EP4665339A1 - Hemmung von alpha-v-beta-8-integrin - Google Patents

Hemmung von alpha-v-beta-8-integrin

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Publication number
EP4665339A1
EP4665339A1 EP24709285.1A EP24709285A EP4665339A1 EP 4665339 A1 EP4665339 A1 EP 4665339A1 EP 24709285 A EP24709285 A EP 24709285A EP 4665339 A1 EP4665339 A1 EP 4665339A1
Authority
EP
European Patent Office
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
mmol
morf
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP24709285.1A
Other languages
English (en)
French (fr)
Inventor
Dawn TROAST
Kerim Babaoglu
Alex BUCKMELTER
Matthew BURSAVICH
Katherine CHONG
Donghui Cui
James Dowling
Bryce Harrison
Fu-Yang Lin
Blaise Lippa
Thomas Andrew MCTEAGUE
Qi Qiao
Inese Smukste
Cheng Zhong
Steven ALBANESE
Aleksey GERASYUTO
Jiaye GUO
Eugene Hickey
Daigo Inoyama
Ana NEGRI
Mats Svensson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Morphic Therapeutic Inc
Original Assignee
Morphic Therapeutic Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Morphic Therapeutic Inc filed Critical Morphic Therapeutic Inc
Publication of EP4665339A1 publication Critical patent/EP4665339A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the major function of ⁇ v ⁇ 8 is activation of growth factor TGF- ⁇ 1 and 3.
  • the TGF- ⁇ s are biosynthesized and stored in tissues as latent forms.
  • the TGF- ⁇ homodimer is kept latent by association with its dimeric prodomain (pro-TGF- ⁇ ).
  • the prodomain-derived homodimer prevents TGF- ⁇ from binding TGF- ⁇ receptor and is called latency-associated peptide (LAP).
  • LAP latency-associated peptide
  • the latent TGF- ⁇ complex is stored in the extracellular matrix or on the cell surface for subsequent, integrin-dependent activation.
  • TGF- ⁇ is a pleiotropic cytokine mediating multiple biological process including development and homeostasis.
  • TGF- ⁇ is a key player in cell growth, differentiation, and apoptosis. It regulates extracellular matrix (ECM) production contributing to tissue repair processes.
  • ECM extracellular matrix
  • TGF- ⁇ Homeostatic role of TGF- ⁇ on immunity is critical to prevent excessive inflammatory responses and essential for maintaining tolerance to self- antigens to prevent autoimmunity.
  • TGF- ⁇ is ubiquitously expressed it activity needs to be tightly regulated and when exacerbated lead to disease states. Dysregulation of TGF- ⁇ signaling is involved in multiple disorders, especially cancer and fibrosis.
  • the TGF- ⁇ pathway has been implicated in many human neoplastic diseases, including solid and hematopoietic tumors.
  • MORF-010WO1 TGF- ⁇ acts as a tumor suppressor; however, in tumor cells, TGF- ⁇ loses its anti-proliferative response and promotes cancer progression.
  • the TGF- ⁇ -promoted tumorigenesis is mainly driven by downregulation of anti-tumor immunity.
  • the immunosuppressive effect leads to tumor immune tolerance.
  • TGF- ⁇ facilitates epithelial to mesenchymal transition (EMT) and angiogenesis to increase tumor invasiveness.
  • EMT epithelial to mesenchymal transition
  • the integrin avb8 expression in cancers correlates with TGF- ⁇ activity. It modulates inflammatory phenotype of the APCs and Tregs, the main cell types fundamental for T/NK cell driven anti-tumor activity.
  • the ⁇ v ⁇ 8 integrin locally activates TGF- ⁇ to regulate cross-talk between APCs and effector cells to skew immunity from inflammation to tolerance.
  • the invention features a compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein: ATTORNEY DOCKET NO.
  • MORF-010WO1 is optionally substituted with 1 to 6 R 4 ;
  • X is -CHR 1c -, -O-, or -NR 2 -; each of R 1a , R 1b , R 1c , R 1d , R 1e , and R 1f is independently H, C1-4alkyl, halogen, C1-4alkyoxy, OH, C1-4alkyl-OH, C1-4alkyl-C1-4alkyoxy, C1-4alkyoxy-C1-4alkyoxy, CF3, CHF2, CH2F, CN, NO2, NR a R b or C 1-4 alkyl-NR a R b , each R 2 is independently H, C 1-4 alkyl, or C 3-5 cycloalkyl; R 3a is C 1-4 alkyoxy, C 3-5 cycloalkoxy, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 or OCH 2 F; R 3b is H, halogen
  • the invention features a compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein: is optionally substituted with 1 to 6 R 4 ; X is -CHR 1c -, -O-, or -NR 2 -; each of R 1a , R 1b , R 1c , R 1d , R 1e , and R 1f is independently H, C1-4alkyl, halogen, C1-4alkyoxy, OH, C 1-4 alkyl-OH, C 1-4 alkyl-C 1-4 alkyoxy, C 1-4 alkyoxy-C 1-4 alkyoxy, CF 3 , CHF 2 , CH 2 F, CN, NO 2 , NR a R b or C 1-4 alkyl-NR a R b , each R 2 is independently H, C 1-4 alkyl, or C 3-5 cycloalkyl; R 3a is cyano, halogen
  • each of R a and R b is independently hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, or R a and R b , together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of F, C 1-4 alkyl, phenyl and benzyl; and n is 1 or 2; and m is 0, 1 or 2.
  • the invention features a compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein: R 3a is methoxy; R 3b is H, halogen, CF 3 or CN; R 3c is H, F, CN, or C1-4alkyl; R 3d is C1-4alkyl, C3-5cycloalkyl, or 4-6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 R 6 ; R 3e is H or F; each R 6 is independently C 1-4 alkyl, C 1-4 alkenyl, C 3-5 cycloalkyl, C 1-4 alkyoxy, C 3- 5 cycloalkoxy, F, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , OCH 2 F, OH, 5-6-membered heteroaryl or NRaRb; each R 7 is independently C1-4alkyl or F; each of Ra and Rb is independently hydrogen, C1-4alkyl or F; each of Ra
  • the Q ring wherein R1c1 and R1c2 are each independently selected from R 1c ; R 1d1 and R 1d2 are each independently selected from R 1d ; and R 1e1 and R 1e2 are each independently selected from R 1e .
  • each of R 1d and R 1e is independently H.
  • each R 1c is independently H.
  • each R 1a is independently H.
  • each R 1b is independently H. ATTORNEY DOCKET NO. MORF-010WO1 [0023] In embodiments, each R 1b is independently OMe.
  • R1c are each independently selected from R1c; and R1d1 and R1d2 are each independently selected from R 1d .
  • each of R 1c1 , R 1c2 , R 1d1 , and R 1d2 are each independently H.
  • the Q ring [0027] In embodiments, the Q ring [0028] In embodiments, the Q ring [0029] In embodiments, each of R 1c and R 1d is independently H.
  • each of R 1a , R 1b and R 1f is independently H.
  • L is and n is 1.
  • R 3a is C 1-4 alkyoxy.
  • R 3a is OMe, OEt, OCF 3 , OCHF 2 or OCH 2 F.
  • R 3a is OMe.
  • R 3a is -CN.
  • R 3a is halogen. ATTORNEY DOCKET NO. MORF-010WO1
  • R 3a is Cl.
  • R 3a is C 1-4 alkyl. [0041] In embodiments, R 3a is methyl.
  • R 3a is ethyl.
  • R 3b is F.
  • R 3c is H.
  • R 3d is C 1-4 alkyl.
  • R 3d is C 3-5 cycloalkyl.
  • R 3d is oxetanyl, tetrahydrofuranyl or tetrahydro-2H-pyranyl, morpholinyl or piperazinyl-C1-4alkyl.
  • R 3d is iso-propyl.
  • R 3e is H.
  • each R 4 is independently methyl. [0051] In embodiments, each R 4 is independently F. [0052] In embodiments, each R 4 is independently CF3, CHF2 or CH2F. [0053] In embodiments, each R 4 is independently H. [0054] In embodiments, each R 6 is independently C1-4alkyl. [0055] In embodiments, each R 6 is independently C 1-4 alkenyl. [0056] In embodiments, each R 6 is independently C 3-5 cycloalkyl. [0057] In embodiments, each R 6 is independently C 1-4 alkyoxy. [0058] In embodiments, each R 6 is independently C3-5cycloalkoxy.
  • each R 6 is independently F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F or OH. [0060] In embodiments, each R 6 is independently a 5-6-membered heteroaryl. [0061] In embodiments, each R 6 is independently H. [0062] In embodiments, each R 7 is independently F. ATTORNEY DOCKET NO. MORF-010WO1 [0063] In embodiments, n is 0. [0064] In embodiments, n is 1. [0065] In embodiments, n is 2. [0066] In embodiments, m is 0. [0067] In embodiments, m is 1. [0068] In embodiments, m is 2.
  • a compound has a structure according to Formula (II), or a pharmaceutically acceptable salt thereof.
  • a compound has a structure according to Formula (IIA), or a pharmaceutically acceptable salt thereof.
  • a compound has a structure according to Formula (III), or a pharmaceutically acceptable salt thereof.
  • ATTORNEY DOCKET NO. MORF-010WO1 In embodiments, a compound has a structure according to Formula (IIIA), or a pharmaceutically acceptable salt thereof.
  • a compound has a structure according to Formula (IV), or a pharmaceutically acceptable salt thereof.
  • a compound has a structure according to Formula (IVA), or a pharmaceutically acceptable salt thereof.
  • a compound has a structure according to Formula (V), or a pharmaceutically acceptable salt thereof.
  • ATTORNEY DOCKET NO. MORF-010WO1 [0076]
  • a compound has a structure according to Formula (VA), or a pharmaceutically acceptable salt thereof.
  • a compound has a structure according to Formula (VI), or a pharmaceutically acceptable salt thereof.
  • a compound has a structure according to Formula (VIA), or a pharmaceutically acceptable salt thereof.
  • the invention features a compound of Formula (VII) or a pharmaceutically acceptable salt thereof: wherein each of L, Q, R 7 , R 3a , R 3b , R 3c , R 3d , R 3e is independently according to any embodiment described herein. .
  • ATTORNEY DOCKET NO. MORF-010WO1 [0080]
  • the invention features a compound of Formula (VII) or a pharmaceutically acceptable salt thereof: n is 1 or 2; R 3a is methoxy; R7 is H or F; R3a is methoxy; and R 3b , R 3c , R 3d , R 3e are as disclosed herein above with respect to Formula (I).
  • n is 1. [0082] In embodiments, n is 2. [0083] In embodiments, R 1b is H, CH 3 , or OCH 3 . [0084] In embodiments, R 3e is H or F. [0085] In embodiments, R 3d is C1-4alkyl optionally substituted with 1 R 6 . [0087] In embodiments, R 3d is 4-6-membered heterocycloalkyl optionally substituted with 1 R 6 . [0088] In embodiments, [0089] In embodiments, R 3d is C3-5cycloalkyl optionally substituted with 1 R 6 . ATTORNEY DOCKET NO.
  • a compound is selected from any compound described in Table 1, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is selected from the group consisting of: ATTORNEY DOCKET NO. MORF-010WO1 ATTORNEY DOCKET NO. MORF-010WO1 ATTORNEY DOCKET NO. MORF-010WO1 or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is acceptable salt thereof.
  • a compound is Compound 1A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound aB, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 2A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 2B, or a pharmaceutically acceptable salt thereof. acceptable salt thereof.
  • a compound is Compound 7A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 7B, or a pharmaceutically acceptable salt thereof. salt thereof.
  • a compound is Compound 11A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 11B, or a pharmaceutically acceptable salt thereof.
  • ATTORNEY DOCKET NO. MORF-010WO1 [0099]
  • a compound of Formula (I) is (Compound 12A/12B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 12A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 12B, or a pharmaceutically acceptable salt thereof. [0100] In embodiments, a compound of Formula (I) is (Compound 17A/17B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 17A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 17B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is (Compound 20A/20B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 20A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 20B, or a pharmaceutically acceptable salt thereof. ATTORNEY DOCKET NO. MORF-010WO1 [0102] In embodiments, a compound of Formula (I) is (Compound 24A/B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 24A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 24B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is (Compound 28A/28B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 24A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 24B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is (Compound 35A/35B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 35A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 35B, or a pharmaceutically acceptable salt thereof.
  • ATTORNEY DOCKET NO. MORF-010WO1 [0105]
  • a compound of Formula (I) is (Compound 36A/36B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 36A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 36B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is (Compound 41A/41B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 41A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 41B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is (Compound 42A/42B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 42A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 42B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is (Compound 47A/47B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 47A, or a pharmaceutically ATTORNEY DOCKET NO. MORF-010WO1 acceptable salt thereof.
  • a compound is Compound 47B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is (Compound 123A/123B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 123A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 123B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is (Compound 125A/125B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 125A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 125B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is (Compound 129A/129B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 129A, or a pharmaceutically ATTORNEY DOCKET NO. MORF-010WO1 acceptable salt thereof.
  • a compound is Compound 129B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is (Compound 135A/136B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 135A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 135B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is (Compound 136A/136B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 136A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 136B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is (Compound 150A/150B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 150A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 150B, or a pharmaceutically acceptable salt thereof. ATTORNEY DOCKET NO.
  • a compound of Formula (I) is (Compound 154A/154B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 154A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 154B, or a pharmaceutically acceptable salt thereof.
  • the invention features a pharmaceutical composition, comprising any compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient [0117]
  • the invention features a method of inhibiting avb8 integrin in a patient, the method comprising administering to the patient in need thereof a therapeutically effective amount of any compound described herein, or a pharmaceutically acceptable salt thereof.
  • the method is for treating a solid tumor in a patient in need thereof.
  • the invention features a method of treating solid tumor in a patient, the method comprising administering to the patient in need thereof (a) a therapeutically effective amount of any compound described herein, or a pharmaceutically acceptable salt thereof, and (b) a therapeutically effective amount of a second active agent.
  • the solid tumor is selected from: anal cancer, bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, fallopian tube cancer, gastric cancer, glioma liver cancer, lung cancer, melanoma, nasopharyngeal carcinoma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, primary peritoneal carcinoma, prostate cancer, renal cell carcinoma, skin cancer, squamous cell carcinoma of the head and neck (SCCHN), testicular cancer, urothelial carcinoma, and uterine cancer.
  • anal cancer bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, fallopian tube cancer, gastric cancer, glioma liver cancer, lung cancer, melanoma, nasopharyngeal carcinoma, neuroblastoma, osteosarcoma, ovarian cancer
  • the solid tumor is selected from: breast cancer, squamous cell carcinoma of the head and neck (SCCHN), renal cell carcinoma, ovarian cancer, gastric cancer, esophageal cancer, lung cancer, pancreatic cancer, bile duct cancer, endometrial cancer, melanoma, and urothelial carcinoma.
  • SCCHN head and neck
  • the second active agent is an immune checkpoint inhibitor (e.g., an anti-PD-1 or an anti-PD-L1 therapy).
  • an immune checkpoint inhibitor is selected from: nivolumab, pembrolizumab, cemiplimab, dostarlimab, atezolizumab, avelumab, and durvalumab.
  • the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law. [0127] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • At least one of A and B can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • compositions of the present invention may exist in particular geometric or stereoisomeric forms.
  • polymers of the present invention may ATTORNEY DOCKET NO. MORF-010WO1 also be optically active.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention. [0131] If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • ⁇ v ⁇ 8 means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body.
  • a pharmaceutically acceptable carrier such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non- pyrogenic.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl ATTORNEY DOCKET NO.
  • sugars such as lactose, glucose, and sucrose
  • starches such as corn starch and potato starch
  • salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like.
  • the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts in these instances refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s).
  • salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine.
  • suitable base such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine.
  • alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like.
  • a patient refers to a mammal in need of a particular treatment.
  • a patient is a primate, canine, feline, or equine.
  • a patient is a human.
  • a term e.g., alkyl or aryl
  • prefix roots e.g., alk- or ar-
  • affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., arylene is the divalent moiety of aryl, heteroarylene is the divalent moiety of heteroaryl, and heterocycloalkylene is the divalent moiety of heterocycloalkyl.
  • affixing the suffix “-oxy” to a group indicates the group is attached to the parent molecular structure through an oxygen atom (-O-) such as “alkyloxy,” “alkoxy” or “cycloalkoxy” as used herein.
  • An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below.
  • a straight aliphatic chain is limited to unbranched carbon chain moieties.
  • the term “aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group.
  • “Alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or 1 up to 30 carbon atoms if no specification is made.
  • alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties.
  • Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl.
  • MORF-010WO1 chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C 1 -C 30 for straight chains, C 3 -C 30 for branched chains), and more preferably 20 or fewer.
  • Alkyl goups may be substituted or unsubstituted.
  • Me and –CH3 both refer to methyl.
  • alkylene refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain.
  • Non-limiting examples of alkylene groups include methylene -(CH 2 )-, ethylene -(CH 2 CH 2 )-, n-propylene -(CH 2 CH 2 CH 2 )-, isopropylene -(CH 2 CH(CH 3 ))-, and the like.
  • Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents.
  • Cycloalkyl means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms.
  • preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure.
  • Cycloalkyl groups may be substituted or unsubstituted.
  • Exemplary cycloalkyl groups include cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cycloheptyl(C7), and cyclooctyl (C8).
  • lower alkyl means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
  • lower alkenyl and “lower alkynyl” have similar chain lengths.
  • preferred alkyl groups are lower alkyls.
  • a substituent designated herein as alkyl is a lower alkyl.
  • aryl as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteroaryl).
  • aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
  • Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10- ATTORNEY DOCKET NO. MORF-010WO1 membered rings, whose ring structures include one to four heteroatoms.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.
  • halo means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro and bromo.
  • heterocyclyl or “heterocyclic group” refer to 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms.
  • Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic.
  • Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazin
  • the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, and the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino
  • heterocycloalkyl is a non-aromatic heterocyclyl wherein at least one atom is a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus, and the remaining atoms are carbon.
  • heterocycloalkyl groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H- pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithiany
  • heterocycloalkyl group can be substituted or unsubstituted as recited, e.g., for heterocyclyls as described herein.
  • carbonyl is art-recognized and includes such moieties as can be represented by the formula: [0151] wherein X’ is a bond or represents an oxygen or a sulfur, and R15 represents a hydrogen, an alkyl, an alkenyl, -(CH 2 ) m -R 10 or a pharmaceutically acceptable salt, R 16 represents a hydrogen, an alkyl, an alkenyl or -(CH 2 ) m -R 10 , where m and R 10 are as defined above.
  • X’ is an oxygen and R 15 or R 16 is not hydrogen
  • the formula represents an “ester.”
  • X’ is an oxygen, and R15 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R15 is a hydrogen, the formula represents a “carboxylic acid”.
  • R16 is a hydrogen
  • the formula represents a “formate.”
  • X’ is a bond, and R 15 is not hydrogen
  • the above formula represents a “ketone” group.
  • X’ is a bond, and R 15 is a hydrogen
  • the above formula represents an “aldehyde” group.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above, and for example substituted with one or more substituents selected from alkyl, cycloalkyl, heterocyclylakyl, halogen, OH, OMe, C(H)F 2 , C(F)H 2 , CF 3 , C(H) 2 CF 3 , SF 5 , CHFCH 2 amine, CH 2 amine, and CN.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • nitro means -NO 2 ;
  • halogen designates - F, -Cl, -Br, or -I;
  • hydroxyl means -OH; and
  • cyano means –CN;.
  • prodrug as used herein encompasses compounds that, under physiological conditions, are converted into therapeutically active agents.
  • a common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal.
  • prodrugs include compounds that are transformed in vivo to yield a disclosed compound or any other pharmaceutically acceptable form of the compound.
  • a prodrug may be inactive when administered to a subject but may be converted in vivo to an active compound, for example, by hydrolysis. See, e.g., Bundgard, H., Design of Prodrugs (1985), pp.7-9, 21-24 (Elsevier, Amsterdam).
  • prodrugs can typically be prepared using well known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995), and Design of Prodrugs (H. Bundgaard ed., Elselvier, New York, 1985).
  • prodrug is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a subject.
  • Prodrugs of compounds described herein may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to provide a compound described herein (i.e., the parent active compound).
  • Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
  • Other examples of prodrugs include compounds that comprise —NO, — NO 2 , —ONO, or —ONO 2 moieties.
  • ATTORNEY DOCKET NO. MORF-010WO1 [0157]
  • the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.
  • Exemplary Compounds of the Invention This disclosure relates to novel chemical compounds and methods useful for inhibiting ⁇ v ⁇ 8 integrin.
