7- [ [ (3S) -tetrahydro-3-furanyl] oxy] -6-quinazolinyl] -4 (dimethylamino) -2-butenamide, sold under the tradename by Boehringer Ingelheim) , cetuximab (sold under the tradename by Bristol-Myers Squibb) , or panitumumab (sold under the tradename by Amgen) ;
  • HER2 receptor inhibitors Trastuzumab (sold under the trademark by Genentech/Roche) , neratinib (also known as HKI-272, (2E) -N- [4- [ [3-chloro-4- [ (pyridin-2-yl) methoxy] phenyl] amino] -3-cyano-7-ethoxyquinolin-6-yl] -4- (d imethylamino) but-2-enamide, and described PCT Publication No. WO 05/028443) , lapatinib (CAS No.
  • lapatinib ditosylate (CAS No: 388082-77-7 ) (sold under the trademark by GlaxoSmithKline) ; or Trastuzumab emtansine (in the United States, ado-trastuzumab emtansine, trade name Kadcyla) -an antibody-drug conjugate consisting of the monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agent mertansine (DM1) ;
  • HER dimerization inhibitors Pertuzumab (sold under the trademark by Genentech) ;
  • FGFR inhibitors Erdafitinib (CAS No. 1346242-81-6) , Pemigatinib (CAS No. 1513857-77-6) or Infigratinib (CAS No. 872511-34-7)
  • Aurora kinase inhibitors TAS-119 (CAS No. 1453099-83-6) , LY3295668 (CAS No. 1919888-06-4) , or alisertib (CAS No. 1028486-01-2) ;
  • CD20 antibodies Rituximab (sold under the trademarks and by Genentech/Roche) , tositumomab (sold under the trademarks by GlaxoSmithKline) , or ofatumumab (sold under the trademark by GlaxoSmithKline) ;
  • Tyrosine kinase inhibitors Erlotinib hydrochloride (CAS No. 183319-69-9, sold under the trademark by Genentech/Roche) , Linifanib (N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N'- (2-fluoro-5-methylphenyl) urea, also known as ABT 869, available from Genentech) , sunitinib malate (CAS No.
  • DNA Synthesis inhibitors Capecitabine (CAS No. 154361-50-9) (sold under the trademark by Roche) , gemcitabine hydrochloride (CAS No. 122111-03-9) (sold under the trademark by Eli Lilly and Company) , or nelarabine ( (2R3S, 4R, 5R) -2- (2-amino-6-methoxypurin-9-yl) -5- (hydroxymethyl) oxolane-3, 4-diol, sold under the tradenames and by GlaxoSmithKline) ;
  • Antineoplastic agents oxaliplatin (CAS No. 61825-94-3) (sold under the tradename ay Sanofi-Aventis and described in US Patent No. 4,169,846) ;
  • G-CSF modulators Human Granulocyte colony-stimulating factor (G-CSF) modulators: Filgrastim (sold under the tradename by Amgen) ;
  • Immunomodulators Afutuzumab (available from ) , pegfilgrastim (sold under the tradename by Amgen) , lenalidomide (CAS No. 191732-72-6, also known as CC-5013, sold under the tradename ) , or thalidomide (CAS No. 50-35-1, sold under the tradename );
  • CD40 inhibitors Dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc) ;
  • PARAs Pro-apoptotic receptor agonists
  • Hedgehog antagonists 2-chloro-N- [4-chloro-3- (2-pyridinyl) phenyl] -4- (methylsulfony 1) -benzamide (also known as GDC-0449, and described in PCT Publication No. WO 06/028958) ;
  • Phospholipase A2 inhibitors Anagrelide (CAS No. 58579-51-4, sold under the tradename );
  • BCL-2 inhibitors 4- [4- [ [2- (4-chlorophenyl) -5, 5-dimethyl-l-cyclohexen-l-yl] met hyl] -1-piperazinyl] -N- [ [4- [ [ (lR) -3- (4-morpholinyl) -l- [ (phenylthio) m ethyl] propyl] amino] -3- [ (trifluoromethyl) sulfonyl] phenyl] sulfonyl] benzamide (also known as ABT-263 and described in PCT Publication No. WO 09/155386) ;
  • MCL-1 inhibitors MIK665 (CAS No. 1799631-75-6, S64315) , AMG 397, and AZD5991 (CAS No. 2143010-83-5) ;
  • Aromatase inhibitors Exemestane (CAS No. 107868-30-4, sold under the trademark by Pfizer) , letrozole (CAS No. 112809-51-5, sold under the tradename by Novartis) , or anastrozole (CAS No. 120511-73-1, sold under the tradename ) ;
  • Topoisomerase I inhibitors Irinotecan (CAS No. 97682-44-5, sold under the trademark by Pfizer) , topotecan hydrochloride (CAS No. 119413-54-6, sold under the tradename by GlaxoSmithKline) ;
  • Topoisomerase II inhibitors etoposide (CAS No. 33419-42-0, also known as VP-
  • Proteasome inhibitor such as carfilzomib (CAS No. 868540-17-4) , MLN9708 (CAS No. 1201902-80-8) , delanzomib (CAS No. 847499-27-8) , or bortezomib (CAS No. 179324-69-7) ;
  • BET inhibitors such as INCB054329 (CAS No. 1628607-64-6) , OTX015 (CAS No. 202590-98-5) , or CPI-0610 (CAS No. 1380087-89-7) ;
  • LSD1 inhibitors such as GSK2979552, or INCB059872;
  • HIF-2 ⁇ inhibitors such as PT2977 (1672668-24-4) , NKT2152, or PT2385 (CAS No. 1672665-49-4) ;
  • Osteoclastic bone resorption inhibitors 1-hydroxy-2-imidazol-l-yl-phosphonoethyl) phosphonic acid monohydrate (sold under the tradename by Novartis) ;
  • CD33 Antibody Drug Conjugates Gemtuzumab ozogamicin (sold under the tradename by Pfizer/Wyeth) ;
  • CD22 Antibody Drug Conjugates Inotuzumab ozogamicin (also referred to as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd. ) ;
  • CD20 Antibody Drug Conjugates Ibritumomab tiuxetan (sold under the tradename );
  • octreotide also known as octreotide acetate, sold under the tradenames and Sandostatin ) ;
  • Synthetic Interleukin-11 (IL-l 1) : oprelvekin (sold under the tradename by Pfizer/Wyeth) ;
