NZ718076B2 - Inhibitors of the fibroblast growth factor receptor - Google Patents

Abstract

Described herein are inhibitors of FGFR-4 of the formulae I and II, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions.

Description

INHIBITORS OF THE FIBROBLAST GROWTH FACTOR OR Claim of Priority This ation claims priority to U.S.S.N. 61/895,472, filed on October 25, 2013, and U.S.S.N. ,782, filed on January 15, 2014, which are hereby incorporated by reference in their entirety.

Background Fibroblast growth factor receptor 4 4) is a protein that in humans is encoded by the FGFR—4 gene. This protein is a member of the last growth factor receptor family, where amino acid sequence was highly conserved between members throughout evolution.

FGFR family members 1—4 differ from one r in their ligand affinities and tissue distribution. A full—length representative protein consists of an extracellular region composed of three immunoglobulin—like domains, a single hydrophobic membrane—spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, g in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. The genomic organization of the FGFR—4 gene encompasses 18 exons. Although alternative splicing has been observed, there is no ce that the inal half of the IgIII domain of this protein varies between three alternate forms, as indicated for FGFR 1—3.

Ectopic mineralization, characterized by inappropriate calcium—phosphorus deposition in soft tissue, has been observed in rats treated with an FGFR—1 inhibitor (Brown, AP et al. (2005), Toxicol. ., p. 449—455). This ts that selective inhibition of FGFR—4 without inhibition of other isoforms of FGFR, including FGFR—1, may be desirable in order to avoid certain toxicities. FGFR-4 preferentially binds fibroblast growth factor 19 (FGF19) and has recently been associated with the progression of certain sarcomas, renal cell cancer, breast cancer, and liver cancer.

Brief Description of the Drawings Figure 1 is a graph depicting the growth inhibition of Compound 27—treated groups against Hep3B xenograft tumors in nude mice.

Figure 2 is a graph depicting the body weight change (%) of Hep3B—bearing nude mice over the course of the study .

Summary of the Invention The present invention describes inhibitors of FGFR—4. The present invention further describes pharmaceutical formulations that include an inhibitor of FGFR—4.

In one aspect, the invention es a compound of Formula I, or a ceutically acceptable salt thereof: Wherein Warhead is a moiety capable of forming a covalent bond with a nucleophile; ring A is a 3—8 membered clic or bicyclic cycloalkyl, or heterocyclyl; each of R1 and R2 is, independently, halo, cyano, C1_6 alkoxy, hydroxy, oxo, amino, amido, sulfonyl, sulfonamido, ester, alkyl urea, C1_6 alkyl, —C(O)O—, —C(O)—C1_6 alkyl, —C(O)—C1_6 alkylamino, C1_6 heteroalkyl, heterocyclyl, or heterocyclylalkyl, wherein each of C1_6 alkoxy, amino, amido, sulfonamido, ester, alkyl urea, C1_6 alkyl, C1_6 heteroalkyl, heterocyclyl or heterocyclylalkyl is independently substituted with 0—5 occurrences of R4; R3 is halo; each R4 is, ndently, selected from C1_6 alkyl, C1_6 alkoxy, halo, hydroxy, oxo, amino, cyano, cycloalkyl and cyclyl; m is 0-3; n is 0-4; and p is 0—2.

In some ments, ring A is monocyclic cycloalkyl. In some embodiments, ring A is cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R3 is, independently, halo.

In some embodiments, ring A is bicyclic cycloalkyl.

In some embodiments, ring A is heterocyclyl. In some embodiments, ring A is pyrrolidinyl, dinyl, ydrofuranyl, or tetrahydropyranyl. In some embodiments, R3 is, independently, halo.

In another aspect, the invention features a compound of Formula II, or a pharmaceutically acceptable salt thereof: Formula 11 wherein ring A is a 3—6 membered cycloalkyl or cyclyl; R1, is, independently, halo, cyano, C1_6 alkoxy, hydroxy, oxo, amino, amido, sulfonyl, sulfonamido, ester, alkyl urea, C1_6 alkyl, —C(O)O—, —C(O)—C1_6 alkyl, —C(O)—C1_6 alkylamino, or C1_6 heteroalkyl; R2 is halo, or C1_6 alkoxy; R3 is halo; and m is 0—1; n is 0—4; andp is 0—1.

In some embodiments, ring A is cycloalkyl.

In some embodiments, ring A is heterocyclyl. In some embodiments, R3 is, independently, halo.

In some embodiments, ring A is cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl.

In the compounds disclosed herein, a warhead is a moiety that is ve with a nucleophile, for example, capable of forming a covalent bond with a nucleophile, Examples of warheads include, without limitation, alkyl halides, alkyl sulfonates, heteroaryl halides, es, haloacetamides, maleimides, sulfonate esters, alpha—beta unsaturated ketones, alpha—beta rated esters, vinyl sulfones, propargyl amides, mides. In some of these instances, e.g. , acrylamide and propargyl amide, the N of the warhead is the adjacent N in the formulae shown above. Structures of exemplary warheads are shown below: R8 0 RC Xdkf /l\/\)kf Fae/K3 “Hm/\SQ flak 571%CN wherein X is a leaving group such as halo, or an activated hydroxyl moiety (e.g., triflate); and each of Ra, Rb, and RC is, independently, H, substituted or unsubstituted C1_4 alkyl, substituted or unsubstituted C1_4 cycloalkyl, or cyano.

In the formulae shown above, the warheads are typically attached to a N atom on the inhibitor. In other embodiments, the d can alternatively be attached to an atom other than N. Examples of ary warheads include, without tion, WQOK/ ”\OJK/ ”NM ”NM E m if)\ 0 H \ /” \l... §\ 1&0._ H / ”m "m H O s §_[:/\ \ \>/_ \iiiHalo \ Halo ?/\Halo ?/\Halo 2 ”M, "W2, "m 3/ | 5/ | Other examples of warheads can be found, e.g., in and .

In certain embodiments, the FGFR—4 tors of the invention inhibit FGFR—4 activity more potently than they inhibit FGFR—l activity. For example, the FGFR—4 inhibitors of the invention can inhibit FGFR—4 ty at least 10 times, at least 50 times, at least 100 times, at least 200 times, or at least 500 times more potently than they inhibit FGFR—l ty.

In one aspect, ivity is measured by comparing the inhibition of FGFR—l and FGFR— 4 caused by the compound of this invention in the same type of assay. In one embodiment, the assays used to measure inhibition of FGFR—l and FGFR—4 are any of the assays described herein.

Typically, inhibition is expressed as IC50 (the concentration of inhibitor at which 50% of the activity of the enzyme is inhibited) and thus fold—selectivity is measured by the equation: (IC50 FGFR—l)/ (IC50 FGFR—4). The same measurements and ations can be used to measure selectivity over FGFR—2 and FGFR—3 as well.

Any other assays of FGFR activity may be utilized to determine the relative inhibition of FGFR—land FGFR—4 by the nds of this invention as long as such assays utilize what one of skill in the art would deem to be the same parameters in ing FGFR activity.

In another aspect, the invention features a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound disclosed .

In another aspect the invention features a method for treating a condition mediated by FGFR-4, a condition characterized by overexpression of FGFR-4, a condition characterized by amplification of FGFR4, a condition mediated by FGF19, a condition characterized by amplified FGF—l9, or a condition characterized by overexpression of FGF19, any of these methods comprising stering a therapeutically effective amount of a compound disclosed herein to a subject.

In another aspect, the invention features a method of treating any of the following conditions by administering a therapeutically effective amount of a nd disclosed herein to a subject: hepatocellular carcinoma, breast cancer, n cancer, lung cancer, liver cancer, a sarcoma, or ipidemia.

In a first aspect of the disclosure, there is ed a compound of Formula I or a pharmaceutically acceptable salt thereof, Formula I wherein: Warhead is a moiety e of forming a covalent bond with a nucleophile; ring A is tetrahydrofuranyl or tetrahydropyranyl; each of R1 and R2 is independently selected from halo, cyano, C1-6 alkoxy, hydroxy, oxo, amino, amido, alkyl urea, C1-6 alkyl, and heterocyclyl, wherein each of C1-6 alkoxy, C1-6 alkyl, and heterocyclyl is optionally substituted with 0-5 groups independently selected from halo, hydroxy, amino, cyano, and heterocyclyl; R3 is halo; m is 0-3; n is 0-4; and p is 0-2, wherein Warhead is selected from: ; ; ; ; O O ; ; and , n X is a leaving group; and each of Ra, Rb, and Rc is, independently, H, C1-4 alkyl, C1-4 cycloalkyl, or cyano.

In a second aspect of the disclosure, there is provided a compound according to the first aspect of the disclosure selected from Cl O HN HN Cl O O N , , , , , , , and , and pharmaceutically acceptable salts thereof.

In a third aspect of the disclosure, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a nd or ceutically acceptable salt according to the first aspect of the disclosure.

In a fourth aspect of the disclosure, there is provided a use of a compound of the first aspect of the disclosure, in the manufacture of a medicament for treating a condition mediated by FGR-4.

In a fifth aspect of the disclosure, there is provided a use of a compound of the first aspect of the disclosure, in the manufacture of a medicament for treating a condition characterized by overexpression of FGR-4.

In a sixth aspect of the invention, there is provided a use of a compound of the first aspect of the disclosure, in the manufacture of a medicament for treating a ion characterized by amplified FGF-19.

In a seventh aspect of the disclosure, there is provided a use of a compound of the first aspect of the disclosure, in the manufacture of a medicament for treating a condition characterized by overexpression of FGF-19 In an eight aspect of the disclosure, there is provided a use of a compound of the first aspect of the disclosure, in the cture of a medicament for treating cancer, n the cancer is selected from the group ting of liver cancer, breast , lung cancer, ovarian cancer, or a sarcoma.

In a ninth aspect of the disclosure, there is provided a use of a compound of the first aspect of the sure, in the manufacture of a medicament for treating hepatocellular carcinoma.

In a tenth aspect of the disclosure, there is provided a compound which is or .

The invention includes all possible combinations of the ments described above and below.

Detailed Description of the Invention The compounds disclosed below can form a covalent bond with FGFR4 protein; for example, the compounds can form a covalent bond with a cysteine residue of FGFR4, for example, the cysteine at residue 552. FGFRs1-3 do not contain this cysteine. The y to form a covalent bond between the compound and FGFR4 is therefore an important factor in the selectivity of the compounds disclosed herein for FGFR4.

The details of construction and the arrangement of components set forth in the following description or illustrated in the drawings are not meant to be limiting. Other embodiments and different ways to practice the invention are expressly included. Also, the phraseology and terminology used herein are for the purpose of description and should not be regarded as limiting. The use of ding,” “includes,” “include,” “comprising,” or g,” “containing”, “involving”, and variations thereof herein, is meant to encompass the items listed thereafter and equivalents f as well as additional items.

Definitions "Aliphatic , as used herein, refers to a straight-chain, branched-chain, or cyclic hydrocarbon group and includes saturated and unsaturated groups, such as an alkyl group, an alkenyl group, and an alkynyl group.

“Alkenyl”, as used herein, refers to an aliphatic group containing at least one double bond.

"Alkoxyl" or "alkoxy", as used herein, refers to an alkyl group having an oxygen radical attached thereto. Representative alkoxyl groups e methoxy, ethoxy, propyloxy, tert-butoxy and the like.

[Followed by page 7] Alkyl” refers to a monovalent radical of a saturated straight or branched hydrocarbon, such as a straight or ed group of 1—12, 1—10, or 1—6 carbon atoms, referred to herein as C1—C12 alkyl, C1—C10 alkyl, and C1—C6 alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2—methy1—l—propyl, 2—methyl—2—propyl, 2—methyl—l—butyl, yl-l-butyl, 2-methyl—3—buty1, 2,2—dimethyl—l—propyl, 2—methyl—l—pentyl, 3—methyl—1—pentyl, 4-methylpentyl, 2—methyl—2—pentyl, 3—methyl—2—pentyl, 4—methyl—2—pentyl, 2,2—dimethylbutyl, 3,3-dimethyl- l, 2-ethy1buty1, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.

“Alkylene” refers to a divalent radical of an alkyl group, e.g., —CH2—, -CH2CH2—, and CH2CH2CH2—.

“Alkynyl” refers to a straight or ed hydrocarbon chain containing 2— 12 carbon atoms and characterized in having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3—hexynyl. One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.

“Alkynylene” refers to an alkynyl having two connecting points. For example, ylene” represents the group —CEC—. Alkynylene groups can also be in an unsubstituted form or substituted form with one or more substituents.

"Alkylthio", as used , refers to a hydrocarbyl group having a sulfur radical ed thereto. In some embodiments, the "alkylthio" moiety is represented by one of —S—alkyl, —S— alkenyl, or ynyl. Representative alkylthio groups include thio, ethylthio, and the like.

"Amido", as used herein, refers to —C(=O)—N(R1)( R2) or —N(R1)—C(=O)—R2 where each of R1 and R2 is H, alkyl, cycloalkyl, alkoxy, or hydroxy.

“Amino”, as used herein, refers to —NH2, —NH(alky1), or —N(alky1)(alky1).

“Amplified,” as used herein, means additional copies of a gene or chromosome segment are produced in cancer cells that may confer a growth or survival advantage.

“Arylalkyl” or "aralkyl", as used herein, refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group). l includes groups in which more than one hydrogen atom has been replaced by an aryl group. es of “arylalkyl” or “aralkyl” include benzyl, 2—phenylethyl, 3—phenylpropy1, 9—fluorenyl, benzhydryl, and trityl groups.

"Aryl", as used , refers to 5—, 6—, and 7—membered single—ring aromatic groups that may include from zero to four heteroatoms, for example, phenyl, yl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics." The aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, l, l, cycloalkyl, polycyclyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, ate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, —CF3, —CN, or the like. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more s are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, lkynyls, aryls and/or heterocyclyls.

Each ring can contain, e.g., 5—7 members.

“Carbocyclic ring system” as used herein refers to a monocyclic, bicyclic or clic hydrocarbon ring system, wherein each ring is either completely ted or contains one or more units of unsaturation, but where no ring is aromatic.

“Carbocyclyl” as used herein refers to a monovalent radical of a carbocyclic ring system.

Representative carbocyclyl groups include cycloalkyl groups (e.g., cyclopentyl, cyclobutyl, cyclopentyl, cyclohexyl and the like), and cycloalkenyl groups (e.g., entenyl, cyclohexenyl, entadienyl, and the like).

“Cycloalkyl” as used herein refers to a cyclic, bicyclic, lic, or polycyclic non— aromatic hydrocarbon groups having 3 to 12 carbons. Any substitutable ring atom can be substituted (e.g., by one or more substituents). The cycloalkyl groups can contain fused or spiro rings. Fused rings are rings that share a common carbon atom. Examples of lkyl moieties include, but are not limited to, cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl.

“Cycloalkylalkyl” as used herein refers to a —(cycloalkyl)-alkyl radical where cycloalkyl and alkyl are as disclosed herein. The “cycloalkylalkyl” is bonded to the parent molecular structure through the cycloalkyl group.

“Cyano” as used herein refers to —CN.

“Covalent inhibitor,” as used herein, means an inhibitor that can form a covalent bond with a protein.

“Ester” as used herein refers to —C(=O)—O(R1) or —O-C(=O)—R1 where R1 is H or alkyl.

“FGFR—4” or “FGFR—4 protein” refers to any form of the FGFR—4 protein, ing wild type and all variant forms (including, without limitation, mutant forms and splice ts).

The FGFR—4 protein is a product of the FGFR—4 gene, and the FGFR—4 protein therefore includes any protein d by any form of the FGFR-4 gene, including all aberrations, e.g., point mutations, , ocation fusions, and focal ications.

“Heteroaromatic ring system” is art-recognized and refers to monocyclic, ic or polycyclic ring system wherein at least one ring is both aromatic and ses at least one heteroatom (6.57., N, O or S); and wherein no other rings are heterocyclyl (as defined below). In certain instances, a ring which is aromatic and comprises a heteroatom contains 1, 2, 3, or 4 ring heteroatoms in such ring.

“Heteroaryl” refers to a monovalent radical of a heteroaromatic ring system.

Representative heteroaryl groups e ring systems where (i) each ring comprises a heteroatom and is aromatic, e.g., olyl, oxazolyl, thiazolyl, triazolyl, pyrrolyl, furanyl, thiophenyl pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolizinyl, purinyl, yridinyl, pyrido[2,3—d]pyrimidine, and pteridinyl; (ii) each ring is aromatic or carbocyclyl, at least one aromatic ring comprises a heteroatom and at least one other ring is a hydrocarbon ring or 6.57., indolyl, isoindolyl, benzothienyl, uranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, pyrido[2,3—b]—l,4—oxazin—3—(4H)—one, 8—tetrahydroquinolinyl and ,6,7,8—tetrahydroisoquinolinyl; and (iii) each ring is aromatic or carbocyclyl, and at least one aromatic ring shares a bridgehead heteroatom with another aromatic ring, e.g., 4H—quinoliziny1.

“Heterocyclic ring system” refers to monocyclic, bicyclic and polycyclic ring systems where at least one ring is ted or partially unsaturated (but not aromatic) and comprises at least one heteroatom. A heterocyclic ring system can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.

“Heterocyclyl” refers to a monovalent radical of a heterocyclic ring system.

Representative cyclyls include ring systems in which (i) every ring is non—aromatic and at least one ring comprises a heteroatom, e.g., tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, pyrrolidinyl, pyranyl, thianyl, pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, zinyl, yl, dioxolanyl, diazepinyl, oxazepinyl, pinyl, morpholinyl, and quinuclidinyl; (ii) at least one ring is non—aromatic and comprises a heteroatom and at least one other ring is an aromatic carbon ring, e.g., 4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl; and (iii) at least one ring is non-aromatic and comprises a heteroatom and at least one other ring is aromatic and ses a heteroatom, e.g., 3,4—dihydro—lH—pyrano[4,3—c]pyridine, and l,2,3,4—tetrahydro—2,6—naphthyridine. In some embodiments, heterocyclyl can e: ‘E S_O_§_:\ NH’_§'_l: EI/N v 0§\|N o / NH H H , ’ ’ N/ \ ~ ’ / N\ *3; o H N K/O |/ NH ’ O, ’ , ,and _§:_/ NH.

“Heterocyclylalkyl” as used herein refers to an alkyl group substituted with a heterocycl group.

“Heteroarylalkyl” as used herein refers to an alkyl group substituted with a heteroaryl group.

“Hydroxy” or “hydroxyl” as used herein refers to —OH.

“Inhibitor" as used herein refers to a compound that inhibits an enzyme such that a reduction in activity of the enzyme can be observed, e.g., in a biochemical assay. In certain embodiments, an inhibitor has an IC50 of less than about 1 uM, less than about 500 nM, less than about 250 nM, less than about 100 nM, less than about 50 nM, or less than about 10 nM. An inhibitor of FGFR—4 refers to a compound that inhibits FGFR—4.

“Nitro” as used herein refers to —N02.

“Nucleophile” as used herein refers to a species that donates an electron—pair to an ophile to form a chemical bond in a reaction. In some embodiments, a phile can be an oxygen phile, e.g., water or hydroxyl, a nitrogen nucleophile, e.g. or a sulfur , amine, nucleophile, e.g., thiol, such as, for example, the thiol in the side chain of a cysteine residue.

“Overexpressed,” as used herein, means there is production of a gene t in a sample that is substantially higher than that observed in a population of control samples (e.g. normal tissue).

"Selective" refers to a compound that inhibits the activity of a target protein, e.g., FGFR- 4, more potently than it inhibits activity of other proteins. In this instance, the isoforms FGFR-l, FGFR—Z, FGFR—3, and FGFR—4 are all considered distinct proteins. In some embodiments, a compound can inhibit the activity of the target protein, e.g., FGFR—4, at least 1.5, at least 2, at least 5, at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 200, at least 500, or at least 1000 or more times potently than it inhibits the activity of a non—target protein.

“Substituted”, Whether preceded by the term “optionally” or not, refers herein to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in ance with permitted valence of the tuted 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. As used , the term “substituted” is contemplated to e all permissible substituents of organic compounds. In a broad aspect, the permissible tuents include acyclic and cyclic, branched and ched, carbocyclic and cyclic, aromatic and non—aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any sible substituents of organic nds bed herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a etate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a ate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be tuted, if appropriate. For instance, the substituents of a substituted alkyl may e substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl ding sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, yls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, ls, alkoxys, alkylthios, aminoalkyls, carbonyl- substituted alkyls, —CF3, —CN, and the like. Analogous substitutions can be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, lkenyls, lkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl—substituted alkenyls or alkynyls.

As used , the definition of each expression, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is ed to be independent of its definition elsewhere in the same structure.

“Sulfonyl” as used herein refers to —SOz—.

“Sulfonamido” as used herein refers to —S(=O)—N(R1)( R2) or —N(R1)—S(=O)—R2 wherein each of R1 and R2 is independently H or alkyl.

“Warhead moiety” or “warhead” refers to a moiety of an inhibitor which participates, either ibly or irreversibly, with the reaction of a donor, e.g. a protein, with a substrate.

Warheads may, for example, form covalent bonds with the protein, or may create stable transition states, or be a reversible or an irreversible alkylating agent. For example, the warhead moiety can be a functional group on an inhibitor that can participate in a bond—forming on, wherein a new covalent bond is formed between a portion of the warhead and a donor, for example an amino acid residue of a protein. The warhead is an electrophile and the "donor” is a nucleophile such as the side chain of a cysteine residue. Examples of suitable warheads include, without limitation, the groups shown below: FMS/kg” Xxx /“|'\/\)k£ /1\E a%/\\s</ 32% 32% n X is a leaving group such as halo, or an activated hydroxyl moiety (e.g., triflate); and each of Ra, Rb, and RC is, independently, H, substituted or unsubstituted C1_4 alkyl, substituted or unsubstituted C1_4 cycloalkyl, or cyano.

The compounds described herein may n ral proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H) or carbon— 14 (14C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention. For e, deuterated nds or compounds containing 13C are intended to be encompassed within the scope of the invention.

Certain compounds can exist in different tautomeric forms, and all possible tautomeric forms of all of the compounds described herein are intended to be encompassed within the scope of the ion.

The “enantiomeric ” or “% enantiomeric excess” of a composition can be calculated using the equation shown below. In the example shown below a composition contains 90% of one enantiomer, 6.57., the S—enantiomer, and 10% of the other enantiomer, i.e., the R— enantiomer. ee 2 (90—10)/100 = 80%.

Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an omeric excess of 80%. Some of the compositions described herein contain an enantiomeric excess of at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of Compound 1 (the S—enantiomer). In other words, the compositions n an enantiomeric excess of the S—enantiomer over the tiomer.

Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational» forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or mational) mixtures of the present compounds are within the scope of the invention. Unless otherwise , all tautomeric forms of the compounds of the invention are within the scope of the ion.

The compounds described herein can be useful as the free base or as a salt.

Representative salts e the hydrobromide, hydrochloride, e, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et a1. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19.) Certain compounds disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are lent to unsolvated forms and are encompassed within the scope of the present invention. Certain nds disclosed herein may exist in multiple crystalline or amorphous forms. In general, all al forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

Pharmaceutical Compositions While it is possible for a compound disclosed herein to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation, where the compound is ed with one or more pharmaceutically acceptable excipients or rs. The compounds disclosed herein may be formulated for administration in any convenient way for use in human or veterinary medicine. In certain embodiments, the compound included in the pharmaceutical preparation may be active itself, or may be a prodrug, e.g., capable of being converted to an active compound in a logical setting. In n embodiments, the compounds provided herein include their hydrates.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, surate with a reasonable benefit/risk ratio.

Examples of pharmaceutically acceptable salts of a nd described herein include those derived from pharmaceutically acceptable inorganic and organic acids and bases.

Examples of suitable acid salts include acetate, adipate, benzoate, benzenesulfonate, butyrate, citrate, onate, dodecylsulfate, e, fumarate, glycolate, lfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, e, maleate, te, methanesulfonate, 2—naphthalenesulfonate, nicotinate, nitrate, palmoate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, te and undecanoate. Salts derived from appropriate bases include alkali metal (6.3., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(alkyl)4+ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds described herein. Water or oil-soluble or dispersible products may be obtained by such quaternization. es of 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 and suppository waxes; (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 oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and um hydroxide; (15) alginic acid; (16) pyrogen—free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21) cyclodextrins such as Captisol®; targeting ligands attached to nanoparticles, such as AccurinsTM; and (22) other non—toxic ible substances, such as polymer—based compositions, employed in pharmaceutical formulations.

Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ic acid, cysteine hloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil—soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl e, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, nediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders, granules and the like) can include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) s or ers, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) s, such as, for example, carboxymethylcellulose, alginates, n, polyvinyl pyrrolidone, sucrose and/or ; (3) humectants, such as glycerol; (4) egrating agents, such as agar—agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as in; (6) absorption accelerators, such as quaternary um compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol earate; (8) absorbents, such as kaolin and ite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and es thereof; and (10) coloring agents.

Liquid dosage forms can include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for e, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl l, benzyl benzoate, propylene glycol, 1,3—butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Suspensions, in addition to the active compounds, may n suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar—agar and tragacanth, and mixtures thereof.

Ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene s, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these nces. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

The formulations may conveniently be ted in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.

Dosage forms for the topical or transdermal administration of a compound of this invention include s, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, s, or propellants that may be required.

When the compounds disclosed herein are administered as pharmaceuticals, to humans and s, they can be given per se or as a pharmaceutical ition containing, for e, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

The formulations can be administered topically, orally, transdermally, rectally, vaginally, parentally, asally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intradermally, intraperitoneally, subcutaneously, subcuticularly, or by inhalation.

Indications FGFR—4 regulates proliferation, survival, and alpha—fetoprotein secretion during hepatocellular carcinoma (HCC) progression; inhibitors of FGFR—4 are therefore promising ial therapeutic agents for this unmet medical need (Ho et al., Journal of Hepatology, 2009, 50: 1 18—27). HCC afflicts more than 0 people worldwide every year and has one of the worst 1—year survival rates of any cancer type.

Further evidence of the link between FGFR—4 and HCC is shown through the involvement of FGF19, a member of the fibroblast growth factor (FGF) family, which ts of hormones that regulate glucose, lipid, and energy tasis. Increased hepatocyte proliferation and liver tumor formation have been observed in FGF19 transgenic mice. FGF19 activates FGFR-4, its predominant receptor in the liver, and it is believed that activation of FGFR-4 is the mechanism whereby FGF19 can increase hepatocyte proliferation and induce hepatocellular carcinoma formation (Wu et al., J Biol Chem (2010) 285(8):5165-5170). FGF19 has been identified as a driver gene in HCC by others as well (Sawey et al., Cancer Cell (2011) 19: 347—358). It is therefore believed that the compounds disclosed herein, which are potent and selective inhibitors of FGFR—4, can be used to treat HCC and other liver cancers.

Oncogenome screening has identified an activating fibroblast growth factor receptor 4 (FGFR—4) Y367C on in the human breast cancer cell line MDA—MB—453. This mutation was shown to elicit constitutive phosphorylation, leading to an activation of the mitogen— activated protein kinase cascade. Accordingly, it has been suggested that FGFR—4 may be a driver of tumor growth in breast cancer (Roidl et al., Oncogene (2010) 29(10): 552). It is therefore believed that the nds disclosed , which are potent and selective inhibitors of FGFR-4, can be used to treat FGFR-4 modulated breast cancer.

Molecular changes (e.g., translocations) in genes upstream of FGFR—4 can lead to activation/overexpression of FGFR—4. For example, a PAX3—FKHR translocation/gene fusion can lead to FGFR—4 overexpression. Overexpression of FGFR—4 due to this mechanism has been associated with myosarcoma (RMS) (Cao et al., Cancer Res (2010) 70(16): 6497-6508).

Mutations in FGFR—4 itself (e.g., kinase domain ons) can lead to over—activation of the protein; this mechanism has been ated with a subpopulation of RMS r et al., J Clin Invest (2009) 119: 3395—3407). It is therefore believed that the compounds disclosed herein, which are potent and selective tors of FGFR—4, can be used to treat FGFR—4 modulated RMS and other sarcomas.

Other diseases have been associated with changes in genes upstream of FGFR—4 or with mutations in FGFR—4 itself. For example, mutations in the kinase domain of FGFR—4 lead to over—activation, which has been associated with lung adenocarcinoma (Ding et al., Nature (2008) 455(7216): 1069—1075). Amplification of FGFR—4 has been associated with conditions such as renal cell carcinoma (TCGA provisional data). In addition, silencing FGFR4 and inhibiting ligand—receptor g significantly decrease ovarian tumor growth, suggesting that inhibitors of FGFR4 could be useful in treating ovarian cancer. (Zaid et al., Clin. Cancer Res. (2013) 809).

Pathogenic elevations of bile acid levels have been linked to variations in FGF19 levels (Vergnes et al., Cell Metabolism (2013) 17, 916-28). Reduction in the level of FGF19 may therefore be of benefit in ing the synthesis of bile acid and thus in the treatment of hyperlipidemia.

Dose Levels Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factors including the activity of the particular compound disclosed herein employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of ion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the ular compound employed, the age, sex, weight, condition, general health and prior medical y of the patient being treated, and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For e, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will be that amount of the nd that is the lowest dose effective to produce a therapeutic effect. Such an ive dose will generally depend upon the factors described above. Generally, doses of the compounds of this ion for a patient will range from about 00001 to about 100 mg per kilogram of body weight per day. For example, the dose could be between 10 and 2000 mg per day.

Alternatively, the dose can be between 100 and 1000 mg per day, or between 200 and 600 mg per day. If desired, the effective daily dose of the active compound may be administered as one, two, three, four, or more sub-doses stered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. ation and Targeted y Administration of the FGFR—4 inhibitors disclosed herein can be combined with other cancer ents. For example, the inhibitors can be administered in combination with surgical treatments, radiation, or other therapeutic agents such as antibodies, other selective kinase inhibitors, or chemotherapeutics. The inhibitors may also be administered in ation with RNAi therapy or antisense therapy. The FGFR—4 inhibitors described herein may be combined with one, two, or more other therapeutic agents. In the examples outlined below, it is understood that “second therapeutic agent” also includes more than one therapeutic agent other than the FGFR—4 inhibitor. For instance, the compounds disclosed herein may be ed with an agent such as sorafenib. A FGFR-4 inhibitor described herein may be administered with one, two, or more other therapeutic agents.

The FGFR-4 inhibitors bed herein and the second therapeutic agent do not have to be administered in the same ceutical composition, and may, because of different physical and chemical characteristics, be stered by different routes. For example, the FGFR—4 inhibitor can be administered orally, while the second therapeutic agent is administered intravenously. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the , modes of administration and times of stration can be modified by the skilled ian.