  • Exemplary formulas and compounds are described herein. Also provided herein are exemplary embodiments of structural features which may be present in any formula described herein. Any exemplary embodiment of a structural feature may occur in combination with any other exemplary structural feature described herein. Further, and unless otherwise indicated herein, any description of a formula or compound also includes any pharmaceutically acceptable forms of the compound, including but not limited to any pharmaceutically acceptable salts, hydrates, solvates, isomers, polymorphs, prodrugs, and isotopically labeled derivatives of disclosed formulas and compounds.
  • a compound described herein is a selective inhibitor of ⁇ v ⁇ 8 integrin.
  • a compound described herein selectively inhibits ⁇ v ⁇ 8 integrin over, e.g., ⁇ v ⁇ 6 integrin (e.g., a selectivity of at least about 10 ⁇ , 20 ⁇ , 50 ⁇ , 100 ⁇ , 500 ⁇ , or 1000 ⁇ as measured according to an assay (e.g., fluorescence polarization assay)).
  • an assay e.g., fluorescence polarization assay
  • the invention features a compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein: ATTORNEY DOCKET NO. MORF-010WO1 is optionally substituted with 1 to 6 R 4 ; X is -CHR 1c -, -O-, or -NR 2 -; each of R 1a , R 1b , R 1c , R 1d , R 1e , and R 1f is independently H, C1-4alkyl, halogen, C1-4alkyoxy, OH, C1-4alkyl-OH, C1-4alkyl-C1-4alkyoxy, C1-4alkyoxy-C1-4alkyoxy, CF3, CHF2, CH2F, CN, NO2, NR a R b or C 1-4 alkyl-NR a R b , each R 2 is independently H, C 1-4 alkyl, or C 3-5 cycloalkyl; R 3a is C 1-4 alkyoxy, C 3-5 cycloalkyl;
  • the invention features a compound of Formula (I) or a pharmaceutically acceptable salt thereof: ATTORNEY DOCKET NO. MORF-010WO1 wherein: is optionally substituted with 1 to 6 R 4 ; X is -CHR 1c -, -O-, or -NR 2 -; each of R 1a , R 1b , R 1c , R 1d , R 1e , and R 1f is independently H, C1-4alkyl, halogen, C1-4alkyoxy, OH, C1-4alkyl-OH, C1-4alkyl-C1-4alkyoxy, C1-4alkyoxy-C1-4alkyoxy, CF3, CHF2, CH2F, CN, NO2, NRaRb or C1-4alkyl-NRaRb, each R 2 is independently H, C 1-4 alkyl, or C 3-5 cycloalkyl; R 3a is cyano, halogen, C 1-4 alkyl, C 1-4 alkyoxy, C 1-4 alkyoxy, C
  • MORF-010WO1 additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of F, C1-4alkyl, phenyl and benzyl; and n is 1 or 2; and m is 0, 1 or 2.
  • the invention features a compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein: R 3a is methoxy; R 3b is H, halogen, CF3 or CN; R 3c is H, F, CN, or C 1-4 alkyl; R 3d is C 1-4 alkyl, C 3-5 cycloalkyl, or 4-6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 R 6 ; R 3e is H or F; each R 6 is independently C1-4alkyl, C1-4alkenyl, C3-5cycloalkyl, C1-4alkyoxy, C3- 5cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, 5-6-membered heteroaryl or NR a R b ; each R 7 is independently C 1-4 alkyl or F; each of R a and R b is independently hydrogen, C 1-4 alkyl or F; each of R
  • MORF-010WO1 sulfur may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of F, C 1-4 alkyl, phenyl and benzyl; and n is 1 or 2; and m is 0, 1 or 2.
  • the Q ring wherein R1c1 and R1c2 are each independently selected from R1c; R1d1 and R1d2 are each independently selected from R1d; and R1e1 and R1e2 are each independently selected from R1e.
  • the Q ring [0167] In embodiments, X is -O-. [0168] In embodiments, X is -NR 2 -.
  • R 2 is methyl.
  • the Q ring [0171] are each independently selected from R1c; and R1d1 and R1d2 are each independently selected from R1d.
  • each of R1c1, R1c2, R1d1, and R1d2 are each independently H.
  • the Q ring ATTORNEY DOCKET NO. MORF-010WO1 In embodiments, the Q ring [0175] In embodiments, the Q ring [0176] In embodiments, each of R 1d and R 1e is independently H. [0177] In embodiments, each R 1c is independently H.
  • each R 1a is independently H.
  • each R 1b is independently H.
  • each R 1b is independently OMe.
  • the Q ring [0182]
  • each of R 1c and R 1d is independently H.
  • each of R 1a , R 1b and R 1f is independently H.
  • [0185] In embodiments, [0186] In embodiments, L is . [0187] In embodiments, [0188] In embodiments, R 3a is C1-4alkyoxy.
  • R 3a is OMe, OEt, OCF 3 , OCHF 2 or OCH 2 F. [0190] In embodiments, R 3a is OMe. [0191] In embodiments, R 3a is -CN. [0192] In embodiments, R 3a is halogen. [0193] In embodiments, R 3a is Cl. ATTORNEY DOCKET NO. MORF-010WO1 [0194] In embodiments, R 3a is C 1-4 alkyl. [0195] In embodiments, R 3a is methyl. [0196] In embodiments, R 3a is ethyl. [0197] In embodiments, R 3b is F. [0198] In embodiments, R 3c is H.
  • R 3d is C 1-4 alkyl. [0200] In embodiments, R 3d is C 3-5 cycloalkyl. [0201] In embodiments, R 3d is oxetanyl, tetrahydrofuranyl or tetrahydro-2H-pyranyl, morpholinyl or piperazinyl-C1-4alkyl. [0202] In embodiments, R 3d is iso-propyl. [0203] In embodiments, R 3e is H. [0204] In embodiments, each R 4 is independently methyl. [0205] In embodiments, each R 4 is independently F. [0206] In embodiments, each R 4 is independently CF 3 , CHF 2 or CH 2 F.
  • each R 4 is independently H.
  • each R 6 is independently C1-4alkyl.
  • each R 6 is independently C1-4alkenyl.
  • each R 6 is independently C 3-5 cycloalkyl.
  • each R 6 is independently C 1-4 alkyoxy.
  • each R 6 is independently C 3-5 cycloalkoxy.
  • each R 6 is independently F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F or OH.
  • each R 6 is independently a 5-6-membered heteroaryl.
  • each R 6 is independently H.
  • each R 7 is independently F.
  • each R 7 is independently F and m is 0 or 1.
  • ATTORNEY DOCKET NO. MORF-010WO1 [0218]
  • each R 7 is independently methyl.
  • each R 7 is independently methyl and m is 0 or 1.
  • n is 0.
  • n is 1.
  • n is 2.
  • m is 0.
  • a compound has a structure according to Formula (II), or a pharmaceutically acceptable salt thereof, wherein each of R 1b , R 3a , R 3b , R 3c , R 3d , R 3e is independently according to any embodiment described herein.
  • a compound has a structure according to Formula (IIA), or a pharmaceutically acceptable salt thereof, wherein each of R 1b , R 3d , and R 3e is independently according to any embodiment described herein.
  • a compound has a structure according to Formula (III), ATTORNEY DOCKET NO.
  • a compound has a structure according to Formula (IIIA), or a pharmaceutically acceptable salt thereof, wherein each of R 1b , R 3d , and R 3e is independently according to any embodiment described herein.
  • a compound has a structure according to Formula (IV), or a pharmaceutically acceptable salt thereof, wherein each of R 1b , R 3a , R 3b , R 3c , R 3d , R 3e is independently according to any embodiment described herein.
  • a compound has a structure according to Formula (IVA), or a pharmaceutically acceptable salt thereof, wherein each of R 1b , R 3d , and R 3e is independently according to any embodiment described herein.
  • a compound has a structure according to Formula (V), ATTORNEY DOCKET NO. MORF-010WO1 or a pharmaceutically acceptable salt thereof, wherein each of n, R 1b , R 3a , R 3b , R 3c , R 3d , R 3e is independently according to any embodiment described herein.
  • a compound has a structure according to Formula (VA), or a pharmaceutically acceptable salt thereof, wherein each of n, R 1b , R 3d , and R 3e is independently according to any embodiment described herein.
  • a compound has a structure according to Formula (VI), or a pharmaceutically acceptable salt thereof, wherein each of n, R 1b , R 3a , R 3b , R 3c , R 3d , R 3e is independently according to any embodiment described herein.
  • a compound has a structure according to Formula (VIA), or a pharmaceutically acceptable salt thereof, wherein each of n, R 1b , R 3d , and R 3e is independently according to any embodiment described herein.
  • the invention features a compound of Formula (VII) or a pharmaceutically acceptable salt thereof: ATTORNEY DOCKET NO. MORF-010WO1 wherein each of L, Q, R7, R3a, R3b, R3c, R3d, R3e is independently according to any embodiment described herein.
  • the invention features a compound of Formula (VII) or a pharmaceutically acceptable salt thereof: n is 1 or 2; R 3a is methoxy; R 7 is H or F; R3a is methoxy; and R3b, R3c, R3d, R3e are as disclosed herein above with respect to Formula (I). [0236] In embodiments, n is 1. [0237] In embodiments, n is 2. [0238] In embodiments, R 1b is H, CH3, or OCH3. [0239] In embodiments, R 3e is H or F. [0240] In embodiments, R 3d is C 1-4 alkyl optionally substituted with 1 R 6 . ATTORNEY DOCKET NO.
  • R 3d is 4-6-membered heterocycloalkyl optionally substituted with 1 R 6 .
  • R 3d is C3-5cycloalkyl optionally substituted with 1 R 6 .
  • the carbon marked by the asterisk (*) has the (R)-configuation.
  • the carbon marked by the asterisk (*) has the (S)-configuation.
  • the compound is selected from any compound described in Table 1, or a pharmaceutically acceptable salt thereof.
  • the Q ring embodiments X is -CHR 1c -. In embodiments, X is -O-. In embodiments, X is -NR 2 -.
  • the Q ring is . In embodiments, the Q ring is ATTORNEY DOCKET NO. MORF-010WO1 embodiments, the Q ring is embodiments, the Q ring embodiments, the Q ring is .
  • the Q ring embodiments, the Q ring embodiments, the Q ring is embodiments, the Q ring [0252]
  • the Q ring embodiments, X is -CHR 1c -. In embodiments, X is -O-. In embodiments, X is -NR 2 -. [0253] In embodiments, the Q ring is . In embodiments, the Q ring is [0254]
  • L is optionally substituted with 1 to 6 R 4 . In embodiments, L is unsubstituted. In embodiments, L is substituted with 1 to 6 R 4 . In embodiments, L is substituted with 1, 2, or 3 R 4 . In embodiments, L is substituted with 1 R 4 .
  • L is substituted with 2 R 4 . In embodiments, L is substituted with 3 R 4 . In ATTORNEY DOCKET NO. MORF-010WO1 embodiments, L is substituted with 4 R 4 . In embodiments, L is substituted with 5 R 4 . In embodiments, L is substituted with 6 R 4 . [0255] In embodiments, L is optionally substituted with 1 to 6 R 4 . In embodiments, L is unsubstituted. In embodiments, L is substituted with 1 to 6 R 4 . In embodiments, L is substituted with 1, 2, or 3 R 4 . In embodiments, L is substituted with 1 R 4 . In embodiments, L is substituted with 2 R 4 .
  • R 1a is H. In embodiments, R 1a is C1-4alkyl. In embodiments, R 1a is halogen (e.g., F). In embodiments, R 1a is C1-4alkyoxy. In embodiments, R 1a is OH. In embodiments, R 1a is C 1-4 alkyl-OH. In embodiments, R 1a is C 1-4 alkyl-C 1-4 alkyoxy. In embodiments, R 1a is C 1-4 alkyoxy-C 1-4 alkyoxy.
  • R 1a is CF 3 . In embodiments, R 1a is CHF 2 . In embodiments, R 1a is CH 2 F. In embodiments, R 1a is CN. In embodiments, R 1a is NO 2 . In embodiments, R 1a is NRaRb. In embodiments, R 1a is C1-4alkyl-NRaRb. [0257] In embodiments, R 1b is H. In embodiments, R 1b is C1-4alkyl. In embodiments, R 1b is halogen (e.g., F). In embodiments, R 1b is C1-4alkyoxy. In embodiments, R 1b is OH. In embodiments, R 1b is C 1-4 alkyl-OH.
  • R 1b is C 1-4 alkyl-C 1-4 alkyoxy. In embodiments, R 1b is C 1-4 alkyoxy-C 1-4 alkyoxy. In embodiments, R 1b is CF 3 . In embodiments, R 1b is CHF 2 . In embodiments, R 1b is CH 2 F. In embodiments, R 1b is CN. In embodiments, R 1b is NO 2 . In embodiments, R 1b is NRaRb. In embodiments, R 1b is C1-4alkyl-NRaRb. [0258] In embodiments, R 1c is H. In embodiments, R 1c is C1-4alkyl. In embodiments, R 1c is halogen (e.g., F).
  • F e.g., F
  • R 1c is C1-4alkyoxy. In embodiments, R 1c is OH. In embodiments, R 1c is C 1-4 alkyl-OH. In embodiments, R 1c is C 1-4 alkyl-C 1-4 alkyoxy. In embodiments, R 1c is C 1-4 alkyoxy-C 1-4 alkyoxy. In embodiments, R 1c is CF 3 . In embodiments, R 1c is CHF 2 . In embodiments, R 1c is CH 2 F. In embodiments, R 1c is CN. In embodiments, R 1b is NO 2 . In embodiments, R 1c is NRaRb. In embodiments, R 1c is C1-4alkyl-NRaRb.
  • R 1d is H. In embodiments, R 1d is C1-4alkyl. In embodiments, R 1d is halogen (e.g., F). In embodiments, R 1d is C1-4alkyoxy. In embodiments, R 1d is OH. In embodiments, R 1d is C 1-4 alkyl-OH. In embodiments, R 1d is C 1-4 alkyl-C 1-4 alkyoxy. In embodiments, R 1d is C 1-4 alkyoxy-C 1-4 alkyoxy. In embodiments, R 1d is CF 3 . In embodiments, R 1d is CHF 2 . In embodiments, R 1d is CH 2 F. In embodiments, R 1d is CN.
  • R 1d is NO 2 . In embodiments, R 1d is NRaRb. In embodiments, R 1d is C1-4alkyl-NRaRb. ATTORNEY DOCKET NO. MORF-010WO1 [0260]
  • R 1e is H. In embodiments, R 1e is C 1-4 alkyl. In embodiments, R 1e is halogen (e.g., F). In embodiments, R 1e is C 1-4 alkyoxy. In embodiments, R 1e is OH. In embodiments, R 1e is C1-4alkyl-OH. In embodiments, R 1e is C1-4alkyl-C1-4alkyoxy. In embodiments, R 1e is C1-4alkyoxy-C1-4alkyoxy.
  • R 1e is CF3. In embodiments, R 1e is CHF2. In embodiments, R 1e is CH2F. In embodiments, R 1e is CN. In embodiments, R 1e is NO2. In embodiments, R 1e is NR a R b . In embodiments, R 1e is C 1-4 alkyl-NR a R b . [0261] In embodiments, R 1f is H. In embodiments, R 1f is C 1-4 alkyl. In embodiments, R 1f is halogen (e.g., F). In embodiments, R 1f is C 1-4 alkyoxy. In embodiments, R 1f is OH. In embodiments, R 1f is C1-4alkyl-OH.
  • R 1f is C1-4alkyl-C1-4alkyoxy. In embodiments, R 1f is C1-4alkyoxy-C1-4alkyoxy. In embodiments, R 1f is CF3. In embodiments, R 1f is CHF2. In embodiments, R 1f is CH2F. In embodiments, R 1f is CN. In embodiments, R 1f is NO2. In embodiments, R 1f R 1e is NR a R b . In embodiments, R 1f is C 1-4 alkyl-NR a R b . [0262] In embodiments, R 2 is H. [0263] In embodiments, R 2 is C 1-4 alkyl. [0264] In embodiments, R 2 is C3-5cycloalkyl.
  • R 3a is C1-4alkyoxy. [0266] In embodiments, R 3a is C3-5cycloalkoxy. [0267] In embodiments, R 3a is CF 3 . [0268] In embodiments, R 3a is CHF 2 . [0269] In embodiments, R 3a is CH 2 F. [0270] In embodiments, R 3a is OCF3. [0271] In embodiments, R 3a is OCHF2. [0272] In embodiments, R 3a is OCH2F. [0273] In embodiments, R 3a is -CN. [0274] In embodiments, R 3a is halogen. [0275] In embodiments, R 3a is Cl.
  • R 3a is C1-4alkyl. [0277] In embodiments, R 3a is methyl. ATTORNEY DOCKET NO. MORF-010WO1 [0278] In embodiments, R 3a is ethyl. [0279] In embodiments, R 3b is H. [0280] In embodiments, R 3b is halogen. [0281] In embodiments, R 3b is CF3. [0282] In embodiments, R 3b is CN. [0283] In embodiments, R 3c is H. [0284] In embodiments, R 3c is F. [0285] In embodiments, R 3c is CN. [0286] In embodiments, R 3c is C1-4alkyl.
  • R 3d is C1-4alkyl optionally substituted with 1 to 4 R 6 .
  • R 3d is unsubstituted C1-4alkyl (e.g., methyl, ethyl, isopropyl, or tert-butyl).
  • R 3d is C 1-4 alkyl substituted with 1 R 6 (e.g., a methyl, ethyl, propyl, isopropyl, or n- butyl group substituted by methyl, ethyl, cyclopropyl, OH, oxazolyl, isoxazolyl, thiazolyl, methoxy, ethoxy, isopropyloxy, dimethylamino, pyrrolidinyl, morpholinyl, piperidinyl; or a methyl, ethyl, propyl, isopropyl, or n-butyl group substituted by NRaRb wherein Ra and Rb together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring (e.g., azanorbornyl or piperidnyl) optionally comprising 1 or 2 substituents selected from methyl, fluoro, cyclopropyl, and me
  • R 3d is C 1-4 alkyl substituted with 2 R 6 . In embodiments, R 3d is C 1-4 alkyl substituted with 3 R 6 . In embodiments, R 3d is C 1-4 alkyl substituted with 4 R 6 . [0288] In embodiments, R 3d is C3-5cycloalkyl optionally substituted with 1 to 4 R 6 . In embodiments, R 3d is unsubstituted C3-5cycloalkyl (e.g., cyclopropyl).
  • R 3d is C3- 5cycloalkyl optionally substituted with 1 R 6 (e.g., a cyclopropyl substituted by methyl, ethyl, methoxy, or trifluoromethyl).
  • R 3d is C 3-5 cycloalkyl optionally substituted with 2 R 6 .
  • R 3d is C 3-5 cycloalkyl optionally substituted with 3 R 6 .
  • R 3d is C 3-5 cycloalkyl optionally substituted with 4 R 6 .
  • R 3d is 4-6-membered heterocycloalkyl optionally substituted with 1 to 4 R 6 .
  • R 3d is unsubstituted 4-6-membered heterocycloalkyl (e.g., tetrayhydrofuranyl, tetrahydropyranyl, oxetanyl, isoxazolyl, morpholinyl, pyrrolidinyl, or piperidinyl).
  • R 3d is 4-6-membered heterocycloalkyl substituted with 1 R 6 (e.g., ATTORNEY DOCKET NO.
  • R 3d is 4-6-membered heterocycloalkyl substituted with 2 R 6 (e.g., tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, isoxazolyl, morpholinyl, pyrrolidinyl, piperidinyl, comprising two substituents independently selected from methyl and fluoro).
  • R 3d is 4-6-membered heterocycloalkyl substituted with 3 R 6 . In embodiments, R 3d is 4-6-membered heterocycloalkyl substituted with 4 R 6 .
  • R 3e is H. [0291] In embodiments, R 3e is F.
  • R 4 is H. [0293] In embodiments, R 4 is C1-4alkyl. [0294] In embodiments, R 4 is halogen (e.g., F). [0295] In embodiments, R 4 is CF 3 . [0296] In embodiments, R 4 is CHF 2 . [0297] In embodiments, R 4 is CH2F.
  • R 4 is cyclopropyl. [0299] In embodiments, two geminal R 4 groups together can form a spiro-cyclopropyl.
  • R 6 is C 1-4 alkyl. [0301] In embodiments, R 6 is C 1-4 alkenyl. [0302] In embodiments, R 6 is C 3-5 cycloalkyl. [0303] In embodiments, R 6 is C1-4alkyoxy. [0304] In embodiments, R 6 is C3-5cycloalkoxy. [0305] In embodiments, R 6 is F. [0306] In embodiments, R 6 is CF 3 . [0307] In embodiments, R 6 is CHF 2 .