  • Receptor Activator for Nuclear Factor k B (RANK) inhibitors Denosumab (sold under the tradename by Amgen) ;
  • Thrombopoietin mimetic peptibodies Romiplostim (sold under the tradename
  • IGF-1R antibodies Anti-insulin-like Growth Factor-l receptor (IGF-1R) antibodies: Figitumumab (also known as CP-751, 871, available from ACC Corp) , robatumumab (CAS No. 934235-44-6) ;
  • Anti-CSl antibodies Elotuzumab (HuLuc63, CAS No. 915296-00-3) ;
  • CD52 antibodies Alemtuzumab (sold under the tradename ) ;
  • Histone deacetylase inhibitors Voninostat (sold under the tradename by Merck) ;
  • Alkylating agents Temozolomide (sold under the tradenames and by Schering-Plough/Merck) , dactinomycin (also known as actinomycin-D and sold under the tradename ) , melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the tradename ) , altretamine (also known as hexamethylmelamine (HMM) , sold under the tradename ) , carmustine (sold under the tradename ) , bendamustine (sold under the tradename ) , busulfan (sold under the tradenames and ) , carboplatin (sold under the tradename ) , lomustine (also known as CCNU, sold under the tradename ) , cisplatin (also known as CDDP, sold under the tradenames and ) , chlorambucil (sold under the tradename ) , cyclophospham
  • Biologic response modifiers bacillus calmette-guerin (sold under the tradenames and BCG) , or Denileukin diftitox (sold under the tradename ) ;
  • Anti-tumor antibiotics doxorubicin (sold under the tradenames and ) , bleomycin (sold under the tradename ) , daunorubicin (also known as dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, sold under the tradename ) , daunorubicin liposomal (daunorubicin citrate liposome, sold under the tradename ) , mitoxantrone (also known as DHAD, sold under the tradename ) , epirubicin (sold under the tradename Ellence TM ) , idarubicin (sold under the tradenames Idamycin ) , or mitomycin C (sold under the tradename ) ;
  • Anti -microtubule agents Estramustine (CAS No. 52205-73-9, sold under the tradename );
  • Cathepsin K inhibitors Odanacatib (CAS No. 603139-19-1, also know as MK-0822 available from Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, and described in PCT Publication no. WO 03/075836) ;
  • Epothilone B analogs Ixabepilone (CAS No. 219989-84-1, sold under the tradename by Bristol-Myers Squibb) ;
  • HSP Heat Shock Protein
  • TpoR agonists Eltrombopag (sold under the tradenames and by GlaxoSmithKline) ;
  • Anti-mitotic agents Docetaxel (CAS No. 114977-28-5, sold under the tradename by Sanofi-Aventis) ; Adrenal steroid inhibitors: aminoglutethimide (CAS No. 125-84-8, sold under the tradename ) ;
  • Anti-androgens Nilutamide (CAS No. 63612-50-0, sold under the tradenames and ) , bicalutamide (CAS No. 90357-06-5, sold under tradename ) , or flutamide (CAS No. 13311-84-7, sold under the tradename Fulexin TM ) ;
  • Androgens Fluoxymesterone (CAS No. 76-43-7, sold under the tradename ) ;
  • CDK inhibitors including but not limited to: Alvocidib (CAS No. 146426-40-6, pan-CDK inhibitor, also known as flovopirdol or HMR-1275, 2- (2-chlorophenyl) -5, 7-dihydroxy-8- [ (3S, 4R) -3-hydroxy-l-methyl -4-piperidinyl] -4-chromenone, and described in US Patent No. 5,621,002) ;
  • CDK2 inhibitor PF-07104091 CDK2 inhibitor PF-07104091
  • CDK4/6 inhibitors pabociclib (CAS No. 827022-33-3) , ribociclib (CAS No. 1211441-98-3) , abemaciclib (CAS No. 1231929-97-7) , PF-06873600 (CAS No. 2185857-97-8) , NUV-422 and Trilaciclib (CAS No. 1374743-00-6) ;
  • CDK9 inhibtiors AZD 4573 (CAS No. 2057509-72-3) , P276-00 (CAS No. 920113-03-7) , AT7519 (CAS No. 844442-38-2) , CYC065 (CAS No. 1070790-89-4) or TP-1287;
  • GnRH Gonadotropin-releasing hormone receptor agonists: Leuprolide or leuprolide acetate (sold under the tradenames by Bayer AG, by Sanofi-Aventis and by Abbott Lab) ;
  • Taxane anti-neoplastic agents Cabazitaxel (l-hydroxy-7, 10 -dimethoxy-9-oxo-5, 20-epoxytax-11-ene-2a, 4, 13a-triyl-4-acetate-2-benzoate-13- [ (2R, 3S) -3- ⁇ [ (tert-butoxy) carbonyl] -amino ⁇ -2-hydroxy-3-phenylpropanoate) , or larotaxel ( (2a, 3x, 4a, 5b, 7a, 10b, 13a) -4, 10-bis (acetyloxy) -l3- ( ⁇ (2R, 3S) -3- [ (tert-butoxycarbonyl) amino] -2-hydroxy-3-phenylpropanoyl ⁇ oxy) -l-hydroxy-9-oxo-5, 20-epoxy-7, l9-cyclotax-11-en-2-ylbenzoate) ;
  • 5HTla receptor agonists Xaliproden (also known as SR57746, l- [2- (2-naphthyl) ethyl] -4- [3- (trifluoromethyl) phenyl] -l, 2, 3, 6-tetrahydropyridine, and described in US Patent No. 5,266,573) ;
  • HPC vaccines sold by GlaxoSmithKline, sold by Merck;
  • Iron Chelating agents Deferasinox (CAS No. 201530-41-8, sold under the tradename by Novartis) ;
  • Anti-metabolites Claribine (2-chlorodeoxyadenosine, sold under the tradename ) , 5-fluorouracil (sold under the tradename ) , 6-thioguanine (sold under the tradename ) , pemetrexed (sold under the tradename ) , cytarabine (also known as arabinosylcytosine (Ara-C) , sold under the tradename ) , cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DepoCyt TM ) , decitabine (sold under the tradename ) , hydroxyurea (sold under the tradenames Droxia TM and Mylocel TM ) , fludarabine (sold under the tradename ) , floxuridine (sold under the tradename ) , cladribine (also known as 2-chlorodeoxyadenosine (2-CdA) sold