The FGFR—4 inhibitor and the second therapeutic agent may be administered concurrently (e.g., simultaneously, ially simultaneously or within the same treatment protocol) or sequentially (i.e., one followed by the other, with an al time interval in between), depending upon the nature of the proliferative disease, the condition of the patient, and the actual choice of second therapeutic agent to be administered.

In addition, the FGFR—4 inhibitors disclosed herein can be administered as part of an antibody—drug conjugate, where the FGFR—4 inhibitor is the “payload” portion of the conjugate.

Compounds The table below shows the structures of nds described herein.

Compound Structure Number 3 \\ Q>NH N/ fi’QN O C0 4 >Ngfi’aN cemate H9341 a P cis—racemate 17 O \ O A O J: cemate c.BJ:acemate IO O 39 0%? HNDH HN HN—-(/ XQ N_ CI 0— 0 l . I KHN‘“ Z Cl 0—- 62 HN HN~</, \ \ _// CI o cemate racemaE cemate C.BmCemate mate Compounds of the invention, including salts and N s thereof, can be prepared using known organic synthesis ques and can be synthesized according to any of numerous possible synthetic routes, such as those in the Schemes below. The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily ed by one of skill in the art of organic synthesis. Suitable solvents can be substantially non—reactive with the starting materials (reactants), the ediates, or products at the temperatures at which the reactions are carried out, e. g., temperatures which can range from the solvent’s freezing temperature to the solvent’s boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable ts for a particular reaction step can be selected by the d artisan.

Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily ined by one d in the art. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, (2006), which is incorporated herein by reference in its entirety.

Reactions can be monitored according to any suitable method known in the art. For e, product ion can be monitored by spectroscopic means, such as nuclear magnetic resonance (NMR) spectroscopy (e.g., 1H or 13C), infrared (IR) spectroscopy, spectrophotometry (e.g., UV—visible), mass spectrometry (MS), or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography Analytical instruments and methods for compound characterization: LC—MS: Unless otherwise ted, all liquid chromatography—mass spectrometry (LC— MS) data (sample analyzed for purity and identity) were obtained with an Agilentmode1—1260 LC system using an Agilent model 6120 mass spectrometer utilizing ES-API ionization fitted with an Agilent Poroshel 120 (EC-C18, 2.7um particle size, 3.0 x 50mm dimensions) reverse- phase column at 22.4 degrees Celsius. The mobile phase consisted of a mixture of solvent 0.1% formic acid in water and 0.1% formic acid in acetonitrile. A constant gradient from 95% aqueous/5% c to 5% aqueous/95% organic mobile phase over the course of 4 minutes was utilized. The flow rate was constant at lmL/min.

Prep LC—MS: Preparative HPLC was performed on a Shimadzu Discovery VP® ative system fitted with a Luna 5u C18(2) 100A, AXIA packed, 250 X 21.2 mm e— phase column at 22.4 degrees Celsius. The mobile phase consisted of a mixture of solvent 0. l% formic acid in water and 0.1% formic acid in acetonitrile. A constant gradient from 95% aqueous/5% organic to 5% aqueous/95% organic mobile phase over the course of 25 minutes was utilized. The flow rate was constant at 20 mL/min. Reactions carried out in a microwave were done so in a e tor microwave unit.

Silica gel chromatography: Silica gel chromatography was performed on either a Teledyne Isco CombiFlash® Rf unit or a Biotage® Isolera Four unit.

Proton NMR: Unless otherwise indicated, all 1H NMR spectra were obtained with a Varian 400MHz Unity Inova 400 MHz NMR instrument (acquisition time = 3.5 seconds with a 1 second delay; 16 to 64 scans). Where terized, all protons were reported in DMSO—d6 solvent as parts—per million (ppm) with respect to al DMSO (2.50 ppm).

EXAMPLES The ing examples are intended to be illustrative, and are not meant in any way to be limiting.

The below Schemes are meant to provide general guidance in connection with preparing the compounds of the invention. One skilled in the art would understand that the preparations shown in the Schemes can be modified or optimized using general knowledge of organic chemistry to e various compounds of the invention.

Synthetic Protocol 1 NH; Z PN R—i C|j\l\/j:>/Br—>nucleophilic aromatic HNjLN/\B:r Pd mediated HN substitution reaction P’N ‘< coupling reaction > , P asZ\/0 /L G R é OH N \C —> )L / HN N / HATU, DIEA '—R DCM Q H Protecting group \ N \ \il removal )L / 0 HN N ? O H2N“'O VLCI \ O —> JL /C HN N DIEA, DCM H P: Protecting group (9.9. Soc) 2: B or Sn or Zn reagent 6—bromo—2—chloroquinazoline can be substituted with a no—protected lkyldiamine under philic aromatic substitution reaction conditions using a base such as diisopropylethylamine (DIPEA) or triethylamine (TEA) in a polar solvent such as dioxane to provide the diamine— substituted quinazoline. The 6-bromoquinazoline can be coupled to a boron, tin or zinc aryl, heteroaryl reagent via a palladium—mediated coupling reaction, ag.

, Suzuki, Stille, Negishi coupling, to provide the intermediate which is subsequently de—protected to reveal the amine. The amine on the cycloalkane can be reacted with propiolic acid using amide ng reaction conditions or reacted with acryloyl chloride to preare the acrylamide. As shown below, nds 2 and 6 were prepared using Synthetic Protocol 1.

Exam le 1: S nthesis of N— lS 1R —2— 6— 2 6 —difluoromethox hen l uinazolin—2— lamino c clo ent 1 r0 iolamide Com ound2 NH2 B\ o/ H _ e Clip/B, W0on; Dioxane [4:3in —> N NCF\ e MHO KPO3 4. Pd am( Phos CI)2 100°C Q(:/‘(NO Dioxane water microwave, 100 °C OXNMO /OJ\OH F HCI,DIDC;:/>l<ane N \C —>H2N1..O|NHA13’CI\?IIEA HNJ‘N/ F Q\‘8““6 Step 1: Synthesis of tert—butyl ((lS,2R)—2—((6—bromoquinazolin—2—yl)amino) cyclopentyl)carbamate l lg O0 CIAN/U DIEA,Dioxane HrgJ‘N/U 100°C H ' Afr” "OO F 9H B‘OH 0/ WEEK) —>1N?CFF K3PO4 Pd(amphos)Cl2 *0\«NO MHO Dioxane water 0 microwave, 100 °C \(N“-HOAN A mixture of tert—butyl ((1S,2R)((6—bromoquinazolin—2—yl)amino)cyclopentyl)carbamate (25 mg, 0.06 mmol), (2,6-difluoromethoxyphenyl)boronic acid (24 mg, 0.12 mmol), Bis(di—tert— 4-dimethylaminophenyl)phosphine)dichloropalladium(ll) (3 mg, 0.003 mmol) and ium phosphate (40 mg, 0.19 mmol) in 1,4-dioxane/water (1 mL/0.2 mL) was degassed with nitrogen for 5 min and stirred at 100 0C for 30 min under microwave. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with saturated ammonium chloride on and dried with sodium sulfate. The residue was purified by silica gel column tography to afford utyl ((lS,2R)—2—((6—(2,6—difluoro—3—methoxyphenyl)quinazolin—2— yl)amino)cyclopentyl)carbamate (21 mg, 37%). MS (ES+) C26H30N405 requires: 470, found: 471 [M+H]+.

Step 3: Synthesis of (1R,2S)—N1—(6—(2,6—difluoro—3—methoxyphenyl)quinazolin—2— yl)cyclopentane—1,2—diamine o/ O/ F F O HCIDioxane' \ O lie . 10F HN N HN N H .

We “”0 A mixture of tert—butyl ((1S,2R)—2—((6—(2,6—difluoro—3—methoxyphenyl)quinazolin—2— yl)amino)cyclopentyl)carbamate (21 mg, 0.045 mmol) and 4M HCl in Dioxane (0.5 mL) in dichloromethane (1 mL) was stirred at room temperature for 16h. LC—MS indicated complete consumption of SM. The reaction mixure was trated and used without r purification in the next step.

Step 4: sis of N—((lS,2R)—2—((6—(2,6—difluoro—3—methoxyphenyl)quinazolin—2— yl)amino)cyclopentyl)propiolamide O F 6"F o A .1ngO~\ HNAN’ F ? = HATsJénlilEA \\\g Q\ H II.

HZN,..O A mixture of (1R,2S)—N1—(6—(2,6-difluoro—3—methoxyphenyl)quinazolin—2—yl)cyclopentane—1,2— diamine (0.045 mmol), propiolic acid (0.004 mL, 0.067 mmol), HATU (25 mg, 0.067 mmol) and DIEA (0.023 mL, 0.135 mmol) in dichloromethane (1 mL) was stirred at room temperature for 60 minutes. LC-MS indicated complete consumption of SM. The reaction mixure was purified by silica gel chromatography to yield ,2R)((6-(2,6-difluoro methoxyphenyl)quinazolin—2—yl)amino)cyclopentyl)propiolamide und 2) (13 mg, 68%).

MS (ES+) C27H27N5O3 requires: 422, found: 423 [M+H]+.

Exam le 2: S nthesis of N— lS 2R —2— 6— 2—chloroethox —6—fluoro hen l uinazolin—2— yl )amino )cyclopentyl )propiolamide 1 Compound 6 2 (:EI B\ NH J _ 2 O H 7 0' \\/ \g0 MO Br N \ N N \ )L , I / F CI N DIEA, e HN N o K3PO4 Pd(amphos)C|2 H 100 C .

Dioxane. water O HO/IN —> TN microwave. 100 °C O‘KNMO 0 0 OJ OJ 0 0 Cl HC|.D[2i:c':/>I(ane N \ /LOH CI ' I —> xk / F —, A / F HN N HN N = HATU, DIEA H : “WI-C7 \«NIO Step 1: Synthesis of tert—butyl ((lS,2R)—2—((6—bromoquinazolin—2— yl)amino)cyclopentyl)carbamate N \ *Owgnh'o CIA/ND/ DIEA, e Phi/D/Br 100°C Afar“HO A mixture of 6—bromo—2—chloroquinazoline (l g, 4.14 mmol) and tert—butyl ((lS,2R)—2— aminocyclopentyl)carbamate (0.826 g, 4.14 mmol) were stirred at 100 0C in Dioxane (10 mL) for 48h. The on mixture was cooled to room temperature, concentrated and the residue was ed by silica gel column chromatography to afford tert—butyl ((lS,2R)—2—((6— bromoquinazolin—Z—yl)amino)cyclopentyl)carbamate (1 g, 59%). MS (ES+) C18H23BrN402 requires: 406, found: 407 [M+H]+.

Step 2: Synthesis of tert-butyl ((1S,2R)((6-(2-chloroethoxyfluorophenyl)quinazolin yl)amino)cyclopentyl)carbamate N\ 7 HN N H T K3PO4, Pd(amphos)C|2 O NIHO Dioxane, water \ig microwave, 100 °C A mixture of tert-butyl ((1S,2R)((6-bromoquinazolinyl)amino)cyclopentyl)carbamate (50 mg, 0.12 mmol), (2-chloroethoxyfluorophenyl)boronic acid (40 mg, 0.18 mmol), Bis(di- tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (4 mg, 0.005 mmol) and ium phosphate (78 mg, 0.37 mmol) in 1,4—dioxane/water (1.15 mL/0.15 mL) was degassed with en for 5 min and d at 100 0C for 30 min under microwave. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with saturated ammonium chloride solution and dried with sodium sulfate. The residue was purified by silica gel column chromatography to afford tert—butyl ((lS,2R)—2—((6—(2—chloro—3—ethoxy—6— fluorophenyl)quinazolin—2—yl)amino)cyclopentyl)carbamate (51 mg, 83%). MS (ES+) C26H30ClFN4O3 es: 500, found: 501 [M+H]+.

Step 3: Synthesis of (lR,2S)—Nl—(6—(2—chloro—3—ethoxy—6—fluorophenyl)quinazolin—Z— yl)cyclopentane—1,2—diamine HCI, Dioxane A mixture of tert-butyl ((1S,2R)((6-(2-chloroethoxyfluoropheny1)quinazolin yl)amino)cyclopentyl)carbamate (51 mg, 0.1 mmol) and 4M HCl in Dioxane (0.5 mL) in dichloromethane (1 mL) was stirred at room temperature for 2h. LC-MS indicated complete consumption of SM. The on mixure was concentrated and used without further purification in the next step.

Step 4: Synthesis of N—((lS,2R)—2—((6—(2—chloro—3—ethoxy—6—fluorophenyl)quinazolin—2— no)cyclopentyl)propiolamide 3 0 N\ %OH N )L/ F HI)! N . HATU, DIEA H ? HZNIUO DCM \‘(N‘I‘O A mixture of (1R,ZS)-N1-(6-(2-chloroethoxyfluorophenyl)quinazolin-2—yl)cyclopentane- 1,2—diamine (0.1 mmol), propiolic acid (0.007 mL, 0.12 mmol), HATU (57 mg, 0.15 mmol) and DIEA (0.052 mL, 0.3 mmol) in dichloromethane (1 mL) was stirred at room temperature for 40 minutes. LC—MS ted complete consumption of SM. The reaction mixure was purified by silica gel chromatography to yield N—((lS,2R)—2—((6—(2—chloro—3—ethoxy—6— fluorophenyl)quinazolin—2—yl)amino)cyclopenty1)propiolamide (Compound 6) (35 mg, 76%). MS (ES+) C24H22ClFN402 requires: 452, found: 453 [M+H]+.

Synthetic Protocol 2 lpor m R ’ A /mgI R nucleophilic aromatic HN N HN N H Pd ted_ substitution reaction H p’ coupiIng reactIon ,N / Q RNH? protecting group N \ removal —> HNA>=Z \\|R —’ /J|\ HN N amide coupling reaction ZI O /\ //LOH \R —> ZI HATU DIEA DCM P= Protecting group 2: B, Sn or Zn reagent CI \\R DIEA DCM / 6—bromo—2—chloroquinazoline can be substituted with a l,2—mono—protected cycloalkyldiamine under nucleophilic aromatic substitution reaction conditions using a base such as diisopropylethylamine (DIPEA) or triethylamine (TEA) in a polar t such as dioxane to provide the diamine— tuted quinazoline. The 6—bromoquinazoline can be d to a boron, tin or zinc aryl, heteroaryl carboxylic acid or ester reagent via a palladium—mediated coupling reaction, e.g., Suzuki, Stille, Negishi coupling. The carboxylic acid can then be reacted with an amine using amide coupling reaction conditions (such as HATU and ropylethylamine) to provide an intermediate which is subsequently de-protected to reveal the amine on the lkane. The amine can be reacted with propiolic acid using amide coupling reaction conditions or d with acryloyl chloride to prepare the acrylamide. As shown below, Compound 13 was prepared using Synthetic Protocol 2.

Compound 13 NH2 B\9%; H ; HO O | O‘KNIHO 0 Br 0 Br 0 O OH N \ \ N \ )L / I I / / 0 Cl N DIEA, Dloxane. HN N HN N 3 K3PO4. Pd(amphos)Cl2 100 0C H - OWNHIO Dioxane, water microwave, 100 1’C 0“ “.0 NH2 O O A H H N HCI Dioxane N N \ V ’ N \ . /C DC” 0 JL /C V HATU,D|EA “'3 N HN N \\( VS0 MO H who2 0 O n /I\OH N \ )L / W HATU, DIEA § N“.

DCM \( Step 1: Synthesis of tert—butyl ((lS,2R)—2—((6—bromoquinazolin—2— yl)amino)cyclopentyl)carbamate CIAN/| | DIEA, Dioxane HNAN/ 100 °c H“ T io S 7 A mixture of 6—bromo—2—chloroquinazoline (1 g, 4.14 mmol) and tert—butyl ((1S,2R)—2— aminocyclopentyl)carbamate (0.826 g, 4.14 mmol) were stirred at 100 0C in Dioxane (10 mL) for 48h. The reaction mixture was cooled to room temperature, trated and the residue was purified by silica gel column chromatography to afford utyl ((1S,2R)—2—((6— bromoquinazolin-Z-yl)amino)cyclopentyl)carbamate (1 g, 59%). MS (ES+) C13H23BI'N4OZ requires: 406, found: 407 [M+H]+.

Step 2: Synthesis of 4—(2—(((1R,2S)—2—((tert— butoxycarbonyl)amino)cyclopentyl)amino)quinazolin—6—y1)—3—methoxybenzoic acid 0 (Ir: HOJKQ/B‘0 | miU —>1N?C K3PO4. Pd(amphos)C|2 *0\«NO MHO Dioxane, water 0 microwave, 100 0C «NMON A mixture of tert—butyl ((1S,2R)((6—bromoquinazolin—2—yl)amino)cyclopenty1)carbamate (100 mg, 0.25 mmol), 3-methoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzoic acid (82 mg, 0.29 mmol), Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (9 mg, 0.01 mmol) and potassium phosphate (157 mg, 0.74 mmol) in 1,4-dioxane/water (2.5 mL/0.25 mL) was degassed with en for 5 min and stirred at 100 0C for 30 min under microwave. The reaction e was cooled to room temperature, diluted with ethyl acetate, washed with saturated ammonium chloride solution and dried with sodium sulfate. The residue was purified by silica gel column chromatography to afford methyl 4—(2—(((1R,2S)—2—((tert— butoxycarbonyl)amino)cyclopentyl)amino)quinazolin—6—yl)—3—methoxybenzoic acid (114 mg, 96%). MS (ES+) C26H30N4O5 requires: 478, found: 479 [M+H]+.

Step 3: sis of tert—butyl ((1S,2R)—2—((6—(4—(cyclopropylcarbamoyl)—2— methoxyphenyl)quinazolin—2—yl)amino)cyclopentyl)carbamate ('3 I 0000 NH 1:0 N \eOOHO HATU, DIEA 4(00‘(N'HON O A mixture of 4—(2—(((1R,2S)—2-((tert-butoxycarbonyl)amino)cyclopentyl)amino)quinazolin—6—yl)— 3—methoxybenzoic acid (57 mg, 0.12 mmol), cyclopropyl amine (0.012 mL, 0.18 mmol), HATU (68 mg, 0.18 mmol) and DIEA (0.052 mL, 0.30 mmol) in dichloromethane (1.5 mL) was stirred at room temperature for 30 minutes. LC-MS indicated complete consumption of SM. The on mixure was ed by silica gel chromatography to yield tert-butyl ((18,2R)((6-(4- (cyclopropylcarbamoyl)—2—methoxyphenyl)quinazolin—2—yl)amino)cyclopentyl)carbamate (58 mg, 93%). MS (ES+) C29H35N5O4 requires: 517, found: 518 [M+H]+.

Step 4: Synthesis of 4—(2—(((lR,2S)—2—aminocyclopentyl)amino)quinazolin—6—yl)—N—cyclopropyl— 3—methoxybenzamide O O \ HCI,Dioxane JNL /O \ O )NL /O 0 HM N HN N \\/o\‘gN"-O O A mixture of tert-butyl ((1S,2R)((6-(4-(cyclopropylcarbamoyl)methoxyphenyl)quinazolin- 2-yl)amino)cyclopentyl)carbamate (58 mg, 0.11 mmol) and 4M HCl in Dioxane (0.8 mL) in dichloromethane (1.5 mL) was stirred at room temperature for 120 s. LC—MS indicated complete consumption of SM. The reaction mixure was concentrated and used without further cation in the next step.

Step 5: Synthesis of N—cyclopropyl—3—methoxy—4—(2—(((1R,2S)—2— propiolamidocyclopentyl)amino)quinazolin—6—yl)benzamide cl) (I) O n 0 O n “0| y /Am “0| y HNAN/ / O HQIAN/ O H2Nl,,O HATU. DIEA Q N...

DCM \\( A mixture of 4—(2—(((lR,2S)—2—aminocyclopentyl)amino)quinazolin—6—yl)—N—cyclopropyl—3— methoxybenzamide (0.11 mmol), propiolic acid (0.010 mL, 0.17 mmol), HATU (64 mg, 0.17 mmol) and DIEA (0.06 mL, 0.34 mmol) in dichloromethane (1.5 mL) was stirred at room temperature for 45 s. LC—MS indicated complete consumption of SM. The reaction mixure was purified by silica gel chromatography to yield N—cyclopropyl—3—methoxy—4—(2— (((1R,2S)—2—propiolamidocyclopentyl)amino)quinazolin—6—yl)benzamide (Compound 13) (35 mg, 69%). MS (ES+) C27H27N503 requires: 469, found: 470 [M+H]+. tic Protocol 3 O/ NH2 0/ 0/ o mH 0' m 0/ o protecting group NI \O N| \C O/ removal O NI \C 0/ CIAN/ —> HNAN/ —> CI CI nucleophilic aromatic HNXN/ Cl PACH substitution reaction or palladium mediated Buchwald coupling reaction H2N© )1 NDQ 0/ ¢ OH HNxN/ Cl —> H \‘g \0\ N HATU,D|EA \ DCM 0/ 0 0” CI HNAN/”fig Cl DIEA, DCM MC 2—chloro—6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazoline (described in WO 2014011900) can be substituted with an 1,2—mono—protected lkyldiamine under various nucleophilic aromatic substitution reaction ions using a base (such as diisopropylethylamine (DIPEA), DBU or NaHCO3) in a polar solvent (such as dioxane, CH3CN or NMP) or via a palladium— mediated Buchwald coupling reaction to e the diamine—substituted quinazoline. The protecting group on the amine is removed to reveal the amine on the lkane. The amine can be reacted with propiolic acid using amide coupling reaction conditions or reacted with acryloyl chloride to prepare the acrylamide. As shown below, Compounds 27, 32, 34, 36, and 40 were ed using Synthetic Protocol 3.

Compound 27 Synthesis of N—[(3R,4S){ [6-(2,6-dichloro—3,5—dimethoxyphenyl)quinazolin—2— yl]amino}oxolanyl]propenamide / / / 0 0 o O C' C' TFA, DCM N. \o 0’ BocHN,.,O O 0 N \c 0’ O N 0’ CIAN/ *N’| —> I 0' C' \e Nchoa, NMP, 95°C N/ C' H ”'é‘ WA \IKOTNMOo H2N/,,O o o \ 0/ wk 1 0 ° CI Cl HN N/ DIEA, DCM, 0 °C /I QN// Step 1: Synthesis of tert—butyl ((3R,4S)—4—((6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—Z— yl)amino)tetrahydrofuran—3—yl)carbamate as a light yellow foam / / 0 0 CI 0' N \ 0/ W0 O o N \ 0/ A / GI JL / CI CI N NaHC03, NMP, 95°C HN N \l/OdOl/NU'Q: A mixture of 2—chloro—6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazoline (1.02 g, 2.76 mmol), tert—butyl ((3R,4S)—4—aminotetrahydrofuran—3—yl)carbamate (0.85 g, 4.20 mmol), and sodium bicarbonate (0.58 g, 6.90 mmol) was stirred in NMP (5.5 mL, 0.5M) at 95°C for 12 hours.

The reaction was removed from the oil bath and while cooling to room temperature was d with about 90 mL of water and then sonicated and stirred for 20 minutes. A yellow—orange solid was isolated by filtration, rinsed several times with small amounts of water, and dried under vacuum for nearly 1 hour to yield 3.35 g of crude, which was purified by silica gel tography to yield 1.10 g (74.5% yield) of tert—butyl ((3R,4S)—4—((6—(2,6—dichloro-3,5— oxyphenyl)quinazolinyl)amino)tetrahydr0furan—3—yl)carbamate as a light yellow foam.

MS (ES+) C25H28C12N405 requires: 534, found: 535 [M+H]+.

Step 2: Synthesis of (3S,4R)-N3-(6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-Z- yl)tetrahydrofuran—3,4—diamine o/ 0/ CI CI 0 TFA, DCM O “I 0 °/ “I \o 0/ N/ C' N/ C' HN HN A solution of utyl ((3R,4S)((6—(2,6—dichloro—3,5—dimethoxypheny1)quinazolin—2— y1)amino)tetrahydrofurany1)carbamate (1.097 g, 2.049 mmol) in DCM (15 mL, 0.137 M) and TFA (11.7 g, 102 mmol) was stirred about 40 minutes at room temperature. The excess solvents were removed under reduced pressure. The yellow oil was dissolved into DCM (~60 mL) and washed with aqueous 1N NaOH (~30 mL). The aqueous layer was then diluted with brine (~15 mL) and extracted with fresh DCM (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated down, and dried to yield (3S,4R)—N3—(6—(2,6—dichloro—3,5— dimethoxyphenyl)quinazolin—2—yl)tetrahydrofuran—3,4—diamine as a very light yellow foam (0.879 g, 99%).

Step 3: Synthesis of N—[(3R,4S)—4—{ [6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2— yl] amino } oxolan—3—yl]prop—2—enamide o/ 0/ CI CI N \ 00/ N \C 00/ JL /C Cl VLC. HNAN/ CI “'1‘ N H : Han.O / N’“ DI EA, DCM, 0 °C W O o 0 To a solution of (3S,4R)—N3—(6—(2,6-dichloro—3,5—dimethoxyphenyl)quinazolin—2— rahydrofuran—3,4—diamine (0.94 g, 2.1 mmol) in romethane (25 mL) at 0 0C was added DIEA (0.37 mL, 2.1 mmol) and acryloyl de (0.17 mL, 2.1 mmol) and the reaction was stirred for 3h. LC-MS indicated complete consumption of SM. The reaction mixure was purified by silica gel chromatography to yield N-((1S,2R)((6-(2,6-dichloro-3,5- dimethoxypheny1)quinazolinyl)amino)cyclohexyl)acrylamide (Compound 27) (0.8 g, 76 %).

MS (ES+) C23H22C12N4O4 requires: 488, found: 489 Compound 32 Synthesis of N—((lS,2R,3S,SS)—2—((6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2— yl)amino)bicyclo[3. l .0]hexan—3—yl)acrylamide NHTefic TeOCHN’Q9, *\:NH NaHCO NMP H‘‘QW HCI/d''Oxane ‘ CO | o/ —3>’ O—> , 100 °C 0. N.

I-T Cl/k Q/ -“ \r \ dd 9.“ \ H‘ CI I DIEA, DCM CO O °°C 0 Step 1: Synthesis of 2—(trimethylsilyl)ethyl ,3S,SS)—2—(6—(2,6—dichloro—3,5— dimethoxyphenyl)quinazolin—2—ylamino)bicyclo[3. 1.0]hexan—3—ylcarbamate \ NHTefic NHTeoc, 9::YN/Q‘ QRgNH O H Ncho3 NMP iii/C 0/ cl) 100 00 o N.

C, 00 A on of 2—(trimethylsilyl)ethyl (lS,2R,3S,SS)—2—aminobicyclo[3.1.0]hexan—3—ylcarbamate (250 mg, 0.977 mmol), 2-chloro-6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazoline (300 mg, 0.814 mmol) and sodium bicarbonate (205 mg, 2.442 mmol) in N-methylpyrrolidone (10 mL) was stirred at 100 OC overnight. The reaction on was cooled to room temperature, diluted with ethyl acetate (100 mL) and washed with water (eight times) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to afford a crude product, which was purified by silica gel column chromatography (ethyl acetatezpetroleum ether 2 4 : 2) to afford the title compound (300 mg, 52%) as a yellow solid. MS (ES+) C23H34C12N4O4Si requires: 588, 590, found: 589, 591 [M + H]+.

Step 2: Synthesis of (1S,2R,3S,5S)—N2—(6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2— yl)bicyclo[3.1.0]hexane—2,3—diamine NHTeoc NH 3 2 H ; H - “N N “\N N 9 \ w “v 11/ \ 11/ / / H‘‘. \vQ 'H 0 'H 0 C' I HCIIdioxane H C' I /O /0 To a solution of methylsilyl)ethy1 (1S,2R,3S,5S)—2—(6—(2,6—dichloro—3,5— dimethoxyphenyl)quinazolin—2—ylamino)bicyclo[3.1.0]hexan—3—ylcarbamate (200 mg, 340 mmol) in dioxane (10 mL) was added 12 M conc. HCl (1 mL) at room temperature. The resulting e was stirred overnight, then quenched with water (50 mL), and the pH of the solution was brought to pH = 8—9 with ted solution of sodium carbonate. The solution mixture was extracted with ethyl acetate (3 x 50 mL), and the ed layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by thin layer chromatography (Prep—TLC) (dichloromethane:methanol 2 15:1), and then further ed by silica gel column chromatography (dichloromethane:methanol 2 20:1) to afford the title compound (70 mg, 46%) as a white solid. MS (ES+) C22H22C12N402 requires: 444, 446, found: 445, 447 [M + H]+.

Step 3: Synthesis of N—((1S,2R,3S,5S)-2—((6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2— yl)amino)bicyclo[3.1.0]hexan—3-yl)acrylamide ‘n \Nlr/ xx \ \ . \JLC. . \Nf/ H“ H 0 Cl l —. H\\ H 0 CI | O DIEA, DCM O O 0 Cl Cl /0 /0 To a solution of (1S,2R,3S,5S)—N2—(6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2— yl)bicyclo[3.l.0]hexane—2,3—diamine (42 mg, 0.094 mmol) in dichloromethane (1.9 mL) at 0 0C was added DIEA (0.025 mL, 0.14 mmol) and acryloyl chloride (0.009 mL, 0.11 mmol) and the reaction was stirred for 1h. LC—MS indicated complete consumption of SM. The reaction mixure was purified by silica gel chromatography to yield N—((1S,2R,3S,5S)—2—((6—(2,6—dichloro—3,5— dimethoxyphenyl)quinazolin—2—y1)amino)bicyclo[3.1.0]hexan—3—yl)acrylamide (36 mg, 76%) as a pale yellow solid. MS (ES+) C25H24C12N4O3 requires: 498, found: 499 Compound 34 sis of N-((1S,2R)((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin yl)amino)cyclohexyl)acrylamide / / / 0 0 o O : 0' CI BocHNhl TFA‘ NI \C 0/ O 0/ DCM 0/ CIAN/ —> —> NI \C DBU, CH3CN HNxN’NI \C 0' Jx / CI 70 °c +02? ,0 HzNh'O O 0/ \jL\ HNXN/N| \ CI CI —> N’ / I.

DIEA, DCM /\H/ 0 Step 1: Synthesis of tert—butyl ((1S,2R)—2—((6—(2,6—dichloro-3,5—dimethoxyphenyl)quinazolin—2— yl)amino)cyclohexyl)carbamate: O o/ C| C' O ‘ BocHN,“ 0/ O 0 “ 0 °’ CIAN/“DO —> | DBU, CH3CN HNAN/ 0' 70 cc \FJTNMo O A e of 2—chloro—6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazoline (0.95 g, 2.6 mmol), tert—butyl ((1S,2R)—2—aminocyclohexyl)carbamate (1.1 g, 5.14 mmol), and DBU (0.77 mL, 5.14 mmol) in acetonitrile (9 mL) was degassed with N2 for 5 mins and heated at 70 0C for 16h. The mixture was cooled to room temperature, trated and the residue was purified by silica gel column chromatography to afford utyl ((1S,2R)—2—((6—(2,6—dichloro—3,5— dimethoxyphenyl)quinazolin—2—yl)amino)cyclohexyl)carbamate (1.1 g, 81%). MS (ES+) C27H32C12N4O4 requires: 546, found: 547 [M+H]+.