  • R 6 is CH 2 F. [0309] In embodiments, R 6 is OCF3. ATTORNEY DOCKET NO. MORF-010WO1 [0310] In embodiments, R 6 is OCHF 2 . [0311] In embodiments, R 6 is OCH 2 F. [0312] In embodiments, R 6 is OH. [0313] In embodiments, R 6 is 5-6-membered heteroaryl. [0314] In embodiments, R 6 is NRaRb. [0315] In embodiments, R 7 is independently C 1-4 alkyl. [0316] In embodiments, R 7 is F. [0317] In embodiments, R 7 is CH 3 or F. [0318] In embodiments, Ra is independently hydrogen.
  • Ra is independently C1-4alkyl.
  • Ra is independently C3-5cycloalkyl.
  • R b is independently hydrogen.
  • R b is independently C 1-4 alkyl.
  • R b is independently C 3-5 cycloalkyl.
  • Ra and Rb together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, wherein said ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of F, C 1-4 alkyl, phenyl and benzyl.
  • Ra and Rb, together with the nitrogen atom to which they are attached form a saturated heterocyclic ring.
  • said heterocyclic ring is unsubstituted.
  • said heterocyclic ring is substituted by 1, 2 or 3 groups independently selected from the group consisting of F, C 1-4 alkyl, phenyl and benzyl. In embodiments, said heterocyclic ring does not contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In embodiments, said heterocyclic ring contains additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • ATTORNEY DOCKET NO. MORF-010WO1 [0326]
  • R a and R b together with the nitrogen atom to which they are attached, form an unsaturated heterocyclic ring. In embodiments, said heterocyclic ring is unsubstituted.
  • said heterocyclic ring is substituted by 1, 2 or 3 groups independently selected from the group consisting of F, C1-4alkyl, phenyl and benzyl. In embodiments, said heterocyclic ring does not contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In embodiments, said heterocyclic ring contains additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. [0327] In embodiments, n is 0. [0328] In embodiments, n is 1. [0329] In embodiments, n is 2. [0330] In embodiments, m is 0, 1 or 2.
  • R 3a is C 1-4 alkyoxy (e.g., OCH 3 ) and/or R 3b is halogen (e.g., F).
  • R 3a is C 1-4 alkyoxy (e.g., OCH 3 ) and R 3b is halogen (e.g., F).
  • R 3c is H and/or R 3e is halogen (e.g., F).
  • R 3c is H and R 3e is halogen (e.g., F).
  • R 3c is H and/or R 3e is H.
  • R 3c is H and R 3e is H.
  • R 3b is H and/or R 3e is H.
  • R 3b is H and R 3e is H.
  • R 3a is C1-4alkyoxy (e.g., OCH3)
  • R 3b is halogen (e.g., F)
  • R 3c is H.
  • R 3a is C1-4alkyoxy (e.g., OCH3)
  • R 3b is halogen (e.g., F)
  • R 3c is H.
  • R 3a is C 1-4 alkyoxy (e.g., OCH 3 ), R 3b is halogen (e.g., F), and/or R 3c is F.
  • R 3a is C1-4alkyoxy (e.g., OCH3), R 3b is halogen (e.g., F), and R 3c is F.
  • R 3a is C1-4alkyoxy (e.g., OCH3), R 3b is H, and/or R 3c is H. ATTORNEY DOCKET NO.
  • R 3a is C 1-4 alkyoxy (e.g., OCH 3 ), R 3b is H, and R 3c is H. [0345] In embodiments, R 3b is H, R 3c is H, and/or R 3e is H. [0346] In embodiments, R 3b is H, R 3c is H, and R 3e is H.
  • R 3a is C1-4alkyoxy (e.g., OCH3)
  • R 3b is halogen (e.g., F)
  • R 3c is H
  • R 3d is C1-4alkyl (e.g., methyl or isopropyl) optionally substituted with 1 to 4 R 6
  • R 3e is H.
  • R 3a is C 1-4 alkyoxy (e.g., OCH 3 )
  • R 3b is halogen (e.g., F)
  • R 3c is H
  • R 3d is C 1-4 alkyl (e.g., methyl or isopropyl) optionally substituted with 1 to 4 R 6
  • R 3e is H.
  • R 3a is C 1-4 alkyoxy (e.g., OCH 3 ), R 3b is halogen (e.g., F), R 3c is F, R 3d is C1-4alkyl (e.g., methyl or isopropyl) optionally substituted with 1 to 4 R 6 , and/or R 3e is H.
  • R 3a is C1-4alkyoxy (e.g., OCH3)
  • R 3b is halogen (e.g., F)
  • R 3c is F
  • R 3d is C1-4alkyl (e.g., methyl or isopropyl) optionally substituted with 1 to 4 R 6
  • R 3e is H.
  • R 3a is C 1-4 alkyoxy (e.g., OCH 3 ), R 3b is halogen (e.g., F), R 3c is H, R 3d is C 1-4 alkyl (e.g., methyl or isopropyl) optionally substituted with 1 to 4 R 6 , and/or R 3e is F.
  • R 3a is C 1-4 alkyoxy (e.g., OCH 3 )
  • R 3b is halogen (e.g., F)
  • R 3c is H
  • R 3d is C1-4alkyl (e.g., methyl or isopropyl) optionally substituted with 1 to 4 R 6
  • R 3e is F.
  • Exemplary compounds include those described in Table 1 herein and pharmaceutically acceptable salts thereof.
  • a compound may be used as a mixture of stereoisomers (e.g., a mixture of diastereomers or a mixture of enantiomers).
  • a stereochemically enriched composition comprising a compound described herein (e.g., a composition of a compound is substantially free of any other stereoisomer of that compound).
  • compositions comprising stereochemical mixtures or as stereochemically-enriched compositions (e.g., compositions of a compound substantially free of any other stereoisomer of that compound).
  • ATTORNEY DOCKET NO. MORF-010WO1 [0356]
  • a compound (Compound 1A/1B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 1A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 1B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 2A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 2B, or a pharmaceutically acceptable salt thereof. [0358] In embodiments, a compound (Compound 3A/3B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 3A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 3B, or a pharmaceutically acceptable salt thereof. [0359] In embodiments, a compound (Compound 4A/4B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 4A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 4B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 5A/5B), or a pharmaceutically acceptable salt thereof In embodiments, a compound is Compound 5A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 5B, or a pharmaceutically acceptable salt thereof. [0361] In embodiments, a compound (Compound 6A/6B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 6A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 6B, or a pharmaceutically acceptable salt thereof. [0362] In embodiments, a compound (Compound 7A/7B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 7A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 7B, or a pharmaceutically acceptable salt thereof. [0363] In embodiments, a compound (Compound 8A/8B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 8A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 8B, or a pharmaceutically acceptable salt thereof. ATTORNEY DOCKET NO. MORF-010WO1 [0364] In embodiments, a compound (Compound 9A/9B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 9A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 9B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 10A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 10B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 11A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 11B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 12A/12B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 12A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 12B, or a pharmaceutically acceptable salt thereof.
  • ATTORNEY DOCKET NO. MORF-010WO1 [0368]
  • a compound is Compound 13A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 13B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 13B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 14A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 14B, or a pharmaceutically acceptable salt thereof. [0370] In embodiments, a compound (Compound 15A/15B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 15A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 15B, or a pharmaceutically acceptable salt thereof. [0371] In embodiments, a compound (Compound 16A/16B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 16A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 16B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 17A/17B), or a pharmaceutically acceptable salt thereof In embodiments, a compound is Compound 17A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 17B, or a pharmaceutically acceptable salt thereof. [0373] In embodiments, a compound (Compound 18A/18B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 18A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 18B, or a pharmaceutically acceptable salt thereof. [0374] In embodiments, a compound (Compound 19A/19B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 19A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 19B, or a pharmaceutically acceptable salt thereof. [0375] In embodiments, a compound (Compound 19C/19D), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 19C, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 19D, or a pharmaceutically acceptable salt thereof. ATTORNEY DOCKET NO. MORF-010WO1 [0376] In embodiments, a compound (Compound 20A/20B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 20A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 20B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 21A/21B), or a pharmaceutically acceptable salt thereof In embodiments, a compound is Compound 21A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 21B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 22A/22B), or a pharmaceutically acceptable salt thereof In embodiments, a compound is Compound 22A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 22B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 23A/23B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 23A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 23B, or a pharmaceutically acceptable salt thereof.
  • ATTORNEY DOCKET NO. MORF-010WO1 [0380]
  • a compound is Compound 24A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 24B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 25A/25B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 25A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 25B, or a pharmaceutically acceptable salt thereof. [0382] In embodiments, a compound (Compound 26A/26B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 26A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 26B, or a pharmaceutically acceptable salt thereof. [0383] In embodiments, a compound (Compound 27A/27B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 27A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 27B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 28A/28B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 28A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 28B, or a pharmaceutically acceptable salt thereof.
  • Compound 29A/29B or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 29A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 29B, or a pharmaceutically acceptable salt thereof.
  • Compound 30A/30B or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 30A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 30B, or a pharmaceutically acceptable salt thereof. [0387] In embodiments, a compound (Compound 31A/31B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 31A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 31B, or a pharmaceutically acceptable salt thereof. ATTORNEY DOCKET NO. MORF-010WO1 [0388] In embodiments, a compound (Compound 32A/32B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 32A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 32B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 33A/33B), or a pharmaceutically acceptable salt thereof In embodiments, a compound is Compound 33A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 33B, or a pharmaceutically acceptable salt thereof.
  • (Compound 34A/34B), or a pharmaceutically acceptable salt thereof In embodiments, a compound is Compound 34A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 34B, or a pharmaceutically acceptable salt thereof. [0391] In embodiments, a compound (Compound 35A/35B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 35A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 35B, or a pharmaceutically acceptable salt thereof. ATTORNEY DOCKET NO. MORF-010WO1 [0392] In embodiments, a compound (Compound 36A/36B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 36A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 36B, or a pharmaceutically acceptable salt thereof. [0393] In embodiments, a compound (Compound 37A/37B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 37A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 37B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 38A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 38B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 39A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 39B, or a pharmaceutically acceptable salt thereof. ATTORNEY DOCKET NO.
  • a compound (Compound 40A/40B), or a pharmaceutically acceptable salt thereof In embodiments, a compound is Compound 40A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 40B, or a pharmaceutically acceptable salt thereof. [0397] In embodiments, a compound (Compound 41A/41B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 41A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 41B, or a pharmaceutically acceptable salt thereof. [0398] In embodiments, a compound (Compound 42A/42B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 42A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 42B, or a pharmaceutically acceptable salt thereof. [0399] In embodiments, a compound (Compound 43A/43B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 43A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 43B, or a pharmaceutically acceptable salt thereof. ATTORNEY DOCKET NO. MORF-010WO1 [0400] In embodiments, a compound (Compound 44A/44B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 44A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 44B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 45A/45B), or a pharmaceutically acceptable salt thereof In embodiments, a compound is Compound 45A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 45B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 46A/46B), or a pharmaceutically acceptable salt thereof In embodiments, a compound is Compound 46A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 46B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 47A/47B), or a pharmaceutically acceptable salt thereof In embodiments, a compound is Compound 47A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 47B, or a pharmaceutically acceptable salt thereof. ATTORNEY DOCKET NO. MORF-010WO1 [0404] In embodiments, a compound (Compound 48A/48B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 48A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 48B, or a pharmaceutically acceptable salt thereof. [0405] In embodiments, a compound (Compound 49A/49B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 49A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 49B, or a pharmaceutically acceptable salt thereof. [0406] In embodiments, a compound (Compound 50A/50B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 50A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 50B, or a pharmaceutically acceptable salt thereof. [0407] In embodiments, a compound (Compound 51A/51B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 51A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 51B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 52A/52B), or a pharmaceutically acceptable salt thereof In embodiments, a compound is Compound 52A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 52B, or a pharmaceutically acceptable salt thereof. [0409] In embodiments, a compound (Compound 53A/53B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 53A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 53B, or a pharmaceutically acceptable salt thereof. [0410] In embodiments, a compound (Compound 54A/54B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 54A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 54B, or a pharmaceutically acceptable salt thereof. [0411] In embodiments, a compound (Compound 100A/100B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 100A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 100B, or a pharmaceutically acceptable salt thereof. ATTORNEY DOCKET NO. MORF-010WO1 pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 101A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 101B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 102A/102B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 102A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 102B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 103A/103B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 103A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 103B, or a pharmaceutically acceptable salt thereof.
  • a compound is (Compound 104A/104B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 107A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 107B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 107B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 108A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 108B, or a pharmaceutically acceptable salt thereof.
  • ATTORNEY DOCKET NO. MORF-010WO1 [0420]
  • a compound (Compound 109A/109B), or a pharmaceutically acceptable salt thereof is ATTORNEY DOCKET NO. MORF-010WO1
  • a compound is Compound 109A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 109B, or a pharmaceutically acceptable salt thereof. [0421] In embodiments, a compound (Compound 110A/110B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 110A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 110B, or a pharmaceutically acceptable salt thereof. [0422] In embodiments, a compound (Compound 111A/111B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 111A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 111B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 112A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 112B, or a pharmaceutically acceptable salt thereof.
  • ATTORNEY DOCKET NO. MORF-010WO1 [0424]
  • a compound is Compound 113A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 113B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 116A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 116B, or a pharmaceutically acceptable salt thereof. ATTORNEY DOCKET NO. MORF-010WO1 [0428] In embodiments, a compound (Compound 117A/117B/117C/117D), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 117A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 117B, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 117C, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 117D, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 118A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 118B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 118C, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 118D, or a pharmaceutically acceptable salt thereof.
  • a compound is (Compound 119A/119B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 119A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 119B, or a pharmaceutically acceptable salt thereof.
  • ATTORNEY DOCKET NO. MORF-010WO1 [0431] (Compound 120A/120B/120C/120D), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 120A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 120B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 120C, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 120D, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 121A/121B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 121A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 121B, or a pharmaceutically acceptable salt thereof. (Compound 122A/122B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 122A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 122B, or a pharmaceutically acceptable salt thereof. [0434] In embodiments, a compound (Compound 123A/123B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 123A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 123B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 124A/124B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 124A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 124B, or a pharmaceutically acceptable salt thereof.
  • compound is Compound 125A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 125B, or a pharmaceutically acceptable salt thereof.
  • Compound 126A/126B or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 126A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 126B, or a pharmaceutically acceptable salt thereof.
  • ATTORNEY DOCKET NO. MORF-010WO1 compound is Compound 127A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 127B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 128A/128B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 128A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 128B, or a pharmaceutically acceptable salt thereof.
  • compound is Compound 129A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 129B, or a pharmaceutically acceptable salt thereof.
  • a compound is (Compound 130A/130B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 130A, or a ATTORNEY DOCKET NO. MORF-010WO1 pharmaceutically acceptable salt thereof.
  • a compound is Compound 130B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 131A/131B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 131A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 131B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 132A/132B), or a pharmaceutically acceptable salt thereof In embodiments, a compound is Compound 132A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 132B, or a pharmaceutically acceptable salt thereof. [0444] In embodiments, a compound (Compound 133A/133B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 133A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 133B, or a pharmaceutically acceptable salt thereof. [0445] In embodiments, a compound (Compound 134A/134B), or a pharmaceutically acceptable salt thereof.
  • a ATTORNEY DOCKET NO. MORF-010WO1 compound is Compound 134A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 134B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 135A/135B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 135A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 135B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 135B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 135A/136B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 136A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 136B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 137A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 137B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 138A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 138B, or a pharmaceutically acceptable salt thereof. ATTORNEY DOCKET NO.
  • a compound (Compound 139A/139B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 139A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 139B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 140A/140B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 140A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 140B, or a pharmaceutically acceptable salt thereof.
  • a compound is (Compound 141A/141B/141C/141D), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 141A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 141B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 141C, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 141D, or a pharmaceutically acceptable salt thereof.
  • ATTORNEY DOCKET NO. MORF-010WO1 [0453]
  • a compound is (Compound 142A/142B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 142A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 142B, or a pharmaceutically acceptable salt thereof.
  • a compound is (Compound 143A/143B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 143A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 143B, or a pharmaceutically acceptable salt thereof.
  • Compound 144A/144B or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 144A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 144B, or a pharmaceutically acceptable salt thereof.
  • Compound 145A/145B or a pharmaceutically acceptable salt thereof.
  • MORF-010WO1 compound is Compound 145A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 145B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 146A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 146B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 147A/147B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 147A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 147B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 148A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 148B, or a pharmaceutically acceptable salt thereof.
  • ATTORNEY DOCKET NO. MORF-010WO1 [0460]
  • a compound is Compound 149A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 149B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 150A/150B), or a pharmaceutically acceptable salt thereof In embodiments, a compound is Compound 150A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 150B, or a pharmaceutically acceptable salt thereof. [0462] In embodiments, a compound (Compound 151A/151B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 151A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 151B, or a pharmaceutically acceptable salt thereof. [0463] In embodiments, a compound (Compound 152A/152B), or a pharmaceutically acceptable salt thereof.
  • a ATTORNEY DOCKET NO. MORF-010WO1 compound is Compound 152A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 152B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 153A/153B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 153A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 153B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 154A/154B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 154A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 154B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 155A/155B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 155A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 155B, or a pharmaceutically acceptable salt thereof.
  • Deuterated Compounds [0467] Compounds described herein can comprise atoms that exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope ATTORNEY DOCKET NO.
  • isotopologue refers to a species that has the same chemical structure and formula as a specific compound provided herein, with the exception of the positions of isotopic substitution and/or level of isotopic enrichment at one or more positions, e.g., hydrogen vs. deuterium.
  • the present invention is meant to include all suitable isotopic variations of the compounds of the compounds described herein.
  • different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H), and tritium ( 3 H), as well as compositions enriched in isotopologues of any compound described herein.
  • one or more of the hydrogens of the compounds described herein is replaced by a deuterium.
  • a position is designated as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.
  • a position is designated as “ 2 H” or “deuterium”, the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., the term “ 2 H” or “deuterium” indicates at least 50.1% incorporation of deuterium).
  • the invention also features compositions enriched in deuterated compounds.
  • compositions of any compound provided herein may have an isotopic enrichment factor for each deuterium present at a site designated as a potential site of deuteration on the compound of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • compositions Compounds described herein (e.g., compounds of any one of Formulas (I)-(VII)) or pharmaceutically acceptable salts thereof can be formulated in various pharmaceutical compositions.
  • a compound described herein e.g., a compound of Formula (I) (including compounds of Formulas (II)-(VI) and any compound of Table 1 as provided herein), as well as pharmaceutically acceptable salts thereof, may be the active pharmaceutical ingredient (API) combined with one or more other ingredients to form a drug substance pharmaceutical composition.
  • the drug substance (DS) pharmaceutical composition can comprise the API (e.g., a ATTORNEY DOCKET NO.
  • the carrier(s), diluent(s) or excipient(s) can be selected to be compatible with the other ingredients of the formulation and appropriately safe and effective for an intended therapy.
  • a desired weight concentration of a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API) can be combined with the other inactive ingredients to form a drug substance (DS) in a formulation batch.
  • Pharmaceutically acceptable compositions can be formulated for administration by an appropriate route, for example by the oral delivery (including as a capsule or tablet) in unit dosage forms.
  • compositions may be prepared by bringing into association the active pharmaceutical ingredient (API) comprising a compound of Formula (I) with the carrier(s) or excipient(s).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition formulated for oral delivery of an ⁇ 4 ⁇ 7 integrin integrin inhibitor, the composition comprising the ⁇ 4 ⁇ 7 integrin inhibitor compound described herein (e.g., a compound of any one of Formulas (I)- (VII) such as any compound of Table 1, or a pharmaceutically acceptable salt thereof) as an API and a pharmaceutically acceptable carrier formulated for oral therapeutic administration of the ⁇ 4 ⁇ 7 integrin inhibitor compound.
  • a pharmaceutically acceptable carrier formulated for oral therapeutic administration of the ⁇ 4 ⁇ 7 integrin inhibitor compound.
  • the invention provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (IIA), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (III), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (IIIA), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • ATTORNEY DOCKET NO. MORF-010WO1 the invention provides a pharmaceutical composition comprising a compound of Formula (IV), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (IVA), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (V), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (VA), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (VI), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (VIA), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (VII), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • Pharmaceutically acceptable compositions comprising a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof can be prepared by various procedures.
  • the compounds of Formula (I) can be formulated with suitable excipients, diluents, or carriers, and formed into tablets, or capsules, and other suitable dosage forms.
  • Pharmaceutical compositions can be provided in unit dose forms containing a predetermined amount of API comprising a compound described herein (e.g., a compound of ATTORNEY DOCKET NO.
  • MORF-010WO1 Formula (I)) or a pharmaceutically acceptable salt thereof per unit dose Such a unit may contain, a desired amount of a compound (e.g., a compound of the Formula (I)) or pharmaceutically acceptable salt thereof, depending on the condition being treated, the route of administration and the age, weight and condition of the patient. Such unit doses may therefore be administered at a desired dose interval.