  • Bisphosphonates Pamidronate (CAS No. 57248-88-1, sold under the tradename ) , zoledronic acid CAS No. 118072-93-8 (sold under the tradename ) ;
  • Demethylating agents 5-azacitidine (CAS No. 320-67-2, sold under the tradename ) , decitabine (CAS No. 2353-33-5, sold under the tradename ) ;
  • Paclitaxel protein-bound (sold under the tradename ) , vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, sold under the tradenames Alkaban- and ) , vincristine (also known as vincristine sulfate, LCR, and VCR, sold under the tradenames and Vincasar ) , vinorelbine (sold under the tradename ) , or paclitaxel (sold under the tradenames Taxol and Onxal TM ) ;
  • Retinoids Ali tretinoin (sold under the tradename ) , tretinoin (all-trans retinoic acid, also known as ATRA, sold under the tradename ) , Isotretinoin (13-cis-retinoic acid, sold under the tradenames and ) , or bexarotene (sold under the tradename ) ;
  • Glucocorticosteroids Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames Hydrocortisone Phosphate, Hydrocort and ) , dexamethazone ( (8S, 9R, 10S, 11S, 13S, 14S, 16R, 17R) -9-fluoro-11, 17-dihydroxy-17- (2-hydroxyacetyl) -10, 13, 16-trimethyl-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [a] phenanthren-3-one) , prednisolone (sold under the tradenames and ) , prednisone (sold under the tradenames Liquid and ) , or methylprednisolone (also known as 6-Methylprednisolone, Methylprednisolone Acetate, Methylpredn
  • Cytokines interleukin-2 (also known as aldesleukin and IL-2, sold under the tradename ) , interleukin-11 (also known as oprevelkin, sold under the tradename ) , alpha interferon alfa (also known as IFN-alpha, sold under the tradenames A, and ) ;
  • Estrogen receptor downregulators Fulvestrant (CAS No. 129453-61-8, sold under the tradename ) ;
  • Anti-estrogens tamoxifen (CAS No. 10540-29-1, sold under the tradename ) ; or Toremifene (CAS No. 89778-27-8, sold under the tradename ) ;
  • SERMs Selective estrogen receptor modulators
  • LfRH Leutinizing hormone releasing hormone
  • Goserelin CAS No. 145781-92-6, sold under the tradename
  • Progesterones megestrol (also known as megestrol acetate, CAS No. 595-33-5, sold under the tradename )
  • megestrol also known as megestrol acetate, CAS No. 595-33-5, sold under the tradename
  • Miscellaneous cytotoxic agents Arsenic trioxide (sold under the tradename ) , or asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, sold under the tradenames and ) ;
  • immune checkpoint inhibitors include inhibitors (smack molecules or biologies) against immune checkpoint molecules such as CD27, CD28, CD40, CD 122, CD96, CD73, CD39, CD47, 0X40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM kinase, arginase, CD137 (also known as 4-1BB) , ICOS, A2AR, A2BR, HIF-2a, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-l, PD-L1 and PD-L2.
  • inhibitors smack molecules or biologies against immune checkpoint molecules
  • immune checkpoint molecules such as CD27, CD28, CD40, CD 122, CD96, CD73, CD39, CD47, 0X40, GITR, CSF1R, JAK, PI3K delta, PI3K
  • the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, 0X40, GITR, CD137 and STING.
  • the immune checkpoint molecule is an inhibitory checkpoint molecule selected from B7-H3, B7-H4, BTLA, CTLA-4, IDO, TDO, Arginase, KIR, LAG3, PD-l, TIM3, CD96, TIGIT and VISTA.
  • the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD 160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-l, e.g., an anti-PD-l monoclonal antibody.
  • the anti-PD-l monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475) , pidilizumab, SHR-1210, PDR001, or AMP -224.
  • the anti-PD-l monoclonal antibody is nivolumab, or pembrolizumab or PDR001.
  • the anti -PD 1 antibody is pembrolizumab.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody.
  • the anti-CTLA-4 antibody is ipilimumab or tremelimumab.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody.
  • the anti-LAG3 antibody is BMS-986016 or LAG525.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody.
  • the anti-GITR antibody is TRX518 or, MK-4166, INCAGN01876 or MK-1248.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of 0X40, e.g., an anti-OX40 antibody or OX40L fusion protein.
  • the anti-OX40 antibody is MED 10562 or, INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600 or LAG525.
  • the OX40L fusion protein is MEDI6383.
  • Compounds of the invention can also be used to increase or enhance an immune response, including increasing the immune response to an antigen; to improve immunization, including increasing vaccine efficacy; and to increase inflammation.
  • the compounds of the invention can be sued to enhance the immune response to vaccines including, but not limited, Listeria vaccines, oncolytic viral vaccines, and cancer vaccines such as (granulocyte-macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine) .
  • Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.
  • immune-modulatory agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4; Sting agonists and Toll receptor agonists.