Step 2: Synthesis of (1R,2S)—N1—(6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2— yl)cyclohexane—1,2—diamine Cl CI 0 TFA, O JNCC 0/ DC“ JN'CC 0/ HM N/ Cl —> HN N/ 0' \i/OINII'O HzN/,,© A mixture of tert—butyl ((lS,2R)—2—((6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2— yl)amino)cyclohexyl)carbamate (1.14 g, 2.1 mmol) and 4N HCl in Dioxane (5.2 mL) in romethane (10 mL) was d at room temperature for 30 minutes. LC—MS indicated complete consumption of SM. The reaction mixure was concentrated to give (1R,2S)—N1—(6—(2,6— dichloro—3,5—dimethoxyphenyl)quinazolin—2—yl)cyclohexane—1,2—diamine (0.94g, 100%) which was used without further purification in the next step.

Step 3: Synthesis of N—((1S,2R)—2—((6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2— yl)amino)cyclohexyl)acrylamide o/ O 0' °' O 0/ O 0 N \ N \ 0/ JL ’ C' Vk.C JL / CI HN N HN N H : : Na. ’ HEN,“ —> O / DIEA.DCM q 0 To a solution of )-N1-(6-(2,6-dichloro—3,5—dimethoxyphenyl)quinazolin—2— yl)cyclohexane-1,2-diamine (0.94 g, 2.1 mmol) in dichloromethane (25 mL) at 0 0C was added DIEA (0.37 mL, 2.1 mmol) and acryloyl chloride (0.17 mL, 2.1 mmol) and the on was stirred for 3h. LC—MS indicated complete consumption of SM. The reaction mixure was purified by silica gel chromatography to yield N—((1S,2R)—2—((6—(2,6—dichloro—3,5— dimethoxyphenyl)quinazolin—2—yl)amino)cyclohexyl)acrylamide (0.8 g, 76 %). MS (ES+) C25H26C12N4O3 requires: 500, found: 501. nd 36 Synthesis of N—((1S,2S)—2—((6—(2,6—dichloro—3,5—dimethoxypheny1)quinazolin—2— yl)amino)cyclohexyl)acrylamide 0/ / / 0 o O 6' CI BocHN," N \O 0/ N \O 0/ TFA,DCM N \ 0/ CIAN/| —> | —> | 052003,X-Phos HNAN/ 0' HNXN/ CI szdbaa‘ DMA o H, 95 °c I HzN/,,© 0 0/ J1 ~\ \ | 0 HNAN/ Cl —> Na, DIEA, DCM q(5 Step 1: Synthesis of utyl ((1S,2R)—2—((6—(2,6—dichloro—3,5—dimethoxypheny1)quinazolin—2— yl)amino)cyclohexyl)carbamate O/ 0/ Cl C' 0 BocHN,,_ O CIAN/ —> CSZCO3.X-Phos HNAN/| 0' szdbag, DMA o N,“ 95°C \[c]: A mixture of 2—chloro—6—(2,6—dichloro—3,5—dimethoxypheny1)quinazoline (0.1 g, 0.27 mmol), tert—butyl ((1S,2S)—2—aminocyclohexyl)carbamate (75 mg, 0.35 mmol), CszCO3 (176 mg, 0.54 mmol), X—Phos (13 mg, 0.027 mmol) and szdba3 (12.5 mg, 0.013 mmol) in DMA (1.8 mL) was degassed with N2 for 5 mins and heated in a microwave reactor at 125 0C for 30 mins. The mixture was cooled to room ature, filtered through celite and washed with water followed by saturated brine solution. The residue was purified by silica gel column chromatography to afford tert-butyl ((1S,2R)((6-(2,6-dichloro-3,5-dimethoxypheny1)quinazolin yl)amino)cyclohexy1)carbamate (67 mg, 45%). MS (ES+) C27H32C12N4O4 requires: 546, found: 547 [M+H]+.

Step 2: sis of (lR,2S)—Nl—(6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2— yl)cyclohexane— l ,2—diamine o/ 0/ CI Cl 3 3 N \C 0/ TFA, N \C O/ HNAN/I DCM HNXN/| Cl Cl +OTN,“ HQNM A e of tert-butyl ((1S,2R)((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-Z- yl)amino)cyclohexyl)carbamate (67 mg, 0.12 mmol) and TFA (0.6 mL) in dichloromethane (0.6 mL) was stirred at room temperature for 60 minutes. LC—MS indicated complete consumption of SM. The reaction mixure was diluted with ted NaHCO3 and then extracted with dichloromethane. The combined organic layers were dried by NazSO4, filtered, concentrated to give (lR,2S)—N l —(6—(2,6—dichloro—3,5—dimethoxypheny1)quinazolin—2—yl)cycloheXane— l ,2— diamine which was used without further purification in the next step.

Step 3: Synthesis of ,2S)—2—((6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2— yl)amino)cyclohexyl)acrylamide O CI o O o / N \ o NI \ O VLCI i /C Cl A / HN N CI H HN N “”0 “orN,/ I.(5 To a solution of (lR,2S)—Nl—(6—(2,6-dichloro—3,5—dimethoxyphenyl)quinazOlin—2— yl)cyclohexane—1,2—diamine (0.12 mmol) in dichloromethane (1.3 mL) at 0 0C was added DIEA (0.004 mL, 0.02 mmol) and acryloyl chloride (0012 mL, 0.15 mmol) and the reaction was stirred for 1h. LC—MS indicated complete consumption of SM. The reaction mixure was purified by silica gel chromatography to yield N-((1S,ZS)((6-(2,6-dichloro-3,5- dimethoxyphenyl)quinazolinyl)amino)cyclohexyl)acrylamide (35 mg, 58 %). MS (ES+) C25H26C12N4O3 requires: 500, found: 501.

Compound 40 Synthesis of ,4S)—3—((6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2— yl)amino)tetrahydro—2H—pyran—4—yl)acrylamide / / / O 0 0 : cu Cl N3]" o/ O N \C 0/ MeOH,EtOAc N \C o/ CIAN/NI \ —, | —> | NaHC03, NMP. 95°C HNAN’ 0' HNAN’ ‘3' N3, ‘ HQN, ' Co Co \i N \ 0/ cu JL / c: —> N, / u DIEA, DCM, 0 °C /\g/ 0 Step 1: Synthesis of N—((3S,4S)—4—azidotetrahydro—2H—pyran—3—yl)—6—(2,6—dichloro—3,5— dimethoxyphenyl)quinazolin—2—amine / / 0 0 CI : CI g N3,“ N \ 0/ O) g N \ 0/ JL / —> cl JL / CI CI N NaHCO3, NMP, 95°C HN N N31,,0) (3S,4S)—4—azidotetrahydro—2H—pyran—3—amine, HCl (0.200 g, 1.120 mmol) and 2—chloro—6—(2,6— dichloro—3,5—dimethoxyphenyl)quinazoline (0.318 g, 0.861 mmol) were taken up in NMP (2 ml) and sodium carbonate (0.217 g, 2.58 mmol) was added. The reaction was heated to 100 °C ght. After cooling to ambient temperature the reaction was poured into 5ml of water and stirred for 30 min. The solid layer was filtered off and washed with water and further dried under high vacuum to give N-((3S,4S)—4—azidotetrahydro—2H—pyran—3—y1)—6—(2,6—dichloro—3,5— dimethoxyphenyl)quinazolin-2—amine (0.300 g, 0.631 mmol, 73.3 % yield). MS (ES+) C21H20C12N603 requires: 474, found: 475 [M + H]+.

Step 2: Synthesis of (3S,4S)—N3—(6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin-2— yl)tetrahydro—2H—pyran—3,4—diamine CI CI 0 0 N \C o/ MeOH, EtOAc N \C 0/ HNAN/I —> I CI HN/kN/ CI Nan.(E H2N,“Co N—((3S,4S)—4—azidotetrahydro-2H—pyran—3—yl)—6—(2,6—dichloro—3,5—dimethoxypheny1)quinazolin— 2-amine (0.063 g, 0.133 mmol) was taken up in Methanol (7 ml) and EtOAc (7.00 ml), Pd-C (0.014 g, 0.133 mmol) was added and stirred under a H2 balloon for 1 hour. After the reaction was completed, it was ed through celite and the solvent removed. (3S,4S)-N3-(6-(2,6- dichloro—3,5—dimethoxyphenyl)quinazolin—2—yl)tetrahydro—2H—pyran—3,4—diamine (0.060 g, 0.134 mmol, 101 % yield) was recovered as a yellow solid, which was carried on without r purification. MS (ES+) C21H22C12N4O3 es: 448, found: 449 [M + H]+.

Step 3: Synthesis of ,4S)—3—((6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2— yl)amino)tetrahydro—2H—pyran—4—yl)acrylamide o/ 0 O O/ 0 O / 1/0 N \O o 0. $0 WA, o. my N H ? H2NI.. ' / ”' DIEA, DCM, o ”C /\H/ o o (3S,4S)—N3—(6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2—yl)tetrahydro—2H—pyran—3,4— diamine (0.060 g, 0.134 mmol) was taken up in CHZClz (2 ml) and cooled to 0 °C, followed by addition of DIEA (0.023 ml, 0.134 mmol) and then acryloyl chloride (0.012 ml, 0.147 mmol) slowly. The reaction was stirred at 0 °C for 30 minutes, then the mixture was loaded directly onto silica and purified by flash chromotography using 0—10% CHzClz/MeOH. N—((3S,4S)—3—((6— (2,6-dichloro-3,5-dimethoxyphenyl)quinazolinyl)amino)tetrahydro-2H—pyrany1)acrylamide (0.041 g, 0.081 mmol, 61% yield) was recovered as an off white solid. MS (ES+) C24H24C12N4O4 requires: 502, found: 503 [M + H]+.

Synthetic Protocol 4 0/ [EH-'2 0/ 0/ 0 P,NI1.O CI CI NBoc / O protecting group O N \O 0/ removal O 0/ N \C HNAN| —> | / c. HNAN/ CI philic aromatic H tution reaction PINWO HZNMO NBoc NBoc 0 00/ VkCI WOJL/N*\ *\ amide urea or TFA DCM sulfonamide formation DIEA, DCM, 0 0C /\\gN NBOC / NH N \C o/ HNAN/I c.

P = protecting group (eg, Teoc) R = amide, urea or sulfonamide mg QR 2—chloro—6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazoline (described in WO 2014011900) can be substituted with a no—protected pyrrolidine diamine under nucleophilic aromatic substitution reaction conditions using a base (such as NaHCO3) in a polar solvent (such as NMP) to provide the diamine—substituted quinazoline. The protecting group on the amine is removed under appropriate conditions to reveal the amine on the pyrrolidine. The amine can be reacted with with acryloyl chloride to prepare the acrylamide. As shown below, Compounds 56 and 83 were prepared using Synthetic Protocol 4.

Compound 56 Synthesis of N-((3S,4R)acetyl((6—(2,6—dichloro—3,5—dimethoxypheny1)quinazolin—2— yl)amino)pyrrolidinyl)acrylamide NH2 0/ 0/ CI - Cl CI TeocHNu.

/ CI JL / c. JL / CI N NaHCOa, NMP, 95 °c Hfgl N ngl N TeocHN.06 PEN/“G NBoc NBoc éo/ 0/ vi “to l o\ 0 o Cl / CI TFA,DCM Hrg N )LCI H _ N...

DIEA,DCM,O°C 'EN WSN q 0 CM,0 oc NBoc NH HNANN|/:.CI§\O/ H : M“-0N Step 1: Synthesis of tert—butyl (3R,4S)—3—((6—(2,6—dichloro—3,5—dimethoxypheny1)quinazolin—2— yl)amino)—4—(((2—(trimethylsily1)ethoxy)carbonyl)amino)pyrrolidine— l—carboxylate / / O NH2 0 O NHTeocl..O 0' N \C 0/ NBOC N \O O CIAN/| | CI NAN/ CI NaH003, NMP, 95 °C H NHTeOCV'GNBoc A mixture of 2—chloro—6—(2,6—dichloro—3,5—dimethoxypheny1)quinazoline (2.65 g, 7.17 mmol), tert—butyl (3R,4S)—3—amino—4—(((2,2,2—trichloroethoxy)carbonyl)amino)pyrrolidine—1—carboxylate (2.97 g, 8.6 mmol), and sodium bicarbonate (2.41 g, 28.7 mmol) was stirred in NMP (40 mL) at 95°C for 16 hours. The reaction was removed from the oil bath, cooled to room temperature and added to 300 mL of water. A yellow—orange solid was isolated by filtration, rinsed several times with small amounts of water, and dried under vacuum to yield 5 g of crude product, which was purified by silica gel chromatography to yield 2.82 g (58% yield) of tert-butyl (3R,4S)((6- (2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2—yl)amino)—4—(((2— thylsi1y1)ethoxy)carbony1)amino)pyrrolidine—l—carboxylate. MS (ES+) C31H41C12N5068i es: 677, found: 678 [M+H]+.

Step 2: Synthesis of tert—butyl )—3—amino—4—((6-(2,6—dichloro—3,5— dimethoxyphenyl)quinazolin—2—yl)amino)pyrrolidine— l—carboxylate o/ 0/ CI CI O TBAF, THF 0 HNAN/ —> CI CI HN N/ NHTeoc.,/ONBoc HZNMONBoc A mixture of tert-butyl (3R,4S)((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-Z- yl)amino)—4—(((2—(trimethylsilyl)ethoxy)carbonyl)amino)pyrrolidine—1—carboxylate (2.77 g, 4.1 mmol) and 1M TBAF in THF (6.1 mL, 6.1 mmol) was stirred in in THF (27 mL) at 50 °C for 4h and then 16h at room temperature. The reaction mixture was diluted with 10% methanol in dichloromethane (100 mL) and washed with water (50 mL). The aqueous layer was then extracted with fresh dichloromethane (3 x 20 mL). The combined organic layers were washed with saturated brine solution, dried over sodium sulfate, filtered, concentrated down, and dried to yield tert—butyl (3S,4R)—3—amino—4—((6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2— no)pyrrolidine—l—carboxylate as a yellow solid (2.1 g, 94%).

Step 3: Synthesis of tert—butyl (3S,4R)—3—acrylamido—4—((6—(2,6—dichloro—3,5— dimethoxyphenyl)quinazolin—2—yl)amino)pyrrolidine- l-carboxylate o/ O/ CI CI O 0/ O ACI O N\01\C 0/ A| / CI / CI HN N HN N i DIEA, DCM, o 00 H a HZNII'O NUIO NBoc fig NBoc To a solution of (3S,4R)amino((6—(2,6—dichloro—3,5—dimethoxypheny1)quinazolin—2— yl)amino)pyrrolidinecarboxylate (2.1 g, 4.1 mmol) in dichloromethane (82 mL) at O 0C was added DIEA (1.07 mL, 6.1 mmol) and acryloyl chloride (0.36 mL, 4.5 mmol) and the reaction was d for 30 mins. LC—MS indicated te consumption of SM. The reaction mixure was purified by silica gel chromatography to yield tert—butyl (3S,4R)-3—acrylamido—4—((6—(2,6— dichloro—3,5—dimethoxyphenyl)quinazolin—2—yl)amino)pyrrolidine—1—carboxylate (1.26 g, 52 %).

MS (ES+) C12N505 requires: 587, found: 588.

Step 4: Synthesis of N—((3S,4R)—4—((6-(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2— no)pyrrolidin—3—yl)acrylamide o/ 0/ Cl 0| I °/ I N \O N \C O/ HNAN/| | Cl CI TFA, DCM HN/kN/ H : H : .,, .,, fig ONBOC q QH A solution of tert—butyl (3S,4R)—3—acrylamido—4—((6—(2,6—dichloro—3,5— dimethoxyphenyl)quinazolin—2—yl)amino)pyrrolidine—l—carboxylate (1.26 g, 2.14 mmol) in DCM (8 mL) and TFA (3 mL, 39 mmol) was stirred 3h at room temperature. The excess solvents were removed under reduced pressure. The yellow oil was dissolved into DCM (~100 mL) and washed with aqueous saturated sodium bicarbonate solution (~50 mL). The aqueous layer was then extracted with fresh DCM (3 x 30 mL). The combined organic layers were dried over sodium e, filtered, trated down, and dried to yield N—((3S,4R)—4—((6—(2,6—dichloro— 3,5—dimethoxyphenyl)quinazolin—2—yl)amino)pyrrolidin—3—yl)acrylamide which was used without further purification in the next step.

Step 5: Synthesis of N—((3S,4R)—1—acetyl—4—((6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2— yl)amino)pyrrolidin—3—yl)acrylamide O/ 0 0 o“ / lo o em 0 N/ Cl 10 HN *0 N H HIE.

H l N,"o M O DIEA.DCM,0°C M N NH O 0 f0 To a solution of N-((3S,4R)((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin yl)amino)pyrrolidin—3—yl)acrylamide (0.37 g, 0.76 mmol) in dichloromethane (15 mL) at 0 0C was added DIEA (0.16 mL, 0.92 mmol) and acetyl chloride (0.054 mL, 0.76 mmol) and the reaction was stirred for 60 mins. LC—MS indicated complete consumption of SM. The reaction mixure was purified by silica gel chromatography to yield N—((3S,4R)—l—acetyl—4—((6—(2,6— dichloro—3,5—dimethoxyphenyl)quinazolin—2—yl)amino)pyrrolidin—3—yl)acrylamide (0.207 g, 51 %). MS (ES+) C25H25C12N504 requires: 529, found: 530. nd 83 Synthesis of (3S,4R)acrylamido((6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazOlin—2— yl)amino)-N-ethylpyrrolidine- l-carboxamide Cl CI i o/ i N \O N \C o/ I I N/ C' \/NCO HNJ‘N/ Cl H - H - N-. N. M'QH TEA, DCM, 0 °C M IQ O O F0 To a on of N—((3S,4R)—4—((6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2— yl)amino)pyrrolidin—3—yl)acrylamide (0.040 g, 0.082 mmol) in dichloromethane (1.5 mL) at 0 0C was added TEA (0.014 mL, 0.098 mmol) and ethyl isocyanate (0.008 mL, 0.098 mmol) and the reaction was stirred for 45 mins. LC—MS indicated complete consumption of SM. The reaction mixure was purified by silica gel chromatography to yield (3S,4R)—3—acrylamido—4—((6—(2,6— dichloro—3,5—dimethoxyphenyl)quinazolin—2—yl)amino)—N-ethylpyrrolidine— l—carboxamide (0.035 g, 76 %). MS (ES+) C26H28C12N604 requires: 558, found: 559.

S nthetic Protocol 5 0/ NH2 0/ 0/ CI P'NC CI CI PL 1””2. 0/ Z protecting group 2‘ 0’ 0/ —» “I“:E fl” HN)\X/ —» Cl X/ Y’ C' Pdmediated Y" 5E “J”y" C' Buchwald coupling- H | p’N H2N %0H Z N \ ~lvv 0/ —> HNJ‘x’(IY’J, HATU, DIEA DCM \fl/N O 0/ \im r\l|/\/EZ\;W 0/ HNAX/ YJ Cl —> H m f)N The 2—Cl heterocycle (described in ) can be substituted with a 1,2— rotected diamine via a palladium—mediated Buchwald coupling on to provide the diamine—substituted heterocycle. The protecting group on the amine is then removed to reveal the amine on the cycloalkane. The amine can be reacted with propiolic acid using amide coupling reaction ions to afford the propargyl amide or reacted with acryloyl chloride to provide the acrylamide. As shown below, Compound 62 was prepared using Synthetic Protocol 5.

Compound 62 Synthesis of N—((lS,2R)—2—((6—(2,6-dichloro—3,S—dimethoxyphenyl)—8—ethyl—7—oxo—7,8— dihydropyrido[2,3—d]pyrimidinyl)amino)cyclopentyl)acrylamide 0/ o/ 0/ CI 6' CI BooHN,,,O N \ \ o/ N \ \ 0/ TFA,DCM N \ \ o/ CIAN/I I —> I 0' ’ C' ’ 0' NK 0 CSZC03,X-Phos HN N N o HN N N o szdba3,DMA ‘ o N,“ l\ ; H2N/,, o o \i ~\ \ o/ \ l N OCI H HE‘XN/ —> N - DIEA,DCM fir 0 Step 1: Synthesis of tert—butyl ((1S,2R)—2—((6—(2,6—dichloro—3,5-dimethoxyphenyl)—8—ethyl—7—oxo— hydropyrido[2,3—d]pyrimidin—2—yl)amino)cyclopentyl)carbamate / / 0 0 CI ,'O- CI NI \ \ O/ N \ \ o/ CIAN/ | 0' C' N o C52C03,X—Phos HN N/ N o K H szdba3, DMA = o N,“ K A mixture of 2—chloro—6—(2,6—dichloro—3,5—dimethoxyphenyl)—8—ethylpyrido[2,3—d]pyrimidin— 7(8H)—one (0.2 g, 0.48 mmol), tert—butyl ((1S,2R)—2—aminocyclopentyl)carbamate (145 mg, 0.72 mmol), CsZCO3 (393 mg, 1.21 mmol), X—Phos (23 mg, 0.048 mmol) and szdba3 (22 mg, 0.024 mmol) in DMA (3.2 mL) was ed with N2 for 5 mins and heated in a ave reactor at 115 0C for 60 mins. The mixture was cooled to room temperature, diluted with EtOAc, filtered through ce1ite and washed with water (4X) followed by saturated brine solution. The residue was purified by silica gel column chromatography to afford tert—butyl tert—butyl ((1S,2R)—2—((6—(2,6— dichloro—3,5—dimethoxyphenyl)ethyl—?—oxo—7,8—dihydropyrido[2,3—d]pyrimidin—2— yl)amino)cyclopentyl)carbamate (60 mg, 22%). MS (ES+) C27H33C12N505 requires: 577, found: 578 [M+H]+.

Step 2: Synthesis of 2-(((1R,2S)aminocyclopentyl)amino)(2,6-dichloro-3,5- dimethoxyphenyl)—8—ethylpyrido[2,3—d]pyrimidin—7(8H)—one o/ 0/ Nflo/CI Cl TFA,DCM N \ \ o/ N oCl HN IN/ N H HNJ‘N/ \l/OTNMO K K o WMO A mixture of tert—butyl tert-butyl ((1S,2R)—2—((6—(2,6—dichloro—3,5—dimethoxyphenyl)—8—ethyl—7— oxo—7,8—dihydropyrido[2,3-d]pyrimidin—2—yl)amino)cyclopentyl)carbamate (60 mg, 0.105 mmol) and TFA (0.5 mL) in dichloromethane (2 mL) was stirred at room temperature for 90 minutes.

LC-MS ted complete consumption of SM. The reaction mixure was diluted with saturated NaHCO3 and then extracted with dichloromethane. The combined organic layers were dried by NaZSO4, filtered, concentrated to give 2—(((1R,ZS)—2—aminocyclopentyl)amino)—6—(2,6—dichloro— 3,5—dimethoxyphenyl)—8—ethylpyrido[2,3—d]pyrimidin—7(8H)—one which was used without further purification in the next step.

Step 3: Synthesis of N—((lS,2R)—2—((6—(2,6—dichloro—3,5—dimethoxyphenyl)—8—ethyl—7—oxo—7,8— dihydropyrido[2,3—d]pyrimidin—Z—yl)amino)cyclopentyl)acrylamide o/ 0’ CI CI N \ \ 0/ M N \ \ O/ | —> I H HNAN/ N oCI HN N/ N oCI +°r”"€> K ”“6 K \i “1‘ \ 0/ CI HNAN/ N 0c. n = u DIEA,DCM fir [‘0 To a solution of 2-(((1R,2S)aminocyclopentyl)amino)(2,6-dichloro-3,5-dimethoxyphenyl)- 8-ethylpyrido[2,3-d]pyrimidin-7(8H)-one (0.105 mmol) in dichloromethane (2.1 mL) at -20 0C was added DIEA (0.018 mL, 0.105 mmol) and acryloyl de (0.008 mL, 0.105 mmol) and the reaction was stirred for 1h. LC—MS indicated complete ption of SM. The reaction mixure was purified by silica gel tography to yield N—((lS,2R)-2—((6—(2,6—dichloro—3,5— dimethoxyphenyl)—8—ethyl—7—oxo—7,8—dihydropyrido[2,3—d]pyrimidin—Z— yl)amino)cyclopentyl)acrylamide (36 mg, 65 %). MS (ES+) C25H27C12N5O4 requires: 531, found: 532.

Synthetic Protocol 6 0/ 0/ 0/ Cl 2 0 ; Cl CI H00 nucleophilic O NI \C 0/ N \O 0/ substitution reaction N \ 0/ CIAN HNkN/| —> | o | / C CI / 0' nucleophilic aromatic substitution reaction HO ' Na, ' ‘O o 0 O %OH / NI \ o o/ —> HNXN/ CI HATU,D|EA \ H 0' a protecting group o VbO N \ 0/ removal | /Q 0/ —’ Cl HN N Cl H2Nn,© O )L O N \ o/ a HNAN/I o or DIEA, DCM, 0 °C H 5 Ar "0 The 2—Cl heterocycle can be substituted with a 1,2—trans—amino alcohol via various philic aromatic substitution reaction ions using a base (such as diisopropylethylamine (DIPEA), DBU or NaHCO3) in a polar t (such as dioxane, CH3CN or NMP) or via a palladium—mediated Buchwald coupling reaction to provide the substituted quinazoline. The alcohol on the lkane is reacted under nucleophilic substitution reaction conditions (such as Mitusnobu reaction) to afford the protected amine. l of the protecting group on the amine (such as hydrazine for the phthalimide protecting group) afforded the amine on the cycloalkane. The amine can be reacted with propargylic acid (using amide coupling conditions such as HATU, DIPEA) or reacted with acryloyl chloride to e the final compounds. As shown below, Compounds 81 and 82 were prepared using Synthetic Protocol 6.

Compounds 81 and 82 Synthesis of (lS,3S,4R)—3—acrylamido—4—((6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2— yl)amino)—N,N—dimethylcyclopentanecarboxamide and (1R,3S,4R)—3—acrylamido—4—((6—(2,6— dichloro—3,5—dimethoxypheny1)quinazolin—Z—yl)amino)-N,N—dimethy1cyc1opentane— 1 — carboxamide / .

HO 0/ 0/ Cl CI N \ 0/ o o/ )L / Cl A\ g C N DBU CH30N 65°C PPha. D'AD go THF 78°C o a 0 CI NHZNHZ N \ 0/ Boczo, TEA g 0/ N \ NaOH E‘OH J'x / Cl M80” A / C. THF, H20 H” N —> —> CI Cl CI NI \ N\ HCI Dioxane DCM , HATU DIEA QFOH BocHN” BocHN DMF 0227—“\ g“ o o o \ o o/ 0/ CI CI CI CI 0 0 N \ o/ 0 N \ o/ N \ o/ HNA CI AN/I G I 0 I 0| \JLCI\ HN/KN/ CI HE‘XN/ CI H H HMO DIEA,DCM “NI/O WNW ' 00° 0 O O%\/ / -, / / N N N N \ Oi— \ \ Step 1: Synthesis of racemic methyl (3R,4R)—3—((6—(2,6—dichloro—3,5—dimethoxypheny1)— quinazolin—Z—y1)amino)—4—hydroxycyc10pentane— 1 —carb0xy1ate CI Ho‘Q/FO/ CI N \ o A / CI DBU CH3CN 65°C HI}! N Hog / 0/—o 2—chlor0—6—(2,6—dich10r0—3,5—dimethoxyphenyl)quinazoline (0.576 g, 1.558 mmol), methyl (3R,4R)—3—amino—4—hydr0xycyc10pentane—l—carboxylate (0.372 g, 2.337 mmol) were taken up in acetonitrile (3 ml) and DBU (0.470 ml, 3.12 mmol) was added. The reaction was purged with N2 for 5 minutes then heated to 65°C ght. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was purified via flash chromatography (0—100% Hex/EtOAc; 12g column), and (1S,3R,4R)—methyl 3—((6—(2,6—dichloro—3,5— dimethoxyphenyl)quinazolinyl)amino)—4—hydroxycyclopentanecarboxylate (0.520 g, 1.056 mmol, 67.8 % yield) was recovered. MS (ES+) C23H23C12N305 requires: 492, found: 493 [M + H]+.

Step 2: Synthesis of racemic methyl (3R,4S)((6-(2,6-dichloro-3,5- dimethoxyphenyl)quinazolin—2—yl)amino)—4—(1,3—dioxoisoindolin—2—yl)cyclopentane—1— carboxylate go THF, —78 °C Ph3P (0.213 g, 0.812 mmol) was taken up in THF (6 m1) and cooled to —78 °C under N2. DIAD (0.126 ml, 0.650 mmol) was added ed by addition of phthalimide (0.105 g, 0.711 mmol) and stirred at —78 °C for 1 hour, followed by on of (18,3R,4R)—methyl 3—((6—(2,6—dichloro— 3,5—dimethoxyphenyl)quinazolin—2—yl)amino)—4—hydroxycyclopentanecarboxylate (0.100 g, 0.203 mmol) in 4 ml of THF at —78 °C. The reaction was stirred overnight while warming to room temperature, after which the t was removed under reduced pressure. The residue was ed via flash chromatography (0- 100% Hex/EtOAc; 12g column) to afford methyl (3R,4S)— 3—((6—(2,6—dichloro—3,5-dimethoxyphenyl)quinazolin—2—yl)amino)—4—(1,3—dioxoisoindolin—2— yl)cyclopentanecarboxylate(0.126g, 0.203 mmol). MS (ES+) C31H26C12N4O6 requires: 621, found: 622 [M + H]+.

Step 3: Synthesis of racemic methyl (3S,4R)—3—amino—4—((6—(2,6-dichloro—3,5- dimethoxyphenyl)quinazolin—2—yl)amino)cyclopentane—1—carboxylate 0/ 0/ Cl Cl O o/ 0 N \ NHzNHz N \C o/ OHNAN/I EtOH Cl HNAN/| CI N.” H2N '1, O :2] / / o :2 O o o (18,3R,4S)—methyl (2,6-dichloro—3,5—dimethoxyphenyl)quinazolin—2—y1)amino)—4—(1,3— dioxoisoindolinyl)cyclopentanecarboxylate (0.500 g, 0.805 mmol) was taken up in EtOH (20 ml) and hydrazine monohydrate (0.079 ml, 1.61 mmol) was added. The reaction was stirred overnight at room temperature. A white precipitate was ed off and solvent was removed under reduced pressure. The precipitate was triturated with ether, followed by removal of the solvent under reduced pressure to give methyl (3S,4R)—3—amino—4—((6—(2,6—dichloro—3,5— dimethoxyphenyl)quinazolin—Z—yl)amino)cyclopentane—l—carboxylate (0.395 g, 0.805 mmol) in quantative yield, which was carried on without further cation. MS (ES+) C23H24C12N4O4 requires: 491, found: 492 [M + H]+.