  • concentration of active compound in the drug composition will depend on various applicable parameters and considerations such as the absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated.
  • compositions will generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • Pharmaceutical compositions comprising a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof formulated for oral delivery can be prepared in a unit dosage form, such as a capsule at a desired dosage strength (e.g., of the compound of Formula (I) or a pharmaceutically acceptable salt thereof).
  • the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • a compound described herein e.g., a compound of Formula (I)
  • a pharmaceutically acceptable salt thereof can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier.
  • excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, and sugars; and binding agents such as cellulose derivatives.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
  • suitable ATTORNEY DOCKET NO. MORF-010WO1 binders include starch, natural sugars, natural and synthetic gums, and the like.
  • Lubricants and/or glidants can be used in these dosage forms.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • the dosage unit form When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil.
  • unit dosage forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, or other enteric agents.
  • the compound can be administered as a component of an elixir, suspension, syrup, wafer, or the like.
  • a syrup can contain, in addition to the active compound(s), sucrose or sweetener as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the compounds can be formulated as solutions appropriate for parenteral administration, for example, by intramuscular, subcutaneous or intravenous routes.
  • a compound described herein e.g., a compound of Formula (I)
  • a pharmaceutically acceptable salt thereof can be dissolved in a suitable buffer.
  • a pharmaceutical composition comprising a desired concentration of a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof can be formulated as an injectable drug solution in (useful, e.g., in preclinical animal studies).
  • Exemplary Therapeutic Methods Compounds described herein can be useful for the treatment of various diseases and disorders that benefit from antagonizing the integrin ⁇ v ⁇ 8 .
  • the invention features a method of inhibiting ⁇ v ⁇ 8 integrin in a patient, said method comprising administering to a patient in need thereof a therapeutically ATTORNEY DOCKET NO.
  • the invention features a method of treating a cancer (e.g., a solid tumor) in a patient, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound of any one of Formulas (I)-(VII) such as any compound of Table 1) or a pharmaceutically acceptable salt thereof.
  • a method further comprises administration of a therapeutically effective amount of a second active agent.
  • Solid Tumors [0494]
  • administration of a compound described herein e.g., a compound of any one of Formulas (I)-(VII) such as any compound of Table 1) or a pharmaceutically acceptable salt thereof can be useful for treating a solid tumor in a patient in need thereof, optionally in combination with one or more additional therapies (e.g., a second active agent).
  • a solid tumor is resistant to one or more previous lines of therapy (e.g., a solid tumor is a treatment-resistant tumor).
  • a solid tumor is resistant to immune checkpoint therapy.
  • a cancer is a solid tumor such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, osteosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma,
  • a solid tumor is an advanced stage solid tumor (e.g., a locally advanced solid tumor).
  • a solid tumor is a metastatic solid tumor.
  • ATTORNEY DOCKET NO. MORF-010WO1 [0497]
  • a cancer e.g., solid tumor
  • bile duct cancer cholangiocarcinoma
  • bladder cancer breast
  • a cancer e.g., solid tumor
  • a cancer is breast cancer, squamous cell carcinoma of the head and neck (SCCHN), renal cell carcinoma, ovarian cancer, gastric cancer, esophageal cancer, lung cancer, pancreatic cancer, bile duct cancer, endometrial cancer, melanoma, or urothelial carcinoma.
  • a cancer e.g., a solid tumor
  • a cancer is advanced (e.g., locally advanced).
  • a cancer e.g., a solid tumor
  • a cancer is metastatic.
  • a cancer is anal cancer.
  • a cancer e.g., solid tumor
  • bile duct cancer cholangiocarcinoma
  • a cancer e.g., solid tumor
  • bladder cancer e.g., bladder cancer.
  • a cancer e.g., solid tumor
  • breast cancer e.g., solid tumor
  • cervical cancer e.g., cervical cancer
  • a cancer e.g., solid tumor
  • colorectal cancer ectal cancer.
  • a cancer e.g., solid tumor
  • a cancer e.g., solid tumor
  • a cancer is endometrial cancer.
  • a cancer e.g., solid tumor
  • an esophageal cancer is adenocarcinoma. In embodiments, an esophageal cancer is squamous cell carcinoma. [0509] In embodiments, a cancer (e.g., solid tumor) is fallopian tube cancer. [0510] In embodiments, a cancer (e.g., solid tumor) is gastric cancer. [0511] In embodiments, a cancer (e.g., solid tumor) is glioma. [0512] In embodiments, a cancer (e.g., solid tumor) is liver cancer. In embodiments, a liver cancer is hepatocellular carcinoma. ATTORNEY DOCKET NO.
  • a cancer is lung cancer.
  • a lung cancer is squamous cell carcinoma of the lung.
  • a lung cancer is non small cell lung cancer (NSCLC).
  • NSCLC non small cell lung cancer
  • a cancer e.g., solid tumor
  • a cancer e.g., solid tumor
  • a cancer is melanoma.
  • a cancer e.g., solid tumor
  • a cancer is neuroblastoma.
  • a cancer is osteosarcoma.
  • a cancer e.g., solid tumor
  • a cancer is ovarian cancer.
  • a cancer e.g., solid tumor
  • pancreatic cancer e.g., a cancer (e.g., solid tumor)
  • a cancer e.g., solid tumor
  • primary peritoneal carcinoma e.g., solid tumor
  • a cancer e.g., solid tumor
  • prostate cancer e.g., prostate cancer.
  • a cancer e.g., solid tumor
  • a cancer e.g., solid tumor
  • a cancer e.g., solid tumor
  • RCC renal cell carcinoma
  • a renal cell carcinoma is clear cell renal cell carcinoma (ccRCC).
  • a renal cell carcinoma is papillary renal cell carcinoma (PRCC).
  • a cancer is skin cancer.
  • a skin cancer is cutaneous squamous cell carcinoma (CSCC).
  • a skin cancer is basal cell carcinoma (BCC).
  • a cancer e.g., solid tumor
  • SCCHN head and neck
  • a cancer e.g., solid tumor
  • SCCHN head and neck
  • a cancer e.g., solid tumor
  • a cancer is testicular cancer.
  • a cancer e.g., solid tumor
  • a cancer is urothelial carcinoma.
  • a cancer is uterine cancer.
  • a patient has a cancer (e.g., a solid tumor such as those described herein) that is therapy resistant.
  • a therapy resistant cancer e.g., a solid tumor
  • checkpoint resistant e.g., a therapy resistant cancer
  • a therapy resistant cancer e.g., a solid tumor
  • is resistant to an anti-PD-1 or anti-PD-L1 therapy collectively, a PD-(L)1 resistant cancer.
  • a compound described herein e.g., a compound of any one of Formulas (I)-(VII) such as any compound of Table 1) or a pharmaceutically acceptable salt thereof, may be used in combination therapies.
  • administration of a compound or pharmaceutically acceptable salt described herein enhances response to one or more additional therapies (e.g., a second active agent).
  • additional therapies e.g., a second active agent
  • administration of a compound or pharmaceutically acceptable salt described herein can improve response to additional therapy (e.g., a second active agent).
  • a compound or pharmaceutically acceptable salt described herein may be administered in combination with one or more additional therapies (e.g., a second active agent) in the treatment of certain diseases and disorders.
  • a compound or pharmaceutically acceptable salt described herein may be administered in combination with an immunotherapy.
  • an immunotherapy is a cancer immunotherapy.
  • a cancer immunotherapy is an immune checkpoint therapy (e.g., therapy comprising administration of an immune checkpoint inihbitor).
  • a cancer immunotherapy is a cellular immunotherapy such as adoptive T cell transfer therapy (e.g., Chimeric Antigen Receptor (CAR) T cell therapy, CAR natural killer (NK) cell therapy, tumor infiltrating lymphocyte (TIL) therapy, or endogenous T cell (ETC) therapy).
  • a cancer immunotherapy is a cancer vaccine.
  • a cancer immunotherapy is monoclonal antibody therapy (e.g., an antibody useful for immune checkpoint therapy such as those described herein).
  • a cancer immunotherapy is cytokine therapy (e.g., interferon or interleukin therapy).
  • a compound or pharmaceutically acceptable salt described herein is administered with a second active agent to a patient in need thereof for the treatment of a solid tumor (e.g., as described herein).
  • a second active agent is an immune checkpoint inhibitor.
  • an immune checkpoint inhibitor targets PD-1 (e.g., inhibition via anti-PD-1, anti- PD-L1, or anti-PD-L2 therapies), CTLA-4, TIM-3, TIGIT, LAGs (e.g., LAG-3), CEACAM (e.g., CEACAM-1, -3 and/or -5), VISTA, BTLA, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GALS, adenosine, TGFR (e.g., TGFR beta), B7-H1, B7-H4 (VTCN1), OX-40, CD137, CD40, IDO, or CSF-1/CSF-1R.
  • PD-1 e.g., inhibition via anti-PD-1, anti- PD-L1, or anti-PD-L2 therapies
  • a checkpoint inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, a toxin, or a binding agent.
  • a checkpoint inhibitor is an antibody, an antibody conjugate, or an antigen-binding fragment thereof.
  • an immune checkpoint inhibitor is an agent that inhibits PD-1, TIM- 3, CTLA-4, LAG-3, TIGIT, IDO or CSF-1/CSF-1R.
  • an immune checkpoint inhibitor is selected from: pembrolizumab (Keytruda®), nivolumab (Opdivo®), cemiplimab (Libtayo®), dostarlimab (Jemperli®), atezolizumab (Tecentriq®), avelumab (Bavencio®), durvalumab (Imfinzi®), ipilimumab (Yervoy®), and relatlimab, as well as biosimilars thereof.
  • a second active agent is an anti-PD-1 therapy or an anti-PD-L1 therapy (collectively referred to as anti-PD(L)-1 therapy).
  • an anti-PD(L)-1 therapy is selected from the group consisting of: pembrolizumab, nivolumab, cemiplimab, dostarlimab, atezolizumab, avelumab, durvalumab, PDR001, Cemiplimab, BGB-A317, LY3300054, BI 754091, IBI308, INCSHR-1210, JNJ- 63723283, JS-001, MEDI0680 (AMP-514), MGA-012, PF-06801591, CX-072, FAZ053, and PD-L1 millamolecule, as well as biosimilars thereof.
  • an anti-PD(L)-1 therapy is selected from atezolizumab, avelumab, BGB-A317, BI 754091, CX-072, durvalumab, FAZ053, IBI308, INCSHR-1210, JNJ-63723283, JS-001, MEDI-0680, MGA-012, nivolumab, PDR001, pembrolizumab, PF-06801591, cemiplimab, dostarlimab, any of the antibodies disclosed in WO2014/179664, as well as biosimilarsthereof.
  • an anti-PD(L)-1 therapy is selected from the group consisting of BGB-A317, BI 754091, CX-072, FAZ053, IBI308, INCSHR-1210, JNJ-63723283, JS-001, LY3300054, MEDI-0680, MGA-012, nivolumab, PD-L1 millamolecule, PDR001, pembrolizumab, PF-06801591, cemiplimab, and dostarlimab, as well as biosimilars thereof.
  • an anti-PD(L)-1 therapy is selected from pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, dostarlimab, PDR-001, tislelizumab (BGB- A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283, MGA012, BI-754091, IBI-308, camrelizumab (HR-301210), BCD-100, JS-001, CX-072, BGB-A333, AMP-514 (MEDI-0680), AGEN-2034, CS1001, Sym-021, SHR-1316, PF-06801591, LZM009, KN-035, AB122, genolimzumab (CBT-501), FAZ-053, CK-301, AK 104, GLS-010, JTX-4014, SHR-1210, AMP-
  • an anti-PD(L)-1 therapy is selected from durvalumab, atezolizumab, avelumab, BGB-A333, SHR-1316, FAZ-053, CK-301, and PD-L1 millamolecule, or derivatives thereof. [0541] In embodiments, an anti-PD(L)-1 therapy is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, atezolizumab, avelumab, and durvalumab.
  • an anti-PD(L)-1 therapy is selected from nivolumab, pembrolizumab, cemiplimab, and dostarlimab. In embodiments, an anti-PD(L)-1 therapy is selected from atezolizumab, avelumab, and durvalumab. [0542] In embodiments, a second active agent is an anti-CTLA-4 therapy. In embodiments, an anti-CTLA-4 therapy is ipilimumab. [0543] In embodiments, a second active agent is an anti-LAG-3 therapy.
  • an anti-LAG-3 therapy is selected from: LAG525 (IMP701), REGN3767 (R3767), BI 754,091, tebotelimab (MGD013), eftilagimod alpha (IMP321), TSR-033, and FS118.
  • a second active agent is an anti-TIM-3 therapy.
  • an anti-TIM-3 therapy is selected from: MBG453, Sym023, and TSR-022.
  • a second active agent is an anti-CSF-1/R therapy.
  • an anti-CSF-1/R therapy is selected from: lacnotuzumab (MCS110), LY3022855, SNDX-6352, emactuzumab (RG7155), and pexidartinib (PLX3397).
  • a second active agent is an anti-TIGIT therapy.
  • an anti-TIGIT therapy is selected from: BMS-986207, ociperlimab, tiragolumab, vibostolimab, domvanalimab, EOS448, COM902, and AGEN307.
  • a second active agent is an anti-CEACAM therapy.
  • an anti-TIGIT therapy is selected from: CM24 and NEO-201.
  • a compound or use of the present invention can be selected from one or more of the enumerated embodiments provided below. ATTORNEY DOCKET NO. MORF-010WO1 1.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein: the Q ring L is each o 4 f which is optionally substituted with 1 to 6 R ; X is -CHR 1c -, -O-, or -NR 2 -; each of R 1a , R 1b , R 1c , R 1d , R 1e , and R 1f is independently H, C 1-4 alkyl, halogen, C 1-4 alkyoxy, OH, C 1-4 alkyl-OH, C 1-4 alkyl-C 1-4 alkyoxy, C 1-4 alkyoxy-C 1-4 alkyoxy, CF 3 , CHF 2 , CH 2 F, CN, NO 2 , NR a R b or C 1-4 alkyl-NR a R b , each R 2 is independently H, C1-4alkyl, or C3-5cycloalkyl; R 3a is C1-4alkyoxy, C3-5cycloalkoxy, CF3, CHF2, CH2F
  • MORF-010WO1 optionally substituted by from one to three groups which may be the same or different selected from the group consisting of F, C 1-4 alkyl, phenyl and benzyl; and n is 1 or 2; and m is 0, 1 or 2.
  • R 2 is methyl.
  • the compound of Embodiment 1, wherein the Q ring is . 7.
  • each R 1c is independently H. 9.
  • the compound of any one of Embodiments 1-8, wherein each R 1a is independently H.
  • the compound of any one of Embodiments 1-9, wherein each R 1b is independently H.
  • the compound of any one of Embodiments 1-9, wherein each R 1b is independently OMe.
  • the compound of Embodiment 1, wherein the Q ring 13 The compound of Embodiment 12, wherein each of R 1c and R 1d is independently H. ATTORNEY DOCKET NO. MORF-010WO1
  • the compound of Embodiment 1 or 12-13, wherein each of R 1a , R 1b and R 1f is independently H.
  • the compound of any one of Embodiments 1-14, wherein L is .
  • the compound of any one of Embodiments 1-14, wherein L is .
  • the compound of any one of Embodiments 1-16, wherein R 3a is C1-4alkyoxy.
  • the compound of any one of Embodiments 1-16, wherein R 3a is OMe, OEt, OCF 3 , OCHF 2 or OCH 2 F.
  • R 3a is OMe.
  • the compound of any one of Embodiments 1-20, wherein R 3c is H.
  • R 3d is C 1-4 alkyl.
  • R 3d is C3-5cycloalkyl.
  • R 3d is oxetanyl, tetrahydrofuranyl or tetrahydro-2H-pyranyl, morpholinyl or piperazinyl-C1-4alkyl.
  • R 3d is iso-propyl.
  • each R 4 is independently methyl.
  • each R 4 is independently F.
  • the compound of any one of Embodiments 1-26, wherein each R 4 is independently CF 3 , CHF 2 or CH 2 F.
  • the compound of any one of Embodiments 1-26, wherein each R 4 is independently H.
  • the compound of any one of Embodiments 1-30, wherein each R 6 is independently C1-4alkyl.
  • ATTORNEY DOCKET NO. MORF-010WO1 The compound of any one of Embodiments 1-30, wherein each R 6 is independently C1- 4alkenyl.
  • the compound of any one of Embodiments 1-30, wherein each R 6 is independently C3- 5cycloalkyl.
  • each R 6 is independently C1- 4alkyoxy.
  • the compound of any one of Embodiments 1-30, wherein each R 6 is independently C 3- 5cycloalkoxy.
  • each R 6 is independently F, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , OCH 2 F or OH.
  • the compound of any one of Embodiments 1-30, wherein each R 6 is independently a 5-6- membered heteroaryl.
  • each R 6 is independently H.
  • n is 0.
  • the compound of any one of Embodiments 49-52, wherein n is 1.
  • the compound of any one of Embodiments 49-52, wherein n is 2.
  • the compound of Embodiment 57, wherein R 3d is The compound of any one of Embodiments 43-56, wherein R 3d is 4-6-membered heterocycloalkyl optionally substituted with 1 R 6 .
  • the compound of Embodiment 59, wherein R 3d is .
  • the compound of any one of Embodiments 43-62, wherein the carbon marked by the asterisk (*) has the (R)-configuation.
  • ATTORNEY DOCKET NO. MORF-010WO1 The compound of any one of Embodiments 43-62, wherein the carbon marked by the asterisk (*) has the (S)-configuation.
  • the compound of embodiment 66, wherein the compound is (Compound 7A/7B), or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 66, wherein the compound is (Compound 11A/11B), or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 66, wherein the compound is (Compound 12A/12B), or a pharmaceutically acceptable salt thereof.
  • ATTORNEY DOCKET NO. MORF-010WO1 The compound of embodiment 66, wherein the compound is (Compound 17A/17B), or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 66, wherein the compound is (Compound 20A/20B), or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 66, wherein the compound is (Compound 24A/B), or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 66, wherein the compound is (Compound 28A/28B), or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 66, wherein the compound is pharmaceutically acceptable salt thereof.
  • the compound of embodiment 66, wherein the compound is pharmaceutically acceptable salt thereof.
  • the compound of embodiment 66, wherein the compound is pharmaceutically acceptable salt thereof.
  • ATTORNEY DOCKET NO. MORF-010WO1 The compound of embodiment 66, wherein the compound is (Compound 136A/136B), or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 66, wherein the compound is pharmaceutically acceptable salt thereof.
  • the compound of embodiment 66, wherein the compound is (Compound 154A/154B), or a pharmaceutically acceptable salt thereof.
  • a method of inhibiting ⁇ v ⁇ 8 integrin in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-87, or a pharmaceutically acceptable salt thereof.
  • the method of embodiment 89 wherein the method is for treating a solid tumor in a patient in need thereof.
  • a method of treating solid tumor in a patient comprising administering to the patient in need thereof (a) a therapeutically effective amount of a compound of any one of ATTORNEY DOCKET NO. MORF-010WO1 embodiments 1-87, or a pharmaceutically acceptable salt thereof, and (b) a therapeutically effective amount of a second active agent.
  • the solid tumor is selected from: anal cancer, bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, fallopian tube cancer, gastric cancer, glioma liver cancer, lung cancer, melanoma, nasopharyngeal carcinoma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, primary peritoneal carcinoma, prostate cancer, renal cell carcinoma, skin cancer, squamous cell carcinoma of the head and neck (SCCHN), testicular cancer, urothelial carcinoma, and uterine cancer.
  • anal cancer bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, fallopian tube cancer, gastric cancer, glioma liver cancer, lung cancer, melanoma, nasopharyngeal carcinoma, neuroblastoma, osteosarcoma, ovarian cancer
  • the solid tumor is selected from: breast cancer, squamous cell carcinoma of the head and neck (SCCHN), renal cell carcinoma, ovarian cancer, gastric cancer, esophageal cancer, lung cancer, pancreatic cancer, bile duct cancer, endometrial cancer, melanoma, and urothelial carcinoma.
  • SCCHN head and neck
  • the second active agent is an immune checkpoint inhibitor.
  • the immune checkpoint inhibitor is an anti-PD-1 or an anti-PD-L1 therapy.
  • the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, atezolizumab, avelumab, and durvalumab.
  • Method A Column: Kinetex C182.1 x 50 mm, 5 um; Flow rate 1.0 mL/min; Mobile phase A: water with 0.04% TFA, Mobile phase B: acetonitrile with 0.02% trifluoroacetic acid; Gradient: 5% B from 0-0.40 min, then a gradient of 5-95% B over 2.60 min, then hold on 95% B for 1.00 min, then 95-5% B over 0.01 min.