  • Other anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer. Compounds of this application may be effective in combination with CAR (Chimeric antigen receptor) T cell treatment as a booster for T cell activation.
  • CAR Chimeric antigen receptor
  • a compound of the invention can also be used in combination with the following adjunct therapies: Anti-nausea drugs: NK-l receptor antagonists: Casopitant (sold under the tradenames and by GlaxoSmithKline) ; and Cytoprotective agents: Amifostine (sold under the tradename ) , leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid) .
  • NK-l receptor antagonists Casopitant (sold under the tradenames and by GlaxoSmithKline)
  • Cytoprotective agents Amifostine (sold under the tradename ) , leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid) .
  • Step 2 tert-butyl (5S) -2-cyano-5- (hydroxymethyl) pyrrolidine-1-carboxylate
  • Step 4 (5S) -1-tert-butyl 2-methyl 5- ( ( (tert-butyldiphenylsilyl) oxy) methyl) pyrrolidine-1, 2-dicarboxylate
  • Step 5 1- (tert-butyl) 2-methyl (2S, 5S) -5- ( ( (tert-butyldiphenylsilyl) oxy) methyl) -2- (2- (chloromethyl) allyl) pyrrolidine-1, 2-dicarboxylate
  • Step 6 methyl (5S, 7aS) -5- ( ( (tert-butyldiphenylsilyl) oxy) methyl) -2-methylenetetrahydro-1H-pyrrolizine-7a (5H) -carboxylate
  • Step 7 ( (5S, 7aS) -5- ( ( (tert-butyldiphenylsilyl) oxy) methyl) -2-methylenetetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol
  • Step 2 1- (tert-butyl) 2-methyl (2R, 5S) -5- (2-oxoethyl) pyrrolidine-1, 2-dicarboxylate
  • Step 3 1- (tert-butyl) 2-methyl (2R, 5S) -5- (2-hydroxyethyl) pyrrolidine-1, 2-dicarboxylate
  • Step 4 1- (tert-butyl) 2-methyl (2R, 5S) -5- (2- ( (tert-butyldiphenylsilyl) oxy) ethyl) pyrrolidine-1, 2-dicarboxylate
  • Step 5 ( (5S, 7aS) -5- (2- ( (tert-butyldiphenylsilyl) oxy) ethyl) -2-methylenetetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol
  • Step 2 tert-butyl (2S) -2-formyl-5-methoxypyrrolidine-1-carboxylate
  • Step 3 tert-butyl (2S) -2- (1-hydroxyethyl) -5-methoxypyrrolidine-1-carboxylate
  • Step 3 tert-butyl (5S) -2-cyano-5- (1-hydroxyethyl) pyrrolidine-1-carboxylate
  • Step 4 1- (tert-butyl) 2-methyl (5S) -5- (1-hydroxyethyl) pyrrolidine-1, 2-dicarboxylate
  • Step 5 1- (tert-butyl) 2-methyl (5S) -5- (1- ( (tert-butyldiphenylsilyl) oxy) ethyl) pyrrolidine 1, 2-dicarboxylate
  • Step 6 ( (5S, 7aS) -5- (1- ( (tert-butyldiphenylsilyl) oxy) ethyl) -2-methylenetetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol
  • Step 2 di-tert-butyl (2, 6-dichloro-3-fluoropyridin-4-yl) carbamate
  • Step 3 tert-butyl 4- ( (tert-butoxycarbonyl) amino) -2, 6-dichloro-5-fluoronicotinate
  • Step 4 4-amino-2, 6-dichloro-5-fluoronicotinic acid hydrochloride
  • Step 5 5, 7-dichloro-8-fluoro-2-mercaptopyrido [4, 3-d] pyrimidin-4-ol
  • Step 6 5, 7-dichloro-8-fluoro-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-ol
  • Step 1 a mixture of tert-butyl (1R, 5S) -2-allyl-8-benzyl-3, 8-diazabicyclo [3.2.1] octane-3-carboxylate and tert-butyl (1S, 5R) -2-allyl-8-benzyl-3, 8-diazabicyclo [3.2.1] octane-3-carboxylate
  • Step 2 a mixture of tert-butyl (1R, 5S) -8-benzyl-2- (2-oxoethyl) -3, 8-diazabicyclo [3.2.1] octane-3-carboxylate and tert-butyl (1S, 5R) -8-benzyl-2- (2-oxoethyl) -3, 8-diazabicyclo [3.2.1] octane-3-carboxylate
  • Step 3 a mixture of tert-butyl (1R, 5S) -8-benzyl-2- (2-hydroxyethyl) -3, 8-diazabicyclo [3.2.1] octane-3-carboxylate and tert-butyl (1S, 5R-8-benzyl-2- (2-hydroxyethyl) -3, 8-diazabicyclo [3.2.1] octane-3-carboxylate
  • Step 4 a mixture of (4aR, 5S, 8R) -11-benzyloctahydro-1H-5, 8-epimino [1, 3] oxazino [3, 4-a] azepin-1-one and (4aS, 5R, 8S) -11-benzyloctahydro-1H-5, 8-epimino [1, 3] oxazino [3, 4-a] azepin-1-one
  • Step 5 a mixture of (4aR, 5S, 8R) -octahydro-1H-5, 8-epimino [1, 3] oxazino [3, 4-a] azepin-1-one and (4aS, 5R, 8S) -octahydro-1H-5, 8-epimino [1, 3] oxazino [3, 4-a] azepin-1-one
  • Step 6 a mixture of tert-butyl (4aR, 5S, 8R) -1-oxooctahydro-1H-5, 8-epimino [1, 3] oxazino [3, 4-a] azepine-11-carboxylate and tert-butyl (4aS, 5R, 8S) -1-oxooctahydro-1H-5, 8-epimino [1, 3] -oxazino [3, 4-a] azepine-11-carboxylate
  • the resulting mixture was extracted with DCM.