Step 4: Synthesis of racemic methyl (3S,4R)—3—((tert—butoxycarbonyl)amino)—4—((6—(2,6—dichloro— methoxyphenyl)quinazolin—2—yl)amino)cyclopentane— 1—carboxylate O/ 0/ CI Cl N \C 0/ Boczo, TEA O 0/ HNAN/| CI MeOH , HNAN/| cu H2N 1,, BocHN 7} .4, O é—o/ O O (3S,4R)—3—amino—4—((6—(2,6—dichloro-3,5—dimethoxypheny1)quinazolin—2—yl)amino)cyclopentane— 1—carboxylate (0.550 g, 1.119 mmol) was taken up in methanol (10 m1) followed by addition of Et3N (0.156 ml, 1.119 mmol) and BOC-Anhydride (0.286 ml, 1.231 mmol). The reaction was d at ambient temperature overnight. After l of the solvent under vacuum, the residue was taken up in DCM and washed with water (2x), dried over sodium sulfate, and the solvent was removed under reduced pressure to give methyl(3S,4R)—3—((tert-butoxycarbonyl)amino)—4— ((6—(2,6—dichloro—3,5—dimethoxyphenyl) quinazolin—2—yl)amino)cyclopentane—1—carboxylate (0.662g, 1.119 mmol), which was carried on without further purification. MS (ES+) C23H32C12N4O6 requires: 591, found: 592 [M + H]+.

Step 5: sis of racemic (3S,4R)((tert—butoxycarbonyl)amino)—4—((6—(2,6—dichloro—3,5— dimethoxyphenyl)quinazolin—2-yl)amino)cyclopentane— 1 —carboxylic acid 0/ 0/ CI CI O 0/ 0 N \O NaOH NI \C o/ HNAN/| Cl —2>THF, H O HNAN/ CI BocHN BocHN .1, .,, ;/—O/ ;*OH O 0 Methyl (3S,4R)—3—((tert—butoxycarbonyl)amino)—4—((6—(2,6—dichloro-3,5—dimethoxyphenyl)— quinazolin—2—yl)amino)cyclopentane—l—carboxylate (0.662g, 1.119 mmol) was taken up in methanol (10ml), THF (4ml) and d with 10ml of 1N NaOH. The reaction mixture was stirred at room temperature for 2 hours. The organic ts were removed under reduced pressure, then the aqueous layer was acidified with 1N HCl to pH ~2. The aqueous layer was extracted with EtOAcx3. The organic layers were combined, dried over sodium sulfate, and the solvent removed to give crude (3S,4R)—3—((tert—butoxycarbonyl)amino)—4—((6—(2,6—dichloro—3,5— dimethoxyphenyl)quinazolin—2—yl)amino)cyclopentane—l—carboxylic acid (0.580 g, 1.00 mmol, 91% yield) which was carried on with r purification. MS (ES+) C12N4O6 requires: 577, found: 578 [M + H]+.

Step 6: Synthesis of tert—butyl ((1S,2R,4S)—2—((6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin— 2—yl)amino)—4—(dimethylcarbamoyl)cyclopentyl)carbamate and tert—butyl ((1S,2R,4R)—2—((6—(2,6— dichloro—3,5—dimethoxyphenyl)quinazolin—2—yl)amino)—4—(dimethylcarbamoyl)cyclopentyl )carbamate i 3 BocHN HATU, DIEA BocHN .,, .,lo .r' / /—OH //—N (3S,4R)—3—((tert—butoxycarbonyl)amino)—4—((6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2— yl)amino)cyclopentane—l—carboxylic acid (0.270g, 0.468 mmol) was taken up in DMF (3ml), HATU (0.267 g, 0.701 mmol), dimethylamine 2M in THF (0.250 ml, 0.500 mmol) and DIEA (0.245 ml, 1.403 mmol) were added and stirred at ambient temperature for 30 minutes. The reaction was complete after monitoring by LCMS, which showed two peaks containing the correct mass. The reaction was purified via reverse phase chromatography (5—60% acetonitrile/water + 0.01% formic acid; 12g column). Peak A: tert-butyl ((1S,2R,4R)((6-(2,6- dichloro-3,5-dimethoxyphenyl)quinazolinyl)amino) (dimethylcarbamoyl)cyclopentyl)carbamate (0.086g, 0.142mmol) MS (ES+) C29H35C12N505 requires: 604, found: 605 [M + H]+, retention time 3.039. Peak B: tert—butyl ((1S,2R,4S)—2—((6— (2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2—yl)amino)—4—(dimethylcarbamoyl )cyclopentyl)carbamate g, 0.103mmol) MS (ES+) C29H35C12N505 requires: 604, found: 605 [M + H]+, retention time 2.879. Note: the absolute configuration was ed arbitrarily.

Step 7a: Synthesis of (lS,3S,4R)—3—amino—4—((6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin— 2—yl)amino)—N,N—dimethylcyclopentane— l —carboxamide / CI HNAN/Pg C' | / CI Dioxane, DCM ”\C HN N BocHNw :' Hwy: :7 N/ '2 / O]— \ orN\ utyl ((lS,2R,4R)—2—((6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—2—yl)amino)—4— (dimethylcarbamoyl)cyclopentyl)carbamate (0.086g, 0.142mmol) was taken up in DCM (2ml) and d with 4M HCl in dioxane(3ml) and stirred for 3 hours. The solvent was removed to give crude (1S,3S,4R)amino((6-(2,6—dichloro—3,5—dimethoxypheny1)quinazolin—2— yl)amino)-N,N-dimethylcyclopentane-l-carboxamide, quantative yield. MS (ES+) C12N503 es: 504, found: 505 [M + H]+, Step 8a: Synthesis of (1R,3S,4R)—3—acrylamido—4—((6—(2,6—dichloro-3,5— dimethoxyphenyl)quinazolin—2—yl)amino)—N,N—dimethylcyclopentane- l—carboxamide CI Cl \ O / N O O N \ O /0 CI VkCI HN N —> HN/kN/| CI HzN” DIEA,DCM H a ,0 Ar 0 .3 O .‘ / / N/ ’ o]— N \ or \ (1S,3S,4R)—3—amino((6-(2,6-dichloro—3,5—dimethoxyphenyl)quinazolin—2—yl)amino)—N,N— dimethylcyclopentanecarboxamide (0.050 g, 0.099 mmol) was taken up in CHZCIZ (25 m1) and cooled to 0 °C, followed by addition of DIEA (0.017 ml, 0.099 mmol) then yl chloride (8.86 ul, 0.109 mmol) slowly. The reaction mixture was stirred at 0 °C for 30 minutes. After the reaction was complete, the reaction mixture was loaded directly onto silica and purified via flash chromatography (0—10% CH2C12/MCOH; 12g column) to afford(lR,3S,4R)—3—acrylamido—4—((6— (2,6—dichloro—3,5—dimethoxyphenyl)quinazolin—Z—y1)amino)—N,N— dimethylcyclopentanecarboxamide (0.043 g, 0.077 mmol, 78 % yield). MS (ES+) C27H29C12N504 es: 558, found: 559 [M + H]+.

Step 7b: sis of (lR,3S,4R)—3—amino—4—((6—(2,6—dichloro—3,5—dimethoxyphenyl)quinazolin— 2—yl)amino)—N,N—dimethylcyclopentane—l—carboxamide o/ O/ C' O 0 O HN N/ Dloxane, DCM HN/kN/ Cl BocHN ,q H2NW g / é / N N O \ \ tert—butyl ((lS,2R,4S)—2—((6—(2,6—dichloro—3,S—dimethoxyphenyl)quinazolin—2—yl)amino)—4— (dimethylcarbamoyl)cyclopentyl)carbamate (0.062g, 0.103mmol) was taken up in DCM (2ml) and treated with 4M HCl in e(3ml) and stirred for 3 hours. The solvent was removed to give crude ,4R)amino((6-(2,6-dichloro-3,5-dimethoxypheny1)quinazolin-Z- yl)amino)-N,N-dimethylcyclopentane-l-carboxamide, quantative yield. MS (ES+) C24H27C12N503 requires: 504, found: 505 [M + H]+.

Step 8b: Synthesis of (lS,3S,4R)—3—acrylamido—4—((6—(2,6—dichloro—3,5— dimethoxyphenyl)quinazolin—Z—yl)amino)—N,N—dimethylcyclopentane— l—carboxamide o 0' N \ O/ O HNAN/I N \ O CI VLCI HNJLN/C CI HQNWCKFN/ Dragon” flag o \ O N\ (1R,3S,4R)—3—amino((6-(2,6-dichloro—3,5—dimethoxyphenyl)quinazolin—2—yl)amino)—N,N— dimethylcyclopentanecarboxamide (0.050 g, 0.099 mmol) was taken up in CHZCIZ (25 m1) and cooled to 0 °C, followed by addition of DIEA (0.017 ml, 0.099 mmol) then yl chloride (8.86 ul, 0.109 mmol) slowly. The reaction mixture was stirred at 0 °C for 30 minutes. After the reaction was complete, it was loaded directly onto silica and purified via flash chromatography (0—10% CH2C12/MCOH; 12g ) to afford (1S,3S,4R)—3—acry1amido—4—((6—(2,6—dichloro—3,5— dimethoxyphenyl)quinazolin—2—yl)amino)—N,N—dimethylcyclopentanecarboxamide (0.029 g, 0.052 mmol, 52.4 % yield). MS (ES+) C27H29C12N5O4 requires: 558, found: 559 [M + H]+.

Pre aration of common intermediates S nthesis of tert—but 1 3R 4S —4—aminotetrah drofuran—3— l carbamate EH2 .

BOCZO, TEA, NHBOC Phthalimide, PPh3, BocHN Hydrazme, EtOH NHBOC (TOH MeOH ? OH DIAD, THF, 0°C E \N 50°C. then 70°C : “(NHZ —~ —» o g (oj O 0 Step 1: Synthesis of tert—butyl ((3S,4R)—4—hydroxytetrahydrofuran—3—yl)carbamate Intermediate (3R,4S)—4—aminotetrahydrofuran—3—ol was prepared as in WO 01/29013 (PCT/US00/28815; pp. 44—45; Example 1). A solution of )—4—aminotetrahydrofuran—3—ol (10.6 g, 103 mmol), triethylamine (26 g, 257 mmol), and BOC anhydride (24.7 g, 113 mmol) in ol (206 mL, 0.5 M) was stirred at room temperature over 45 hours. The solvents were then d under reduced pressure. The beige solid was treated with water (about 120 mL). A white crystalline solid was isolated by filtration and dried ght under vacuum to yield tert- butyl ((3S,4R)hydroxytetrahydrofuranyl)carbamate as a white solid (17.08 g, 82%).

Step 2: Synthesis of tert—butyl ((3R,4S)—4—(1,3—dioxoisoindolin—2—yl)tetrahydrofuran—3— yl)carbamate A mixture of tert—butyl ((3S,4R)—4—hydroxytetrahydrofuran—3—yl)carbamate (15.36 g, 76 mmol), phthalimide (13.34 g, 91 mmol), and triphenylphosphine (23.8 g, 91 mmol) was stirred in THF (378 mL, 0.2 M) at 0°C for 10 minutes before dropwise addition of DIAD (18.34 g, 91 mmol) over 20 minutes. The reaction was stirred about 40 minutes at 0°C. The solvent was removed under reduced pressure, and the crude oil was treated with less than 50 mL of diethyl ether and sonicated. A white precipitate was formed. The solid was isolated by filtration, washed with small s of ether, and dried to yield 10.62 g of white solid. The cooled-down filtrate was refiltered to yield onal 2.54 g of white solid for a total yield of 13.16 g of utyl ((3R,4S)(1,3-dioxoisoindolinyl)tetrahydrofurany1)carbamate.

Step 3: Synthesis of tert—butyl ((3R,4S)—4—aminotetrahydrofuran—3-yl)carbamate Tert—butyl ((3R,4S)—4—(1,3—dioxoisoindolin—2—y1)tetrahydrofuran—3—yl)carbamate (13.08 g, 39.4 mmol) was dissolved into l (98 mL, 0.4 M)). Hydrazine monohydrate (1.97 g, 39.4 mmol) was added, and the reaction was stirred 30 minutes at 50°C and then 2 hours at 75°C. The reaction was then cooled to room temperature and the white solid was removed by filtration. The filtrate was trated down and dried, then treated with ethanol (about 15 mL). onal white solid was removed by filtration, then filtrate was concentrated down and dried to yield tert— butyl ((3R,4S)—4—aminotetrahydrofuran—3—yl)carbamate as a thick, clear oil (8.724 g at 90% purity; 99%).

S nthesis of 3S 4S —4—azidotetrah dro—2H— ran—3—amine 8H2 HEIAOJ< HNJLOJ<O HNJLOJ<O BOCZO, TEA, MSCI, TEA ; NaNg, NaOAc 3 HO ' HO MsO MeOH DCM, 00C WP, 9500 N3,“ 0 —> o —> o —> o HCI in Dioxane —, 0 Step 1: Synthesis of (3R,4R)—4—hydroxytetrahydro—2H—pyran—3—yl)carbamate O J< gHz HNJLO Bocgo, TEA, : HO ' “0 ' U MeOH U (3R,4R)—3—(((S)—1—phenylethyl)amino)tetrahydro—2H—pyran—4—ol (2.0 g, 9.04 mmol) was taken up in methanol (10 ml) followed by addition of Et3N (1.260 ml, 9.04 mmol) and BOC—anhydride (2.308 ml, 9.94 mmol). The reaction mixture was stirred at room temperature overnight. The solvents were then removed in vaccuo and the residue was taken up in DCM (10ml) and hexane (20ml) and heated to 80°C until the solvent level was reduced by half. The reaction mixture was removed from heat and cooled to room temperature while stirring. 5 ml of ether was then added and the reaction was stirred at room temperature for 2 hours. The reaction mixture was filtered to remove the solids, washed with ether and dried to afford tert—butyl ((3R,4R)—4— hydroxytetrahydro—2H—pyran—3—yl)carbamate (1.6 g, 7.36 mmol, 81 % yield) as a white solid.

Step 2: Synthesis of (3R,4R)—3—((tert—butoxycarbony1)amino)tetrahydro—2H—pyran—4—yl methanesulfonate ; MsCl, TEA ; HO M50 DCM, 0°C 0 o Tert—butyl ((3R,4R)—4—hydroxytetrahydro—2H—pyran—3-yl)carbamate (1.6 g, 7.36 mmol) was taken up in CH2C12 (20 ml) and cooled to 0 OC followed by addition of Et3N (1.232 ml, 8.84 mmol). After 5 minutes methanesulfonyl de (0.631 ml, 8.10 mmol) in DCM (5ml) was added se. The reaction mixture was stirred at 0 °C for 30 minutes and allowed to warm to ambient temperature while stirring for 2 hours. The reaction mixture was diluted with water and DCM and the layers were ted. The organic layers were combined and washed with water twice, dried over , and the solvent removed in vacuo. The e was dried under high vacuum overnight to afford recovered (3R,4R)((tert-butoxycarbonyl)amino)tetrahydro-2H— pyran—4—yl methanesulfonate (2.2 g, 7.45 mmol, 100 % yield) as a white solid.

Step 3: sis of tert—butyl ((3S,4S)—4—azidotetrahydro—2H—pyran—3—yl)carbamate Jot J< JOL J< ”E“ O NaN3,NaOAc “'3‘ 0 DMF, 95°C N31- 0 o (3R,4R)—3—((tert—butoxycarbonyl)amino)tetrahydro—2H—pyran—4—yl methanesulfonate (2.2 g, 7.45 mmol), sodium azide (0.968 g, 14.90 mmol) and sodium e (1.222 g, 14.90 mmol) were taken up in DMF (15 ml). The reaction mixture was heated to 95 °C overnight. The reaction mixture was removed from heat and 20ml of water was added and stirred while cooling. The reaction mixture was extracted with EtOAc. The organic layers were combined and washed with water. The organics were dried and solvent removed to give tert—butyl S)—4— azidotetrahydro—2H—pyran—3—yl)carbamate (1.8 g, 7.43 mmol, 100 % yield) as a yellow oil. MS (ES+) C10H18N4O3 requires: 242, found: 265 [M + Na]+.

Step 4: Synthesis of (3S,4S)—4—azidotetrahydro—2H—pyran—3—amine HNJkOJ<o NHz HCI in Dioxane N3 ’1. —> O utyl ((3S,4S)—4—azidotetrahydro—2H—pyran—3—yl)carbamate (1.5 g, 6.19 mmol) was taken up in DCM (5 ml) and 4N HCl dioxane (4.64 ml, 18.57 mmol) added. The reaction e was stirred at room temperature for 2 hours. The solvent was removed to give (3S,4S)—4— azidotetrahydro—2H—pyran—3—amine (1.1 g, 6.16 mmol, 99 % yield) as an HCl salt. MS (ES+) C5H10N4O requires: 142, found: 143 [M + H]+.

S nthesis of 2— trimeth lsil l eth l 18 2R 38 SS —2—aminobic clo 3.1.0 hexan—3— lcarbamate O )L OH OJLNH \/\)OJ\ n-BuLi CH0MgCI2NaSbFe Ci 0‘ (N Grubbsll + \ —> g -, é \_{ C' THF,—78°C TMSCI TEA ’Bn W toluene, RT an [LG/V 0 o 0 O o OTBS OTBS J! OH Ho’lla.

TBSOTf OJLNJI, N EtZZn OJOLNJ, 0\ (N a LiOH, H202 _‘IH DPPA, TEA H —>ON\_.’ ,n —> —H a, CHZI2, DCM a, 26-lutiine, DCM EBn THF, H20 toluene, BnOH Bn Bn . l; H OTBS OH 03 :20 CszN,,' Cbz-HNQ 0 E2, o Pphsx D'ADv to'uene .\\H—> «\H —> CszN N TMSI, CHCI3 HZN, Teoc—OSu _78 oC—RT, OHN Et3N’ dioxane II QflH QuH In.

H g 09:0 NH2 _:N w.NHTeocb. .~‘ NHTeoc,’ QM H EtOH, 75 °C, 0.5 h Q Ii H Step 1: Synthesis of (R)—4—benzyl—3—pent—4—enoyloxazolidin—2—one fr O 0 )L n-BUlL' o N 0 NH + Wm THF, -78 °C a, '1 Bn To a on of (4R)—4—(phenylmethyl)—1,3—oxazolidin—2—one (50 g, 282 mmol) in THF (300 mL) was dropwise added n—BuLi in THF (2.4 M, 176 mL, 423 mmol) under nitrogen at —78°C, and the resulting mixture was stirred at -78°C for lhour. Then enoyl chloride (49 mL, 423 mmol) was dropwise added. After ng at -78°C for another 1 hour, the on mixture was d to warm up to room temperature and d overnight. After diluting with water, the mixture was extracted with ethyl acetate (2 x 400 mL). The combined ethyl acetate extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.

The crude residue was purified by silica gel column chromatography (ethyl acetatezpetroleum ether 2 1 : 10) to afford the title compound (68 g, 93%) as a light yellow oil. MS (ES+) C15H17NO3 requires: 259, found: 260 [M + H]+.

Step 2: Synthesis of (R)—3—((2S,3S,E)-2—allyl—3—hydroxy—5—phenylpent—4—enoyl)—4— benzyloxazolidin—2—one o N CH0II/IgCI2NaSbFe \ 1’ :- TMSCI TEA ’Bn W A mixture of (R)—4—benzyl—3—pent—4—enoyloxazolidin—2—one (50 g, 193 mmol), magnesium chloride (18.3 g, 193 mmol), sodium hexafluorostibate(V) (14.9 g, 58 mmol), triethylamine (80 mL, 579 mmol), )—cinnamaldehyde (30.6 g, 232 mmol) and chlorotrimethylsilane (37.2 mL, 290 mmol) in ethyl acetate (500 mL) was stirred at room temperature for l7hours. The mixture was d with ethyl e and filtered to remove solids. The filtrate was concentrated to small volume, and then diluted with ol (500 mL) and a small amount of ethyl acetate. After treatment with trifluoroacetic acid (3 mL), the resulting solution was stirred at room temperature for 1 h, and then concentrated to dryness under d pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether 2 1 : ) to afford the title compound (60 g,80 %) as a yellow semi—solid. MS (ES+) C24H25NO4 requires: 391, found: 374 [M + H — H20]+.

Step 3: Synthesis of (S)—5—benzyl—1—((1S,2S)—2—hydroxycyclopent—3—enecarbonyl)pyrrolidin—2— 0116 Grubbs II toluene RT COLEJ/BnéH A solution of (R)—3—((2S,3S,E)—2—allyl—3—hydroxy—5—phenylpent—4—enoyl)—4—benzyloxazolidin—2— one (50 g, 128 mmol) and Grubbs 2‘1d generation catalyst (5.4 g, 6.4 mmol) in toluene (300 mL) was degassed with nitrogen three times, and d at room temperature overnight. The reaction e was then concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetatezpetroleum ether 2 l : 4) to afford the title compound (32 g, 87 %) as a dark brown oil, which solidified upon standing. MS (ES+) C17H19NO3 requires: 285, found: 270 [M + H—H20]+.

Step 4: Synthesis of (R)—4-benzyl((1S,2S,3S,5S)—2—hydroxybicyclo[3.1.0]hexane—3— carbonyl)oxazolidinone 6:”J/ 01NJ. OH —>0‘ { "‘H CH2|2 DCM , A solution of (S)—5—benzyl—l—((lS,2S)—2—hydroxycyclopent—3—enecarbonyl)pyrrolidin—2—one (25 g, 87.1 mmol) in dichloromethane (300 mL) was cooled in an ice bath and treated with l M diethylzinc in hexane (435 mL, 435 mmol) by dropwise addition. After stirring at 0 °C for 20 minutes, diiodomethane (69.6 mL, 871 mmol) was added dropwise. The resulting cloudy on was stirred at 0 °C for another 20 minutes, and then allowed to warm up to room temperature. After stirring for 6hours at room temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined c extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness under d pressure. The crude material was purified by silica gel column chromatography (ethyl acetate:petroleum ether 2 l : 4) to afford the title nd (308 mg, 89%) as a light brown Viscous oil. MS (ES+) C17H19NO4 requires: 301, found: 284 [M + H — H20]+.

Step 5: Synthesis of benzyl((1S,2S,3S,5S)—2—(tert—butyldimethylsilyloxy)— bicyclo[3.1.0]hexanecarbonyl)oxazolidin—2—one O 0 JL J/ OH )L J, OTBS TBSOTf 0 N o N ..

\ I “H—> \_/ ,uH a, 2,6-lutiine, DCIVI $8” Bn . 5 g H To a stirred solution of (R)—4—benzyl—3—((lS,2S,3S,5S)—2—hydroxybicyclo[3.l.0]hexane—3— carbonyl)oxazolidin—2—one (25 g, 83 mmol) and 2,6—lutidine (38.2 mL, 332 mmol) in dichloromethane (300 mL) was added tert—butyldimethylsilyl trifluoromethanesulfonate (47.6 mL, 207.5 mmol) at 0 °C under nitrogen. The resulting mixture was stirred at 0 °C for 30 minutes and then room temperature for lhour. After diluted with methanol (25 mL), the mixture was poured into water and extracted with ether (2 x 400 mL). The combined ether extracts were washed with brine, dried over sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (ethyl acetatezpetroleum ether = 1 : 8) to afford the title compound (29 g, 86 %) as a colorless oil. MS (ES+) C23H33NO4Si es: 415, found: 416 [M + H - H20]+.

Step 6: sis of (lS,2S,3S,5S)—2—(tert—butyldimethylsilyloxy)bicyclo[3.1.0]hexane—3— carboxylic acid 0 O JL J/ HOJL O N I" '.

\ , LIOH, H202 .\\H 'an THF,H20 : ~‘ H To a solution of (R)—4—benzyl—3—((lS,2S,3S,5S)—2—(tert—butyldimethylsilyloxy)bicyclo[3.1.0] hexane—3—carbonyl)oxazolidin—2—one (40 g, 96.4 mmol) in THF (200 mL) and water (50 mL) was added 30% aqueous hydrogen peroxide (88 mL, 771 mmol) dropwise at 0 OC, followed by the addition of a on of lithium hydroxide monohydrate (16 g, 386 mmol) in water (100 mL).

After stirring for lhour at 0°C, the reaction mixture was stirred at room temperature overnight.

The excess hydrogen peroxide was completely consumed by the on of saturated aqueous sodium bisulfate. The mixture was then ed to pH = 14 with l N NaOH and washed with ether (400 mL). The s layer was then acidified to pH = 3 with l M aqueous potassium hydrogen sulfate, and ted with ethyl acetate (3 x 400 mL). The ed organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the title compound (22 g, 88 %) as a colorless oil.

Step 7: Synthesis of benzyl (1S,2S,3S,5S)—2—(tert—butyldimethylsilyloxy)bicyclo[3.1.0]hexan—3— ylcarbamate J1, OTBS OTBS HO CszN’ . DPPA, TEA ,, ,le —> ,,\H toluene, BnOH I-l H To a solution of (1S,2S,3S,5S)(tert—butyldimethylsilyloxy)bicyclo[3.1.0]hexane—3—carboxylic acid (4 g, 15.625 mmol), triethylamine (22 mL, 156 mmol) and benzyl alchol (17 mL, 156 mmol) in toluene (50 mL) at room temperature was added diphenyl phosphoryl azide (33.7 mL, 156 mmol) dropwise, and the resulting mixture was stirred at 100 OC ght. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL) and washed with water (3 X 50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, ed and concentrated to afford a crude product, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether 2 1 : 8) to afford the title compound (3.0 g, 54%) as a white solid. MS (ES+) C20H31NO3Si requires: 361, found: 362 [M + H]+.

Step 8: Synthesis of benzyl (lS,2S,3S,5S)—2—hydroxybicyclo[3.1.0]hexan—3—ylcarbamate OTBS OH CszN, Cbz-HN, '-QflH—>TBAF '- .\\ H q a To a solution of benzyl ,3S,5S)—2—(tert—butyldimethylsilyloxy)bicyclo[3.1.0]hexan—3— ylcarbamate (2.0 g, 5.540 mmol) in THF (20) at room temperature was added 1 M tetrabutylammonium fluoride in THF (55 mL, 55.4 mmol), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate (100 mL), and washed with water (3 X 50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to afford the title compound (1.2 g, 92 %) as a white solid. MS (ES+) N03 requires: 247, found: 230 [M + H - H20]+.

Step 9: Synthesis of benzyl ,3S,5S)(1,3-diox0isoindolinyl)bicyclo[3.1.0]hexan ylcarbamate Cbz-HN,’Q‘H PPh3, DIAD, toluene o 0 u‘ —> N -78°C-RT,O.N. Cmeo. =‘ i (A..\H H A solution of triphenylphosphine (6.4 g, 24.292 mmol), phthalimide (6.2 g, 42.511 mmol) and benzyl (1S,2S,3S,SS)hydroxybicyclo[3.1.0]hexanylcarbamate (3.0 g, 12.146 mmol) in toluene (250 mL) was stirred at -78 0C for 30 s under nitrogen protection, followed by the addition of diisopropyl azodicarboxylate (8.6 mL, 42.511 mmol) dropwise. The resulting mixture was stirred at —78 0C for r 1 hour and then at room temperature overnight. The reaction mixture was treated with 10 mL of methanol, and the solvents were d under reduced pressure. The crude material was purified by silica gel column chromatography (ethyl acetatezpetroleum ether 2 l : 2) to afford the title compound (3.0 g, 65 %) as a light yellow oil.

MS (ES+) C22H20N204 requires: 376, found: 399 [M + 23]+.

Step 10: Synthesis of 2—((lS,2R,3S,5S)—3—aminobicyclo[3. 1.0]hexan—2—yl)isoindoline—1,3—dione O N N D CszN” , HCI3 HZN, : : —> ., Q“ Q“ q H To a solution of benzyl (1S,2R,3S,5S)—2—(1,3—dioxoisoindolin—2—yl)bicyclo[3.1.0]hexan—3— ylcarbamate (4.0 g, 10.638 mmol) in chloroform (30 mL) at room temperature was added hylsilyl iodide (14.6 mL, 106.380 mmol) dropwise, and the resulting mixture was stirred at room temperaturefor 1hour. The reaction was quenched with methanol (5 mL), diluted with ethyl acetate (150 mL), and washed with water (3 x 50 mL) and brine (50 mL). The c layer was dried over sodium sulfate, filtered and concentrated to afford a crude compound, which was directly used in the next reaction without further purification. MS (ES+) C14H14N202 requires: 242, found: 243 [M + H]+.

Step 11: Synthesis of 2—(trimethylsilyl)ethyl (1S,2R,3S,5S)—2—(1,3—dioxoisoindolin—2— yl)bicyclo[3. l .0]hexan—3—ylcarbamate I“ o 0 HZN, 5 Teoc-OSu NHTeoc, .~ I. ‘ QM —> a Et3N, dioxane QnH s S s H H A solution of 2—((lS,2R,3S,5S)—3—aminobicyclo[3.1.0]hexan—2-yl)isoindoline-1,3-dione (2.0 g, 8.264 mmol), oxopyrrolidin—1—yl 2—(trimethylsilyl)ethyl carbonate (3.2 g, 12.396 mmol) and triethylamine (3.4 mL, 24.792 mmol) in dioxane/water (100 mL, V/V = 1/ 1) was stirred at room temperature for l.5hours. The reaction mixture was then diluted with ethyl acetate (100 mL), washed by l M hydrochloric acid (2 x 50 mL), saturated sodium bicarbonate solution (2 x 50 mL) and brine (50 mL). The organic layer was trated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetatezpetroleum ether 2 l : 4) to afford the title compound (2.5 g, 78 %) as a yellow oil. MS (ES+) C20H26N204Si requires: 386, found: 410 [M + 23]+.