  • Method B Column: Xbridge C182.1 x 50 mm column (5 um particles); Flow rate 0.8 mL/min; Mobile phase A: water with 10 mM NH 4 HCO 3 ; Mobile phase B: acetonitrile; Gradient: 5% B from 0-0.40 min, then a gradient of 5-95% B from 0.40-3.40 min, then hold 95% B for 0.45 min, then 95-5% B over 0.01 min.
  • Chiral SFC B column: AD 4.6*100mm, 5 ⁇ m (Daicel), column temperature: 40 °C
  • mobile phase CO2/methanol (0.2% methanol ammonia)
  • isocratic elution as in text flow rate: 4 g/min, back pressure: 120 bar.
  • Chiral SFC H column: (S,S)-Whelk-O1, 4.6*100mm, 5 ⁇ m (Daicel), column temperature: 40 °C
  • mobile phase CO2/methanol (0.2% methanol ammonia
  • isocratic elution as in text flow rate: 4 g/min, back pressure: 120 bar.
  • the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 100% Ethyl ATTORNEY DOCKET NO. MORF-010WO1 acetate/Petroleum ether gradient @ 150 mL/min).
  • the racemic product was purified by prep-HPLC (column: Phenomenex luna C18 (250 x 70 mm, 15 um); mobile phase: A water (TFA 0.1%), B MeCN 1%-30%, 20 min; Flow Rate (25 mL/min).
  • (R)-7-(5-(pyrrolidin-3- ATTORNEY DOCKET NO. MORF-010WO1 yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (3.4 g, 11.75 mmol, 82.18% yield) was obtained as a yellow oil.
  • LCMS (ESI) m/z 290.3 (M+1).
  • Step 2 (R)-tert-butyl 3-((5-(4-methoxy-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1- carboxylate1 [0601] To a solution of (R)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (4.42 g, 17.31 mmol) in THF (30 mL) was added 9-BBN (0.5 M in THF, 92.32 mL) at 0 °C, after stirring at 25 °C for 2 h, the solution was added into a suspension of 2-chloro-4-methoxy-1,8- naphthyridine (2.25 g, 11.56 mmol), Pd(OAc) 2 (259.07 mg, 1.15 mmol) and tricyclohexylphosphine (323.60 mg, 1.15 mmol) and K2CO3 (3.19 g, 23.08
  • Step 4 (R)-5-methoxy-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8- naphthyridine hydrochloride [0603] To a solution of (R)-tert-butyl 3-((5-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridin- 2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (2 g, 4.77 mmol) in MeOH (10 mL) was added HCl/MeOH (4M, 20 mL) at 25 °C, the reaction was stirred at 50 °C for 16 h.
  • Step 2 (S)-tert-butyl 7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pentyl)-3,4-dihydro- 1,8-naphthyridine-1(2H)-carboxylate [0605] To a solution of (S)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (10 g, 39.16 mmol) in THF (100 mL) was added 9-BBN (0.5 M, 156.64 mL) at 0 °C.
  • Step 3 (S)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine [0606]
  • a solution of (S)-tert-butyl 7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pentyl)- 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (5 g, 10.21 mmol) in HCl/MeOH (4M, 50 mL) was stirred at 50 °C for 16 h. The mixture was concentrated in vacuum.
  • the racemic product was purified by prep-HPLC (column: Phenomenex Luna 80 x 30 mm x 3 um; mobile phase: A water with 0.1% TFA; B MeCN 1%-30%, 20 min; Flow Rate 25 mL/min).
  • (S)-7-(5-(pyrrolidin- 3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (2.3 g, 7.95 mmol, 77.83% yield) was obtained as yellow oil.
  • Step 2 (R)-tert-butyl 3-(2-hydroxyethoxy)pyrrolidine-1-carboxylate [0608] DIBAL-H (1 M, 3.66 mL) was added dropwise to a solution of (R)-tert-butyl 3-(2- ethoxy-2-oxoethoxy)pyrrolidine-1-carboxylate (0.5 g, 1.83 mmol) in THF (10 mL) at 0 °C. The mixture was stirred for 2 h at 20 °C. The reaction mixture was quenched with aqueous NH4Cl (50 mL) at 0 °C and extracted with ethyl acetate (50 mL x 3).
  • Step 3 tert-butyl 7-ethynyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate
  • Step 4 (R,E)-tert-butyl 7-(2-(2-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)ethoxy)vinyl)- 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0610] To the solution of tert-butyl 7-ethynyl-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate (0.375 g, 1.45 mmol) and (R)-tert-butyl 3-(2-hydroxyethoxy)pyrrolidine-1- carboxylate (470.07 mg, 2.03 mmol) in DMSO (8 mL) was added KOH (81.46 mg, 1.45 mmol).
  • Step 2 (R)-tert-butyl 3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1- carboxylate ATTORNEY DOCKET NO. MORF-010WO1 [0614] To a solution of (R)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (4.7 g, 18.41 mmol) in THF (70 mL) was added 9-BBN (0.5 M, 73.62 mL) at 0 °C under N 2 . The mixture was stirred at 50 °C for 2 h.
  • Step 3 (R)-tert-butyl 3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1- carboxylate [0615] To the mixture of 2-methoxyethanol (1.67 g, 21.91 mmol) in THF (16 mL) was added NaH (876.22 mg, 21.91 mmol, 60% purity) at 0 °C. The mixture was stirred at 25 °C for 1 h.
  • Step 4 (R)-tert-butyl 3-((5-(4-(2-methoxyethoxy)-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate [0616] To a suspension of Pd/C (1.2 g, 10% purity) in MeOH (80 mL) was added (R)-tert- butyl 3-((5-(4-(2-methoxyethoxy)-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (2.4 g, 5.22 mmol) in MeOH (40 mL) under Ar at 25 o C.
  • Step 5 (R)-5-(2-methoxyethoxy)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8- naphthyridine [0617] To the mixture of (R)-tert-butyl 3-((5-(4-(2-methoxyethoxy)-5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (3 g, 6.47 mmol) in EtOAc (20 mL) was added HCl/EtOAc (4 M, 30 mL). The mixture was stirred at 25 o C for 2 h.
  • the mixture was stirred for 2 h at 20 °C.
  • the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO ®; 10 g Sepa Flash ® Silica Flash Column, Eluent of 0 ⁇ 100% Ethyl acetate/Petroleum ether gradient @ 50 mL/min).
  • Step 2 (R)-tert-butyl 3-((5-(3-bromo-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate
  • NBS (868.15 mg, 4.88 mmol) was added to a solution of (R)-tert-butyl 3-((5-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.9 g, 4.88 mmol) in CH3CN (20 mL) at 0 °C.
  • Step 3 (R)-6-methoxy-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8- naphthyridine
  • NaOMe 0.9 g, 5.00 mmol, 3 mL, 30% purity
  • CuI (195.16 mg, 1.02 mmol) in DME (6 mL) was stirred for 0.5 h at 125 °C under MW condition (inner pressure 4 bar).
  • the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (column: Phenomenex Luna C18100 x 30 mm x 5 um; mobile phase: A water with 0.1% TFA; B MeCN 5%-35%, 10 min; Flow Rate (25 mL/min).
  • the mixture was stirred at 100 °C for 16 h. Two paralleled reactions were carried out and worked up together.
  • the mixture was extracted with ethyl acetate (100 mL x 3), washed with brine (100 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum.
  • the residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 20% Ethyl acetate/Petroleum ether gradient @ 150 mL/min).
  • Step 3 phenyl 2-allyl-1,8-naphthyridine-1(2H)-carboxylate [0623] To a solution of 1,8-naphthyridine (10 g, 76.84 mmol) in CH3CN (150 mL) was added phenyl chloroformate (18.05 g, 115.25 mmol, 14.44 mL) and AgOTf (1.97 g, 7.68 mmol) at 20 °C. The mixture was stirred for 0.5 h at 20 °C.
  • allyltrimethylsilane 13.17 g, 115.25 mmol, 18.39 mL
  • the mixture was stirred for 16 h at 20 °C.
  • the mixture was diluted with MTBE (100 mL) and filtered.
  • the filtrate was washed with aqueous NaHCO3 (100 mL) and brine (100 mL).
  • the organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to give product.
  • Step 5 phenyl 2-(5-(((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pentyl)-3,4-dihydro- 1,8-naphthyridine-1(2H)-carboxylate [0625] To a solution of Pd/C (3 g, 10% purity) in MeOH (300 mL) was added phenyl 2-((E)- 5-(((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pent-2-en-1-yl)-1,8-naphthyridine-1(2H)- carboxylate (7 g, 13.84 mmol) under Ar atmosphere.
  • the suspension was degassed and purged with H2 for 3 times.
  • the mixture was stirred under H2 (50 psi) at 50 °C for 16 h.
  • the reaction mixture was filtered through a celite pad and washed by MeOH (100 mL). The filtrate was concentrated in vacuum.
  • Step 6 (3R)-tert-butyl 3-((5-(1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate [0626] To a solution of phenyl 2-(5-(((R)-1-(tert-butoxycarbonyl)pyrrolidin-3- yl)oxy)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (6.9 g, 13.54 mmol) in H2O (35 ATTORNEY DOCKET NO.
  • Peak 1 arbitrarily assigned as (R)-tert-butyl 3-((5-((S)-1,2,3,4-tetrahydro-1,8- naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (420 mg, 1.08 mmol, 38.18% yield) which was obtained as a white solid.
  • Step 3 (R)-tert-butyl 3-((5-(4-isopropoxy-1, 8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1- carboxylate ATTORNEY DOCKET NO.
  • Step 5 (R)-tert-butyl 3-((5-(4-isopropoxy-5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate [0636] To a mixture of (R)-tert-butyl 3-((5-(4-isopropoxy-5, 6, 7, 8-tetrahydro-1,8- naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.5 g, 3.35 mmol) in MeOH (5 mL) was added HCl/MeOH (4 M, 20 mL) at 25 °C under N2.
  • Step 2 (R)-tert-butyl 3-((5-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6- yl)pentyl)oxy)pyrrolidine-1-carboxylate [0638] To a solution of (R)-tert-butyl 3-(pent-4-en-1-yloxy) pyrrolidine-1-carboxylate (12 g, 46.99 mmol) in THF (120 mL) was added 9-BBN (0.5 M, 187.98 mL). The mixture was stirred at 25 °C for 16 h and used to next step directly.
  • the reaction mixture was quenched by addition H 2 O (60 mL) and ethyl acetate (50 mL), the mixture was filtered with celite pad and the filtrate was concentrated in vacuum to get a residue.
  • the filtrate was extracted with ethyl acetate (30 mL x 3).
  • the combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO ®; 40 g Sepa Flash ® Silica Flash Column, Eluent of 0 ⁇ 100% Ethyl acetate/Petroleum ether gradient @ 80 mL/min).
  • Step 3 (R)-6-(5-(pyrrolidin-3-yloxy)pentyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine [0639] A solution of (R)-tert-butyl 3-((5-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6- yl)pentyl)oxy)pyrrolidine-1-carboxylate (3 g, 7.66 mmol) in HCl/MeOH (4M, 30 mL) was stirred at 50 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue.
  • Step 2 ethyl 2-((tert-butoxycarbonyl)(6-chloro-3-nitropyridin-2-yl)amino)acetate
  • Et3N 8.57 g, 84.73 mmol, 11.79 mL
  • DMAP 517.57 mg, 4.24 mmol
  • Boc2O 15.72 g, 72.02 mmol, 16.55 mL
  • Step 3 ethyl 2-((3-amino-6-chloropyridin-2-yl)(tert-butoxycarbonyl)amino)acetate ATTORNEY DOCKET NO. MORF-010WO1 [0642] To a mixture of ethyl 2-((tert-butoxycarbonyl)(6-chloro-3-nitropyridin-2- yl)amino)acetate (14 g, 38.91 mmol) and NH4Cl (10.41 g, 194.57 mmol) in EtOH (280 mL) and H2O (90 mL) was added Fe (10.87 g, 194.57 mmol) at 20 °C.
  • Step 4 tert-butyl 6-chloro-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate
  • ethyl 2-((3-amino-6-chloropyridin-2-yl)(tert- butoxycarbonyl)amino)acetate 9 g, 27.29 mmol
  • DMF 100 mL
  • t-BuOK 3.37 g, 30.02 mmol
  • Step 5 tert-butyl 6-chloro-1-methyl-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)- carboxylate
  • tert-butyl 6-chloro-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)- carboxylate 3.65 g, 12.87 mmol
  • NaH 566.02 mg, 14.15 mmol, 60% purity
  • MeI (1.83 g, 12.87 ATTORNEY DOCKET NO. MORF-010WO1 mmol, 800.91 uL) was added dropwise at 0 °C under N 2 . Then the mixture was stirred at 20 °C for 12 h. The mixture was added into sat. NH 4 Cl (100 mL) at 0 °C. Ethyl acetate (100 mL) was added to the mixture. The layers were separated and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (200 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuum.
  • Step 7 (R)-tert-butyl 3-((5-(1-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-6- yl)pentyl)oxy)pyrrolidine-1-carboxylate ATTORNEY DOCKET NO.
  • Step 8 (R)-1-methyl-6-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazine [0647] A solution of (R)-tert-butyl 3-((5-(1-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-6- yl)pentyl)oxy)pyrrolidine-1-carboxylate (300 mg, 741.57 ⁇ mol) in HCl/MeOH (2 mL) was stirred at 25 °C for 12 h. The mixture was concentrated.
  • Step 2 (R)-tert-butyl 3-((5-(4-(dimethylamino)-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate [0649] To a solution of Pd/C (2 g, 10% purity) in MeOH (60 mL) was added (R)-tert-butyl 3- ((5-(4-(dimethylamino)-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (3.5 g, 8.17 mmol) under Ar atmosphere.
  • Step 3 (R)-N,N-dimethyl-2-(5-(pyrrolidin-3-yloxy)pentyl)-5,6,7,8-tetrahydro-1,8- naphthyridin-4-amine [0650] A mixture of (R)-tert-butyl 3-((5-(4-(dimethylamino)-5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (3 g, 6.93 mmol) in HCl/MeOH (4 M, 50 mL) was stirred at 50 °C for 16 h. The reaction was concentrated in vacuo.
  • Step 2 tert-butyl 7-(5-((trans-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)pentyl)- 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0652] To a solution of tert-butyl trans-3-fluoro-4-(pent-4-en-1-yloxy)pyrrolidine-1- carboxylate (730 mg, 2.67 mmol) in THF (dry, 10 mL) under Ar, was added 9-BBN (0.5 M in THF, 10.8 mL, 5.4 mmol).
  • reaction mixture was stirred at 50°C for 1.5 hours, then cooled to rt, added 2-chloro-4-methoxy-1,8-naphthyridine (718 mg, 2.67 mmol), Pd(OAc)2 (29 mg, 0.13 mmol), PCy3 (73 mg, 0.26 mmol) and KOH (146 mg, 2.6 mmol).
  • 2-chloro-4-methoxy-1,8-naphthyridine 718 mg, 2.67 mmol
  • Pd(OAc)2 29 mg, 0.13 mmol
  • PCy3 73 mg, 0.26 mmol
  • KOH 146 mg, 2.6 mmol
  • Step 3 7-(5-((trans-4-fluoropyrrolidin-3-yl)oxy)pentyl)-1,2,3,4-tetrahydro-1,8- naphthyridine ATTORNEY DOCKET NO. MORF-010WO1 [0653] To a solution of tert-butyl 7-(5-((trans-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3- yl)oxy)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (1.2 g, 2.36 mmol) in dioxane (40 mL) was added HCl/dioxane (4M, 10 mL).
  • Step 3 tert-butyl cis-3-fluoro-4-((5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate
  • tert-butyl cis-3-fluoro-4-(pent-4-en-1-yloxy)pyrrolidine-1- carboxylate 360 mg, 1.32 mmol
  • 9-BBN 0.5 N in THF, 5.3 mL, 2.65 mmol
  • Step 4 7-(5-((cis-4-fluoropyrrolidin-3-yl)oxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
  • Tert-butyl cis-3-fluoro-4-((5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate (480 mg, 1.18 mmol) was added to a solution of HCl/dioxane (5 mL, 4N).
  • Step 2 tert-butyl (R)-3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1- carboxylate
  • tert-butyl (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate 2.5 g, 9.8 mmol
  • 9-BBN 9-BBN (35.2 mL, 17.6 mmol, 0.5 N in THF)
  • Step 4 tert-butyl (R)-3-((5-(4-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate
  • Step 5 (R)-5-methyl-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
  • Tert-butyl (R)-3-((5-(4-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.15 g, 2.85 mmol) was added to a solution of HCl/dioxane (10 mL, 4N). The mixture was stirred at room temperature for 16 hours and ATTORNEY DOCKET NO.
  • MORF-010WO1 concentrated to give the desired product (R)-5-methyl-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4- tetrahydro-1,8-naphthyridine as a white solid (700 mg), which was used to the next step without further purification. Yield 100% (ESI 304.2 (M+H) +).
  • Step 4 tert-butyl (R)-3-((5-(3-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate
  • Step 5 (R)-6-methyl-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine hydrochloride [0667] Tert-butyl (R)-3-((5-(3-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.5 g, 3.72 mmol) was added to a solution of HCl/dioxane (15 mL, 4N).
  • Step 2 tert-butyl (R)-3-((5-(4-vinyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1- carboxylate
  • Step 3 tert-butyl (R)-3-((5-(4-(2-(dimethylamino)ethyl)-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate
  • Step 4 (R)-N,N-dimethyl-2-(2-(5-(pyrrolidin-3-yloxy)pentyl)-5,6,7,8-tetrahydro-1,8- naphthyridin-4-yl)ethan-1-amine [0671]
  • Step 2 (R)-5-(2-methoxyethyl)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8- naphthyridine [0673] To a solution of tert-butyl (R)-3-((5-(4-(2-methoxyethyl)-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate (376 mg, 0.85 mmol) in 15 mL of EtOAc was added Pd/C (10%, 76 mg).
  • Step 2 tert-butyl (R)-3-((5-oxopentyl)oxy)pyrrolidine-1-carboxylate
  • Step 3 tert-butyl (3R)-3-((5-hydroxyhept-6-en-1-yl)oxy)pyrrolidine-1-carboxylate [0676] To a solution of tert-butyl (R)-3-((5-oxopentyl)oxy)pyrrolidine-1-carboxylate (4.9 g, 18 mmol) in THF (50 mL) was added vinylmagnesium bromide (1.0 M in THF, 36 mL, 36 mmol) dropwise over 30 min at -10°C. The mixture was stirred at rt overnight, then quenched with water (20 mL).
  • Step 4 tert-butyl (R)-3-((7-(2-chloropyridin-3-yl)-5-oxoheptyl)oxy)pyrrolidine-1- carboxylate
  • Step 5 tert-butyl (3R)-3-((5-amino-7-(2-chloropyridin-3-yl)heptyl)oxy)pyrrolidine-1- carboxylate
  • tert-butyl (R)-3-((7-(2-chloropyridin-3-yl)-5- oxoheptyl)oxy)pyrrolidine-1-carboxylate 1.5 g, 3.65 mmol
  • ammonium acetate 2.81 g, 36.5 mmol
  • the mixture was stirred at rt for 10 min, then added sodium cyanoborohydride (692 mg, 11 mmol).
  • Step 6 tert-butyl (3R)-3-(4-(1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1- carboxylate ATTORNEY DOCKET NO. MORF-010WO1 [0679] To a solution of tert-butyl (3R)-3-((5-amino-7-(2-chloropyridin-3- yl)heptyl)oxy)pyrrolidine-1-carboxylate (1.4 g, 3.4 mmol) in DMF (20 mL) was added caesium carbonate (3.33 g, 10.2 mmol). The mixture was stirred at 130 °C for 20 hours.
  • the racemic product was separated by Prep chiral SFC to give P1 (270 mg, arbitrarily assigned as tert-butyl (R)-3-(4-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)butoxy)pyrrolidine-1-carboxylate) and P2 (250 mg, arbitrarily assigned as tert-butyl (R)-3-(4- ((R)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-carboxylate) as pale yellow oils.