  • the combined organic layers were dried over anhydrous Na 2 SO 4 and then concentrated to provide a mixture of the title compounds (2.1 g) .
  • Step 8 a mixture of tert-butyl (1S, 2R, 5R) -2- (2- ( (7-chloro-8-fluoro-4-hydroxy-2- (methylthio) -pyrido [4, 3-d] pyrimidin-5-yl) oxy) ethyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate and tert-butyl (1R, 2S, 5S) -2- (2- ( (7-chloro-8-fluoro-4-hydroxy-2- (methylthio) pyrido [4, 3-d] pyrimidin-5-yl) oxy) -ethyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
  • Step 9 a mixture of tert-butyl (6aR, 7S, 10R) -2-chloro-1-fluoro-13- (methylthio) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta- [1, 2, 3-de] naphthalene-15-carboxylate and tert-butyl (6aS, 7R, 10S) -2-chloro-1-fluoro-13- (methylthio) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta- [4, 5] cycloocta [1, 2, 3-de] naphthalene-15-carboxylate
  • Step 10 a mixture of tert-butyl (6aR, 7S, 10R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) -ethynyl) -naphthalen-1-yl) -13- (methylthio) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalene-15-carboxylate and tert-butyl (6aS, 7R, 10S) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -13- (methylthio) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a
  • Step 11 a mixture of tert-butyl (6aR, 7S, 10R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) -naphthalen-1-yl) -13- (methylsulfonyl) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalene-15-carboxylate and tert-butyl (6aS, 7R, 10S) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -13- (methylsulfonyl) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-
  • Step 1 tert-butyl (1S, 2R, 5R) -2- (2- ( (7-chloro-8-fluoro-4-hydroxy-2- (methylthio) pyrido [4, 3-d] -pyrimidin-5-yl) oxy) ethyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
  • Step 2 tert-butyl (6aR, 7S, 10R) -2-chloro-1-fluoro-13- (methylthio) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalene-15-carboxylate
  • Step 3 tert-butyl (6aR, 7S, 10R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -13- (methylthio) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclo-hepta [4, 5] cycloocta [1, 2, 3-de] naphthalene-15-carboxylate
  • Step 4 tert-butyl (6aR, 7S, 10R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -13- (methylsulfinyl) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methano-cyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalene-15-carboxylate and tert-butyl (6aR, 7S, 10R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -13- (methylsulfonyl) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3
  • Step 5 tert-butyl (6aR, 7S, 10R) -13- ( ( (5S, 7aS) -5- ( ( (tert-butyldiphenylsilyl) oxy) methyl) -2-methylenetetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -1-fluoro-2- (7-fluoro-8- ( (triisopropyl-silyl) ethynyl) naphthalen-1-yl) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalene-15-carboxylate
  • Step 7 tert-butyl (6aR, 7S, 10R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-13- ( ( (5S, 7aS) -2-methylene-5- ( ( ( (4-nitrophenoxy) carbonyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methano cyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalene-15-carboxylate
  • Step 1 2- (trimethylsilyl) ethyl (6aR, 7S, 10R) -1-fluoro-2- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsily l) ethynyl) naphthalen-1-yl) -13- (methylthio) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalene-15-carboxylate
  • Step 2 tert-butyl (6aR, 7S, 10R) -2- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -1-fluoro-13- (methylthio) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclo-hepta [4, 5] cycl oocta [1, 2, 3-de] naphthalene-15-carboxylate
  • Step 3 a mixture of tert-butyl (6aR, 7S, 10R) -2- (8-ethynyl-7-fluoro-3- (methoxymethoxy) -naphthalen-1-yl) -1-fluoro-13- (methylsulfinyl) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclo-hepta [4, 5] cycloocta [1, 2, 3-de] naphthalene-15-carboxylate and tert-butyl (6aR, 7S, 10R) -2- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -1-fluoro-13- (methylsulfonyl) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a
  • reaction mixture was diluted with water, extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (0-5%) to afford the title compound (70 mg) .
  • Step 1 2- (trimethylsilyl) ethyl (1S, 2R, 5R) -2- (2- ( (7-chloro-8-fluoro-4-hydroxy-2- (methylthio) -pyrido [4, 3-d] pyrimidin-5-yl) oxy) ethyl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
  • Step 2 2- (trimethylsilyl) ethyl (6aR, 7S, 10R) -2-chloro-1-fluoro-13- (methylthio) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] -naphthalene-15-carboxylate
  • Step 3 2- (trimethylsilyl) ethyl (6aR, 7S, 10R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) -naphthalen-1-yl) -13- (methylthio) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalene-15-carboxylate
  • Step 4 a mixture of 2- (trimethylsilyl) ethyl (6aR, 7S, 10R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) -ethynyl) -naphthalen-1-yl) -13- (methylsulfinyl) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalene-15-carboxylate and 2- (trimethylsilyl) -ethyl (6aR, 7S, 10R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -13- (methylsulfonyl) -5, 6, 6a,
  • Step 5 2- (trimethylsilyl) ethyl (6aR, 7S, 10R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) -naphthalen-1-yl) -13- ( (1- (hydroxymethyl) cyclopropyl) methoxy) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalene-15-carboxylate