Step 12: Synthesis of 2—(trimethylsilyl)ethyl (lS,2R,3S,5S)—2—aminobicyclo[3.l.0]hexan—3— ylcarbamate 05 i O NHTeoc,‘ _:N Hydrazine NHTeocQ QM EtOH, 75 00, 0.5 h Q“ I; H To a on of 2-(trimethylsilyl)ethyl ,3S,5S)(1,3-dioxoisoindolin yl)bicyclo[3.1.0]hexanylcarbamate (1.5 g, 3.886 mmol) in ethanol (20 mL) at room temperature was added hydrazine (1.9 ml, 38.860 mmol), and the resulting mixture was stirred at 75 0C for 2hours. The reaction solution was trated, and the residue was purified by silica gel column chromatography (ethyl acetate2petroleum ether 2 l : 4) to afford the title compound (800 mg, 80 %) as a light yellow semi—solid.

S nthesis of cis—tert—but l—3—h drox —l l—dioxohexah thio ran—4— lcarbamate O O /S / / 9 SOCI2,MeOH o Boc20 Et3N WLO/ mchA OH 053 —> 0/ ”“2 2 CH2C'2 NHBoc NHBoc Q‘s’p O“ NHQOHHCI Q‘s” Q‘s”0 " KHMDS NazCOgH20 Reny-Ni H2 —> —>HO / THF 78°C 050°C 4h N MeOH THF RT HzN 2 NHBoc NHBoc NHBoc NHBoc Low-polar compound olar compound racemic racemic Step 1: Synthesis of (S)—methyl 2—amino—4—(methylthio)butanoate /s\/\HKOH S SOClz, MeOH / Mo/ To a flame dried flask under nitrogen was added methanol (60 mL). The stirred solution was cooled to 0 °C before thionyl chloride (7.32 mL, 100.34 mmol) was added dropwise. The solution was stirred at 0 °C for 10 min before methionine (10 g, 33.8 mmol) was added in one portion. The reaction was d at room temperature overnight after which time the volatiles were removed under reduced pressure to give the title compound as a yellowish solid.

Step 2: Synthesis of (S)—methyl 2—(tert-butoxycarbonylamino)—4—(methylthio)butanoate / MO/ 30020, Et3N NH2 /S\/\Hko/ CHZCIZ NHBoc To a solution of thyl 2-amino(methylthio)butanoate in dichloromethane (300 mL) at 0 °C was added triethylamine (35 mL), followed by the addition of di—tert-butyl dicarbonate (26.98 g, 125 mmol). After ng at room temperature for 3 h, the reaction mixture was d with dichloromethane (200 mL) and washed with water (2* 150 mL). The combined organic layers were dried (magnesium sulfate), filtered and concentrated under reduced pressure. The product (Rf = 0.5, ethyl acetatezpetroleum ether, 1:4) was purified by flash column chromatography to afford the title compound (15g, 85% yield) as a clear oil.

Step 3: Synthesis of (S)—methyl 2—(tert—butoxycarbonylamino)—4—(methylsulfonyl)butanoate o o o )k / —>mCPBA OjSMO/ NHBoc DCM NHBoc N-(tert-Butoxycarbonyl)-L-methionine methyl ester (8.76 g, 33.3 mmol) was added to a 1000 mL round bottom flask and dissolved in dichloromethane (150 mL). The stirred solution was cooled to 0 °C, followed by the addition of 3—chloroperoxybenzoic acid (70%, 18.0 g, 7.32 mmol) in 30 mL of dichloromethane over a period of 5 min. The reaction e was stirred at room temperature for l.5hours at which time it was diluted with dichloromethane (200 mL) and sodium en carbonate (300 mL of a saturated aqueous solution). The organic layer was separated, washed successively with sodium hydrogen carbonate (2 * 300 mL of a saturated aqueous solution), dried (magnesium sulfate), filtered, and concentrated under d pressure.

The product was purified by flash column chromatography (ethyl acetatezpetroleum ether, 6:4) to afford the title compound (5 g, 51% yield) as a yellow solid.

Step 4: Synthesis of tert—butyl (l,l—dioxido—3—oxotetrahydro—2H—thiopyran—4—yl)carbamate \‘S// O O osng KHMDS / 0/ —> THE-78°C Oi? NHBoc NHBoc A solution of thyl 2—(tert-butoxycarbonylamino)—4—(methylsulfonyl)butanoate (2 g, 6.78 mmol) in tetrahydrofuran (50 mL) was cooled to —78 0C, to which potassium bis(trimethylsily)amide (1.0 M, toluene on, 15 ml) was added dropwise, and the mixture was stirred at -78 0C for 2hours and at room temperature for another 2hours. An s solution of ammonium chloride (1 M) was added, and the mixture was stirred. The reaction mixture was subjected to liquid separation. The resultant organic layer was then washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the formed solid was collected by filtration to obtain the title compound. The water layer separated previously was extracted twice with ethyl acetate. The resultant organic layers were combined, washed with water and brine, and dried over anhydrous magnesium sulfate. The ethyl acetate extracts were combined, dried and then concentrated under reduced pressure to obtain the title compound. The combined product was purified by flash column chromatography (ethyl acetate:petroleum ether, 3:1) to afford the title compound (55 mg, yield 22%) as a yellow solid.

Step 5: sis of (Z)-tert-butyl (3-(hydroxyimino)-1,1-dioxidotetrahydro-2H—thiopyran yl)carbamate OMO ON? 8 NHZOHHCI 8 Na CO H O AHO / O 50 °C, 4 h N NHBOC NHBOC Hydroxylamine hydrochloride (26 mg, 0.379 mmol) was added to a e of compound 5 (50 mg, 0.189 mmol) and sodium carbonate (64 mg, 0.757 mmol) in water (5 mL). After stirred at 50 0C for 4 h, the reaction e was cooled to RT and filtered to get the title compound (50 mg, 95% yield) as a white solid. MS (ES+) C10H18N205S requires: 278, found: 179 [M + H — lOO]+, 223 [M + H — 56]+.

Step 6: Synthesis of rt—butyl—3—hydroxy—1,1—dioxohexahydro—l—thiopyran—4—ylcarbamate Reny--Ni H2 E34} H2”NEE MeOH THF RT H2N NHBoc NHBoc NHBoc lar nd High-polar compound racemic racemic A mixture of compound (Z)-tert-butyl (3—(hydroxyimino)—1,1—dioxidotetrahydro—2H—thiopyran—4— yl)carbamate (2.5 g, 7.6mmol) and Raney-Nickel (excessive amount) in methanol (200 mL) and THF (200 mL) was stirred at room temperature under hydrogen balloon for 24hours. The mixture was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (methanol:dichloromethane, 1:2) to afford a low—polar compound racemic mixture (400 mg, 16% yield) and a high—polar compound (600 mg, 25% yield).

Step 7: Synthesis of (3R,4S)—tert—butyl 3—amino—4—(benzyloxycarbonylamino)piperidine—1— carboxylate and (3S,4R)—tert—butyl 3—amino—4—(benzyloxycarbonylamino)piperidine—1— carboxylate NH2 NHCbz NHCbz NHCbz HO ' HO MsO : CbZOSU U 3 MsCI Et3N NaN3 ~ N DCM RT O/N DCM 0°C 2h ‘0 DMSO 90 00 DIN N Boc Boc Boc Boc NHCbz NHCbz NHCbz PPh3 H2 '0[\1, NH2 +©’ 2 chiral-HPLC THF/H20 70 °C 2 h Boc BOC Boc Step 8: Synthesis of trans—tert—butyl 4—(benzyloxycarbonylamino)—3—hydroxypiperidine—1— carboxylate lngz NHCbz HO ' : U HO CszSu —> U N DCM, RT, O/N N Boo Boo To a stirred mixture of trans—tert—butyl 4—amino—3—hydroxypiperidine—1—carboxylate (1.05 g, 4.86 mmol) in 80 mL of dichloromethane was added triethyl amine (5.89 g, 5.83 mmol), ed by the addition of N—(benzyloxycarbonyloxy)succinimide (1.27 g, 5.10 mmol) at 0 0C. The reaction was stirred at room temperature for s and then diluted with 100 mL of dichloromethane.

The solution mixture was washed with 5% citric acid solution (2 X 100 mL), 5% ium carbonate solution (2 X 100 mL) and brine (200 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, ed by concentration under reduced pressure. The resultant oily matter was purified by silica gel column chromatography (ethyl acetate : petroleum ether 2 1:4~1:2) to afford the title compound (1.7 g, ~100%, crude) as a colorless oil. MS (ES+) C18H26N205 requires: 350, found: 251 [M + H — 100]+.

Step 9: Synthesis of trans—tert—butyl 4—(benzyloxycarbonylamino)—3—(methylsulfonyloxy)— piperidine— 1 —carboxylate NHCbz NHCbz HO MsO ' U MsCl, EN 0 —> N DCM, o 0c, 2 h N Boo Boo To a solution of trans-tert-butyl 4-(benzyloxycarbonylamino)hydroxypiperidine ylate (5.0 g, 14.3 mmol) and triethylamine (4.5 g, 43.0 mmol) in dichloromethane (100 mL) was added methanesulfonyl chloride (4.9 g, 43.0 mmol) at 0 0C, and the mixture was stirred at 0 0C for 2hours. The solution was washed with water (150 mL X 3) and brine, dried over ous sodium sulfate and filtered, followed by concentration under reduced pressure to give the title compound (6.0 g, crude) as a yellow oil. MS (ES+) C19H28N207S requires: 428, found: 329 [M + H .

Step 10: sis of trans—tert—butyl o—4—(benzyloxycarbonylamino)piperidine—1— carboxylate NHCbz NHCbz MsO T N DMSO, 90 °C, O/N N Boo 800 To a solution of trans—tert—butyl 4—(benzyloxycarbonylamino)—3—(methylsulfonyloxy)piperidine— l—carboxylate (6.0 g, 14 mmol) in dimethyl ide (40 mL) was added sodium azide (9.11 g, 140 mmol), and the reaction mixture was stirred at 90 0C overnight under N2. The solution mixture was cooled to ~30 OC, diluted with ethyl acetate (~300 mL), and washed with water (700 mL X 3) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to the title compound (3.8 g, 72%) as a yellow oil. MS (ES+) C18H25N5O4 requires: 375, found: 276 [M + H - 100]+, 373 [M + Na]+.

Step 11: Synthesis of (3R,4S)—tert—buty1 3—amino—4—(benzyloxycarbonylamino)piperidine—l— carboxylate and (3S,4R)—tert—butyl 3—amino—4—(benzyloxycarbonylamino)piperidine—1— carboxylate NHCbz NHCbz NHCbZ NHCbz NI, HN,, NH 3 O NH 2 O ‘ 2 +(1lj’ 2 PPh3 chiral-HPLC N 0 Boc Boc Boc 70 cc, 2 h A mixture of crude trans—tert-butyl 3-azid0—4—(benzyloxycarbonylamino)piperidine—l— carboxylate (12 g, ~32 mmol) and triphenylphosphine (41.9 g, 160 mmol) in THF (100 mL) and water (5 mL) was stirred at 70 0C for 2hours. The reaction mixture was cooled to room temperature and d with ethyl acetate (500 mL). The organic layer was washed with brine (50 mL) and directly evaporated under d pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2 4/1~1:1) to afford trans—tert—butyl 3— amino—4—(benzyloxycarbonylamino)piperidine—l—carboxylate (5.0 g, 44%) as a yellow oil. MS (ES+) C13H27N3O4 requires: 349, found: 350 [M + H]+. 2 g of the above racemic sample was separated by Chiral—HPLC to afford )—tert—butyl 3— 4—(benzyloxycarbonylamino)piperidine—l—carboxylate (550 mg, peak 1 in chiral—HPLC) and (3S,4R)—tert—butyl 3—amino—4—(benzyloxycarbonylamino)piperidine—l—carboxylate (620 mg, peak 2 in chiral—HPLC).

S nthesis of cis—tert—but l—4—amino—3— 2— trimeth lsil lethox carbon lamino i eridine—l— carboxylate NH2 NHCbz NHCbz NHCbz HO ' ‘ = U HO MsO N , CszSu MsCl E13N NaN3 3 ~ pph3 —> —> N DCM. RT, O/N \(j DCM 0°C 2h N DMSO, 90 00, DIN N THF/H2O BOC Boc Boc Boc 70 0C, 2 h gHCbZ H NHCbz H NH2 H N2 ' Teoc-OSu EtsN \ /\/0 N,‘ PdIC H2 No N, /8[ \Ir —>/Si \n/ N dioxane/H20 /| O IPA RT O/N I O N N Boc RT 4 h Boc Boc Step 1: Synthesis of trans—tert—butyl 4—(benzyloxycarbonylamino)—3—hydroxypiperidine—1— carboxylate EH2 NHCbz HO ' HO - U CszSu —> U N DCM, RT, O/N N Boo Boo To a stirred mixture of trans—tert-butyl o—3—hydroxypiperidine—1—carboxy1ate (1.05 g, 4.86 mmol) in 80 mL of romethane was added triethylamine (5.89 g, 5.83 mmol), followed by the addition of zyloxycarbonyloxy)succinimide (1.27 g, 5.10 mmol) at 0 OC. The reaction mixture was stirred at room temperature for 16 hours and then diluted with 100 mL of dichloromethane. The solution mixture was washed with 5% citric acid solution (2 x 100 mL), % potassium carbonate solution (2 x 100 mL) and brine (200 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, followed by concentration under reduced pressure.

The resultant oily matter was ed by silica gel column tography (ethyl acetate : petroleum ether 2 1:4~1:2) to afford the title compound (1.7 g, ~100%, crude) as a colorless oil.

MS (ES+) C13H26N205 requires: 350, found: 251 [M + H — 100]+.

Step 2: Synthesis of trans—tert—butyl 4—(benzyloxycarbonylamino)—3— (methylsulfonyloxy)piperidine— 1 —carboxy1ate NHCbz NHCbz HO MsO ' U MsCl, Et3N —> U N DCM, 0 OC, 2 h N Boo Boo To a on of trans—tert—butyl 4—(benzyloxycarbonylamino)—3—hydroxypiperidine—1— carboxylate (5.0 g, 14.3 mmol) and triethylamine (4.5 g, 43.0 mmol) in dichloromethane (100 mL) was added methanesulfonyl chloride (4.9 g, 43.0 mmol) at 0 0C, and the mixture was stirred at 0 0C for 2hours. The solution was washed with water (150 mL x 3) and brine, dried over anhydrous sodium sulfate and ed, followed by concentration under reduced pressure to give the title compound (6.0 g, crude) as a yellow oil. MS (ES+) C19H23N207S requires: 428, found: 329 [M + H -100]+.

Step 3: Synthesis of cis—tert—butyl 3—azido—4—(benzyloxycarbonylamino)piperidine—l—carboxylate NHCbz NHCbz M300 N3," NaN3 DMSO 90 00, ON N Boo Boo To a on of trans—tert—butyl 4-(benzyloxycarbonylamino)—3—(methylsulfonyloxy)piperidine— 1—carboxylate (6.0 g, 14 mmol) in dimethyl sulfoxide (40 mL) was added sodium azide (9.11 g, 140 mmol), and the reaction e was stirred at 90 OC overnight under N2. The solution mixture was cooled to ~30 OC, diluted with ethyl acetate (~300 mL), and washed with water (700 mL X 3) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to the title compound (3.8 g, 72%) as a yellow oil. MS (ES+) C13H25N504 requires: 375, found: 276 [M + H — 100]+, 373 [M + Na]+.

Step 4: Synthesis of cis—tert—butyl 3—amino—4—(benzyloxycarbonylamino)piperidine—l—carboxylate and (3S,4R)—tert—butyl o—4—(benzyloxycarbonylamino)piperidine—l—carboxylate NHCbz NHCbz N3“O—>PPh3 H2N’- THF/H20 N 800 Boc 70 cc, 2 h A e of crude cis—tert—butyl 3—azido—4—(benzyloxycarbonylamino)piperidine—l—carboxylate (12 g, ~32 mmol) and triphenylphosphine (41.9 g, 160 mmol) in THF (100 mL) and water (5 mL) was stirred at 70 0C for 2hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (500 mL). The organic layer was washed with brine (50 mL) and directly evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2 4/l~ l : l) to afford the title compound (racemate, 5.0 g, 44%) as a yellow oil. MS (ES+) C13H27N304 requires: 349, found: 350 [M + H]+.

Step 5: sis of cis-tert-butyl 4-(benzyloxycarbonylamino)((2-(trimethylsilyl)ethoxy)- carbonylamino)piperidine—l—carboxylate NHCbz NHCbZ —’Teoc-OSu Et3N dioxane/HZO \SIi/\/O\n/HlIO Boc RT 4 h Boc A solution of cis—tert—butyl 3—amino-4—(benzyloxycarbonylamino)piperidine—l—carboxylate (3.0 g, 8.6 mmol), oxopyrrolidinyl 2—(trimethylsilyl)ethyl carbonate (2.5 g, 9.5 mmol) and triethylamine in dioxane/water(40 mL, v/v = 1/ 1) was stirred at room temperature for 4hours.

After that, the solution was diluted with ethyl acetate (200 mL), and washed by 1 M hydrochloric acid (50 mL), saturated sodium bicarbonate solution (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl e 2 4/ 1) to afford the title compound (3.5 g, 83%) as a white solid. MS (ES+) C24H39N3O6Si requires: 493, found: 516 [M + 23]+.

Step 6: Synthesis of cis—tert—butyl 4—amino—3—((2—(trimethylsilyl)ethoxy)— carbonylamino)piperidine—l—carboxylate NHCbz H NH2 o ' H \ ./\/ 1,, - /S' T I PMS—H2- N N IPA, RT, O/N /I O Boo N A mixture of cis—tert—butyl 4—(benzyloxycarbonylamino)—3—((2— thylsilyl)ethoxy)carbonylamino)piperidine—l—carboxylate (1.8 g, 3.6 mmol) and 10% palladium on carbon (180 mg) in panol (60 mL) was stirred under 1 atm hydrogen atmosphere (hydrogen balloon) at room temperature for 3hours. After that, the mixture was filtered through a pad of celite. The filtrate was concentrated and purified by silica gel column chromatography (methanol/dichloromethane = 1/30 to 1/10) to afford the title compound (800 mg, 61%) as a yellow oil. MS (ES+) C16H33N3O4Si requires: 359, found: 360 [M + H]+.

Synthesis of Racemate-ethyl 4-aminogtert-butoxycarbonylamino )cyclohexanecarboxylate NHBoc I2 KI NaHCOs film 2 N-NaOH NaNs NH4C| 5"“;H2 Pd/C ; DCM H20 (0 EtOH g Bocz—>OEtOAc _ : OAOH 0A0 0A0 o/‘o K K K (from te) QMs NHBoc NHBoc ' NHBoc “(NHZ MsCI, Eth, CHZCI2 NaN3 DMSO PdiC H2 0 —. ; /'\ ' 0 O O O/i\0 K r Step 1: sis of Racemate—4—iodo—6—oxa—bicyclo[3.2.1]octan-7—one I2, KI, NaH003 DCM, H20 (VD-no( OAOH (from racemate) To a mixture of cyclohex—3—enecarboxylic acid (racemate, 42.0 g, 333 mmol), potassium iodide (72.0 g, 433 mmol) and sodium hydrogencarbonate (36.4 g, 433 mmol) in methylene chloride (750 mL) and water (750 mL) was added iodine (110.0 g, 433 mmol) at an internal temperature of 5 0C, and the reaction mixture was stirred at room temperature for 3hours. After quenched with l N aqueous sodium thiosulfate (1500 mL), the resulting mixture was extracted with methylene chloride (1000 mL X 2). The combined organic layers were washed with aqueous sodium hydrogencarbonate (1000 mL), water (2000 mL) and brine (1000 mL), dried over anhydrous magnesium e, filtered, then concentrated under d pressure. The precipitated crystals were collected by tion and washed with hexane, followed by drying, to thereby give the title compound (80.2 g, 95%) as a white solid.

Step 2: Synthesis of Racemate-ethyl 7-oxa-bicyclo[4.1.0]heptanecarboxylate I .\\Q ('j-uo 2 N—NaOH EtOH ., ( To a suspension of Racemateiodo—6—oxa—bicyclo[3.2.1]octan—7—one (45.0 g, 180 mmol) in ethanol (400 mL) was added 2 N aqueous sodium hydroxide (110 mL, 220 mmol) at room temperature while being stirred, and the resulting mixture was d for 3hours. The reaction e was concentrated in a bath at a temperature of 35 0C under d pressure. Water (500 mL) was added to the resultant oily , and the resulting mixture was extracted with ethyl acetate (500 mL). The organic layer was washed with water (500 mL), dried over anhydrous sodium sulfate, filtered and followed by concentration under reduced pressure. The resultant oily matter was ed by silica gel column chromatography (ethyl acetate:petroleum ether 2 1:10 ~ 1:5), to thereby give the tile compound (15.9 g, 52%) as a pale yellow oil.

Step 3: sis of Racemate—ethyl 3—azido—4—hydroxycyclohexanecarboxylate \9 9H 0: . N3 NaN3, NH4C| 0’ i DMF 0%0 0A0 K K A mixture of Racemate—ethyl 7—oxa—bicyclo[4.l.0]heptane—3-carboxylate (24.0 g, 140 mmol), ammonium chloride (13.6 g, 210 mmol) and sodium azide (13.7 g, 210 mmol) in N,N— dimethylformamide (120 mL) was stirred at 76 0C for s. After any insoluble matter was collected by filtration, the filtrate was concentrated under reduced pressure while not allowing the solvent to evaporate to dryness. The residue was combined with the solid matter collected by the previous filtration, and the thus-obtained mixture was dissolved in water (500 mL). The solution was extracted with ethyl acetate (500 mL). The extract was washed with water (500 mL x 5) and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the tile compound (28 g, crude) as an yellow oil. MS (ES+) C9H15N3O3 requires: 213, found: 214 [M + H]+, 236 [M + Na]+.

Step 4: Synthesis of Racemate—ethyl 3—(tert—butoxycarbonylamino)—4— ycyclohexanecarboxylate O’NB—’ NHBoc H2 Pd/C Boc20 EtOAc 5 o/:\oK O’:\OK A mixture of Racemate-ethyl 3-azidohydroxycyclohexanecarboxylate (14.0 g, 66 mmol), di- tert—butyldicarbonate (18.5 g, 85 mmol) and 5% palladium on carbon (50% wet, 2.5 g) in ethyl acetate (300 mL) was d at room temperature overnight at a hydrogen pressure of ~1 atm.

After the reaction mixture was ed, the filtrate was concentrated, and the thus—obtained oily matter was purified by silica gel column chromatography (petroleum ether:ethyl acetate 2 4: l— 3: l). The thus—obtained compound was crystallized from hexane to thereby give the title compound (12.0 g, 62%) as a white solid. MS (ES+) C14H25N05 requires: 287, found: 188 [M + H - 100]+.

Step 5: Synthesis of Racemate—ethyl 3—(tert—butoxycarbonylamino)—4—(methylsulfonyloxy) cyclohexanecarboxylate 0’NHBoc NHBoc MsCI Et3N CHZCIZ 0A0 0A0 K K To a solution of Racemate -ethyl 3-(tert—butoxycarbonylamino)—4— hydroxycyclohexanecarboxylate (12.0 g, 42 mmol) and triethylamine (12.7 g, 126 mmol) in dichloromethane (150 mL) was added methanesulfonyl chloride (9.5 g, 84 mmol) dropwise at 0 °C, and the mixture was stirred at 0 0C for 3hours. The solution was washed with water (100 mL x 3) and brine, dried over anhydrous sodium e, filtered and concentrated to afford the title compound (15 g, crude) as a yellow oil. MS (ES+) NO7S requires: 365, found: 266 [M + H — 100]+.

Step 6: Synthesis of Racemate—ethyl o—3—(tert—butoxycarbonylamino)— cyclohexanecarboxylate ? N3 ””300 NHBoc NaN3, DMSO : —> O 0 /2 K K To a solution of Racemate-ethyl 3-(tert-butoxycarbonylamino)(methylsulfonyloxy) cyclohexanecarboxylate (11.0 g, 30 mmol) in dimethyl sulfoxide (110 mL) was added sodium azide (20 g, 300 mmol), and the mixture was stirred at 90 OC overnight under N2. The solution was cooled to ~30 0C, dissolved in ethyl acetate (~500 mL), washed with water (500 mL X 5) and brine, dried over ous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column tography (petroleum ether:ethyl acetate 2 4: l~2: l) to thereby give the title compound (4.1 g, 44%) as an colorless oil. MS (ES+) C14H24N4O4 requires: 312, found: 213 [M + H -100]+.

Step 7: Synthesis of Racemate—ethyl 4—amino—3—(tert—butoxycarbonylamino)— cyclohexanecarboxylate NHBoc N3 ; NHBoc n‘NHZ Pd/C H2 0 é o 0A0 r A mixture of te-ethyl 4-azido(tert-butoxycarbonylamino)cyclohexanecarboxylate (14.0 g, 66 mmol) and 5% palladium on carbon (50% wet, 1.0 g) in ethyl acetate (100 mL) was stirred at room ature overnight at a hydrogen pressure of ~1 atm. After the reaction mixture was filtered, the filtrate was concentrated. The resulting oily residue was purified by silica gel column chromatography (petroleum ethyl acetate 2 4: l~l:l) to thereby give the title compound (2.0 g, 59%) as a yellow solid.

S s of Racemate—4—amino—3— 6— 2 6—dichloro—3 5—dimethox hen l uinazolin—2— ylamino )cyclohexanecarboxamide OH OH NH2 ~“NHg NHCbz \NHCbz MNHCbz H2Pd/C CszSu £thI) MsCl DCM é; PPh3 EtOAc ii) NaN3 DMF o o o 0 K K 5 K racemate NHTeoc NHTeoc : ; “\NHCbz _“NH2 TEA, TeocOSu Pd/C, H2 dioxane/HZO IPA, RT 0 O o 0 K K racemate Step 1: Synthesis of Racemate—ethyl 3—amino—4—hydroxycyclohexanecarboxylate OH OH ‘\\N3 ,\\NH2 Pd/C, H2 EtOAc 0 OK 0 OK racemate A suspension mixture of Racemate—ethyl 3—azido—4—hydroxycyclohexanecarboxylate (8.0 g, 37.5 mmol) and 5% palladium on carbon (50% wet, 2.0 g) in ethyl acetate (250 mL) was d under hydrogen atmosphere (~1 atm) at room ature overnight. After the reaction mixture was filtered, the filtrate was concentrated to y give the title compound (5.8 g, 83%) as a yellow solid. MS (ES+) C9H17N03 requires: 187, found: 188 [M + H]+.

Step 2: Synthesis of Racemate-ethyl 3-(benzyloxycarbonylamino) hydroxycyclohexanecarboxylate OH OH “\NHZ Z O O O O K K To a stirred mixture of Racemate-ethyl 3—amino—4—hydroxycyclohexanecarboxylate (4.7 g, 25 mmol) in 120 mL of dichloromethane was added triethylamine (3.03 g, 30 mmol), ed by the addition of N-(benzyloxycarbonyloxy)succinimide (6.55 g, 26.3 mmol) at 0 OC. The reaction mixture was stirred at room temperature for s and then diluted with 200 mL of dichloromethane. The solution was washed with 5% citric acid solution (2 x 150 mL), 5% potassium carbonate solution (2 x 150 mL) and brine (200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and filtered, followed by concentration under reduced pressure. The resultant oily matter was purified by silica gel chromatography (ethyl acetatezpetroleum ether 2 1:4 ~ 2:5), to thereby give the title compound (7.0 g, 87%) as a yellow oil. MS (ES+) C17H23NO5 requires: 321, found: 322 [M + H]+.

Step 3: Synthesis of Racemate—ethyl o—3—(benzyloxycarbonylamino)— cyclohexanecarboxylate OH N3 bz ' _‘\NHCbz i) MsCl, Et3N, DCM ii) NaN3, DMF O O O O K K To a solution of Racemate-ethyl 3-(benzyloxycarbonylamino)—4—hydroxycyclohexanecarboxylate (7.0 g, 22 mmol) and triethylamine (6.7 g, 66 mmol) in dichloromethane (100 mL) was dropwise added methanesulfonyl chloride (5.1 g, 44 mmol) at 0 0C, and the mixture was stirred at this temperature for 2hours. The reaction mixture was washed with water (200 mL x 3) and brine.

The organic layer was dried over anhydrous sodium sulfate, ed and concentrated to thereby give crude product (8.0 g, crude) as a yellow oil. A mixture of the above residue (8.0 g, 20 mmol) and sodium azide (7.8 g, 120 mmol) in dimethylsulfoxide (50 mL) was stirred at 100 0C for s. The reaction mixture was cooled to ~30 °C, dissolved in water (~300 mL) and extracted with ethyl acetate (200 mL X 2). The combined organic layers were washed with brine (~200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (3.5 g, 46% total yield for two steps) as a colorless oil. MS (ES+) C17H22N4O4 requires: 346, found: 347 [M + H]+, 369 [M + Na]+.

Step 4: Synthesis of Racemate-ethyl 3-(tert—butoxycarbonylamino)—4— hydroxycyclohexanecarboxylate N3 NH2 z ' “\NHCbz O O O O K K A mixture of Racemate—ethyl 4—azido—3—(benzyloxycarbonylamino)cyclohexanecarboxylate (3.5 g, 10 mmol) and triphenylphosphine (10.4 g, 40 mmol) in THF (200 mL) and water (10 mL) was d at 65 0C for 18hours. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate (200 mL), washed with brine (200 mL) and evaporated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 2 2/1 ~ dichloromethane/methanol 2 10:1) to afford the title compound (2.4 g, 75%) as a yellow oil. MS (ES+) C17H24N204 es: 320, found: 321 [M + H]+.

Step 5: Synthesis of Racemate—ethyl 3—(benzyloxycarbonylamino)—4—((2— (trimethylsilyl)ethoxy)carbonylamino)cyclohexanecarboxylate NH2 NHTeoc NHCbz “\NHCbz TEA u dioxane/H20 O O A solution of Racemate—ethyl 3—(tert—butoxycarbonylamino)—4—hydroxycyclohexanecarboxylate (1.6 g, 5.0 mmol), 1,3—dioxoisoindolin—2—yl 2—(trimethylsilyl)ethyl carbonate (1.42 g, 5.5 mmol) and triethylamine (760 mg, 7.5 mmol) in dioxane/water (25/25 mL) was stirred at room temperature for 3hours. The reaction e was diluted with ethyl acetate (200 mL), and washed by l M hydrochloric acid (100 mL), saturated sodium bicarbonate on (100 mL) and brine (100 mL). The organic layer was concentrated and ed by silica gel chromatography (petroleum ether/ethyl acetate 2 4/1) to afford the title compound (23 g, 99%) as a white solid.

MS (ES+) C23H36N2068i requires: 464, found: 487 [M + Na]+.