  • P1 270 mg, arbitrarily assigned as tert-butyl (R)-3-(4-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)butoxy)pyrrolidine-1-carboxylate
  • P2 250 mg, arbitrarily assigned as tert-
  • Step 7 (S)-2-(4-(((R)-pyrrolidin-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
  • Step 2 tert-butyl (R)-3-((7-oxoheptyl)oxy)pyrrolidine-1-carboxylate
  • Step 4 tert-butyl (R)-3-((9-(2-chloropyridin-3-yl)-7-oxononyl)oxy)pyrrolidine-1-carboxylate
  • Step 5 tert-butyl (3R)-3-((7-amino-9-(2-chloropyridin-3-yl)nonyl)oxy)pyrrolidine-1- carboxylate
  • tert-butyl (R)-3-((9-(2-chloropyridin-3-yl)-7- oxononyl)oxy)pyrrolidine-1-carboxylate 2.6 g, 5.9 mmol
  • methanol 20 mL
  • MORF-010WO1 ammonium acetate 1.g, 18.0 mmol
  • Step 6 tert-butyl (3R)-3-((6-(1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)hexyl)oxy)pyrrolidine-1-carboxylate
  • tert-butyl (3R)-3-((7-amino-9-(2-chloropyridin-3- yl)nonyl)oxy)pyrrolidine-1-carboxylate 2.5 g, 5.7 mmol
  • DMF 20 mL
  • caesium carbonate 5.0 g, 15.3 mmol
  • the racemic product was separated by Prep chiral SFC to give P1 (502 mg, arbitrarily assigned as tert-butyl (R)-3-((6-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)hexyl)oxy)pyrrolidine-1-carboxylate) and P2 (490 mg, arbitrarily assigned as tert-butyl (R)-3- ((6-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)hexyl)oxy)pyrrolidine-1-carboxylate) as pale yellow oils.
  • Step 7 (S)-2-(6-(((R)-pyrrolidin-3-yl)oxy)hexyl)-1,2,3,4-tetrahydro-1,8-naphthyridine
  • (R)-3-((6-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)hexyl)oxy)pyrrolidine-1-carboxylate P1, 250 mg, 0.62 mmol
  • 4M HCl/dioxane 5 mL
  • Step 2 tert-butyl (R)-3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1- carboxylate
  • tert-butyl (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate 2.5 g, 9.8 mmol
  • 9-BBN 9-BBN (35.2 mL, 17.6 mmol, 0.5 N in THF) under N2 ATTORNEY DOCKET NO. MORF-010WO1 atmosphere.
  • the mixture was stirred at 60 °C for 1.5 h and cooled to room temperature.
  • Step 3 tert-butyl (R)-3-((5-(4-methyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1- carboxylate
  • Step 4 tert-butyl (R)-3-((5-(4-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate
  • Step 2 tert-butyl (R)-3-((5-(4-chloro-3-methyl-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate
  • R tert-butyl
  • 9-BBN 9-BBN
  • Step 3 tert-butyl (R)-3-((5-(4-methoxy-3-methyl-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate
  • Step 2 1-(3-bromo-5-fluoro-4-hydroxyphenyl)ethanone ATTORNEY DOCKET NO. MORF-010WO1 [0701] To a solution of 1-(3-bromo-5-fluoro-4-hydroxyphenyl)ethanone (37.5 g, 160.92 mmol) in DMF (450 mL) was added K 2 CO 3 (55.60 g, 402.30 mmol) at 0 °C.
  • Step 3 1-bromo-3-fluoro-2-methoxy-5-(prop-1-en-2-yl)benzene [0702] To a solution of methyl triphenyl)phosphanium bromide (48.00 g, 134.38 mmol) in THF (200 mL) was added t-BuOK (18.85 g, 167.97 mmol) at 0 °C, the mixture was stirred at 0 °C for 0.5 h.
  • Step 4 1-bromo-3-fluoro-5-isopropyl-2-methoxybenzene [0703] To a solution of 1-bromo-3-fluoro-2-methoxy-5-(prop-1-en-2-yl)benzene (8.1 g, 33.05 mmol) in THF (100 mL) was added Pd/C (4 g, 10% purity). The suspension was degassed ATTORNEY DOCKET NO. MORF-010WO1 under vacuum and purged with H 2 several times. The mixture was stirred under H 2 (15 psi) at 25 °C for 12 h. The reactions (Five paralleled reactions) was filtered and the filtrate was concentrated.
  • Step 5 (3-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid [0704] n-BuLi (2.5 M, 6.07 mL) was added dropwise to a solution of 1-bromo-3-fluoro-5- isopropyl-2-methoxybenzene (2.5 g, 10.12 mmol) and triisopropyl borate (2.85 g, 15.18 mmol, 3.49 mL) in THF (50 mL) at -78 °C under N 2 . The resulting mixture was stirred for 1 h at -78 °C and 1 h at 20 °C. The reaction mixture was quenched with ice water (100 mL).
  • Step 2 ethyl 2-(4-(cyclopropylmethyl)-2-methoxyphenyl)acetate
  • 1-bromo-4-(cyclopropylmethyl)-2-methoxybenzene (466 mg, 1.93 mmol)
  • Q-phos(43 mg, 0.06 mmol) and Pd2(dba)3 55 mg, 0.06 mmol
  • 2-ethoxy-2-oxoethyl)zinc(II) bromide 1 M in THF, 4.8 mL.
  • the reaction mixture was stirred at 50 °C under N2 for 1 hour.
  • Step 3 ethyl 2-bromo-2-(4-(cyclopropylmethyl)-2-methoxyphenyl)acetate
  • ethyl 2-(4-(cyclopropylmethyl)-2-methoxyphenyl)acetate 460 mg, 1.85 mmol
  • lithium diisopropylamide solution 2.0 M in THF/hexanes 2.3 mL, 4.6 mmol
  • MORF-010WO1 chlorotrimethylsilane (0.49 g, 4.51 mmol) was added and the reaction was stirred at -78°C for another 30 min. Then a solution of NBS (0.80 g, 4.51 mmol) in THF (10 mL) was added and the reaction was stirred at -78°C for 30 min. The reaction was quenched with H2O (10 mL), then extracted with EtOAc (20 mL ⁇ 3). The combined organic phase was washed with Sat. NaHCO3 solution, brine, dried over Na2SO4, filtered and concentrated in vacuo.
  • Step 2 1-bromo-3-chloro-5-(cyclopropylmethyl)-2-methoxybenzene [0709] To a solution of 3-bromo-5-chloro-4-methoxybenzaldehyde (1.8 g, 7.26 mmol) in MeOH (20 mL) was added TsNHNH2 (1.49 g, 7.986 mmol). The reaction mixture was stirred at rt overnight. The solvent was removed in vacuo and the residue was dissolved in 1,4-dioxane (30 mL), added cyclopropylboronic acid (1.25 g, 14.52 mmol) and DBU (2.2 g, 14.52 mmol). The ATTORNEY DOCKET NO.
  • MORF-010WO1 reaction mixture was stirred at 100 °C for 2 hours.
  • the reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (3x 100 mL).
  • the combined organic layer was washed with saturated NaCl (aq.), dried over Na2SO4, filtered and concentrated in vacuo.
  • the residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product 1-bromo-3- chloro-5-(cyclopropylmethyl)-2-methoxybenzene as a colourless oil (1.1 g). Yield 55% (ESI 275 (M+H) +).
  • Step 3 ethyl 2-(3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl)acetate
  • 1-bromo-3-chloro-5-(cyclopropylmethyl)-2-methoxybenzene (1100 mg, 3.99 mmol)
  • Q-phos(89 mg, 0.12 mmol) and Pd2(dba)3 114 mg, 0.12 mmol
  • 2-ethoxy-2-oxoethyl)zinc(II) bromide 1 M in THF, 10 mL.
  • the reaction mixture was stirred at 50 °C under N2 for 1 hour.
  • Step 4 ethyl 2-bromo-2-(3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl)acetate
  • ethyl 2-(3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl)acetate 282 mg, 1.0 mmol
  • THF 20 mL
  • -78°C lithium diisopropylamide solution 2.0 M in THF/hexanes
  • Step 2 ethyl 2-(5-(cyclopropylmethyl)-2-methoxyphenyl)acetate
  • 2-bromo-4-(cyclopropylmethyl)-1-methoxybenzene 370 mg, 1.53 mmol
  • Q-phos(34 mg, 0.05 mmol) and Pd2(dba)3 44 mg, 0.05 mmol
  • 2-ethoxy-2-oxoethyl)zinc(II) bromide 1 M in THF, 3.8 mL.
  • the reaction mixture was ATTORNEY DOCKET NO.
  • MORF-010WO1 stirred at 50 °C under N2 for 1 hour.
  • Step 3 ethyl 2-bromo-2-(5-(cyclopropylmethyl)-2-methoxyphenyl)acetate
  • ethyl 2-(5-(cyclopropylmethyl)-2-methoxyphenyl)acetate 248 mg, 1.0 mmol
  • lithium diisopropylamide solution 2.0 M in THF/hexanes 2.5 mL, 2.5 mmol
  • the reaction was stirred at -78°C for 30 min, then chlorotrimethylsilane (272 mg, 2.5 mmol) was added and the reaction was stirred at -78°C for another 30 min.
  • Step 2 ethyl 2-(5-chloro-2-(cyclopropylmethoxy)phenyl)acetate
  • 2-bromo-4-chloro-1-(cyclopropylmethoxy)benzene 940 mg, 3.59 mmol
  • Q-phos(80 mg, 0.12 mmol) and Pd2(dba)3 103 mg, 0.12 mmol
  • 2-ethoxy-2-oxoethyl)zinc(II) bromide 1 M in THF, 8.9 mL.
  • the reaction mixture was stirred at 50 °C under N2 for 1 hour.
  • Step 3 ethyl 2-bromo-2-(5-chloro-2-(cyclopropylmethoxy)phenyl)acetate
  • ethyl 2-(5-chloro-2-(cyclopropylmethoxy)phenyl)acetate was added lithium diisopropylamide solution 2.0 M in THF/hexanes (2.5 mL, 2.5 mmol) dropwise.
  • the reaction was stirred at -78°C for 30 min, then chlorotrimethylsilane (272 mg, 2.5 mmol) was added and the reaction was stirred at -78°C for another 30 min.
  • Step 2 1-(3-bromo-4-methoxybenzyl)cyclopropan-1-ol
  • EtMgBr 6.5 mL, 13 mmol, 2N in THF
  • EtMgBr 6.5 mL, 13 mmol, 2N in THF
  • Ti(i-PrO) 4 1.57 g, 5.5 mmol
  • THF 20 mL
  • the mixture was stirred at room temperature for 12 h, quenched by adding 1 M sulfuric acid solution and extraced with EtOAc (20 mL x 2).
  • Step 3 2-bromo-1-methoxy-4-((1-methoxycyclopropyl)methyl)benzene
  • NaH 188 mg, 4.7 mmol, 60% in mineral oil
  • 1-(3- bromo-4-methoxybenzyl)cyclopropan-1-ol 800 mg, 3.1 mmol
  • MeI 666 mg, 4.7 mmol
  • the mixture was stirred at room temperature for 8 h, quenched with water (20 mL) and extraced with EtOAc (20 mL x 2).
  • Step 4 ethyl 2-(2-methoxy-5-((1-methoxycyclopropyl)methyl)phenyl)acetate
  • (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (6.5 mL, 6.5 mmol, 1 N in THF) was added to a solution of 2-bromo-1-methoxy-4-((1-methoxycyclopropyl)methyl)benzene (330 mg, 1.3 mmol), Pd2(dba)3 (65 mg, 0.067 mmol) and Q-phos (50 mg, 0.07 mmol) in 6 mL of THF under argon atmosphere.
  • Step 5 ethyl 2-bromo-2-(2-methoxy-5-((1-methoxycyclopropyl)methyl)phenyl)acetate
  • LDA 1.25 mL, 2.5 mmol, 2N in THF
  • TMSCl 270 mg, 2.5 mmol
  • NBS 470 mg, 2.5 mmol
  • Step 2 ethyl 2-(5-(cyclopropylmethyl)-2-(trifluoromethoxy)phenyl)acetate
  • (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (4.5 mL, 4.5 mmol, 1 N in THF) was added to a mixture of 2-bromo-4-(cyclopropylmethyl)-1-(trifluoromethoxy)benzene (441 mg, 1.5 mmol), Pd 2 (dba) 3 (55 mg, 0.05 mmol) and Q-phos (69 mg, 0.05 mmol) in 8 mL of THF under argon atmosphere.
  • Step 3 (3-bromo-4-(methoxymethyl)phenyl)methanol [0728] DIBAL-H (1M in THF, 19 mL, 19 mmol) was added to a mixture of methyl 3-bromo- 4-(methoxymethyl)benzoate (1.9 g, 7.36 mmol) in THF (20 mL) at room temperature. The mixture was stirred at 60 °C for 8 h. The mixture was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc (25 mL x 2).
  • Step 4 2-bromo-4-(bromomethyl)-1-(methoxymethyl)benzene
  • NBS (1.8 g, 10.4 mmol) was added to a mixture of (3-bromo-4- (methoxymethyl)phenyl)methanol (1.6 g, 7 mmol) and PPh3 (2.7 g, 10.4 mmol) in DCM (20 mL) at 0 °C under argon.
  • the mixture was stirred at room temperature for 2 h, quenched with water (25 mL) and extracted with DCM (25 mL x 2).
  • Step 6 ethyl 2-(5-(cyclopropylmethyl)-2-(methoxymethyl)phenyl)acetate
  • (2-ethoxy-2-oxoethyl)zinc(II) bromide (4.5 mL, 4.5 mmol, 1 N in THF) was added to a solution of 2-bromo-4-(cyclopropylmethyl)-1-(methoxymethyl)benzene (381 g, 1.5 mmol), Pd2(dba)3 (55 mg, 0.07 mmol) and Q-phos (69 mg, 0.07 mmol) in 8 mL of THF under argon atmosphere.
  • the aqueous phase was extracted with ethyl acetate (200 mL x 2).
  • the combined organic phase was washed with brine (200 Ml x 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum.
  • the residue was purified by MPLC (Biotage®; 80 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 3% ethyl acetate/petroleum ether gradient @ 150 mL/min) to give 1-bromo-2,5-difluoro-4- methoxybenzene (10.4 g, 46.63 mmol, 97.5% yield) as a white solid.
  • Step 3 1,4-difluoro-2-isopropyl-5-methoxybenzene
  • a suspension of 1,4-difluoro-2-methoxy-5-(prop-1-en-2-yl)benzene (2.2 g, 11.94 mmol) and Pd/C (0.5 g, 10% purity) in MeOH (100 mL) was stirred at 25 °C for 3 h under H2 (40 psi). The mixture was filtered and the filtrate was concentrated under reduced pressure.
  • the mixture was purified by MPLC (Biotage®; 40 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 1% ethyl acetate/petroleum ether gradient @ 120 mL/min) to give 1,4-difluoro-2-isopropyl-5- methoxybenzene (1.9 g, 10.20 mmol, 78.4% yield) as colorless oil.
  • Step 4 (2,5-difluoro-3-isopropyl-6-methoxyphenyl)boronic acid [0736] To a solution of 1,4-difluoro-2-isopropyl-5-methoxybenzene (1.8 g, 9.67 mmol) in THF (30 mL) was added LDA (2 M, 6.28 mL) at -78 °C under N2 atmosphere. The reaction was stirred at -78 °C for 0.5 h. trimethyl borate (3.01 g, 29.00 mmol) in THF (5 mL) was added into ATTORNEY DOCKET NO. MORF-010WO1 the reaction. The reaction was stirred at -78 °C for 2 h.
  • reaction mixture was quenched by aq.NH 4 Cl (40 mL) at 0 °C and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the mixture was cooled to 25 °C and partitioned between MTBE (300 mL) and water (500 mL). The mixture was filtered and the aqueous phase was extracted with MTBE (150 mL x 2). The combined organic phase was washed with brine (200 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by MPLC (Biotage®, 220 g SepaFlash® Silica Flash Column, Eluent of petroleum ether gradient @ 150 mL/min). The crude product was purified by RP- MPLC (neutral, MeCN/H2O).
  • Step 2 2,3-difluoro-1-isopropyl-4-methoxybenzene ATTORNEY DOCKET NO. MORF-010WO1
  • a suspension of 2,3-difluoro-1-methoxy-4-(prop-1-en-2-yl)benzene (7.2 g, 39.09 mmol) and Pd/C (2 g, 10% purity) in MeOH (150 mL) was stirred at 25 °C for 3 h under H 2 (40 psi). The mixture was filtered and the filtrate was concentrated under reduced pressure.
  • Step 3 1-bromo-3,4-difluoro-5-isopropyl-2-methoxybenzene [0739] A solution of 2,3-difluoro-1-isopropyl-4-methoxybenzene (3 g, 16.11 mmol) and NBS (3.44 g, 19.33 mmol) in AcOH (40 mL) was stirred at 80 °C for 16 h. The reaction was quenched by water (20 mL) and adjusted to pH ⁇ 7 by adding sat.NaHCO3. The aqueous layer was extracted with ethyl acetate (100 mL x 2).
  • Step 2 1-(3-bromo-5-fluoro-4-methoxyphenyl)ethanone [0742] To a solution of 1-(3-bromo-5-fluoro-4-hydroxyphenyl)ethanone (37.5 g, 160.92 mmol) in DMF (450 mL) was added K 2 CO 3 (55.60 g, 402.30 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h.
  • Step 3 1-bromo-5-(1,1-difluoroethyl)-3-fluoro-2-methoxybenzene
  • NBS (2.63 g, 14.79 mmol) in THF (30 mL) was added dropwise. The reaction was stirred at -70 °C for 1 h. The residue was quenched with sat.NH 4 Cl (20 mL) and extracted with ethyl acetate (20 mLx 2). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • N'-(3-bromo-4-methoxybenzylidene)-4-methylbenzenesulfonohydrazide (27.6 g, crude) was obtained as white solid.
  • Step 2 2-bromo-4-(cyclopropylmethyl)-1-methoxybenzene [0750] To a solution of N'-(3-bromo-4-methoxybenzylidene)-4- methylbenzenesulfonohydrazide (5 g, 13.05 mmol) and cyclopropylboronic acid (1.68 g, 19.57 mmol) in dioxane (100 mL) was added Cs2CO3 (7.65 g, 23.48 mmol) at 25 °C, the reaction was stirred at 100 °C for 16 h.
  • Step 2 (2-fluoro-3-isopropyl-6-methoxyphenyl)boronic acid [0753] To a solution of 2-fluoro-1-isopropyl-4-methoxybenzene (590 mg, 3.51 mmol) in THF (6 mL) was added LDA (2 M, 2.63 mL) at -78 °C. The reaction was stirred at -78 °C for 0.5 ATTORNEY DOCKET NO. MORF-010WO1 h. A solution of trimethyl borate (1.09 g, 10.52 mmol, 1.19 mL) in THF (2 mL) was added into the reaction. The reaction was stirred at -78 °C for 0.5 h.
  • the crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18250 x 50mm x 10 um; mobile phase: A water with 0.1% TFA, B acetonitrile 40%-60%, 10 min; Flow Rate 25 mL/min) to give (2-fluoro-3-isopropyl-6-methoxyphenyl)boronic acid (370 mg, 1.75 mmol, 49.7% yield) as yellow solid.
  • the reaction mixture was quenched ATTORNEY DOCKET NO. MORF-010WO1 by H 2 O (30 mL) at 0 °C, extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO ®; 4 g Sepa Flash ® Silica Flash Column, Eluent of 10 ⁇ 30% Ethyl acetate/Petroleum ether gradient @ 120 mL/min).
  • Step 3 methyl 2-(2-methoxy-5-(2-methoxypropan-2-yl)phenyl)acetate
  • (2-methoxy-2-oxoethyl)zinc(II) bromide (1 M, 7.72 mL) in THF (3 mL) was added Pd(t-Bu3P)2 (118.33 mg, 231.54 ⁇ mol) and 2-bromo-1-methoxy-4-(2- methoxypropan-2-yl)benzene (0.4 g, 1.54 mmol), the reaction was stirred at 70 °C for 3 h. The mixture was concentrated.
  • Step 4 methyl 2-bromo-2-(2-methoxy-5-(2-methoxypropan-2-yl)phenyl)acetate
  • TMSCl methyl 2-bromo-2-(2-methoxy-5-(2-methoxypropan-2-yl)phenyl)acetate
  • Step 2 3-bromo-5-isopropyl-2-methoxybenzaldehyde [0759] To a mixture of 5-isopropyl-2-methoxybenzaldehyde (12.5 g, 70.14 mmol) in DMF (200 mL) was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (21.06 g, 73.64 mmol) at 25 °C under N2 and the mixture was stirred at 25 °C for 16 h.
  • Step 3 3-bromo-5-isopropyl-2-methoxybenzonitrile
  • Step 4 methyl 2-(3-cyano-5-isopropyl-2-methoxyphenyl)acetate [0761] To a solution of HCl (2 M, 125.00 mL) was added Zn (16.25 g, 248.51 mmol) at 25 °C which was stirred at 25 °C for 1 h, the reaction mixture was filtered, the filter cake was washed with THF (50 mL) and concentrated to give a activated zinc.