  • Step 1 2- (trimethylsilyl) ethyl (6aR, 7S, 10R) -1-fluoro-2- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -13- (methylthio) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalene-15-carboxylate
  • Step 2 a mixture of 2- (trimethylsilyl) ethyl (6aR, 7S, 10R) -1-fluoro-2- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -13- (methylsulfinyl) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] -cycloocta [1, 2, 3-de] naphthalene-15-carboxylate and 2- (trimethylsilyl) ethyl (6aR, 7S, 10R) -1-fluoro-2- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl
  • Step 3 2- (trimethylsilyl) ethyl (6aR, 7S, 10R) -1-fluoro-2- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -13- ( (1- (hydroxymethyl) cyclopropyl) methoxy) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclo-hepta [4, 5] -cycloocta [1, 2, 3-de] naphthalene-15-carboxylate
  • Step 1 1- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) piperidine-4-carboxylic acid
  • Step 2 tert-butyl (3R) -4- (1- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) piperidine-4-carbonyl) -3-methylpiperazine-1-carboxylate
  • Step 3 3- (5- (4- ( (R) -2-methylpiperazine-1-carbonyl) piperidin-1-yl) -1-oxoisoindolin-2-yl) piper idine-2, 6-dione
  • Step 4 tert-butyl (6aR, 7S, 10R) -13- ( ( (5S, 7aS) -5- ( ( ( (3R) -4- (1- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) piperidine-4-carbonyl) -3-methylpiperazine-1-carbonyl) oxy) methyl) -2-methylenetetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1- fluoro-5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] -cycloocta [1, 2, 3-de] naphthalene-15-carboxylate
  • Step 5 ( (3S, 7aS) -7a- ( ( ( (6aR, 7S, 10R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] -cycloocta [1, 2, 3-de] naphthalen-13-yl) oxy) methyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl (3R) -4- (1- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) piperidine-4-carbonyl) -3-methylpiperazine-1-carboxylate
  • Step 1 tert-butyl 4- ( (1- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) piperidin-4-yl) oxy) -piperidine-1-carboxylate
  • Step 2 3- (1-oxo-5- (4- (piperidin-4-yloxy) piperidin-1-yl) isoindolin-2-yl) piperidine-2, 6-dione
  • Step 3 ( (3S, 7aS) -7a- ( ( ( (6aR, 7S, 10R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta- [1, 2, 3-de] naphthalen-13-yl) oxy) methyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl 4- ( (1- (2- (2, 6-dioxopiperidin-3-yl) -1-oxoisoindolin-5-yl) piperidin-4-yl) oxy) piperidine-1-carboxylate
  • Step 1 tert-butyl (6aR, 7S, 10R) -2- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -1-fluoro-13- ( ( (5S, 7aS) -5- ( ( (4- (5- (1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) -ethyl) -carbamoyl) pyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl) isoxazol-3-yl) piperazine-1-carbonyl) -oxy) -methyl) -2-methylene tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14,
  • Step 2 ( (3S, 7aS) -7a- ( ( ( (6aR, 7S, 10R) -2- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta- [1, 2, 3-de] naph thalen-13-yl) oxy) methyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl 4- (5- (1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamoyl) pyrrolidin-1-yl) -3-methyl-1-oxobutan-2-yl) isoxazol-3
  • Step 1 2- (3- (4- (tert-butoxycarbonyl) piperazin-1-yl) isoxazol-5-yl) -3-methylbutanoic acid
  • Step 1 2- (trimethylsilyl) ethyl (6aR, 7S, 10R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) -naphthalen-1-yl) -13- ( (1- ( ( (methylsulfonyl) oxy) methyl) cyclopropyl) methoxy) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalene-15-carboxylate
  • Step 2 2- (trimethylsilyl) ethyl (6aR, 7S, 10R) -13- ( (1- ( (4- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -1-methyl-1H-indazol-6-yl) piperidin-1-yl) methyl) cyclopropyl) methoxy) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalene-15-carboxylate
  • Step 3 1- (6- (1- ( (1- ( ( ( (6aR, 7S, 10R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] -cycloocta [1, 2, 3-de] naphthalen-13-yl) oxy) methyl) cyclopropyl) methyl) piperidin-4-yl) -1-methyl-1H-indazol-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 1 tert-butyl 9- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) -3, 9-diazaspiro [5.5] -undecane-3-carboxylate
  • Step 3 2- (trimethylsilyl) ethyl (6aR, 7S, 10R) -13- ( (1- ( (9- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) -3, 9-diazaspiro [5.5] undecan-3-yl) methyl) cyclopropyl) methoxy) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalene-15-carboxylate
  • Step 1 tert-butyl 4- ( (4- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -1-methyl-1H-indazol-6-yl) -piperidin-1-yl) methyl) piperidine-1-carboxylate
  • Step 3 2- (trimethylsilyl) ethyl (6aR, 7S, 10R) -13- ( (1- ( (4- ( (4- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -1-methyl-1H-indazol-6-yl) piperidin-1-yl) methyl) piperidin-1-yl) methyl) cyclopropyl) methoxy) -1- fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] -cycloocta [1, 2, 3-de] naphthalene-15-carboxylate
  • Step 4 1- (6- (1- ( (1- ( (1- ( (1- ( ( ( (6aR, 7S, 10R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta- [4, 5] cycloocta [1, 2, 3-de] naphthalen-13-yl) oxy) methyl) cyclopropyl) methyl) piperidin-4-yl) methyl) piperidin-4-yl) -1-methyl-1H-indazol-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 1 2- (trimethylsilyl) ethyl (6aR, 7S, 10R) -1-fluoro-2- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -13- ( (1- ( ( (methylsulfonyl) oxy) methyl) -cyclopropyl) methoxy) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalene-15-carboxylate