Step 6: Synthesis of Racemate-ethyl 3-amino—4—((2—(trimethylsilyl)ethoxy)carbony1amino) cyclohexanecarboxylate NHTeoc NHTeoc NHCbz : ,\\NH2 Pd/C, H2 IPA RT 0 o A mixture of Racemate—ethyl 3—(benzyloxycarbonylamino)—4—((2— thylsilyl)ethoxy)carbonylamino)cyclohexanecarboxylate (1.7 g, 3.7 mmol) and 5% palladium on carbon (50%wet, 300 mg) in isopropanol (35 mL) was stirred under 1 atm hydrogen atmosphere at room temperature for 18hours. The mixture was filtered through a pad of celite. The filtrate was concentrated and purified by silica gel chromatography (methanol/dichloromethane = l/30 to 1/ 10) to afford the title compound (1.0 g, 89%) as a yellow oil. MS (ES+) C15H30N204Si requires: 330, found: 331 [M + H]+.

S nthesis of tert—but 1 48 SS no—2 2—dimeth ah dro—2H— ran—4— lcarbamate and tert—but 1 4R 5R —5—amino—2 2—dimeth l—tetrah dr0—2H— ran—4— lcarbamate AMQC] acetone /\/\\ allyIbromide Grubbs cat. —> / NaH DMF n C—> DCM IPA 90°C 6days Flo/CK Ho“ QY H2N/,, NHTeoc,“ O O H2. Pd/C Su MsCI HN/ —> —> —> LCo< HO HO Et3N, DCM NHTeoc n. O NHTeoc,, NHTeoc 0 I NaN3, NaOAc ' H2, Pd/C " o —> —> Mso DMF, 95 oc, O/N \- N3“ ‘.

H2N\ NHT8°C , H2N], 80020, Et3N '- o TBAF in THF ' O —, —> 90“” BocHN“. 50 OC- 2“ BocHN‘“ Step 1: Synthesis of 2—methylpenten—2—ol MgCl acetone A —> / To a solution of allylmagnesium Chloride in anhydrous THF (1.7 M, 200 mL, 340 mmol) was slowly added acetone (13.2 g, 227 mmol) at 0 0C. After stirring for 15 min at 0 0C, the reaction mixture was stirred at room temperature for another 2h0urs. The reaction was quenched with aq. ammonium de solution and extracted with tert—butyl methyl ether. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure The e was purified by distillation under reduced pressure (~10—15 bars, b.p. 50 0C) to give the title compound (15 g, 66%) as a colorless oil.

Step 2: Synthesis of 4—(allyloxy)methylpent—l—ene Mallyl bromide v0 NaH, DMF To a suspension of sodium e (60%, 24 g, 60 mmol) in methylformamide (150 mL) at 0 0C was slowly added 2—methylpent—4—en—2—ol (20.0 g, 200 mmol). After lhour at 0 OC, allyl bromide (48.0 g 400 mmol) was slowly added at 0~5 0C, and the reaction mixture was stirred at 0 0C for r lhour. The reaction was quenched with aq. ammonium chloride solution and extracted with tert—butyl methyl ether. The combined organic layers were washed with water and brine, dried over sodium sulfate, ed and concentrated under reduced pressure to give the title compound (44 g, crude) as a yellow oil, which was directly used in the next step t further purification.

Step 3: Synthesis of 2,2—dimethyl—3,6—dihydro—2H—pyran v0 Grubbs cat.

M RCM C? Grubbs II catalyst (1.20 g, 1.43 mmol) was added to a solution of 4—(allyloxy)—4—methylpent—1— ene (10.0 g, 71.4 mmol) in dichloromethane (300 mL) and the reaction mixture was refluxed overnight. After the solvent was evaporated, the residue was distilled under reduced pressure to give the title nd (4.0 g, 50%) as a colorless oil.

Step 4: Synthesis of 4,4-dimethyl-3,7-dioxa-bicyclo[4.1.0]heptane I mCPBA O To a solution of 2,2—dimethyl—3,6—dihydro—2H—pyran (4.0 g, 36 mmol) in dichloromethane (20 mL) was added 3—chloroperoxybenzoic acid (18.4 g, 107 mmol), and the mixture was stirred at room temperature overnight. The on mixture was then diluted with dichloromethane, and washed with saturated aqueous sodium sulfite and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under d pressure to give the title compound (5.0 g, crude) as a yellow oil, which was directly used in the next step without further purification.

Step 5: sis of (4R,5R)-2,2-dimethyl—5—((R)—1—phenylethylamino)—tetrahydro—2H—pyran—4— 01 (6a) and (4S,5S)-2,2-dimethy1—5-((R)—1—phenylethylamino)—tetrahydro—2H—pyran—4—ol (6b) @@@IPA90°C6days HO’CK \/K A mixture of 4,4—dimethyl—3,7—dioxa—bicyclo[4.1.0]heptane (7.0 g, 54 mmol) and (R)—1— phenylethanamine (9.9 g, 82 mmol) in isopropanol (50 mL) was stirred at 80 0C for 6 days. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elutezpetroleum ether:dichloromethane containing 1% ammonia—methanol (7 M), 10:1 to dichloromethane containing 1% ammonia/ methanol (7 M) to afford (4R,5R)—2,2—dimethyl—5—((R)—1—phenylethylamino)—tetrahydro—2H— pyran—4—ol (6a) (more polar fraction, 1.5 g) and (4S,5S)—2,2—dimethyl—5—((R)—1— phenylethylamino)—tetrahydro—2H—pyran—4—ol (6b) (less polar fraction, 1.7 g) as a yellow oil.

Note: The absolute configuration of the products was assigned randomly. MS (ES+) C15H23N02 requires: 249, found: 250 [M + H]+. Mobile phase for TLC: ethyl acetate/ dichloromethane = 2/1.

Step 6: sis of (4R,5R)—5—amino-2,2—dimethyl—tetrahydro—2H—pyran—4—ol : HZN’I.

I H2, PdlC @ HO FIN/LCOK—> HO A e of (4R,5R)—2,2—dimethyl—5—((R)—1—phenylethylamino)—tetrahydro—2H—pyran—4—ol (600 mg, 2.40 mmol) and 10% palladium on carbon (100 mg) in methanol (50 mL) was stirred at room temperature under hydrogenation overnight. After that, the mixture was filtered through a pad of celite, and the filtrate was concentrated to afford the title compound (550 mg, crude) as a yellow oil, which was used directly for the next step without further purification.

Step 7: Synthesis of 2—(trimethylsilyl)ethyl )—4—hydroxy—6,6—dimethyl—tetrahydro—2H— pyran—3—ylcarbamate To a solution of (4R,5R)amino-2,2-dimethyl-tetrahydro-2H-pyranol (550 mg, 2.40 mmol) and triethylamine (484 mg, 4.80 mmol) in dioxane (5 mL) and water (5 mL) was added 2— (trimethylsilyl)ethyl oxopyrrolidine—l—carboxylate (750 mg, 2.90 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4hours. After that, the solution was diluted with ethyl acetate and washed with brine. The organic layer was concentrated, and the residue was purification by silica gel column with eum ether /ethyl acetate = 4/1 to l/l to afford the title compound (360 mg, 52% for 2 steps) as a gray solid.

Step 8: sis of (4R,5R)—2,2—dimethyl—5—((2—(trimethylsilyl)ethoxy)carbonylamino)— tetrahydro—2H—pyran—4—yl methanesulfonate NHTeoc,“ NHTeoch, O O MsCl HO Et3N, DCM MsO To a solution of 2—(trimethylsilyl)ethyl (3R,4R)—4—hydroxy—6,6—dimethyl—tetrahydro—2H—pyran—3— ylcarbamate (360 mg, 1.25 mmol) and ylamine (378 mg, 3.75 mmol) in dichloromethane (5 mL) was dropwise added mesyl chloride (213 mg, 1.87 mmol) at 0 0C. The reaction mixture was stirred at room temperature for 4 h, and then diluted with dichloromethane (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (550 mg, crude) as a yellow oil, which was ly used in the next step without further purification.

Step 9: Synthesis of 2—(trimethylsilyl)ethyl (3S,4S)—4—azido—6,6—dimethyl-tetrahydro—2H—pyran—3— ylcarbamate NHTeocm NaN3, NaOAc MsO DMF, 95 00, DIN NHTeOC/“QNs‘“.

To a solution of (4R,5R)—2,2—dimethyl—5—((2—(trimethylsilyl)ethoxy)carbonylamino)—tetrahydro— an—4—yl methanesulfonate (550 mg, 1.25 mmol) in N,N—dimethylformamide (10 mL) was added sodium azide (812 mg, 12.5 mmol) and sodium acetate (1.05 mg, 12.5 mmol) at room temperature. The resultant mixture was stirred at 95 0C for 2 days. After that, the mixture was cooled to room temperature and diluted with ethyl acetate (100 mL), The organic phase was washed with water (100 mLx 8) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated to afford the title compound (510 mg, crude) as a yellow oil which was ly used in the next step without further cation.

Step 10: sis of methylsilyl)ethyl )—4—amino—6,6—dimethyl—tetrahydro—2H—pyran— 3—ylcarbamate NHTeocl, NHTeoc, , 0 H2, Pd/C ,' O N3“ HZN‘“ A mixture of 2—(trimethylsilyl)ethyl (3S,4S)—4—azido—6,6—dimethyl—tetrahydro—2H—pyran—3— ylcarbamate (510 mg, 1.25 mmol), 10% palladium on carbon (50 mg) in methanol (10 mL) was stirred at room temperature under 1 atm hydrogen atmosphere (hydrogen balloon) overnight.

After that, the mixture was filtered through a pad of celite. The filtrate was concentrated to get the title compound (450 mg, crude) as a brown oil, which was used directly for the next step without further purification.

Step 11: Synthesis of 2—(trimethylsilyl)ethyl (3S,4S)—(4—tert—butoxycarbonylamino)—6,6—dimethyl— tetrahydro—2H—pyranylcarbamate TeocHN,, TeocHN, ' 0 80020, Et3N " O HZN‘“ 00'“ BocHN‘“ To a solution of 2—(trimethylsilyl)ethyl (3S,4S)—4—amino—6,6—dimethy1—tetrahydro—2H—pyran—3— ylcarbamate (450 mg, 1.25 mmol) and triethylamine (379 mg, 3.75 mmol) in dichloromethane (10 mL) at room temperature was added di—tert—butyl dicarbonate (410 mg, 1.88 mmol). The reaction mixture was stirred at room temperature for 2hours. After that, the solution was concentrated, and the residue was purified by silica gel chromatography using petroleum ether/ethyl acetate 2 4/1 as the eluent to afford the title compound (160 mg, 33% for 4 steps) as a yellow solid.

Step 12: Synthesis of tert-butyl (4S,5S)—5—amino—2,2—dimethyl—tetrahydro—2H—pyran—4— ylcarbamate NHTeoc H N, ”- 2 " o TBAF in THF O BocHN‘“ 50 00' 2“ BocHN“.

To a on of compound 2—(trimethylsilyl)ethy1 (3S,4S)—(4—tert—butoxycarbonylamino)—6,6— dimethyl—tetrahydro—2H—pyran—3—ylcarbamate (160 mg, 0.41 mmol) in ydrofuran (2 mL) at room temperature was added tetrabutylammonium fluoride in tetrahydrofuran (l M, 1.23 mL, 1.23 mmol). The reaction mixture was stirred 50 0C for 2hours. After that, the solution was concentrated, and the residue was ed by silica gel chromatography with ethyl acetate as the eluent to afford the title compound (110 mg, crude) as a yellow oil.

QY H2N N HTeoc H2. Pd/C O Teoc—OSu O “”501 HN —. —. —.

NHTeoc NHTeoc NHTeoc OAc 0 H2, Pd/C 0 M30‘ DMF 95 OC O/N N H2N NHTeoc H N 80020 Et3N 2 o TBAFm THF 0 BocHN 50°C 2“ BocHN Step 1: Synthesis of (4S,5S)—5—amino—2,2—dimethyl—tetrahydro-2H—pyran—4—ol (l/ H2N H2, Pd/C 0 HN —.\OZ HO“- A suspension mixture of (4S,SS)-2,2-dimethyl—5—((R)—1—phenylethylamino)—tetrahydro—2H— pyran—4—ol (1.0 g, 4.0 mmol) and 10% palladium on carbon (200 mg) in methanol (20 mL) was stirred at room ature under latm hydrogen atmosphere (hydrogen balloon) overnight.

After that, the e was filtered through a pad of celite, and the te was concentrated to get the title compound (1.1 g, crude) as a yellow oil, which was used ly for the next step without further purification.

Step 2: Synthesis of methylsilyl)ethyl (3S,4S)—4—hydroxy-6,6—dimethyl—tetrahydro—ZH— pyran—3—ylcarbamate H2N NHTeoc Teoc-OSu 0 Ho“'a Ho“ To a solution of (4S,5S)—5—amino—2,2—dimethyl—tetrahydro—2H—pyran—4—ol (1.1 g, 4.0 mmol) and triethylamine (1.1 mL, 8.0 mmol) in a mixed solvent of dioxane (5 mL) and water (5 mL) at room temperature was added 2— (trimethylsilyl)ethy1 2,5-dioxopyrrolidine— l—carboxylate (1.2 g, 4.8 mmol). The reaction mixture was stirred at room temperature for 4hours. After that, the solution was diluted with ethyl acetate and washed with brine. The c layer was separated and concentrated. The resulting residue was purified by silica gel chromatography using petroleum ether/ethyl acetate = 4/1 to l/l as the eluent to afford the title compound (1.0 g, 86% for 2 steps) as a yellow oil.

Step 3: Synthesis of (4S,SS)-2,2-dimethyl((2-(trimethylsilyl)ethoxy)carbonylamino)- tetrahydro-2H-pyranyl methanesulfonate NHTeoc NHTeoc O MsCl O HO‘“ Et3N, DCM MSO‘V To a solution of methylsilyl)ethyl (3S,4S)—4—hydroxy—6,6—dimethyl—tetrahydro—2H—pyran—3— ylcarbamate (1.0 g, 3.5 mmol) and triethylamine (1.4 mL, 10 mmol) in dichloromethane (10 mL) at 0 0C was dropwise added mesyl chloride (600 mg, 5.20 mmol). The on mixture was stirred at room temperature for 4hours and then diluted with dichloromethane (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (1.6 g, crude) as a yellow oil which was directly used in the next step t further purification.

Step 4: Synthesis of 2-(trimethylsilyl)ethyl (3R,4R)azido-6,6-dimethyl-tetrahydro-2H—pyran- 3—ylcarbamate NHTeoc O NHTeOC NaN3, NaOAc o Mso“ DMF, 95 00, DIN To a solution of (4S,5S)—2,2—dimethyl—5—((2—(trimethylsilyl)ethoxy)carbonylamino)—tetrahydro— 2H—pyran—4—yl methanesulfonate ( 1.6 g, 3.5 mmol) in methylformamide (10 mL) was added sodium azide (2.3 g, 35 mmol) and sodium acetate (2.8 g, 35 mmol) at room temperature.

The resultant mixture was stirred at 95 0C for 2 days. After that, the mixture was cooled to room temperature and diluted with ethyl e (100 mL). The organic layer was washed by water (100 mLx 8) and brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (1.3 g, crude) as a yellow oil, which was directly used in the next step without further purification.

Step 5: Synthesis of 2—(trimethylsilyl)ethyl (3R,4R)—4—amino—6,6—dimethyl—tetrahydro—2H—pyran— 3—ylcarbamate NHTeoc N3 H2N A mixture of 2—(trimethylsilyl)ethyl (3R,4R)—4—azido—6,6—dimethyl-tetrahydro-2H-pyran—3— ylcarbamate (1.3 g, 3.5 mmol) and 10% ium on carbon (200 mg) in methanol (10 mL) was stirred at room temperature under 1 atm hydrogen atmosphere (hydrogen balloon) overnight.

After that, the e was filtered through a pad of celite. The filtrate was concentrated to get the title nd (12 g, crude) as a yellow oil, which was used directly for the next step without further purification.

Step 6: Synthesis of 2—(trimethylsilyl)ethyl (3R,4R)—(4— tert—butoxycarbonylamino)—6,6—dimethyl— tetrahydro—2H—pyran—3—ylcarbamate NHTeoc NHTeoc 0 30020, Et3N O H2N 00'“ BocHN To a solution of 2-(trimethylsilyl)ethyl )amino-6,6-dimethyl-tetrahydro-2H—pyran ylcarbamate (1.2 g, 3.5 mmol) and triethylamine (1.4 mL, 10.5 mmol) in dichloromethane (10 mL) was added t—butyl dicarbonate (1.1 g, 5.2 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2hours. After that, the mixture was directly concentrated and purified by silica gel tography using petroleum ether/ethyl acetate 2 4/1 as the eluent to afford the title compound (440 mg, 32% for 4 steps) as a gray solid.

Step 7: Synthesis of tert—butyl (4R,5R)—5—amino—2,2—dimethyl—tetrahydro—2H—pyran—4— ylcarbamate NHTeoc H N2 O TBAF in THF O 50 °C' 2“ BocHN BocHN To a solution of 2—(trimethylsilyl)ethyl (3R,4R)—(4— tert—butoxycarbonylamino)—6,6—dimethyl— tetrahydro—2H—pyran—3—ylcarbamate (440 mg, 1.13 mmol) in tetrahydrofuran (2 mL) at room temperature was added tetrabutylammonium fluoride in tetrahydrofuran (l M, 3.4 mL, 3.4 mmol). The reaction mixture was stirred 50 0C for 2hours. After that, the on was cooled to room temperature, concentrated and purified by silica gel chromatography using ethyl acetate as the elute to afford the title compound (80 mg, 29%) as a yellow oil.

(S)OH ”Br \/\0\ Grubbs cat CK mCPBA 0Q / NaH, DMF / DCM 40°C O/N 0°C to RT, O/N, RT,3h \(\(\/K whim HO Pd/C, H2 IPA, RT, O/N H2N IPA 85 °c 1week o‘“CKGJL HO N31,. N3 ' COR,.

(Boc)2O, TEA o MsCl. TEA NaN3. DMF DCM, 2 h BocHN“ DCM, 2 h BocHN“ COR 95 °C, O/N BocHN“ NHBofi . “\NYN\I H2N I /@ N / I. .

Pd/C, H2 O NaHC03, MAP 0 0 CI I oxane IPA, 4 h BocHN‘“ 100 °C, O/N O RT, O/N '2‘”? H / ‘ “N N o Cl | Step 1: Synthesis of (S)(allyloxy)pent—l—ene OH Br v (8) L, (3)0 / NaH, DMF / RT, 3 h To a suspension of sodium hydride (21 g, 34 mmol) in N,N—dimety1formamide (100 mL) was dropwise added (S)—pent—4—en—2—ol (10 g, 116 mmol) at 0 0C. The reaction mixture was stirred at 0 0C for 1hour. After that, a11y1 bromide (14.0 g, 116.2 mmol) was dropwise added to the mixture at 0 0C. The resultant e was d at 0 0C for r 3 h, and the mixture was quenched by saturate ammonium chloride solution (500 mL). The aqueous layer was extracted with tert— butyl methyl ether (200 mL x 3), and the combined organic layers were washed with water (100 mL x 3) and brine (100 mL), dried over sodium sulfate, filtered and concentrated to afford (S)—4— (allyloxy)pent—l—ene (~20 ml tert-butyl methyl ether solution), which was used in the next step without further purification.

Step 2: Synthesis of (S)methyl-3,6-dihydro-2H-pyran v0 Grubbs cat. a MDCM, 40 00, ON A mixture of (S)—4—(allyloxy)pent—l—ene (~20 mL solution, 116 mmol), 2nd generation Grubbs catalyst (1.8 g) in dichloromethane (500 mL) was stirred at 40 0C overnight. After that, the solution was cooled to room temperature and the title compound (~35 g, 31% for 2 steps) was obtained by vacuum distillation.

Step 3: Synthesis of (4S)—4—methyl—3,7—dioxabicyclo[4.1.0]heptane Ci mCPBA Ca 0 °C to RT, O/N, To a solution of (S)—2—methyl—3,6—dihydro—2H—pyran (~1 g, 10 mmol) in dichloromethane (20 mL) was added 3—chloroperoxybenzoic acid (1.8 g, 20 mmol) at 0 0C. The resultant e was stirred at room temperature overnight. After that, the mixture was washed by saturated sodium e solution (15 mL), sodium carbonate (15 mL) and brine (15 mL). The organic layer was dried over sodium e and concentrated to get the title compound (~3 mL dichloromethane solution), which was used directly for the next step without further purification.

Step 4: Synthesis of (3R,4S,6S)methyl((S)phenylethylamino)tetrahydro-2H—pyranol 0Q )—© HN“' IPA, 85 °C, 1 week A mixture of (4S)—4—methyl—3,7—dioxabicyclo[4.1.0]heptane (~3 mL dichloromethane on, mmol) and (R)—l—phenylethanamine (2.4 g, 20 mmol) in isopropyl alcohol (20 mL) was stirred at 85 0C for 1 week. After that, the solution was cooled to room temperature and purified by prep—HPLC to get the title compound (more polar, 120 mg, 10% for 2 steps) as a yellow solid and a side product (less polar, 400 mg, 32% for 2 steps) as a white solid. MS (ES+) C14H21N02 requires: 235, found: 236 [M + H]+.

Step 5: Synthesis of (3R,4S,6S)aminomethyltetrahydro-2H-pyranol HN“ Pd/C, H2 m ©A —> ' IPA, RT, OIN HzN‘ A mixture of )—tert—butyl tert—butyl (2S,4S,5R)—5—hydroxy—2—methyltetrahydro—2H—pyran— 4—ylcarbamate (200 mg, 0.85 mmol) and 10% palladium on carbon (50 mg) in isopropanol (10 mL) was stirred at room temperature under hydrogenation overnight. After that, the mixture was filtered h a pad of celite and concentrated to get the title compound (150 mg, crude) as a yellow oil, which was used directly for the next step without r purification.

Step 6: Synthesis of tert—butyl (2S,4S,5R)—5—hydroxymethyltetrahydro—2H—pyran—4— ylcarbamate HOm HO (Boc)20, TEA H2N‘ I DCM, 2 h BocHN“\COK To a solution of (3R,4S,6S)amino-6—methyltetrahydro—2H—pyran—3—ol (150 mg, 1.1 mmol) and triethylamine (333 mg, 3.3 mmol) in dichloromethane (80 mL) at 0 0C was dropwise added di— tert-butyl dicarbonate (475 mg, 2.2 mmol). The reaction mixture was stirred at room temperature for 4hours. After that, the on was concentrated and purified by silica gel column with methanol/dichloronethane = 1/30 to 1/ 15 as elute to afford the title nd (130 mg, 51% for 2 steps) as a yellow oil.

Step 7: Synthesis of tert—butyl (2S,4S,5S)—5—azido—2—methyltetrahydro—2H—pyran—4—ylcarbamate HO‘CCL MsCI, TEA BocHN‘“ N3"’©0\ DCM, 2 h BocHN‘“ To a solution of tert—butyl ,5R)-5—hydroxy—2—methyltetrahydro—2H—pyran—4—ylcarbamate 7 (130 mg, 0.6 mmol) and triethylamine (202 mg, 2.0 mmol) in dichloromethane (10 mL) at 0 0C was dropwise added mesyl chloride (194 mg, 1.7 mmol). The reaction mixture was stirred at room ature for 4h0urs and then diluted with dichloromethane (100 mL). The organic layers were washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (190 mg, crude) as a yellow oil (4.0 g , 98%), which was directly used in the next step without further purification.

Step 8: Synthesis of tert—butyl (2S,4S,5S)—5—azido—2—methyltetrahydro—2H—pyran—4—ylcarbamate MiaNaN3DMF N3“ BocHN‘ 95 00, DIN BooHN‘ To a solution of tert—butyl (2S,4S,5S)—5—azido—2—methyltetrahydro—2H—pyran—4—ylcarbamate (190 mg, 0.6 mmol) in N,N—dimethylformamide (10 mL) was added sodium azide (375 mg, 5.6 mmol) and sodium acetate (459 mg, 5.6 mmol) at room temperature. The ant mixture was d at 95 0C for 2 days. After that, the mixture was diluted with ethyl acetate (100 mL), washed by water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (180 mg, crude) as a yellow oil (4.0 g which was directly used in the , 98%), next step without further cation.

Step 9: Synthesis of tert—butyl (2S,4S,SS)—5—amino—2—methyltetrahydro—2H—pyran—4—ylcarbamate N H 3 ‘0:,, 2 N,“ Pd/C “ IPA, 4 h BocHN‘“COK A mixture of tert-butyl (2S,4S,SS)azidomethyltetrahydro-2H-pyranylcarbamate (1.8 g, 3.6 mmol) and 10% ium on carbon (50 mg) in isopropanol (10 mL) was stirred at room temperature under hydrogenation overnight. After that, the mixture was filtered through a pad of celite. Concentrated to get the title compound (150 mg, crude) as a yellow oil, which was used directly for the next step without further purification.

S nthesis of 2 loro—6— 2 6—dichloro—3 5—dimethox hen l line NBS DCM MnOz, DCM RT,2h THF,RTO..N HNZ H2N RTO..N Br N \ 130 00 reflux, 5 h (3| N .

HzN OH Pd(PPh3)2C|2 802% O o/ \ N \ CSZCO3,THF/HZO,80°C,3h NINOOCIA THF 0°C 1h )L /O c.

CI N Cl CI Step 1: Synthesis of 2—amino—5—bromo—3—chlorobenzoic acid NBS DCM 0 RT 2 h To a solution of 2—amino—3—fluorobenzoic acid (10.0 g, 58.5 mmol) in dichloromethane (150 mL) was added N—bromosuccinimide (10.4 g, 58.5 mmol), and the mixture was stirred at room temperature for 2hours. LCMS showed the on was completed. The solid was filtered and washed with dichloromethane (100 mL x 3) to give the title compound as a white solid (13.0 g, 89 %), which was directly used in the next step without further purification. MS (ES+) C7H5BrClNOz requires: 249, 251, found: 250, 252 [M + H]+.

Step 2: Synthesis of (2-aminobromochlorophenyl)methanol Br r 0 8H3 H0 THF, RT, O.N.

H2N H2N CI CI To a solution of 2—amino—S—bromochlorobenzoic acid (13.0 g, 52.0 mmol) in THF (200 mL) was added borohydride in THF (300 mL, 1N) at ice/water bath, and the reaction mixture was stirred at room temperature overnight. The e was quenched with methanol (100 mL) and concentrated to a volume of 50 mL. The e was diluted with aqueous sodium bicarbonate (400 mL) and extracted with ethyl acetate (200 mL x 3). The organic layers were separated, combined, washed by brine (100 mL), dried over sodium sulfate, filtered and concentrated to afford the title product (10.0 g, 82%). MS (ES+) C7H7BrClNO requires: 234, 236, found: 236, 238 [M + H]+.

Step 3: Synthesis of 2—amino—5—bromo—3—chlorobenzaldehyde Br Br HO MnOz, DCM 0/ HZN RT, O.N. H2N CI CI A mixture of no—S—bromo—3—chlorophenyl)methanol (10.0 g, 42.5 mmol) and ese oxide (21.9 g, 255 mmol) in dichloromethane (400 mL) was stirred at room temperature overnight. The solid was filtered off, and the filtrate was concentrated to give the title compound as a light yellow solid (9.0 g, 91%), which was directly used in the next step without further purification.

Step 4: Synthesis of 6-bromochloroquinazolin—2—ol Br 0 Br 0/ JL 180°C N \ + —’ H N2 NH2 i / HZN 2h HO N A mixture of 2—amino—5—bromo—3—chlorobenzaldehyde (9.0 g, 38.6 mmol) and urea (34.7 g, 579 mmol) was heated to 180 0C and stirred for 2hours. The reaction mixture was cooled to room temperature, and the resulting precipitate was diluted with water (1 L) and stirred for 2hours. The resulting precipitate was filtered, and the moisture trapped was completely d by the co— evaporation with toluene three times. The title compound (9.0 g, 90%) was obtained as a yellow solid. MS (ES+) C8H4BrClN20 requires: 257, 259, found: 258, 260 [M+H]+.

Step 5: Synthesis of 6-bromo-2,8-dichloroquinazoline POCI N \ reflux 5h 0| N A solution of 6—bromo—8—chloroquinazolin—2—ol (9.0 g, 35 mmol) in phosphorus oxychloride (100 mL) was refluxed for 5hours. Most of phosphorus oxychloride was removed under reduced pressure, and the residue was added to a stirring ice water (500 mL). The resulting itate was collected via filtration and then refluxed in THF. The solid was filtered off, and the filtrate was concentrated to give the title compound a yellow solid (7.0 g, 78 %). MS (ES+) C8H4BrClN2 es: 275, 277, found: 276, 278 [M + H]+.

Step 6: Synthesis of 2,8—dichloro—6—(3,5—dimethoxyphenyl)quinazoline N \ Pd(PPh)C|3“ O )L / + Has N \ 0/ 0/ .

CI N I 032C03,THF/H20,80 C,3h A / A e of 6—bromo-2,8-dichloroquinazoline (4.0 g, 14.5 mmol), 3,5—dimethoxypheny1boronic acid (4.23 g, 16.0 mmol), cesium carbonate (9.42 g, 29.0 mmol) and 3)2C12 (220 mg, 0.70 mmol) in THF (200 mL) and water (10 mL) was degassed with nitrogen three times, and stirred at 80 0C for 5hours. The reaction e was cooled to room temperature, ly concentrated and purified by silica gel chromatography (petroleum ether: dichloromethane = 2: 1~1:1) to get the title compound as a yellow solid (2.0 g, 41 %). MS (ES+) C16H12C12N202 requires: 334, 336, found: 335, 337 [M + H]+.

Step 7: Synthesis of 2,8—dichloro—6—(2,6—dichloro—3,5-dimethoxyphenyl)quinazoline 0/ o/ O O/—>SOQCIQ N \ CIOO/ )L / THF 0°C 1h A\ CI N CIA CI CI To a solution of 2,8-dichloro(3,5-dimethoxyphenyl)quinazoline (2.0 g, 6.0 mmol) in dry THF (40 mL) was dropwise added sulfuryl chloride (1.59 g, 1.75 mmol) at 0 OC, and the mixture was stirred for 30 min at 0 OC. The reaction was ed with water (1 mL), and the precipitate was collected Via filtration to give the title compound (1.3 g, 54%) as a yellow solid. MS (ES+) C16H10C14N202 requires: 402, 404, found: 403, 405 [M+H]+; 1H—NMR (400 MHz, CDC13) 5 ppm 9.36 (s, 1H), 7.94 (s, 1H), 7.79 (s, 1H), 6.69 (s, 1H), 4.01 (s, 6H).

S nthesis of 2 7—dichloro—6— 2 loro—3 5—dimethox hen 1 uinazoline Br BH 0 Br2 (1.02 eq) 3 HO 0 MnOz, DCM —> —> —> MeOH, -78 OC, 2 h THF, RT, O.N. RT, ON.