  • TMSCl (2.72 g, 25.00 mmol, 3.17 mL) at 25 °C and stirred at 40 °C for 0.5 h, then cooled to 0 °C and the mixture was added dropwise methyl 2- bromoacetate (19.12 g, 0.125 mol, 11.80 mL) at 0 °C under N2 and the mixture was stirred at 25 °C for 16 h under N2. The mixture was used the next step directly without further work up and the excess product was quenched with 3 M HCl aqueous.
  • Step 5 methyl 2-bromo-2-(3-cyano-5-isopropyl-2-methoxyphenyl)acetate
  • LiHMDS 1 M, 1.82 mL
  • TMSCl 184.52 mg, 1.70 mmol, 215.56 uL
  • NBS 647.77 mg, 3.64 mmol
  • the reaction mixture was diluted with water (150 mL) and quenched with aqueous Na2SO3 (200 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (150 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO ®; 80 g Sepa Flash ® Silica Flash Column, Eluent of 0 ⁇ 60% Ethyl acetate/Petroleum ether gradient @ 150 mL/min).
  • Step 2 methyl 3-bromo-5-fluoro-4-methoxybenzoate [0764] MeI (10.26 g, 72.28 mmol, 4.50 mL) was added dropwise to a suspension of methyl 3-bromo-5-fluoro-4-hydroxybenzoate (6 g, 24.09 mmol), K2CO3 (9.99 g, 72.28 mmol) in DMF (150 mL) at 25 °C. The mixture was stirred for 2 h at 50 °C.
  • the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (150 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO ®; 40 g Sepa Flash ® Silica Flash Column, Eluent of 0 ⁇ 50% Ethyl acetate/Petroleum ether gradient @ 120 mL/min), methyl 3-bromo-5-fluoro-4-methoxybenzoate (5 g, 19.01 mmol, 78.9% yield) was obtained as a yellow oil.
  • Step 4 1-bromo-3-fluoro-2-methoxy-5-(methoxymethyl)benzene [0766] (3-bromo-5-fluoro-4-methoxyphenyl)methanol (2 g, 8.51 mmol) was added dropwise to a suspension of NaH (680.64 mg, 17.02 mmol, 60% purity) in DMF (20 mL) at 0 °C. After stirred for 2 h at 25 °C, MeI (3.62 g, 25.53 mmol, 1.59 mL) was added to the mixture, the resulting mixture was stirred for 2 h at 25 °C.
  • reaction mixture was quenched with aqueous NH 4 Cl (50 mL) at 0 °C and then the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and the filtrate was concentrated under reduced pressure to give a residue.
  • Step 5 (3-fluoro-2-methoxy-5-(methoxymethyl)phenyl)boronic acid [0767] To a solution of 1-bromo-3-fluoro-2-methoxy-5-(methoxymethyl)benzene (1.4 g, 5.62 mmol) in THF (14 mL) was added n-BuLi (2 M, 4.22 mL) at -78 °C, after stirred at -78 °C for 1 h, trimethyl borate (1.75 g, 16.86 mmol, 1.90 mL) was added and stirred at -78 °C for 1 h.
  • Step 2 1-(3-bromo-5-fluoro-4-methoxyphenyl)ethanone [0769] To a solution of 1-(3-bromo-5-fluoro-4-hydroxyphenyl)ethanone (9.4 g, 40.34 mmol) in DMF (200 mL) was added K2CO3 (11.15 g, 80.67 mmol) and MeI (11.45 g, 80.67 mmol, 5.02 mL), the mixture was stirred at 25 °C for 16 h. Water (200 mL) was added, the mixture was extracted with ethyl acetate (100 mL x 2).
  • Step 3 1-bromo-5-ethyl-3-fluoro-2-methoxybenzene ATTORNEY DOCKET NO. MORF-010WO1
  • TFA TFA
  • triethylsilane 2.35 g, 20.24 mmol, 3.23 mL
  • Water 50 mL was added, the mixture was extracted with ethyl acetate (15 mL x 2).
  • Step 4 (5-ethyl-3-fluoro-2-methoxyphenyl)boronic acid [0771] To a solution of 1-bromo-5-ethyl-3-fluoro-2-methoxybenzene (1 g, 4.29 mmol) in THF (15 mL) was added n-BuLi (2.5 M, 2.57 mL) at -78 °C, the reaction was stirred at -78 °C for 0.5 h. Then trimethyl borate (1.34 g, 12.87 mmol, 1.45 mL) was added in the reaction at -78 °C, the reaction was stirred at -78 °C for 0.5 h.
  • Step 2 1-bromo-2-ethoxy-3-fluoro-5-(prop-1-en-2-yl)benzene [0773] To a solution of 1-(3-bromo-4-ethoxy-5-fluorophenyl)ethanone (7.46 g, 28.57 mmol) in THF (100 mL) was added methyl(triphenyl)phosphanium bromide (20.41 g, 57.15 mmol) and t-BuOK (6.41 g, 57.15 mmol), the mixture was stirred at 25°C for 16 h. Water (100 mL) was added, the mixture was extracted with ethyl acetate (100 mL x 2).
  • Step 4 (2-ethoxy-3-fluoro-5-isopropylphenyl)boronic acid [0775] n-BuLi (2.5 M, 3.45 mL) was added dropwise to a solution of 1-bromo-2-ethoxy-3- fluoro-5-isopropylbenzene (1.5 g, 5.74 mmol) and triisopropyl borate (1.62 g, 8.62 mmol, 1.98 mL) in THF (35 mL) at -78 °C under N 2 . The resulting mixture was stirred for 1 h at -78 °C and 1 h at 25 °C.
  • Step 2 1-bromo-3-fluoro-2-methoxy-5-methylbenzene [0777] To a solution of 2-bromo-6-fluoro-4-methylphenol (10 g, 48.77 mmol) in DMF (100 mL) was added K 2 CO 3 (13.48 g, 97.55 mmol) and MeI (17.31 g, 121.94 mmol, 7.59 mL). The mixture was stirred at 50 °C for 2 h. The reaction mixture was quenched by addition H 2 O (400 mL) at 0 °C, and extracted with ethyl acetate (100 mL x 3).
  • Step 3 (3-fluoro-2-methoxy-5-methylphenyl)boronic acid ATTORNEY DOCKET NO. MORF-010WO1
  • THF triisopropylborate
  • n-BuLi 2.5 M, 2.74 mL
  • the mixture was stirred at 20 °C for 2 h.
  • Step 2 1-(3-bromo-5-fluoro-4-methoxyphenyl)ethanone [0780] To a solution of 1-(3-bromo-5-fluoro-4-hydroxyphenyl)ethanone (5.43 g, 23.30 mmol) in DMF (55 mL) was added K 2 CO 3 (6.44 g, 46.60 mmol) at 0 °C. MeI (4.96 g, 34.95 ATTORNEY DOCKET NO. MORF-010WO1 mmol, 2.18 mL) was slow dropwise added into the reaction at 0 ⁇ 5 °C. The mixture was stirred at 25 °C for 16 h.
  • Step 3 1-bromo-5-(tert-butyl)-3-fluoro-2-methoxybenzene [0781]
  • TiCl 4 13.82 g, 72.86 mmol was added dropwise to DCM (130 mL) at -40 °C under N2, then the mixture was cooled to -50 °C and treated with ZnMe2 (1 M in toluene, 72.86 mL) dropwise, the temperature was maintained at -40 °C. After stirred for 10 min, a solution of 1-(3- bromo-5-fluoro-4-methoxyphenyl)ethanone (3 g, 12.14 mmol) in DCM (30 mL) was added dropwise to the mixture at -40 °C.
  • the resulting mixture was stirred for 0.5 h at -40 °C and 16 h at 20 °C.
  • the mixture was added dropwise to ice water (400 mL) with stirring slowly and the aqueous layer was extracted with ethyl acetate (100 mL x 3).
  • the combined organic extracts were washed with saturated NaHCO3 (100 mL), water (100 mL) and brine (100 mL), dried and concentrated.
  • the residue was purified by flash silica gel chromatography (ISCO®; 20 g Sepa Flash ® Silica Flash Column, Eluent of 0 ⁇ 100% Ethyl acetate/Petroleum ether gradient @70 mL/min).
  • Step 4 (5-(tert-butyl)-3-fluoro-2-methoxyphenyl)boronic acid [0782] To a solution of 1-bromo-5-(tert-butyl)-3-fluoro-2-methoxybenzene (1.5 g, 5.74 mmol) in THF (15 mL) was added triisopropylborate (3.24 g, 17.23 mmol, 3.96 mL), n-BuLi (2.5 ATTORNEY DOCKET NO. MORF-010WO1 M, 3.45 mL) dropwise at -78 °C under N 2 . The mixture was stirred at 20 °C for 2 h.
  • the residue was purified by flash silica gel chromatography (ISCO ®; 20 g Sepa Flash ® Silica Flash Column, Eluent of 0 ⁇ 100% Ethyl acetate/Petroleum ether gradient @ 70 mL/min).
  • the reaction mixture was diluted with water (200 mL) and quenched with aqueous Na2SO3 (200 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO ®; 120 g Sepa Flash ® Silica Flash Column, Eluent of 0 ⁇ 20% petroleum ether/Ethyl acetate gradient @ 120 mL/min), methyl 3-bromo-5- fluoro-4-hydroxybenzoate (31.5 g, crude) was obtained as a white solid.
  • the reaction mixture ATTORNEY DOCKET NO. MORF-010WO1 was filtered and the filtrate was concentrated in vacuum to get a residue.
  • the residue was purified by flash silica gel chromatography (ISCO ®; 40 g Sepa Flash ® Silica Flash Column, Eluent of 0 ⁇ 100% petroleum ether/Ethyl acetate gradient @ 120 mL/min), 2-(3-(5,5-dimethyl- 1,3,2-dioxaborinan-2-yl)-5-fluoro-4-methoxyphenyl)propan-2-ol (900 mg, 3.04 mmol, 40.0% yield) was obtained as yellow oil.
  • LCMS (ESI) m/z 297.1 (M-86+1).
  • Step 2 4-(3-fluoro-4-methoxyphenyl)tetrahydro-2H-pyran [0788] To a solution of 4-(3-fluoro-4-methoxyphenyl)-3,6-dihydro-2H-pyran (9.8 g, 47.06 mmol) in MeOH (300 mL) was added Pd(OH) 2 /C (10%, 3 g) under Ar atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 psi) at 50 °C for 16 h. The reaction mixture was filtered through a celite pad and washed by MeOH (50 mL). The filtrate was concentrated in vacuum.
  • Step 3 2-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenol
  • Step 4 2-bromo-6-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenol [0790] To a solution of 2-fluoro-4-(tetrahydro-2H-pyran-4-yl)phenol (1 g, 5.10 mmol) in DMF (15 mL) was added NBS (1.09 g, 6.12 mmol) at 0 °C and the mixture was stirred at 20 °C for 2 h. The reaction was quenched by ice water (50 mL) slowly, extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum.
  • Step 2 (3-bromo-5-fluoro-4-methoxyphenyl)boronic acid [0794] i-PrMgCl (1.3 M, 6.97 mL) was added dropwise to a solution of 1-bromo-3-fluoro-5- iodo-2-methoxybenzene (2 g, 6.04 mmol) in THF (20 mL) at 0 °C. The mixture was stirred for 1 h at 0 °C and then the mixture was cooled to -78 °C. Then trimethyl borate (942.04 mg, 9.07 mmol, 1.02 mL) was added and the resulting mixture was stirred for 1 h at -78 °C and 1 h at 25 °C.
  • reaction mixture was quenched with 0.5 M HCl (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO ®; 40 g Sepa Flash ® Silica Flash Column, Eluent of 0 ⁇ 100% THF/Petroleum ether gradient @ 100 mL/min). (3-bromo-5-fluoro-4- methoxyphenyl)boronic acid (0.7 g, 2.81 mmol, 46.54% yield) was obtained as a white solid.
  • Step 4 (3-fluoro-2-methoxy-5-(oxetan-3-yl)phenyl)boronic acid [0796] n-BuLi (2.5 M, 2.30 mL) was added dropwise to a solution of 3-(3-bromo-5-fluoro-4- methoxyphenyl)oxetane (1 g, 3.83 mmol) and triisopropylborate (1.08 g, 5.75 mmol, 1.32 mL) in THF (15 mL) at -78 °C under N 2 . The resulting mixture was stirred for 1 h at -78 °C and 1 h at 20 °C. The reaction mixture was quenched with ice water (100 mL).
  • Step 2 5-(3-bromo-5-fluoro-4-methoxyphenyl)isoxazole [0798] A mixture of 1-(3-bromo-5-fluoro-4-methoxyphenyl)-3-(dimethylamino)prop-2-en-1- one (5.4 g, 17.87 mmol) and hydroxylamine hydrochloride (2.48 g, 35.75 mmol) in EtOH (80 mL) was stirred at 80 °C for 3 h. The mixture was filtered and concentrated to give a residue.
  • the reaction mixture was diluted with water (150 mL) and extracted with MTBE (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO ®; 40 g Sepa Flash ® Silica Flash Column, Eluent of 0 ⁇ 50% Ethyl acetate/Petroleum ether gradient @ 100 mL/min). methyl 3-bromo-4-(difluoromethoxy)benzoate (6.2 g, 22.06 mmol, 84.95% yield) was obtained as yellow oil.
  • Step 3 2-bromo-1-(difluoromethoxy)-4-(2-methoxypropan-2-yl)benzene
  • a solution of NaH 563.46 mg, 14.09 mmol, 60% purity
  • DMF 16 mL
  • 2-(3-bromo-4-(difluoromethoxy)phenyl)propan-2-ol 2.64 g, 9.39 mmol
  • MeI 2.67 g, 18.78 mmol, 1.17 mL
  • the reaction was stirred at 25 °C for 0.5 h.
  • MORF-010WO1 To a solution of aqueous HCl (2 M, 100.00 mL) was added Zn (13.17 g, 201.41 mmol) at 25 °C which was stirred at 25 °C for 1 h, then the mixture was filtered, and the filtrate was washed with THF (50 mL) and concentrated to give a activated zinc.
  • TMSCl (2.17 g, 20.00 mmol, 2.54 mL) at 25 °C and stirred at 40 °C for 0.5 h, then cooled to 0 °C and the mixture was added dropwise methyl 2- bromoacetate (15.30 g, 0.1 mol, 9.44 mL) at 0 °C under N2, then the mixture was stirred at 25 °C for 16 h under N 2 .
  • bromo-(2-methoxy-2-oxo-ethyl)zinc (125 mL, 1 M) was obtained which was used the next step directly.
  • Step 5 methyl 2-bromo-2-(2-(difluoromethoxy)-5-(2-methoxypropan-2-yl)phenyl)acetate
  • methyl 2-(2-(difluoromethoxy)-5-(2-methoxypropan-2-yl)phenyl)acetate 250 mg, 867.19 ⁇ mol
  • LiHMDS 1 M, 1.30 mL
  • reaction mixture was diluted with water (200 mL) and quenched with aqueous Na2SO3 (200 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (150 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 2 methyl 3-bromo-5-fluoro-4-methoxybenzoate
  • MeI 26.16 g, 184.31 mmol, 11.47 mL
  • K 2 CO 3 25.47 g, 184.31 mmol
  • DMF 300 mL
  • the mixture was stirred for 2 h at 50 °C.
  • Water (1000 mL) was added, the mixture was extracted with ethyl acetate (300 mL x 2).
  • Step 3 2-(3-bromo-5-fluoro-4-methoxyphenyl)propan-2-ol [0807] To a solution of methyl 3-bromo-5-fluoro-4-methoxybenzoate (3 g, 11.40 mmol) in THF (30 mL) was added MeMgBr (3 M, 19.01 mL) at 0 °C, the reaction was stirred at 0 °C for 16 h. Water (90 mL) was added, the mixture was extracted with ethyl acetate (90 mL x 2).
  • Step 4 2-(3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-4-methoxyphenyl)propan-2-ol
  • 2-(3-bromo-5-fluoro-4-methoxyphenyl)propan-2-ol (1 g, 3.80 mmol) in dioxane (15 mL) was added 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (2.58 g, 11.40 mmol), Pd(dba) 2 (218.55 mg, 380.08 ⁇ mol), tricyclohexylphosphine (159.88 mg, 570.12 ⁇ mol) and KOAc (1.12 g, 11.40 mmol), the mixture was stirred at 90 °C for 4 h.
  • Step 2 1-(3-bromo-5-fluoro-4-methoxyphenyl)ethanone [0810] To a solution of 1-bromo-5-(dibromomethyl)-3-fluoro-2-methoxybenzene (2 g, 5.31 mmol), DIEA (1.03 g, 7.96 mmol, 1.39 mL) in THF (80 mL) was added diethyl phosphite (732.94 mg, 5.31 mmol, 684.99 uL) in THF (20 mL) at 0 °C under N 2 . The mixture was stirred at 25 °C for 16 h.
  • Step 4 (5-((dimethylamino)methyl)-3-fluoro-2-methoxyphenyl)boronic acid [0812] To a solution of 1-(3-bromo-5-fluoro-4-methoxyphenyl)-N, N-dimethylmethanamine (460 mg, 1.75 mmol), B2Pin2 (1.34 g, 5.26 mmol) in dioxane (20 mL) was added KOAc (344.47 mg, 3.51 mmol) and Pd(dba) 2 (151.36 mg, 263.24 ⁇ mol), tricyclohexylphosphine (73.82 mg, 263.24 ⁇ mol). The mixture was stirred at 90 °C for 16 h.
  • reaction mixture was quenched by addition H 2 O (80 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the mixture was further purification by pre-HPLC (column: Phenomenex Luna 250 x 50 mm x 10 um; mobile phase: A water with 0.1% TFA; B ACN 5%- 45%, 10 min; Flow Rate 25 mL/min).
  • N-methoxy-N-methyloxazole- 5-carboxamide (8.6 g, 55.08 mmol) was obtained as a yellow solid.
  • Step 2 (3-bromo-5-fluoro-4-methoxyphenyl)(oxazol-5-yl)methanone [0814] To a solution of N-methoxy-N-methyloxazole-5-carboxamide (7 g, 21.15 mmol) in THF (100 mL) was added i-PrMgCl (2 M, 15.86 mL) at 0 °C and the mixture was stirred for 1 h.
  • Step 3 5-(2-(3-bromo-5-fluoro-4-methoxyphenyl)propan-2-yl)oxazole [0815]
  • TiCl 4 (2.02 g, 10.66 mmol) was added to DCM (20 mL) at 20 °C under N 2 , then mixture was cooled to -40 °C and treated with ZnMe 2 (1 M, 10.66 mL) dropwise, the mixture was stirred at -40 °C for 0.16 h.
  • the reaction mixture was diluted with saturated aqueous NH 4 Cl (100 mL), extracted with ethyl acetate (30 mL x 3), washed with brine (50 mL x 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO ®; 80 g Sepa Flash ® Silica Flash Column, Eluent of 0 ⁇ 10% Ethyl acetate/Petroleum ether gradient @ 120 mL/min). 3-bromo-5-fluoro-4- methoxybenzaldehyde (4.87 g, 20.90 mmol, 91.00% yield) was obtained as yellow oil.
  • Step 2 N'-(3-bromo-5-fluoro-4-methoxybenzylidene)-4-methylbenzenesulfonohydrazide
  • 3-bromo-5-fluoro-4-methoxybenzaldehyde (4.87 g, 20.90 mmol) in MeOH (60 mL) was added 4-methylbenzenesulfonohydrazide (4.09 g, 21.94 mmol) at 25 °C under N2.
  • the mixture was stirred at 25 °C for 1 h.
  • the mixture was concentrated in vacuum to give a residue.
  • Step 4 (3-fluoro-5-(isoxazol-4-ylmethyl)-2-methoxyphenyl)boronic acid
  • 4-(3-bromo-5-fluoro-4-methoxybenzyl)isoxazole (280 mg, 978.69 ⁇ mol)
  • 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (884.28 mg, 3.91 mmol) in dioxane (6 mL)
  • KOAc (192.10 mg, 1.96 mmol
  • Pd(dba) 2 56.28 mg, 97.87 ⁇ mol
  • tricyclohexylphosphine 27.45 mg, 97.87 ⁇ mol
  • Step 2 1-bromo-3-fluoro-4-iodo-5-isopropyl-2-methoxybenzene [0822] To a solution of 2,2,6,6-tetramethylpiperidine (6.86 g, 48.56 mmol, 8.24 mL) in THF (40 mL) was added n-BuLi (2.5 M, 19.43 mL) at -70 °C, after stirred at -70 °C for 0.16 h, a solution of 1-bromo-3-fluoro-5-isopropyl-2-methoxybenzene (6 g, 24.28 mmol) in THF (15 mL) was added at -70 °C, after stirred at -70 °C for another 0.83 h, a solution of I 2 (7.40 g, 29.14 mmol, 5.87 mL) in THF (15 mL) was added at -70 °C and stirred at -70 °C for 1 h.