  • Step 2 2- (trimethylsilyl) ethyl (6aR, 7S, 10R) -13- ( (1- ( (4- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -1-methyl-1H-indazol-6-yl) piperidin-1-yl) methyl) cyclopropyl) methoxy) -1-fluoro-2- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalene-15-carboxylate
  • Step 3 1- (6- (1- ( (1- ( ( ( (6aR, 7S, 10R) -2- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -1-fluoro-5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta- [4, 5] cycloocta [1, 2, 3-de] naphthalen-13-yl) oxy) methyl) cyclopropyl) methyl) piperidin-4-yl) -1-methyl-1H-indazol-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 4 1- (6- (1- ( (1- ( ( ( (6aR, 7S, 10R) -2- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta- [4, 5] cycloocta [1, 2, 3-de] naphthalen-13-yl) oxy) methyl) cyclopropyl) methyl) piperidin-4-yl) -1-methyl-1H-indazol-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 2 2- (2, 6-dioxopiperidin-3-yl) -5- (9- ( (1- ( ( ( (6aR, 7S, 10R) -2- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -1-fluoro-5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalen-13-yl) oxy) methyl) -cyclopropyl) methyl) -3, 9-diazaspiro [5.5] undecan-3-yl) isoindoline-1, 3-dione
  • Step 3 2- (2, 6-dioxopiperidin-3-yl) -5- (9- ( (1- ( ( ( (6aR, 7S, 10R) -2- (8-ethynyl-7-fluoro-3-hydroxy-naphthalen-1-yl) -1-fluoro-5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalen-13-yl) oxy) methyl) cyclopropyl) methyl) -3, 9-diazaspiro [5.5] undecan-3-yl) isoindoline-1, 3-dione
  • Step 1 3- (2, 6-bis (benzyloxy) pyridin-3-yl) -6-bromo-1-methyl-1H-indazole
  • Step 2 tert-butyl 4- (3- (2, 6-bis (benzyloxy) pyridin-3-yl) -1-methyl-1H-indazol-6-yl) -3, 6-dihydro-pyridine-1 (2H) -carboxylate
  • Step 4 3- (1-methyl-6- (piperidin-4-yl) -1H-indazol-3-yl) piperidine-2, 6-dione hydrochloride
  • Step 5 2- (trimethylsilyl) ethyl (6aR, 7S, 10R) -1-fluoro-2- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) -naphthalen-1-yl) -13- ( (1- ( (tosyloxy) methyl) cyclopropyl) methoxy) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalene-15-carboxylate
  • Step 6 2- (trimethylsilyl) ethyl (6aR, 7S, 10R) -13- ( (1- ( (4- (3- (2, 6-dioxopiperidin-3-yl) -1-methyl-1H-indazol-6-yl) piperidin-1-yl) methyl) cyclopropyl) methoxy) -1-fluoro-2- (7-fluoro-8- ( (triisopropyl- silyl) ethynyl) naphthalen-1-yl) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalene-15-carboxylate
  • Step 7 3- (6- (1- ( (1- ( ( ( (6aR, 7S, 10R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalen-13-yl) oxy) methyl) cyclopropyl) methyl) piperidin-4-yl) -1-methyl-1H-indazol-3-yl) piperidine-2, 6-dione
  • Step 1 tert-butyl 2- (4- (3- (2, 6-dioxopiperidin-3-yl) -1-methyl-1H-indazol-6-yl) piperidin-1-yl) -7-azaspiro [3.5] nonane-7-carboxylate
  • Step 2 3- (6- (1- (7-azaspiro [3.5] nonan-2-yl) piperidin-4-yl) -1-methyl-1H-indazol-3-yl) piperidine-2, 6-dione
  • Step 3 3- (6- (1- (7- ( (1- ( ( ( (6aR, 7S, 10R) -2- (8-ethynyl-7-fluoronaphthalen-1-yl) -1-fluoro-5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] -cycloocta [1, 2, 3-de] naphthalen-13-yl) oxy) methyl) cyclopropyl) methyl) -7-azaspiro [3.5] nonan-2-yl) piperidin-4-yl) -1-methyl-1H-indazol-3-yl) piperidine-2, 6-dione
  • Step 1 2- (trimethylsilyl) ethyl (6aR, 7S, 10R) -1-fluoro-2- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -13- ( (1- ( (tosyloxy) methyl) cyclopropyl) methoxy) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] -cycloocta [1, 2, 3-de] naphthalene-15-carboxylate
  • Step 2 2- (trimethylsilyl) ethyl (6aR, 7S, 10R) -13- ( (1- ( (2- (4- (3- (2, 6-dioxopiperidin-3-yl) -1-methyl-1H-indazol-6-yl) piperidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) methyl) cyclopropyl) methoxy) -1-fluoro-2- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] -naphthalene-15-carboxylate
  • Step 3 3- (6- (1- (7- ( (1- ( ( ( (6aR, 7S, 10R) -1-fluoro-2- (7-fluoro-3-hydroxy-8- ( (triisopropylsilyl) -ethynyl) naphthalen-1-yl) -5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10- methanocyclohepta [4, 5] cycloocta [1, 2, 3-de] naphthalen-13-yl) oxy) methyl) cyclopropyl) methyl) -7-azaspiro [3.5] nonan-2-yl) piperidin-4-yl) -1-methyl-1H-indazol-3-yl) piperidine-2, 6-dione
  • Step 4 3- (6- (1- (7- ( (1- ( ( ( (6aR, 7S, 10R) -2- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -1-fluoro-5, 6, 6a, 7, 8, 9, 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methanocyclohepta [4, 5] cyclo-octa [1, 2, 3-de] naphthalen-13-yl) oxy) methyl) cyclopropyl) methyl) -7-azaspiro [3.5] nonan-2-yl) piperidin-4-yl) -1-methyl-1H-indazol-3-yl) piperidine-2, 6-dione
  • AsPC-1 cells were seeded into 96-well round black/clear bottom, ultra-low attachment surface plate in 100 ⁇ l cell culture medium (RPMI1640 with 10%FBS) . After 3 days incubation at 37 °C and 5%CO 2 , compounds solubilized in DMSO were added by Tecan D300e dispenser (0.5%DMSO final) . The cells were incubated for 4 days at 37 °C and 5%CO 2 . Cell proliferation was quantitated by addition of 50 ⁇ l/well of 3D reagent (Promega) . The solutions were well mixed by shaking the plate for 10 minutes using an orbital plate shaker and then incubated at room temperature for a total of 30 minutes.
  • 3D reagent Promega
  • the HiBiT KRAS G12D AsPC-1 cell line was generated using CRISPR-Cas9 method to knock-in the HiBiT tag onto the N-terminal of the endogenous KRAS allele (ACS Chem. Biol. 13 (2) , 467-474 . 2018) .