H2N CI CI H N CI H2N Br 0 Br 0/ JL 180°C Pool8 N \ H2N NHz—> A / + H2N CI Cl , 5 h CI N CI \§ 0/ Pd(PPh3)2CI2 8020b C52C03 THF/H20 85 0 3h0 Nl \NCO 1—’_OOCTHF 1 h /J\‘ 0' UMCIC Step 1: Synthesis of 2-aminobromochlorobenzoic acid Brz (102 eq) 0 CIVIeOH, °C—78 2h HZN CI To a solution of 2—amino—4—chlorobenzoic acid (10.0 g, 58.5 mmol) in methanol (150 mL) was added bromine (15.7 mL) at —78 OC, and the reaction mixture was stirred at —78 0C for 2hours.

The reaction mixture was quenched with ice water (100 mL) and aq. sodium thiosulfate, and extracted with ethyl acetate (150 mL x3). The organic layers were separated, combined, washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and trated to afford the title compound (9 g, 62%).

Step 2: Synthesis of (2-aminobromochlorophenyl)methanol QQUBr HO/D:Br BH3 THF, RT, O.N. 0' H2N Cl H2N To a on of 2—amino—5—bromo—4—chlorobenzoic acid (9.0 g, 36.0 mmol) in THF (150 mL) was added borohydride in THF (144 mL, 1 M) at room temperature, and the reaction mixture was stirred overnight.. The reaction mixture was quenched with methanol (50 mL), and concentrated to a volume of 50 mL. The residue was diluted with water (100 mL) and extracted with ethyl acetate (150 mL x 3). The c layers were separated, ed, washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (crude, 6 g, 71%).

Step 3: Synthesis of 2—amino—5—bromo—4—chlorobenzaldehyde H2N c1 RT. O-N- H2N CI A mixture of (2—amino—5—bromochlorophenyl)methanol (6 g, 25.5 mmol) and manganese(IV) oxide (15.5 g, 0.178 mol) in dichloromethane (100 mL) was stirred at room temperature overnight. The solid was filtered off, and the filtrate was concentrated to give the title compound as a light yellow solid (5 g, 81%). MS (ES+) ClNO requires: 233, 235, found: 234, 236 [M + H]+.

Step 4: Synthesis of 6—bromo—7—Chloroquinazolin—2—ol HN2 NH2 HN CI HOJLN/ A mixture of 2—amino—5—bromo—4—chlorobenzaldehyde (5 g, 21.46 mmol) and urea (18 g, 300.0 mmol) was stirred at 180 0C for 5hours. LCMS monitored the reaction was completed. The mixture was cooled to room ature, washed with water (100 mL x 3) and ed. The filtration cake was dried to get the title compound as a yellow solid (6 g (crude, 100%). MS (ES+) C8H4BrClN2O requires: 258, 260, found: 259, 261 [M + H]+.

Step 5: Synthesis of 6-bromo-2,7-dichloroquinazoline 1U; mgrCl Br —>c|/kN/reflux 5h CI A solution of 6—bromo—7—chloroquinazolin—2—ol (6.0 g, 23 mmol) in phosphorus oride (50 mL) was refluxed for 5hours. The on was cooled to room temperature, and most of phosphorus oride was removed under reduced pressure. The residue was dropwise added to ice water (500 mL), and the resulting precipitate was collected by the filtration to give the title compound as a yellow solid (3 g, 48%).

Step 6: Synthesis of 2,7—dichloro—6—(3,5—dimethoxyphenyl)quinazoline Pd(PPh3”on2 O N \Q 0/ CIiDCEZWCEO 032003 THF/H20 85°C 3h CI/kN/ CI A mixture of 6—bromo—2,7-dichloroquinazoline (3 g, 10.8 mmol), 3,5—dimethoxypheny1boronic acid (2.2 g, 11.9 mmol), cesium carbonate (1.06 g, 32.4 mmol) and Pd(PPh3)2C12 (702 mg, 1.08 mmol) in THF (50 mL) and water (10 mL) was degassed with nitrogen three times, and the reaction mixture was stirred at 85 0C for 3hours. The reaction e was cooled to room temperature and directly concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate 2 10:1~4: 1) to give the title compound (2.0 g, 55%) as a yellowish solid. MS (ES+) requires: 334, 336, C16H12C12N202, found: 335, 337 [M + H]+.

Step 7: Synthesis of 2,7—dichloro—6—(2,6—dichloro—3,5-dimethoxyphenyl)quinazoline O \O N \ 0/ &. 000/ )L / THF —,1o°c 1h CI N CI Cl/J\/l\\ CIC To a solution of 2,7-dichloro(3,5-dimethoxyphenyl)quinazoline (2.0 g, 6.0 mmol) in THF (30 mL) was added sulfuryl chloride (1.77 g, 13.2 mmol) at -10 OC, and the mixture was stirred at - °C for 1hour. The solution was quenched with water (1 mL) and concentrated under reduced pressure. The residue was purified by silica gel chromatography leum etherzethyl acetate 2 :l~4:l) to the title compound (1.2 g, 50%) as a white solid. MS (ES+) C16H10C14N202 requires: 402, 404, found: 403, 405 [M + H]+.

Step 8: Synthesis of ro—6—(2,6—dichloro—3,5—dimethoxyphenyl)pyrido[2,3—d]pyrimidine HO N CI N \f \ B Br 0 H \ \f \ | )L 180 °c, 2 h DIPEA (3.0 eq.), N N + H N NH \ —> \ + / 2 2 H2N N N| POCI3, 180°C, O/N \ / / NI / 0 O Br Br Pd(P(t-BU))3)2 C52C03 SOQCI2 N \ THF water 85 °C 1.5 h THF, 0°C Step 9: Synthesis of 6-bromopyrido[2,3—d]pyrimidin—2—ol HJEL/j/ HO N Br 0 \ JL 180°C,2h \N'r / H2N NH2 |\ HZN N A mixture of 2—amino—5—bromonicotinaldehyde (2.0 g, 10.0 mmol) and urea (9.0 g, 150.0 mmol) was heated at 180 °C and d vigorously for Zliours. The reaction mixture was cooled to room temperature,. and the ing precipitate was collected, washed with water (3 x 100 mL) and co—evaporated with toluene three times to completely remove the moisture trapped. The title compound (2.1 g, 93%) was obtained as a yellow solid. MS (ES+) CgHsBrNZO requires: 225, 227, found: 226, 228 [M + H]+.

Step 10: Synthesis of 6—bromochloropyrido[2,3—d]pyrimidine HO N CI N \f‘ \f‘ DIPEA 3.0e N ( q . ) , N \ \ N| POCI3. 180 °C, O/N / NI / Br Br To a stirred mixture of 6—bromopyrido[2,3—d]pyrimidin—2—ol (1.1 g, 4.9 mmol) in 30 mL of phosphoryl oride was added diisopropylethylamine (1.6 g, 12.2 mmol) at room ature, and the reaction mixture was then d at 120 0C for 12hours. Most of phosphoryl oride was removed under reduced pressure. The residue was diluted with ethyl acetate (200 mL) and added to ted sodium bicarbonate solution (300 mL) at 0 0C. The mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (800 mg, 67%) as a yellow solid.

MS (ES+) C7H3BrClN3 requires: 243, 245, found: 244, 246 [M + H]+.

Step 11: Synthesis of 2—chloro—6—(3,5—dimethoxyphenyl)pyrido[2,3—d]pyrimidine: CI N \W \ HOBOH N / Pd(P(t-BU)3)2, C82CO3 I N \ O\ THF, water, 85 00.15 h A mixture of 6-bromochloropyrido[2,3-d]pyrimidine (800 mg, 3.3 mmol), 3,5- dimethoxyphenylboronic acid (655 mg, 3.6 mmol), bis(tri-tert-butylphosphine)palladium (83 mg, 0.16 mmol) and cesium carbonate (1.06 g, 3.3 mmol) in THF (30 mL) and water (6 mL) was degassed with nitrogen for three times and then heated at 85 0C for 0.5hour. The mixture was cooled to room temperature and concentrated under reduced re. The residue was purified by silica gel column chromatography (dichlorometbane/ethyl acetate 2 3/ 1) to get the title t as a yellow solid (460 mg, 47%) as a yellow solid. MS (ES+) C15H12C1N302 requires: 301, 302, found: 302, 304 [M + H]+.

Step 12: Synthesis of ro—6—(2,6-dichloro—3,5—dimethoxyphenyl)pyrido[2,3—d]pyrimidine CI N CIWN\ F \/ N / CI I so Cl | 2 N\ N\ o\ —>2 O\ THF 0% 0 °\ To a solution of 2—chloro—6—(3,5—dimethoxyphenyl)pyrido[2,3—d]pyrimidine (300 mg, 1.0 mmol) in THF (30 mL) was dropwise added sulfuryl chloride (337 mg, 2.5 mmol) at 0 OC, and the mixture was stirred for 20 min at 0 0C. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (dichloromethane/ethyl acetate 2 5/1) to get the title t as a tan solid (240 mg, 65%). MS (ES+) C15H10C13N302 requires: 369, found: 370, 372 [M + H]+.

S nthesis of 2—chloro—6— 2 6—dichloro—3 5—dimethox hen l —7—fluoro line B Br Pd(PPh3)QC|2 OAK): r HNO3,H2804 o/ 082C03 [ o/ o/ TsOH toluene —> —> —>o o/ RT 3 h dioxaneiH O 130 °C 3 h F . o N F 2 90 00, om O2N F NaBH4Pd/C 4:0 O O/ triphosgene1. POCI3 EtOH/H2O 2. ammonia o | C 2h CAIN/ 90 00 1h H2NO F 3. HCIIn dioxane HOJ\135 30ch2 0 °C, 0.5 h Step 1: Synthesis of 5—bromo—4—fluoro—2—nitrobenzaldehyde O%\©:Br Br HN03, H2804 RT, 3 h o7\/©: F 0 N2 F To a stirred on of concentrated nitric acid (6.8 mL, 1010 mmol) in concentrated sulfuric acid (60 mL) was slowly added 3-bromo—4—fluorobenzaldehyde (10 g, 49.5 mmol) at 0 0C. After the addition was completed, the ice bath was removed, and the reaction was allowed to warm to room temperature and stirred for . The mixture was poured into ice water and extracted with ethyl acetate (200 mL). The organic layer was concentrated to give the title compound as a yellow solid , 12 g, 100%), which was used directly for the next step without r purification.

Step 2: Synthesis of 6—fluoro—3',5'—dimethoxy—4—nitrobiphenyl—3—carbaldehyde Pd(PPh3)2C|2, coonBr <1 —. 0 o/ 02N F HO\B 0/ dioxane/HZO 0 (5H 90°C, O/N 02N F A mixture of 5—bromo—4—fluoro—2—nitrobenzaldehyde (10.0 g, 40.0 mmol), 3,5— dimethoxyphenylboronic acid (7.3 g, 40.0 mmol), iphenylphosphino) palldium(ll) chloride (1.4 g, 2.0 mmol) and cesium carbonate (32.6 g, 100.0 mmol) in dioxane/water (550 mL, V/V = /1) was degassed with nitrogen for three times and heated at 90 0C for 3hours. The mixture was cooled to room temperature, concentrated, diluted with ethyl acetate (1000 mL), and washed by water (500 mL) and brine (500 mL). The organic layer was dried, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2 8/1 to /1) to afford the title compound (9 g, 61%) as a yellow solid. MS (ES+) C15H12FN05 requires: 305, found: 306 [M + H]+.

Step 3: Synthesis of 2-(6-fluoro-3',5'-dimethoxynitrobiphenylyl)-1,3-dioxolane \O \O O / TsOH, toluene [\ o’ o —, o 130 0c, 3 h OZN F OZN A mixture of 6—fluoro-3',5'-dimethoxy—4—nitrobipheny1—3—carbaldehyde (1.7 g, 5.6 mmol) and 4— toluenesulfonic acid (95.8 mg, 0.6 mmol) in 1,2-ethanediol (4.3 mL) and toluene (60 mL) was heated at 130 0C for 3h0urs. After that, the reaction mixture was cooled to room temperature, diluted with ethyl e (100 mL), and washed by water (100 mL * 3) and brine (100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was ed by silica gel column chromatography (petroleum ether/ethyl acetate 2 8/1 to 5/ 1) to afford the title nd (1.8 g, 89%) as a yellow solid. MS (ES+) C17H16FN06 es: 349, found: 350 [M + H]+.

Step 4: Synthesis of 5—(1,3—dioxolan—2—yl)—2—fluoro—3',5'—dimethoxybiphenyl—4—amine \o \o [O O f o O o/ Pd/C, NaBH4 o o/ EtOH/HZO OZN F HZN F 90 0C, 1 h A e of 2—(6—fluoro—3',5'—dimethoxy—4—nitrobiphenyl—3-yl)—1,3—dioxolane (1.8 g, 5.2 mmol), sodium borohydride (587.9 mg, 15.5 mmol) and 10% palladium on carbon (02 g) in ethanol/water (33 mL, V/V = 10/ 1) was heated at 90 0C for 1hour. After that, the mixture was diluted with ethyl acetate (150 mL), and washed by water (50 mL) and brine (50 mL). The organic layer was dried over sodium, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1 to 4/1) to afford the title compound (1.4 g, 88%) as a yellow solid. MS (ES+) C17H13FNO4 requires: 319, found: 320 [M + H]+.

Step 5: Synthesis of 6—(3,5—dimethoxyphenyl)—7—fluoroquinazolin—2—ol / 1. triphosgene O O —> N / O 2. ammonia * H2N F 3. HCI in dioxane HO N F To a on of 5—(1,3—dioxolanyl)—2—fluoro—3',5'—dimeth0xybipheny1—4—amine (1.9 g, 6.0 mmol) and triethylamine (3.0 mL, 21.4 mmol) in THF (20 mL) at 0 0C was added triphosgene (0.6 g, 2.0 mmol), and d at 0 0C for 0.5hour. After that, ammonia in methanol (3 mL, 21 mmol, 7 mol/L) was added. The reaction was stirred at 0 0C for 30 mins and quickly warmed to ambient temperature. After stirred for additional 30 mins at room temperature, the reaction e was acidified with 4 mol/L HCI in dioxane (8.2 mL) to pH 2 and then stirred at room temperature for lhour. Then the resultant solution was concentrated and purified by silica gel column chromatography (dichloromethane/methanol = 50/1 to 10/1) to afford the title compound (2.0 g, 99%) as a yellow solid. MS (ES+) C16H13FN203 requires: 300, found: 301 [M + H]+.

Step 6: Synthesis of 2—chloro—6—(3,5—dimethoxyphenyl)—7—fluoroquinazoline \o \o O I A solution of 6—(3,5—dimethoxyphenyl)—7—fluoroquinazolin-2—ol (2.0 g, 6.7 mmol) in POCl3 (30 mL) was heated at 135 0C for . After that, the reaction solution was cooled to room temperature and se added to saturated sodium bicarbonate solution (800 mL) at 0 0C. The mixture was extracted with ethyl acetate (200 mL * 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (1.1 g, 52%) as a pale yellow solid. MS (ES+) C16H12C1FN202 requires: 318, found: 319 [M + H]+.

Step 7: Synthesis of 2-chloro(2,6-dichloro-3,5-dimethoxyphenyl)fluoroquinazoline \o \o A\ /—> /I\\ CIA 0 °C 0.5 h 'o To a solution of 2—chloro—6-(3,5-dimethoxyphenyl)—7—fluoroquinazoline (1.2 g, 3.8 mmol) in acetonitrile/tetrahydrofuran (200 mL, v/v = 1/ 1) was added sulfuryl chloride (1.7 mL, 18.9mmol) at 0 OC. The resultant solution was stirred at 0 0C for 0.5hour. After that, the solution was concentrated and d with ethyl e (500 mL). The organic phase was washed by saturated sodium bicarbonate solution (200 mL) and brine (200 mL), dried over anhydrous sodium e, filtered and concentrated to afford the title compound (946 mg, 65%) as a yellow solid. MS (ES+) C16H10C13FN202 requires: 386, found: 387 [M + H]+.

Step 8: Synthesis of 2—chloro—6—(2,6—dichloro—3,5—dimethoxyphenyl)—8—fluoroquinazoline NBS DCM Mno2 DCM RT2h THF,RT,..0N H2N RTO..N Br Br 0/ POCI3 N \ 0 I + Q / S020'2 O o/ Pd(PPh3)2CI2 —~ it ~\ THF10°Cy1h CIAN/ CI 032CO3,THF/H20,80°C,3h A /O Step 9: Synthesis of 2-aminobromofluorobenzoic acid OH OH 0 NBS, DCIVI 0 RT, 2 h H2N H2N F F A solution of o—3—fluorobenzoic acid (10.85 g, 70 mmol) in dichloromethane (175 mL) was added N—bromosuccinimide (12.46 g, 70 mmol), and the mixture was stirred at room ature for 2hours. The precipitate was filtered and washed with dichloromethane (100 mL*3) to give the title compound (12.7 g, 78%) as a grey solid, which was ly used in the next step without further purification. MS (ES+) C7H5BrFN02 requires: 233, 235, found: 232, 234 [M + H]+.

Step 10: Synthesis of (2-aminobromofluorophenyl)methanol Br r 8H3 H0 THF, RT, O.N.

H2N HzN To a solution of 2—amino—5—bromo—3—fluorobenzoic acid (14.5 g, 62.2 mmol) in THF (150 mL) at 0 0C was added borohydride in THF (1 M, 310 mL), and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with methanol (150 mL), concentrated in vacuum, diluted with aqueous sodium bicarbonate (400 mL) and extracted with ethyl acetate (200 mL*3). The organic layers were separated, combined, washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (13.0 g, crude), which was directly used in the next step without the further purification. MS (ES+) C7H7BrFNO requires: 219, 221, found: 220, 222 [M + H]+.

Step 11: Synthesis of o—5—bromo—3—fluorobenzaldehyde Hz/NUQ/Br H:N\/©/Br HO MnOZ, DCM 0/ RT, O.N.

F F A e of (2-aminobromofluorophenyl)methanol (13 g, 59.4 mmol) and manganese oxide (31 g, 356.4 mmol) in dichloromethane (400 mL) was stirred at room temperature overnight. The solid was ed off, and the filtrate was concentrated to give the title compound (11 g, 85%) as a light yellow solid, which was directly used in the next step without further purification.

Step 12: Synthesis of 6—bromo—8—fluoroquinazolin—2—ol Br 0 Br 0/ JL 180°C N \ + — ’ H N2 NH2 )L / HZN 2h HO N F F A stirred mixture of 2-aminobromo—3—fluorobenzaldehyde (2.17 g, 10 mmol) and urea (9 g, 150 mmol) was heated at 180 0C for 2hours. The reaction mixture was cooled to room temperature, and the resulting precipitate was filtered and washed with water (500 mL >*‘3). The moisture trapped was completely removed by the co—evaporation with toluene three times. The title compound (2 g, 83%) was obtained as a yellow solid. MS (ES+) C8H4BrFNZO requires: 242, 244, found: 243, 245 [M + H]+.

Step 13: Synthesis of 6—bromo—2—chloroquinazoline HOJLN POCI3 NI \ N’reflux 5h A solution of 6—bromoquinazolin—2—ol (9.72 g, 40 mmol) in phosphorus oxychloride (100 mL) was refluxed for Shours. The on was cooled to room temperature, and most of phosphorus oxychloride was removed under reduced pressure. The residue was dropwise added to ice water (500 mL), and the resulting precipitate was collected by the filtration to give the title nd (9 g, 87 %) as a yellow solid. MS (ES+) C8H3BrClFN2 requires: 260, 262, found: 261, 263 [M + H]+.

Step 14: sis of 2—chlor0(3,5-dimethoxyphenyl)—8—fluoroquinazoline N \ 3)ZC|2 O / A / + HO\B N \ 0 CI N . CSZCO3,THF/H20,80°C,3h A / A e of 6—bromo—2—chloro—8—fluoroquinazoline (4.0 g, 15.4 mmol), 3,5— dimethoxyphenylboronic acid (4.47 g, 16.9 mmol), cesium carbonate (10.0 g, 30.8 mmol) and Pd(PPh3)2C12 (236 mg, 0.77 mmol) in THF (200 mL) and water (10 mL) was degassed with en three times, and stirred at 80 0C for 3hours. The reaction mixture was cooled to room temperature and directly concentrated. The residue was purified by silica gel chromatography (petroleum ether:dichloromethane = 2:1 to 1:1) to afford the title compound (2.5 g, 51%) as a yellow solid. MS (ES+) C16H12C1FN202 requires: 318/320, found: 1 [M + H]+.

Step 15: Synthesis of 2-chloro(2,6-dichloro-3,5-dimethoxyphenyl)fluoroquinazoline o/ o/ O O 0/ / SOzclz 0 —> CIAN/”00 THF,0°C,1h Cl/kN/“we CI F F To a solution of 2—chloro—6—(3,5—dimethoxyphenyl)—8—fluoroquinazoline (1.5 g, 4.7 mmol) in dry THF (40 mL) was dropwise added sulfuryl chloride (1.59 g, 1.75 mmol) at 0 0C, and the mixture was d for lhour. The reaction was quenched with water (1 mL), and the solvents were removed under reduced pressure. The residue was washed with acetonitrile and dried to give the title compound (700 mg, 38%) as a white solid. (MS (ES+) C16H10Cl3FN202 requires: 386, 388, found: 387, 389 [M + HT“.

S nthesis of 2—chloro—6— 2 6—dichloro—3 5—dimethox hen l —5—fluoro line :Soi» 5h; SEED cl) F EEEBr CH30H 78 0c H2N THF, ooc CH20|2 H2N 180°C POCI B —’3 r t HOJLN + H0 ”ea ‘B / 135°C,5h * o Pd(t—BU3P)2, C32003 so Cl2 2 —> 0/ FCOO/ THF/H20 CH3CN/THF Cl/k/J\\ 80 Oc, O/N. 0°C, 1h Step 1: Synthesis of 6—amino—3—bromo—2—fluorobenzoic acid HS-78 °cHjb/B To a solution of 2—amino—6—fluorobenzoic acid (12.0 g, 77.35 mmol) in methanol (150 mL) was added bromine (15.7 mL) at —78 0C, and the mixture was d 2hours at —78 0C. The reaction mixture was ed with ice—water (100 mL) and aqueous solution of sodium sulfothioate, and extracted with ethyl acetate (150 mL X 3). The organic layers were separated, combined, washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated to afford the title crude product (9.0 g, 50%). MS (ES+) C7H5BrFNOZ requires: 232, found: 233, 235 [M + H]+.

Step 2: Synthesis of (6-aminobromofluorophenyl)methanol OH F 0H F Ogb/Br Br BH3_THF b THF, 0 0C H2N H2N To a solution of 6—amino—3—bromo—2—fluorobenzoic acid (9.0 g, 38.46 mmol) in THF (150 mL) was added BH3—THF (l M, 193 mL) at 0 0C, and the mixture was stirred at room temperature overnight. The on was slowly quenched with methanol (50 mL), and the ts were removed under reduced pressure. The residue was diluted with 200 mL of ethyl acetate, washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, filtered and trated to afford the title product (8.3 g, 98%), which was directly used in the next step without further purification. MS (ES+) C7H7BrFNO requires: 219, found: 220, 222 [M + H]+.

Step 3: Synthesis of obromofluorobenzaldehyde OH F O F b3 | Mn02 —> fiBr H2N CH2C|2 HzN A suspension mixture of (6—amino—3—bromo—2—fluorophenyl)methanol (8.3 g, 37.72 mmol) and manganese(IV) oxide (19.68 g, 226.32 mmol) in dichloromethane (400 mL) was stirred at room temperature overnight. The solid was filtered off, and the filtrate was concentrated to give the title product as a light yellow solid (6.0 g, 73%), which was directly used in the next step without further purification. MS (ES+) C7H5BrFNO requires: 217, found: 218, 220 [M + H]+.

Step 4: Synthesis of 6—bromo—5—fluoroquinazolin—2—ol O F Br 0 Br +HZNJLNHH2 180°C neat H2N HOJ\\N A mixture of 6—amino—3—bromo—2—fluorobenzaldehyde (3.0 g, 13.76 mmol) and urea (12.40 g, 206.40 mmol) was heated to 180 OC and stirred for 2hours. The reaction mixture was cooled to room temperature. The resulting precipitate was collected, washed with water (3 x 100 mL) and co—evaporated with toluene three times to tely remove the moisture trapped. The title compound (3.3 g, 99%) was obtained as a yellow solid. MS (ES+) C8H4BrFNzO requires: 242, found: 243, 245 [M + H]+.

Step 5: Synthesis of 6-bromochlorofluoroquinazoline Br POCI3 HOJ\\N —>C|/k\N135 °C, 5 h Nib/Br A solution of 6—bromo—5—fluoroquinazolin—2—ol (3.0 g, 12.34 mmol) in phosphoryl trichloride (10 mL) was refluxed at 135 0C for 5hours. Most of phosphoryl trichloride was removed under reduced pressure, and the residue was dropwise added to ice water (200 mL). The resulting precipitate was ted via filtration as a yellow solid (31 g, 96%). MS (ES+) CSH3BrClFN2 requires: 260, found: 261, 263 [M + H]+.

Step 6: Synthesis of 2-chloro(3,5-dimethoxyphenyl)—5—fluoroquinazoline A +HO\C$);©£\O/Pd(t—BU3P)2, 052003 N/ \ THF/H20 80 °C, O/N. CI*N A mixture of 6—bromo—2—chloro—5—fluoroquinazoline (1.5 g, 5.74 mmol), 3,5— dimethoxyphenylboronic acid (1.15 g, 6.31 mmol), cerium carbonate (1.87 g, 5.74 mmol) and bis(tri—tert—butylphosphine)palladium (148 mg, 0.29 mmol) in THF (30 mL) and water (3 mL) was degassed with nitrogen for three times and stirred at 80 0C overnight. The mixture was cooled to room temperature and extracted with ethyl acetate (3 x 200 mL). The ed organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography leum ether:ethyl acetate 2 8: 1) to get the title product as a white solid (1.3 g, 70%). MS (ES+) ClFN202 requires: 318, found: 319, 321 [M + H]+.

Step 7: Synthesis of 2—chloro—6—(2,6—dichloro—3,5—dimethoxyphenyl)—5—fluoroquinazoline S020'2 FCIOO/ CH3CN/THFC /l\\ 0°C, 1h To a solution of 2—chloro—6—(3,5—dimethoxyphenyl)—5—fluoroquinazoline (1.25 g, 3.92 mmol) in dry acetontrile/THF (20 mL/10 mL) was se added sulfuryl chloride (1.32 g, 9.80 mmol) at —20 0C, and the mixture was stirred for lhour. The reaction was quenched with water (1 mL), and the solvents were d under reduced pressure. The precipitate was washed with acetontrile and dried to give the title product (886.5 mg, 56%) as a white solid. MS (ES+) C13FN202 requires: 386, found: 387, 389 [M + H]+.

S nthesis of 2—chloro—6— 2 6—dichloro-3 thox hen l —7—methox uinazoline NH2 0 NH2 NH2 OH BH3-THF OH IV"‘02 NBS(1eq) —> —> —> CHzClz, RT \o THF, o 00— RT \o \0 CHZCIZ NH2 i H2N NH2 Br CH0 N \ POCI3 180 C neat° A \ HO N/ 0/ 130°C 5h Cl1N: Cszcog, Pd(PPh3)2C|2 SOZCIZ O/—> N\ THFdioxane, H08°C3h> N \ 2 5 CHsCN 20% 1h , , , CI/kN/| O CIN 0 Step 1: Synthesis of (2—amino—4—methoxyphenyl)methanol NHZO NH2 BH3—THF OH THF OOC- RT \0 To a solution of 2—amino—4—methoxybenzoic acid (15.0 g, 89.8 mmol) in THF (300 mL) was added borohydride in THF (450 mL, 450 mmol) at 0 0C, and the reaction mixture was stirred at room ature overnight. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (500 mL x3). The organic layers were separated, combined, washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound. MS (ES+) C8H11NOZ requires: 153, found: 154 [M + H]+.

Step 2: Synthesis of 2—amino—4—methoxybenzaldehyde NH2 NH2 CH CI RT \0 2 2 , \O A mixture of (2—amino—4—methoxyphenyl)methanol (20 g, 131.0 mmol) and manganese oxide (68 g, 786.0 mmol) in romethane (300 mL) was stirred at room temperature overnight. The solid was filtered off, and the filtrate was trated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 6: 1) to give the title compound (7 g, 35%) as a yellow solid. MS (ES+) C3H9N02 requires: 151, found: 152 [M + H]+.

Step 3: Synthesis of 2—amino—5—bromo—4—methoxybenzaldehyde NH2 NH2 NBS (1 eq) \OOCHO CH2C|2 \0 To a stirred solution of o—4—methoxybenzaldehyde (6 g, 39.7 mmol) in dichloromethane (100 mL) was added N—bromosuccinimide (7 g, 39.7 mmol). The reaction e was diluted with dichloromethane and water. The separated organic layer was dried sodium sulfate, filtered and concentrated to give the title compound (5 g, 56%) as a yellow solid. MS (ES+) CsHsBI'NOZ requires: 229, 231, found: 230, 232 [M + H]+.

Step 4: Synthesis of 6—bromo—7—methoxyquinazolin—2—ol CH0 0 180°C neat + H2NJJ\NHZ—> ml/UZL A mixture of 2-aminobromomethoxybenzaldehyde (3 g, 13.1 mmol) and urea (12 g, 196.5 mmol) was stirred at 180 0C for 2hours. The reaction mixture was cooled to room temperature and washed with water (3 x 100 mL). The precipitate was collected and dried to give the title compound (3 g, crude) as a yellow solid. MS (ES+) C3H7BI'N202 requires: 254, 256, found: 255, 257 [M + H]+.

Step 5: Synthesis of 6—bromo—2—chloro—7—methoxyquinazoline HOAN/ 63Br 0/ —>Cl)\N130°C 5h 33L: To a solution of 6—bromo—7—methoxyquinazolin—2—ol (3.0 g, 11.8 mmol) in phosphoryl trichloride (30 mL) was refluxed at 130 0C for Shours. The on was cooled to room temperature, and most of phosphoryl trichloride was evaporated. The residue was dropwise added to ice water (100 mL), and the resulting precipitate was collected via tion to give the title compound as a yellow solid (2.4 g, 75%). MS (ES+) C9H6BrClNZO requires: 272, 274, found: 273, 275 [M + H]+.