  • Step 3 4-bromo-2-fluoro-6-isopropyl-3-methoxybenzonitrile
  • 1-bromo-3-fluoro-4-iodo-5-isopropyl-2-methoxybenzene (3.7 g, 9.92 mmol) in DMF (50 mL) was added CuCN (1.78 g, 19.84 mmol, 4.33 mL) and L-proline (1.14 g, ATTORNEY DOCKET NO. MORF-010WO1 9.92 mmol)
  • the reaction was stirred at 80 °C for 12 h. Water (50 mL) was added, the mixture was extracted with ethyl acetate (50 mL x 2).
  • Step 4 tert-butyl 2-(4-cyano-3-fluoro-5-isopropyl-2-methoxyphenyl)acetate
  • 4-bromo-2-fluoro-6-isopropyl-3-methoxybenzonitrile 0.9 g, 3.31 mmol
  • Q-phos 470.12 mg, 661.49 ⁇ mol
  • Pd2(dba)3 605.74 mg, 661.49 ⁇ mol
  • Step 5 tert-butyl 2-bromo-2-(4-cyano-3-fluoro-5-isopropyl-2-methoxyphenyl)acetate
  • tert-butyl 2-(4-cyano-3-fluoro-5-isopropyl-2-methoxyphenyl)acetate (0.55 g, 1.79 mmol) in THF (8 mL) was added LiHMDS (1 M, 2.68 mL) at -70 °C, after stirred at -70 °C for 0.67 h, TMSCl (291.61 mg, 2.68 mmol, 340.67 uL) was added and stirred at -70 °C for 0.33 h, then a solution of NBS (955.47 mg, 5.37 mmol) in THF (8 mL) was added and stirred at ATTORNEY DOCKET NO.
  • Step 2 (3-fluoro-2-methoxy-5-(pyrrolidin-1-ylmethyl)phenyl)boronic acid
  • 1-(3-bromo-5-fluoro-4-methoxybenzyl)pyrrolidine 400 mg, 1.39 mmol
  • 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (1.25 g, 5.55 mmol)
  • dioxane 8 mL
  • KOAc 272.47 mg, 2.78 mmol
  • Pd(dba) 2 79.82 mg, 138.81 ⁇ mol
  • tricyclohexylphosphine 38.93 mg, 138.81 ⁇ mol
  • Step 3 1-bromo-3-fluoro-2-methoxy-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene [0832] To a solution of methyl(triphenyl)phosphanium bromide (12.82 g, 35.88 mmol) and t- BuOK (4.23 g, 37.67 mmol) in THF (50 mL) was stirred at 25 °C for 1 h. Then 1-(3-bromo-5- fluoro-4-methoxyphenyl)-2,2,2-trifluoroethanone (5.4 g, 17.94 mmol) in THF (50 mL) was added dropwise to the mixture at 0 °C.
  • Step 5 (3-fluoro-2-methoxy-5-(1-(trifluoromethyl)cyclopropyl)phenyl)boronic acid
  • 1-bromo-3-fluoro-2-methoxy-5-(1- (trifluoromethyl)cyclopropyl)benzene 800 mg, 2.56 mmol
  • triisopropyl borate 961.12 mg, 5.11 mmol, 1.17 mL
  • THF 25 mL
  • n-BuLi 2.5 M, 1.53 mL
  • Step 2 1-bromo-5-(but-1-en-2-yl)-3-fluoro-2-methoxybenzene [0836] To a solution of methyl(triphenyl)phosphanium bromide (16.42 g, 45.96 mmol) and t- BuOK (6.45 g, 57.45 mmol) in THF (60 mL), the mixture was stirred at 25 °C for 0.5 h. Then 1- (3-bromo-5-fluoro-4-methoxyphenyl)propan-1-one (6 g, 22.98 mmol) in THF (10 mL) was added dropwise in the mixture at 0 °C, the reaction was stirred at 25 °C for 16 h..
  • Step 3 1-bromo-5-(1-ethylcyclopropyl)-3-fluoro-2-methoxybenzene [0837] To a solution of ZnEt2 (1 M, 17.37 mL) in CH2Cl2 (10 mL) was added dropwise a solution of TFA (1.98 g, 17.37 mmol, 1.29 mL) in CH 2 Cl 2 (8 mL) at 0 °C under N 2 , after stirring ATTORNEY DOCKET NO.
  • Step 4 tert-butyl 2-(5-(1-ethylcyclopropyl)-3-fluoro-2-methoxyphenyl)acetate
  • 1-bromo-5-(1-ethylcyclopropyl)-3-fluoro-2-methoxybenzene 0.2 g, 732.22 ⁇ mol
  • 2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (1 M, 7.32 mL
  • Pd (t-Bu3P)2 93.55 mg, 183.06 ⁇ mol
  • Step 2 methyl 1-bromo-3-fluoro-2-methoxy-5-(tert-pentyl)benzene
  • 2-bromo-6-fluoro-4-(tert-pentyl)phenol 3.5 g, 13.40 mmol
  • DMF 35 mL
  • MeI 2-bromo-6-fluoro-4-(tert-pentyl)phenol
  • K 2 CO 3 3.70 g, 26.81 mmol
  • Step 3 methyl (3-fluoro-2-methoxy-5-(tert-pentyl)phenyl)boronic acid
  • n-BuLi 2.5 M, 2.18 mL
  • 1-bromo-3-fluoro-2- methoxy-5-(tert-pentyl)benzene (1 g, 3.63 mmol)
  • triisopropyl borate (1.03 g, 5.45 mmol) in THF (15 mL) at -78 °C under N 2 .
  • the resulting mixture was stirred for 1 h at -78°C and 1 h at 25 °C.
  • Step 3 tert-butyl 2-(3-fluoro-2-methoxy-5-(trifluoromethyl)phenyl)acetate
  • Pd(t-Bu 3 P) 2 374.37 mg, 732.54 ⁇ mol
  • bromo-(2-tert- butoxy-2-oxo-ethyl)zinc 1 M, 20 mL
  • the mixture was stirred at 70 °C for 16 h under N2 atmosphere.
  • Step 2 4-(3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-4-methoxyphenyl)morpholine ATTORNEY DOCKET NO. MORF-010WO1 [0848] To a solution of 4-(3-bromo-5-fluoro-4-methoxyphenyl)morpholine (0.9 g, 3.10 mmol) and 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (2.10 g, 9.31 mmol) in dioxane (15 mL) was added tricyclohexylphosphine (130.49 mg, 465.31 ⁇ mol), Pd(dba) 2 (178.37 mg, 310.21 ⁇ mol) and KOAc (913.33 mg, 9.31 mmol), the reaction was stirred at 90 °C for 12 h.
  • Step 2 3-bromo-5-fluoro-4-methoxybenzaldehyde
  • K 2 CO 3 55.60 g, 402.30 mmol
  • the mixture was stirred at ATTORNEY DOCKET NO. MORF-010WO1 0 °C for 0.5 h.
  • MeI 45.68 g, 321.84 mmol, 20.04 mL was slowly dropwise added into the reaction at 0 ⁇ 5 °C. The mixture was stirred at 25 °C for 15.5 h.
  • Step 3 (E)-N'-(3-bromo-5-fluoro-4-methoxybenzylidene)-4-methylbenzenesulfonohydrazide
  • 3-bromo-5-fluoro-4-methoxybenzaldehyde (5 g, 21.46 mmol) was added into a solution of 4-methylbenzenesulfonohydrazide (4.08 g, 21.89 mmol) in MeOH (50 mL). The reaction was stirred at 25 °C for 2 h. The mixture was concentrated in vacuum.
  • Step 4 1-bromo-5-(cyclopropylmethyl)-3-fluoro-2-methoxybenzene [0852] To a solution of (E)-N'-(3-bromo-5-fluoro-4-methoxybenzylidene)-4- methylbenzenesulfonohydrazide (8.61 g, 21.46 mmol) and cyclopropylboronic acid (5.53 g, 64.37 mmol) in dioxane (157 mL) was added DBU (4.90 g, 32.18 mmol, 4.85 mL) at 25 °C. The reaction was stirred at 100 °C for 12 h.
  • the pH of the mixture was adjusted to about 6 with HCl (2 M) and concentrated to remove dioxane.
  • Water (500 mL) and ethyl acetate (250 mL) were added.
  • the aqueous phase was extracted with ethyl acetate (100 mL x 2).
  • the combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under ATTORNEY DOCKET NO. MORF-010WO1 reduced pressure to give a residue.
  • the residue was purified by MPLC (Biotage ®; 20 g Sepa Flash ® Silica Flash Column, Eluent of 0 ⁇ 10% Ethyl acetate/Petroleum ether gradient @ 150 mL/min).
  • Step 5 (5-(cyclopropylmethyl)-3-fluoro-2-methoxyphenyl)boronic acid [0853] To a solution of 1-bromo-5-(cyclopropylmethyl)-3-fluoro-2-methoxybenzene (2 g, 7.72 mmol) in THF (40 mL) was added triisopropyl borate (4.35 g, 23.16 mmol, 5.32 mL) and n- BuLi (2.5 M, 4.01 mL) at -78 °C. The reaction was stirred at -78 °C for 2 h.
  • the reaction mixture was filtered, and treated with water (50 mL), the resulting mixture was extracted with ethyl acetate (30 mL x 2).
  • the ATTORNEY DOCKET NO. MORF-010WO1 combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO ®; 40 g Sepa Flash ® Silica Flash Column, Eluent of 0 ⁇ 30% petroleum ether/Ethyl acetate gradient @ 120 mL/min).
  • Step 2 1-ethyl-2,5-difluoro-4-methoxybenzene [0855] To a solution of 1,4-difluoro-2-methoxy-5-vinylbenzene (2.6 g, 15.28 mmol) in MeOH (50 mL) was added Pd/C (1.3 g, 10% purity), the mixture was stirred at 25 °C under H2 (15 psi) for 12 h. The reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. 1-ethyl-2,5-difluoro-4-methoxybenzene (1.38 g, crude) was obtained as yellow oil.
  • Step 3 (3-ethyl-2,5-difluoro-6-methoxyphenyl)boronic acid [0856] To a solution of 1-ethyl-2,5-difluoro-4-methoxybenzene (500 mg, 2.90 mmol) in THF (10 mL) was added LDA (2 M, 2.18 mL) at -78 °C under N 2 atmosphere. The reaction was stirred at -78 °C for 0.5 h. Trimethyl borate (905.32 mg, 8.71 mmol, 984.04 uL) in THF (2 mL) was added into the reaction. The reaction was stirred at -78 °C for 2 h.
  • the reaction mixture was added dropwise to ice water (200 mL) at 0 °C, then the mixture was extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with ATTORNEY DOCKET NO. MORF-010WO1 aqueous NaHCO 3 (100 mL), brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO ®; 25 g Sepa Flash ® Silica Flash Column, Eluent of 0 ⁇ 100% Ethyl acetate/Petroleum ether gradient @ 100 mL/min).
  • Step 3 (3-fluoro-2-methoxy-5-(4-methyltetrahydro-2H-pyran-4-yl)phenyl)boronic acid
  • n-BuLi 2.5 M, 990.00 uL
  • n-BuLi 2.5 M, 990.00 uL
  • triisopropylborate 930.95 mg, 4.95 mmol, 1.14 mL
  • 4-(3-bromo-5-fluoro-4-methoxyphenyl)-4- methyltetrahydro-2H-pyran 0.5 g, 1.65 mmol
  • THF 10 mL
  • the resulting mixture was stirred for 1 h at -78 °C and 1 h at 20 °C.
  • the residue was purified by flash silica gel chromatography (ISCO ®; 20 g Sepa Flash ® Silica Flash Column, Eluent of 0 ⁇ 100% THF/Petroleum ether gradient @ 100 mL/min).
  • Step 2 (5-((4,4-difluoropiperidin-1-yl)methyl)-3-fluoro-2-methoxyphenyl)boronic acid [0861] To a solution of 1-(3-bromo-5-fluoro-4-methoxybenzyl)-4,4-difluoropiperidine (1 g, 2.96 mmol) and triisopropyl borate (1.11 g, 5.91 mmol) in THF (10 mL) was added n-BuLi (2.5 M, 1.77 mL) dropwise at -78 °C under N 2 and the mixture was stirred at -78 °C for 1 h. The mixture was stirred at 20 °C for 1 h.
  • n-BuLi 2.5 M, 1.77 mL
  • Step 2 (5-(7-azabicyclo [2.2.1] heptan-7-ylmethyl)-3-fluoro-2-methoxyphenyl) boronic acid [0863] To a solution of 7-(3-bromo-5-fluoro-4-methoxybenzyl)-7-azabicyclo [2.2.1] heptane (450 mg, 1.43 mmol) and triisopropyl borate (538.73 mg, 2.86 mmol, 658.59 uL) in THF (5 mL) was added n-BuLi (2.5 M, 859.35 uL) dropwise at -78 °C and the mixture was stirred at - 78 ⁇ 20 °C for 2 h.
  • n-BuLi 2.5 M, 859.35 uL
  • Step 2 3-bromo-5-fluoro-4-methoxy-benzaldehyde [0865] To a solution of 3-bromo-5-fluoro-4-hydroxy-benzaldehyde (38.53 g, 175.93 mmol) in DMF (400 mL) was added K2CO3 (72.95 g, 527.79 mmol) and MeI (74.91 g, 527.79 mmol, 32.86 mL), the mixture was stirred at 60 °C for 2 h. The reaction mixture was quenched by water (800 mL), extracted with Ethyl acetate (400 ml x 3).
  • Step 4 1-(3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluoro-4-methoxybenzyl)-4,4- dimethylpiperidine [0867] To a solution of 1-(3-bromo-5-fluoro-4-methoxybenzyl)-4,4-dimethylpiperidine (0.61 g, 1.85 mmol), 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (1.25 g, 5.54 mmol) in dioxane (10 mL) was added KOAc (725.14 mg, 7.39 mmol), Pd(dppf)Cl2 (202.74 mg, 277.08 ⁇ mol), the reaction was stirred at 100 °C for 3 h.
  • Step 2 4-(3-bromo-5-fluoro-4-methoxyphenyl)-1-methylpiperidin-4-ol
  • i-PrMgCl 6-(3-bromo-5-fluoro-4-methoxyphenyl)-1-methylpiperidin-4-ol
  • Step 3 4-(3-bromo-5-fluoro-4-methoxyphenyl)-1-methyl-1,2,3,6-tetrahydropyridine [0870] To a solution of 4-(3-bromo-5-fluoro-4-methoxyphenyl)-1-methylpiperidin-4-ol (2.4 g, 7.54 mmol) in TFA (50 mL) was added Et 3 SiH (4.39 g, 37.71 mmol, 6.02 mL), the reaction was stirred at 30 °C for 12 h.
  • Step 5 (3-fluoro-2-methoxy-5-(1-methylpiperidin-4-yl)phenyl)boronic acid
  • n-BuLi 2.5 M, 1.06 mL
  • 4-(3-bromo-5-fluoro-4- methoxyphenyl)-1-methylpiperidine 536 mg, 1.77 mmol
  • triisopropylborate 500.39 mg, 2.66 mmol, 611.73 uL
  • THF 15 mL
  • the resulting mixture was stirred for 1 h at -78 °C and 1 h at 25 °C.
  • Step 2 ethyl 4-(3-bromo-5-fluoro-4-methoxyphenyl)-4-chloropiperidine-1-carboxylate
  • Step 3 ethyl 4-(3-bromo-5-fluoro-4-methoxyphenyl)-4-methylpiperidine-1-carboxylate ATTORNEY DOCKET NO. MORF-010WO1 [0875] To a solution of ethyl 4-(3-bromo-5-fluoro-4-methoxyphenyl)-4-chloropiperidine-1- carboxylate (1.2 g, 3.04 mmol) in DCM (25 mL) was added AlMe 3 (2 M, 6.08 mL) at 0 °C, the reaction was stirred at 20 °C for 2 h. The mixture was poured into ice water (10 mL), the mixture was extracted with DCM (10 mL x 2).
  • Step 4 4-(3-bromo-5-fluoro-4-methoxyphenyl)-4-methylpiperidine [0876] To a solution of ethyl 4-(3-bromo-5-fluoro-4-methoxyphenyl)-4-methylpiperidine-1- carboxylate (0.6 g, 1.60 mmol) in dioxane (5 mL) and ethane-1,2-diol (10 mL) was added KOH (6 M, 10 mL), the reaction was stirred at 130 °C for 12 h. Water (50 mL) was added, the mixture was extracted with ethyl acetate (20 mL x 2).
  • Step 5 4-(3-bromo-5-fluoro-4-methoxyphenyl)-1,4-dimethylpiperidine
  • 4-(3-bromo-5-fluoro-4-methoxyphenyl)-4-methylpiperidine 1.5 g, 4.96 mmol
  • formaldehyde 931.53 mg, 12.41 mmol, 854.62 uL, 40% purity
  • DCM 20 mL
  • Sodium triacetyloxyboranuide 3.16 g, 14.89 mmol
  • Step 6 (5-(1, 4-dimethylpiperidin-4-yl)-3-fluoro-2-methoxyphenyl)boronic acid [0878] To a solution of 4-(3-bromo-5-fluoro-4-methoxyphenyl)-1,4-dimethylpiperidine (0.45 g, 1.42 mmol) and triisopropyl borate (802.94 mg, 4.27 mmol, 981.59 uL) in THF (15 mL) was added n-BuLi (2.5 M, 1.14 mL) at -70 °C, the reaction was stirred at -70 °C for 2 h.
  • n-BuLi 2.5 M, 1.14 mL
  • Step 2 3-bromo-5-isopropyl-2-methoxybenzaldehyde [0880] To a mixture of 5-isopropyl-2-methoxybenzaldehyde (12.5 g, 70.14 mmol) in DMF (200 mL) was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (21.06 g, 73.64 mmol) at 25 °C under N 2 and the mixture was stirred at 25 °C for 16 h.
  • Step 3 3-bromo-5-isopropyl-2-methoxybenzonitrile
  • TMSCl (2.72 g, 25.00 mmol, 3.17 mL) at 25 °C and stirred at 40 °C for 0.5 h, then cooled to 0 °C and the mixture was added dropwise methyl 2- bromoacetate (19.12 g, 0.125 mol, 11.80 mL) at 0 °C under N2 and the mixture was stirred at 25 °C for 16 h under N2. The mixture was used the next step directly without further work up and the excess product was quenched with 3 M HCl aqueous.
  • Step 5 methyl 2-bromo-2-(3-cyano-5-isopropyl-2-methoxyphenyl)acetate
  • methyl 2-(3-cyano-5-isopropyl-2-methoxyphenyl)acetate 300 mg, 1.21 mmol
  • LiHMDS Li, 1.82 mL
  • TMSCl 184.52 mg, 1.70 mmol, ATTORNEY DOCKET NO.
  • Step 2 ethyl 2-(3-(cyclopropylmethyl)-2-methoxyphenyl)acetate
  • 1-bromo-3-(cyclopropylmethyl)-2-methoxybenzene 610 mg, 2.53 mmol
  • Q-phos(56 mg, 0.08 mmol) and Pd2(dba)3 72 mg, 0.08 mmol
  • THF 10 mL
  • (2-ethoxy-2-oxoethyl)zinc(II) bromide 1 M in THF, 6.3 mL.
  • the reaction mixture was stirred at 50 °C under N2 for 1 hour.
  • Step 3 ethyl 2-bromo-2-(3-(cyclopropylmethyl)-2-methoxyphenyl)acetate
  • ethyl 2-(3-(cyclopropylmethyl)-2-methoxyphenyl)acetate 248 mg, 1.0 mmol
  • lithium diisopropylamide solution 2.0 M in THF/hexanes 2.5 mL, 2.5 mmol
  • the reaction was stirred at -78°C for 30 min, then chlorotrimethylsilane (272 mg, 2.5 mmol) was added and the reaction was stirred at -78°C for another 30 min.
  • Step 3 ethyl 2-(5-chloro-3-(cyclopropylmethyl)-2-methoxyphenyl)acetate
  • 1-bromo-5-chloro-3-(cyclopropylmethyl)-2-methoxybenzene 1.1g, 4.01 mmol
  • Q-phos(146 mg, 0.2 mmol) and Pd2(dba)3 183 mg, 0.2 mmol
  • 2-ethoxy-2-oxoethyl)zinc(II) bromide (1 M in THF, 10 mL).
  • the reaction mixture was stirred at 50 °C under N2 for 1 hour.

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EP24709285.1A 2023-02-14 2024-02-14 Hemmung von alpha-v-beta-8-integrin Withdrawn EP4665339A1 (de)

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