  • Individual clones were isolated by limited dilution and screened using the Nano-Glo HiBiT Detection System (Promega #N3050) to identify clones with the highest luminescence signal. The selected clones were verified for the insertion of HiBiT by PCR and subsequent sequencing. Finally, a clone harboring the desired HiBiT-KRAS G12D sequence at one allele and exhibiting high Luminescence signal was chosen for further studies.
  • AsPC-1 HiBiT-KRAS G12D cells were seeded at 10000 cells per well in culture medium into 384 well plates (Greiner, #781098) . The plates were incubated at 37 °C, 5 %CO 2 in a humidified incubator overnight to allow cell adhesion. The test compounds were diluted by Biomek i7 and applied to the plated cells by Mosquito, resulting in a final concentration titration from 3 mM to 150 pM in 0.2%DMSO. Plates were further incubated at 37°C for 24 hours.
  • Nano-Glo HiBiT lytic detection reagent mix Promega, Nano-Glo HiBiT lytic detection system cat#N3050
  • the plates were incubated on an orbital shaker (300 rpm) for 3 minutes and then further incubated for 10 minutes at RT.
  • luminescence was measured using an Envision plate reader (PerkinElmer) .
  • %Degradation (1- (Sample HiBiT signal-Ave Min signal) / (Ave Max signal-Ave Min signal) ) *100%.
  • DC 50 the data with the hook effect were removed first and DC 50 was reported using a 4-parameter fit of dose response curve using XLfit 5.5. x. Dmax values represent the maximal extent of degradation observed and are stated as percent of control (%Ctrl) treatment.
  • Compound of the disclosure e.g., compound 1 in 2%HPMC, 1%Tween 80 in DI water, pH 2.2 with MSA, q. s. to at least 20 mg/mL
  • a pharmaceutical composition for inhalation delivery 20 mg of a compound disclosed herein is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9%sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration.
  • an inhalation delivery unit such as a nebulizer
  • a pharmaceutical topical gel composition 100 mg of a compound disclosed herein is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then ncorporated into containers, such as tubes, which are suitable for topical administration.
  • a pharmaceutical ophthalmic solution composition 100 mg of a compound disclosed herein is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.
  • a pharmaceutical nasal spray solution 10 g of a compound disclosed herein is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4) .
  • the solution is placed in a nasal administrator designed to deliver 100 ul of spray for each application.

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Abstract

La présente divulgation concerne certains dérivés tétracycliques qui inhibent certaines protéines K-Ras et sont par conséquent utiles pour le traitement de cancers médiés par de telles protéines. La présente invention concerne également des compositions pharmaceutiques contenant de tels composés et des procédés de préparation de tels composés.
PCT/CN2024/071245 2023-01-10 2024-01-09 Composés bifonctionnels pour dégrader kras-12d par l'intermédiaire de la voie ubiquitine-protéasome WO2024149214A1 (fr)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018206539A1 (fr) * 2017-05-11 2018-11-15 Astrazeneca Ab Composés hétéroaryle inhibant des protéines ras portant la mutation g12c
WO2019215203A1 (fr) * 2018-05-08 2019-11-14 Astrazeneca Ab Composés hétéroaryles tétracycliques
WO2022173678A1 (fr) * 2021-02-09 2022-08-18 Genentech, Inc. Composés d'oxazépine tétracycliques et leurs utilisations
WO2022188729A1 (fr) * 2021-03-07 2022-09-15 Jacobio Pharmaceuticals Co., Ltd. Dérivés cycliques fusionnés utiles en tant qu'inhibiteurs de kras g12d
WO2022194245A1 (fr) * 2021-03-17 2022-09-22 劲方医药科技(上海)有限公司 Composé cyclique fusionné à une pyrimidine, procédé de préparation s'y rapportant et son utilisation
WO2022199587A1 (fr) * 2021-03-24 2022-09-29 南京明德新药研发有限公司 Composé hétérocyclique de pyrimidine et son application
WO2022206723A1 (fr) * 2021-03-30 2022-10-06 浙江海正药业股份有限公司 Dérivé hétérocyclique, son procédé de préparation et son utilisation en médecine
WO2022268051A1 (fr) * 2021-06-21 2022-12-29 江苏恒瑞医药股份有限公司 Composé tétracyclique fusionné, son procédé de préparation et son utilisation en médecine

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018206539A1 (fr) * 2017-05-11 2018-11-15 Astrazeneca Ab Composés hétéroaryle inhibant des protéines ras portant la mutation g12c
WO2019215203A1 (fr) * 2018-05-08 2019-11-14 Astrazeneca Ab Composés hétéroaryles tétracycliques
WO2022173678A1 (fr) * 2021-02-09 2022-08-18 Genentech, Inc. Composés d'oxazépine tétracycliques et leurs utilisations
WO2022188729A1 (fr) * 2021-03-07 2022-09-15 Jacobio Pharmaceuticals Co., Ltd. Dérivés cycliques fusionnés utiles en tant qu'inhibiteurs de kras g12d
WO2022194245A1 (fr) * 2021-03-17 2022-09-22 劲方医药科技(上海)有限公司 Composé cyclique fusionné à une pyrimidine, procédé de préparation s'y rapportant et son utilisation
WO2022199587A1 (fr) * 2021-03-24 2022-09-29 南京明德新药研发有限公司 Composé hétérocyclique de pyrimidine et son application
WO2022206723A1 (fr) * 2021-03-30 2022-10-06 浙江海正药业股份有限公司 Dérivé hétérocyclique, son procédé de préparation et son utilisation en médecine
WO2022268051A1 (fr) * 2021-06-21 2022-12-29 江苏恒瑞医药股份有限公司 Composé tétracyclique fusionné, son procédé de préparation et son utilisation en médecine

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