Step 6: Synthesis of 2—chloro—6—(3,5—dimethoxyphenyl)—7—methoxyquinazoline )NL/IZBr\ ‘ Pd(PPh3)ZCIZ CI N/ o HO‘B 0/ THF.dioxane,H20, 85°C,3h | I A mixture of 6—bromo—2—chloro—7—methoxyquinazoline (2.4 g, 8.82 mmol), 3,5— dimethoxyphenylboronic acid (1.6 g, 8.82 mmol), cerium carbonate (8.6 g, 26.46 mmol) and Pd(PPh3)2Clg (1.4 g, 2.1 mmol) in THF (10 mL), dioxane (10 mL) and water (2 mL) was degassed with nitrogen three times and stirred at 85 °C for 3hours. The mixture was cooled to room temperature and extracted with romethane (3 x 50 mL). The organic layers were separated, combined, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate 2 1:4) to give the title compound (1.1 g, 38%) as a white solid. MS (ES+) C1N203 requires: 330, 332, found: 331, 333 [M + H]+.

Step 7: Synthesis of 2-chloro(2,6-dichloro-3,5-dimethoxyphenyl)methoxyquinazoline SOZCIZ N \ CH CN, -20°C, 1 h l 3 CI/kN/ C' To a solution of ro—6—(3,5—dimethoxyphenyl)—7-methoxyquinazoline (200 mg, 0.61 mmol) in acetonitrile (5 mL) was added sulfuryl chloride (205 mg, 1.52 mmol), and the mixture was stirred at —20 0C for lhour. The reaction was quenched with water (1 mL) and trated under reduced re. The precipitate was washed by acetonitrile and dried to give the title compound as a white solid (120 mg, 50%). MS (ES+) C17H13C13N203 requires: 398, found: 399, 401 [M+H]+.

NMR and LC-MS data for certain compounds is shown in the table below. The synthetic protocol used to prepare the compounds is also indicated.

Compound Synthetic LC-MS Number Protocol 1HNMR (M+1) 1 358 1H NMR (400 MHz, DMSO—d6) 8 9.19 (s, 1H), 8.47 (d, J : 8.0 Hz, 1H), 8.12 (s, 1H), 8.01 (d, J : 2.2 Hz, 1H), 7.96 — 7.84 (m, 2H), 7.82 (dd, J : 8.7, 2.1 Hz, 1H), 7.69 (d, J : p—i 423 8.3 Hz, 1H), 7.62 — 7.45 (m, 2H), 7.12 (d, J : 8.1 Hz, 1H), 4.45 (s, 1H), 4.34 (s, 1H), 1.97 (dd, J : 17.7, 9.8 Hz, 3H), 1.81 — 1.62 (m, 3H), 1.56 (s, 1H). 1H NMR (400 MHz, DMSO—d6) 8 9.19 (s, 1H), 8.47 (d, J : 8.0 Hz, 1H), 8.12 (s, 1H), 8.01 (d, J : 2.2 Hz, 1H), 7.96 — 7.84 (m, 2H), 7.82 (dd, J : 8.7, 2.1 Hz, 1H), 7.69 (d, J : 8.3 Hz, 1H), 7.62 — 7.45 (m, 2H), 7.12 (d, J : 8.1 Hz, 1H), 4.45 (s, 1H), 4.34 (s, 1H), 1.97 (dd, J : 17.7, 9.8 Hz, 3H), 1.81 — 1.62 (m, 3H), 1.56 (s, 1H). 1H NMR (400 MHz, DMSO-d6) 8 9.11 (s, 1H), 8.41 (d, J : 8.0 Hz, 1H), 7.77 (d, J: 1.9 Hz, 1H), 7.59 (dd, J: 8.6, 2.0 Hz, 1H), 7.49 (d, J: 8.7 Hz, 1H), 7.36 (dd, J: 9.0, 1.8 Hz, 1H), 7.21 (t, J: 9.0 Hz, 1H), 7.09 (d, J: 8.0 Hz, 1H), 4.39 (s, 1H), 4.28 (s, 1H), 3.84 (s, 3H), 1.91 (m, 1H), 1.88 (m, 1H), 1.71 (m, 1H), 1.62 (m, 2H), 1.51 (s, 1H).

H NMR (400 MHz, DMSO-dfi) 8 9.11 (s, 1H), 8.41 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.64 — 7.43 (m, 2H), 7.26 (t, J = 9.0 Hz, 1H), 7.17 (dd, J: 9.3, 5.0 Hz, 1H), 7.07 (d, J: p—n 453 8.1 Hz, 1H), 4.39 (m, 1H), 4.28 (m, 1H), 4.11 (q, J: 7.0 Hz, 2H), 4.03 (s, 1H), 1.89 (m, 2H), 1.67 (m, 3H), 1.50 (m, 1H), 1.32 (t, J: 7.0 Hz, 3H).

H NMR (400 MHz, DMSO—d6) 8 9.17 (s, 1H), 8.44 (dd, J = 20.1, 6.1 Hz, 2H), 7.81 (d, J: 2.1 Hz, 1H), 7.78 — 7.71 (m, 3H), 7.54 (d, J: 8.6 Hz, 1H), 7.40 (d, J: 8.5 Hz, 1H), 454 7.05 (d, J: 8.1 Hz, 1H), 4.51 — 4.40 (m, 1H), 4.33 (m, 1H), 2.85 (tq, J: 7.9, 4.1 Hz, 1H), 2.31 (s, 3H), 1.96 (m, 2H), 1.84 — 1.62 (m, 3H), 1.55 (m, 1H), 0.67 (m, 2H), 0.56 (m, 2H). 1H NMR (400 MHz, DMSO-d6) 8 9.17 (s, 1H), 8.06 (d, J : 8.3 Hz, 1H), 7.86 (d, J : 2.1 Hz, 1H), 7.75 (dd, J : 8.7, 2.1 Hz, 1H), 7.52 (d, J : 8.7 Hz, 1H), 7.15 (d, J : 7.9 Hz, 1H), 6.75 (d, J : 2.8 Hz, 1H), 6.61 (d, J : 2.8 Hz, 1H), 6.21 (dd, J :17.1, 10.2 Hz, 1H), 6.00 (dd, J : 17.1, 2.2 455 Hz, 1H), 5.54 (dd, J : 10.2, 2.2 Hz, 1H), 4.78 (p, J : 6.8 Hz, 1H), 4.65 (dt, J : 12.8, 6.1 Hz, 1H), 4.09 (dd, J : 8.6, 6.9 Hz, 1H), 4.04 — 3.98 (m, 1H), 3.88 (s, 3H), 3.80 (s, 3H), 3.68 (ddd, J : 14.0, 8.8, 5.7 Hz, 2H).

H NMR (400 MHz, DMSO'd6) 8 9.14 (s, 1H), 8.42 (d, J : 4.3 Hz, 1H), 7.83 (d, J: 8.0 Hz, 1H), 7.80 (d, J: 2.1 Hz, 1H), 7.78 — 7.69 (m, 3H), 7.52 (d, J : 8.6 Hz, 1H), 7.40 (d, J: 8.5 Hz, 1H), 7.00 (d, J: 7.8 Hz, 1H), 6.20 (dd, J: 17.1, 10.1 Hz, 1H), 6.00 (dd, J: 17.1, 2.3 Hz, 1H), 5.52 (dd, J: 10.2, 2.3 Hz, 1H), 4.50 — 4.43 (m, 1H), 4.38 (q, J: 6.6 Hz, 1H), 2.85 (td, J: 7.3, 3.7 Hz, 1H), 2.31 (s, 3H), 2.06 — 1.97 (m, 1H), 1.93 (dd, J: 12.4, 6.4 Hz, 1H), 1.76 (d, J: 5.9 Hz, 1H), 1.75 —1.55(m,3H), 0.73 — 0.63 (m, 2H), 0.60 — 0.51 (m, 2H). 1H NMR (400 MHz, DMSO—d6) 8 9.14 (s, 1H), 8.54 (t, J : 5.7 Hz, 1H), 8.42 (d, J : 7.9 Hz, 1H), 8.15 (d, J : 2.2 Hz, 1H), 8.07 (dd, J : 8.8, 2.2 Hz, 1H), 7.75 (s, 1H), 7.51 (d, J : 8.8 Hz, 1H), 7.41 — 7.30 (m, 2H), 7.02 (d, J : 8.1 458 Hz, 1H), 4.44 — 4.36 (m, 1H), 4.31 — 4.22 (m, 1H), 4.03 (s, 1H), 3.84 (s, 3H), 1.89 (dq, J : 15.6, 7.7, 6.3 Hz, 2H), 1.77 — 1.57 (m, 3H), 1.50 (dd, J : 9.4, 5.1 Hz, 1H), 1.20 (d, J : 6.6 Hz, 1H), 1.10 (t, J : 7.2 Hz, 3H). 1H NMR (400 MHz, DMSO-d6) 8 9.18 (s, 1H), 8.61 (t, J : 5.6 Hz, 1H), 8.46 (d, J : 8.0 Hz, 1H), 7.94 (dd, J : 13.2, 2.1 Hz, 2H), 7.83 (ddd, J : 21.0, 8.5, 2.2 Hz, 2H), 7.68 (d, J : 8.4 Hz, 1H), 7.55 (t, J : 8.3 Hz, 1H), 7.10 (d, J : 8.1 11 462 Hz, 1H), 6.76 (d, J : 7.9 Hz, 1H), 4.51 — 4.39 (m, 1H), 4.33 (s, 1H), 2.95 (s, 2H), 2.05 — 1.82 (m, 1H), 1.82 — 1.63 (m, 3H), 1.54 (d, J : 7.9 Hz, 1H), 1.29 — 1.20 (m, 3H), 0.91 — 0.77 (m, 1H). 1H NMR (400 MHz, 6) 8 11.93 (s, 1H), 9.19 (s, 1H), 8.92 (s, 1H), 8.48 (d, J : 7.9 Hz, 1H), 7.94 (d, J : 2.1 Hz, 1H), 7.87 (d, J : 2.1 Hz, 1H), 7.81 (td, J : 8.8, 2.1 Hz, 2H), 7.72 (d, J : 8.4 Hz, 1H), 7.56 (d, J : 8.9 Hz, 1H), 12 464 7.14 (d, J : 7.9 Hz, 1H), 4.39 (d, J : 46.7 Hz, 2H), 3.72 (s, 3H), 2.03 — 1.85 (m, 1H), 1.83 — 1.64 (m, 2H), 1.61 — 1.50 (m, 1H), 1.41 (ddd, J : 17.0, 11.1, 6.3 Hz, 1H), 0.88 — 0.78 (m, 1H). 13 1H NMR (400 MHz, DMSO—dg) 8 9.18 (s, 1H), 8.53 (d, J 470 = 4.1 Hz, 1H), 8.46 (d, J: 8.0 Hz, 1H), 8.18 (d, J: 2.2 Hz, 1H), 8.10 (dd, J: 8.8, 2.2 Hz, 1H), 7.75 (d, J: 1.5 Hz, 1H), 7.55 (d, J: 8.7 Hz, 1H), 7.42 (t, J: 2.0 Hz, 1H), 7.35 (t, J: 1.8 Hz, 1H), 7.06 (d, J: 8.1 Hz, 1H), 4.49 — 4.40 (m, 1H), 4.31 (m, 1H), 3.88 (s, 3H), 2.87 (dd, J: 7.4, 3.8 Hz, 1H), 1.93 (m, 2H), 1.81 — 1.60 (m, 3H), 1.55 (m, 1H), 0.71 (dt, 12 6.8, 3.3 Hz, 2H), 0.59 (p, J: 4.5 Hz, 2H). 14 471 1H NMR (400 MHz, 6) 8 9.13 (s, 1H), 8.48 (d, J : 8.1 Hz, 1H), 7.87 (d, J : 8.5 Hz, 1H), 7.65 (s, 1H), 7.54 — 7.44 (m, 2H), 7.00 (s, 1H), 6.28 — 6.12 (m, 1H), 6.04 (dd, 473 J : 17.1, 2.3 Hz, 1H), 5.56 (dd, J : 10.1. 2.3 Hz, 1H), 4.66 — 4.51 (m, 1H), 4.51 — 4.32 (m, 1H), 3.97 (s, 6H), 2.22 — 1.93 (m, 2H), 1.77 — 1.47 (m, 2H). 1H NMR (400 MHz, DMSO—d6) 8 9.19 (s, 1H), 8.57 (d, J : 4.3 Hz, 1H), 8.46 (d, J : 8.0 Hz, 1H), 7.93 (dd, J : 8.4, 2.2 Hz, 2H), 7.83 (ddd, J : 20.7, 8.5, 2.2 Hz, 2H), 7.69 (d, 16 8.3 Hz, 1H), 7.55 (d, J : 8.8 Hz, 1H), 7.12 (d, J : 8.1 Hz, 474 1H), 4.45 (s, 1H), 4.34 (s, 1H), 3.61 (dd, J : 18.4, 11.5 Hz, 1H), 3.15 (dd, J : 7.3, 4.4 Hz, 2H), 2.86 (td, J : 7.3, 3.7 Hz, 2H), 1.95 (d, J : 8.2 Hz, 3H), 1.87 — 1.61 (m, 3H), 1.56 (s, 1H). 1H NMR (400 MHz, DMSO—d6) 8 9.18 (s, 1H), 8.57 (d, J : 4.2 Hz, 1H), 7.93 (dd, J: 8.6, 2.2 Hz, 2H), 7.83 (ddd, J : 19.8, 8.6, 2.2 Hz, 2H), 7.69 (d, J: 8.4 Hz, 1H), 7.52 (dd, J: 21.6, 8.4 Hz, 2H), 7.07 (s, 1H), 4.47 — 4.38 (m, 1H), 17 4.36 — 4.20 (m, 1H), 2.86 (td, J: 7.3, 3.7 Hz, 1H), 2.01 478 (qd, J: 75,27 Hz, 3H), 1.88 (dd, J: 12.1, 6.9 Hz, 1H), 1.82 — 1.50 (m, 3H), 1.25 (q, J: 7.1, 6.6 Hz, 1H), 1.14 (d, J: 13.2 Hz, 1H), 0.88 (t, J: 7.6 Hz, 2H), 0.69 (dt, J: 6.9, 3.3 Hz, 2H), 0.61 — 0.51 (m, 2H). 1H NMR (400 MHz, DMSO-d6) 8 9.18 (s, 1H), 8.57 (d, J : 4.2 Hz, 1H), 7.93 (dd, J : 8.6, 2.2 Hz, 2H), 7.83 (ddd, J : 19.8, 8.6, 2.2 Hz, 2H), 7.69 (d, J : 8.4 Hz, 1H), 7.52 (dd, J : 21.6, 8.4 Hz, 2H), 7.07 (s, 1H), 4.47 — 4.38 (m, 1H), 18 4.36 — 4.20 (m, 1H), 2.86 (td, J : 7.3.3.7 Hz, 1H), 2.01 478 (qd, J : 7.5, 2.7 Hz, 3H), 1.88 (dd, J : 12.1, 6.9 Hz, 1H), 1.82 — 1.50 (m, 3H), 1.25 (q, J : 7.1, 6.6 Hz,1H),1.14(d, J : 13.2 Hz, 1H), 0.88 (t, J : 7.6 Hz, 2H), 0.69 (dt, J : 6.9. 3.3 Hz, 2H), 0.61 — 0.51 (m, 2H). 1H NMR (400 MHz, DMSO—d6) 8 11.72 (s, 1H), 9.16 (s, 1H), 8.45 (d, J : 8.1 Hz, 1H), 7.89 (s, 1H), 7.80 — 7.64 (m, 19 482 2H), 7.53 (d, J : 8.6 Hz, 1H), 7.11 (d, J : 8.0 Hz, 1H), 4.43 (s, 1H), 4.32 (s, 1H), 3.71 (s, 3H), 1.94 (s, 2H), 1.71 (d, J = 33.6 Hz, 3H), 1.55 (s, 1H), 1.24 (q, J = 7.0, 6.5 Hz, 2H). 1H NMR (400 MHz, DMSO-d6) 8 9.15 (s, 1H), 8.46 (d, J : 8.0 Hz, 1H), 7.67 (s, 1H), 7.59 — 7.45 (m, 2H), 7.10 (d, J : 8.0 Hz, 1H), 7.01 (s, 1H), 4.44 (s, 1H), 4.33 (s, 1H), 3.97 486 (s, 6H), 2.05 — 1.85 (m,2H), 1.72 (d, J : 30.6 Hz, 3H), 1.55 (s, 1H). 1H NMR (400 MHz, DMSO—d6) 8 9.36 (br s, 1H), 8.65 (br s, 1H), 7.87—7.60 (m, 4H), 7.04 (s, 1H), 6.28 (dd, J : 17.0, 21 10.2 Hz, 1H), 6.22 (dd, J = 17.0, 2.3 Hz, 1H), 5.70 (dd, J = 487 .2, 2.3 Hz, 1H), 4.23 (m, 2H), 3.97 (s, 6H), 2.14 (m, 2H), 2.01 (m, 2H), 1.81-1.65 (m, 2H). 1H NMR (400 MHz, DMSO-d6) 8 9.49 (br s, 1H), 8.95 (br s, 1H), .86 (m, 4H), 7.05 (s, 1H), 6.34 (dd, J : 17.0, 22 10.2 Hz, 1H), 6.25 (dd, J : 17.0, 2.3 Hz, 1H), 5.76 (dd, J : 487 .2, 2.3 Hz, 1H), 4.24 (m, 2H), 3.99 (s, 6H), 2.13 (m, 2H), 2.02 (m, 2H), 1.87—1.74 (m, 2H). 1H NMR (400 MHz, DMSO—d6) 8 9.3 (s, 1H), 8.01—7.72 (m, 5H), 7.04 (s, 1H), 6.21 (dd, J: 17.0, 10.2 Hz, 1H), 23 5.94 (dd, J: 17.0, 2.3 Hz, 1H), 5.50 (dd, J: 10.2, 2.3 Hz, 487 1H), 4.49 (m, 2H), 3.96 (s, 6H), 2.04 (m, 2H), 1.85 (m, 2H), 1.69—1.61 (m, 2H) 1H NMR (400 MHz, DMSO—d6) 8 9.13 (s, 1H), 7.82 (d, J : 8.1 Hz, 1H), 7.65 (s, 1H), 7.57 — 7.38 (m, 2H), 7.09 — 6.92 (m, 2H), 6.21 (dd, J : 17.1, 10.2 Hz, 1H), 6.00 (dd, J 24 488 : 17.1, 2.2 Hz, 1H), 5.52 (dd, J : 10.2, 2.2 Hz, 1H), 4.41 (d, J : 31.7 Hz, 2H), 3.97 (s, 6H), 2.11 — 1.88 (m, 1H), 1.84 — 1.52 (m, 3H), 1.25 (m, J : 10.0 Hz, 1H). 488 1H NMR (400 MHz, DMSO-d6) 5 9.16 (s, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.73 — 7.64 (m, 1H), 7.61 — 7.46 (m, 2H), 7.18 (d, J = 7.9 Hz, 1H), 7.00 (s, 1H), 6.22 (dd, J 217.0, 26 10.2 Hz, 1H), 6.01 (dd, J = 17.0, 2.2 Hz, 1H), 5.54 (dd, J = 489 .2, 2.2 Hz, 1H), 4.79— 4.75 (m, 1H), 4.69— 4.64 (m, 1H), 4.17 — 4.05 (m, 1H), 4.04— 3.99 (m, 1H), 3.96 (s, 6H), 3.75— 3.69 (m, 2H). 1H NMR (400 MHZ, DMSO—d6) 8 9.16 (s, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.71 — 7.65 (m, 1H), 7.59 — 7.50 (m, 2H), 7.18 (d, J = 7.9 Hz, 1H), 7.00 (s, 1H), 6.22 (dd, J =17.1, 27 10.2 Hz, 1H), 6.01 (dd, J =17.1, 2.2 Hz, 1H), 5.54 (dd, J = 489 .2, 2.2 Hz, 1H), 4.79— 4.75 (m, 1H), 4.69— 4.64 (m, 1H), 4.17— 4.05 (m, 1H), 4.04— 3.99 (m, 1H), 3.96 (s, 6H), 3.73— 3.66 (m, 2H). 28 489 29 b.) 490 1H NMR (400 MHz, DMSO—d6) 8 9.17 (s, 1H), 8.49 (dd, J 492 = 20.3, 6.2 Hz, 2H), 7.90 (d, J = 2.1 Hz, 1H), 7.78 (dd, J = 8.7, 2.2 Hz, 1H), 7.67 (dd, J = 20.4, 8.7 Hz, 2H), 7.54 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 4.44 (s, 1H), 4.33 (s, 1H), 2.83 (td, J = 7.3, 3.7 Hz, 1H), 2.04 — 1.88 (m, 2H), 1.84 — 1.64 (m, 3H), 1.55 (d, J = 7.7 Hz, 1H), 0.70 (td, J = 7.0, 4.7 Hz, 2H), 0.59 — 0.48 (m, 2H). 1H NMR (400 MHz, é) 8 9.16 (s, 1H), 8.51 (d, J : 7.5 Hz, 1H), 7.67 (d, J = 1.9 Hz, 1H), 7.57 — 7.45 (m, 31 2H), 7.04 (d, J = 7.6 Hz, 1H), 7.01 (s, 1H), 4.21 (s, 2H), 499 3.97 (s, 6H), 1.89 (s, 1H), 1.79 (m, 2H), 1.62 (s, 2H), 1.54 (m, 2H), 1.39 (s, 2H).

H NMR (400 MHz, DMSO-dé) 8 9.13 (s, 1H), 7.71 (d, J : 8.5 Hz, 1H), 7.66 — 7.60 (m, 1H), 7.55 — 7.42 (m, 2H), 7.05 (d, J: 8.1 Hz, 1H), 6.99 (s, 1H), 6.09 (dd, J :17.1, .1 Hz, 1H), 5.95 (dd, J: 17.0, 2.3 Hz, 1H), 5.44 (dd, J: 32 499 .0, 2.3 Hz, 1H), 4.52 (t, J: 7.2 Hz, 1H), 4.18 — 4.07 (m, 1H), 3.96 (s, 6H), 2.00 (td, J: 11.8, 4.4 Hz, 1H), 1.89 (dd, J: 12.3, 7.5 Hz, 1H), 1.44 (s, 1H), 1.40 — 1.32 (m, 1H), 0.48 (m, 1H), 0.45 — 0.39 (m, 1H). 33 501 1H NMR (400 MHz, DMSO—d6) 8 9.22 (br s, 2H), 7.86 (d, J : 8.2 Hz, 1H), 7.74 (m, 1H), 7.59 (m, 2H), 7.02 (s, 1H), 34 6.34 (dd, J : 17.0, 10.2 Hz, 1H), 6.03 (dd, J : 17.0, 2.3 501 Hz, 1H), 5.55 (dd, J : 10.2, 2.3 Hz, 1H), 4.31 (m, 2H), 3.97 (s, 6H), 1.76 (m, 4H), 1.61 (m, 2H), 1.42 (m, 2H) 1H NMR (400 MHz, DMSO—d6) 8 9.21 (br s, 2H), 7.84 (d, J : 8.2 Hz, 1H), 7.73 (m, 1H), 7.58 (m, 2H), 7.01 (s, 1H), 6.34 (dd, J :17.0, 10.2 Hz, 1H), 6.03 (dd, J : 17.0, 2.3 501 Hz, 1H), 5.55 (dd, J : 10.2, 2.3 Hz, 1H), 4.27 (m, 2H), 3.97 (s, 6H), 1.75 (m, 4H), 1.60 (m, 2H), 1.43 (m, 2H). 1H NMR (400 MHz, DMSO-d6) 8 9.10 (br s, 1H), 8.07 (br s, 1H), 7.64 (br s, 1H), 7.54 (m, 1H), 7.47 (m, 1H), 7.12 (br s, 1H), 7.02 (s, 1H), 6.11 (dd, J :17.0, 10.0 Hz, 1H), 36 501 6.02 (dd, J = 17.0, 2.3 Hz, 1H), 5.48 (dd, J : 10.0, 2.3 Hz, 1H), 3.97 (s, 6H), 3.85 (m, 2H), 2.15 (m, 1H), 1.93 (m, 1H), 1.71 (m, 2H), 1.33 (m, 4H). 37 501 38 502 39 502 1H NMR (500 MHz, DMSO-d6) 8 9.17 (s, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.68 (d, J =1.9 Hz, 1H), 7.58 — 7.45 (m, 2H), 6.99 (d, J = 10.5 Hz, 2H), 6.25 (dd, J = 17.1, 10.2 Hz, 40 1H), 6.07 (dd, J = 17.0, 2.3 Hz, 1H), 5.55 (dd, J = 10.2, 2.3 503 Hz, 1H), 4.33 (d, J = 13.4 Hz, 2H), 3.97 (s, 6H), 3.84 (dd, J = 10.8, 5.8 Hz, 2H), 3.65 (dd, J = 11.7, 2.6 Hz, 1H), 3.54 (ddd, J = 11.9, 8.8, 3.2 Hz, 1H), 1.96 (dq, J = 10.9, 7.0, 5.4 Hz, 1H), 1.76 — 1.62 (m, 1H). 1H NMR (400 MHz, DMSO-d6) 8 9.14 (s, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.67 (s, 1H), 7.51 (t, J = 11.2 Hz, 2H), 7.14 (d, J = 7.3 Hz, 1H), 7.00 (s, 1H), 6.44 (dd, J = 17.0, 10.2 41 Hz, 1H), 6.03 (d, J =17.0 Hz, 1H), 5.56 (d, J = 10.4 Hz, 503 1H), 4.36 (s, 1H), 3.96 (s, 7H), 3.78 (d, J = 11.7 Hz, 1H), 3.68 — 3.50 (m, 1H), 1.96 (d, J = 11.9 Hz, 1H), 1.80 (s, 1H), 1.23 (s, 1H), 0.84 (d, J = 9.5 Hz, 1H). 42 503 1H NMR (400 MHz, DMSO-d6) 8 9.16 (s. 1H). 8.00 (d. J = 7.6 Hz, 1H), 7.68 — 7.60 (m, 1H), 7.59 — 7.39 (m, 2H), 6.97 (d, J = 16.3 Hz, 2H), 6.23 (dd, J = 17.1, 10.1 Hz, 1H), 43 6.05 (dd, J =17.1, 2.2 Hz, 1H), 5.54 (dd, J = 10.1, 2.3 Hz, 503 1H), 4.32 (s, 2H), 3.96 (s, 6H), 3.88 — 3.80 (m, 2H), 3.64 (d, J = 10.6 Hz, 1H), 3.54 (d, J = 9.1 Hz, 1H), 2.04 — 1.90 (m, 1H), 1.69 (s, 1H). 44 504 1H NMR (400 MHz, DMSO—d6) 8 9.17 (s, 1H), 7.80 (s, 1H), 7.50 (s, 1H), 7.43 (d, J = 11.4 Hz, 1H), 7.33 (s, 1H), 7.00 (s, 1H), 6.19 (dd, J = 17.0, 10.0 Hz, 1H), 5.98 (d, J = 45 505 17.0 Hz, 1H), 5.50 (d, J = 10.2 Hz, 1H), 4.53 — 4.33 (m, 3H), 3.96 (s, 6H), 2.11 — 1.89 (m, 2H), 1.81 — 1.43 (m, 3H). 1H NMR (400 MHz, DMSO—d6) 8 9.22 (s, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.54 (s, 1H), 7.51 — 7.40 (m, 1H), 7.01 (s, 1H), 6.22 (dd, J = 17.1, 10.2 Hz, 1H), 6.05 — 5.97 (m, 1H), 46 507 .58 — 5.49 (m, 1H), 4.79 (dt, J = 16.9, 9.3 Hz, 1H), 4.72 — 4.59 (m, 1H), 4.16 — 4.06 (m, 1H), 4.06 — 3.99 (m, 1H), 3.96 (s, 6H), 3.70 (ddd, J = 15.5, 8.6, 5.7 Hz, 2H). 1H NMR (400 MHz, DMSO-dé) 8 9.16 (s, 1H), 8.28 (s, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.57 — 7.45 (m, 2H), 7.00 47 513 (m, 2H), 4.21 (s, 1H), 4.16 (s, 1H), 3.97 (s, 6H), 1.91 (s, 3H), 1.77 (m, 2H), 1.67 _ 1.49 (m, 4H), 1.38 (m, 2H). 1H NMR (400 MHz, DMSO-d6) 8 9.12 (s, 1H), 8.48 (s, 1H), 7.22 (s, 1H), 7.00 (s, 1H), 6.96 (s, 1H), 4.46 (s, 1H), 48 515 4.30 (s, 1H), 3.97 (s, 6H), 3.86 (s, 4H), 1.97 (s, 2H), 1.75 (s, SH). 49 515 H NMR (400 MHz, DMSO-d6) 8 9.32 (s, 1H), 7.99 (d, J = 7.6 , 7.51 (t, J: 8.3 Hz,1H), 7.35 (d, J = 8.8 Hz, 1H), 7.30 (m, 1H), 7.03 (s, 1H), 6.23 (dd, J=17.1, 10.1 50 Hz, 1H), 6.05 (dd, J=17.1, 2.3 Hz, 1H), 5.53 (dd, J: 521 .1, 2.3 Hz, 1H), 4.32 (m, 2H), 3.97 (s, 6H), 3.89 — 3.80 (m, 2H), 3.68 — 3.60 (m, 1H), 3.59 — 3.49 (m, 1H), 1.97 (m, 1H), 1.67 (d, J: 13.1 Hz, 1H). 51 1H NMR (400 MHz, DMSO—dg) 8 9.14 (s, 1H), 7.98 (d, J 521 : 7.4 Hz, 1H), 7.80 (d, J: 8.1 Hz, 1H), 7.29 (d, J: 11.3 Hz, 17(s,1H), 7.04 (s, 1H), 6.24 (dd, J: 17.1, 10.1 Hz, 1H), 6.10 — 6.00 (m, 1H), 5.54 (dd, J: 10.1, 2.3 Hz, 1H), 4.32 (m, 2H), 3.97 (s, 6H), 3.84 (m, 2H), 3.63 (d, J: 11.5 Hz, 1H), 3.53 (t, J: 10.1 Hz, 1H), 1.96 (m, 1H), 1.67 (m, 1H). 1H NMR (400 MHz, DMSO—dé) 8 9.23 (d, J: 1.6 Hz, 1H), 7.99 (s, 1H), 7.53 (d, J: 1.8 Hz, 1H), 7.45 (dd, J: 11.5, 1.8 Hz, 1H), 7.30 (d, J: 7.7 Hz, 1H), 7.01 (s, 1H), 6.24 52 (dd, J: 17.0, 10.1Hz, 1H), 6.05 (dd, J: 17.1, 2.3 Hz, 521 1H), 5.54 (dd, J: 10.1, 2.3 Hz, 1H), 4.33 (s, 2H), 3.96 (s, 6H), 3.90 — 3.79 (m, 2H), 3.64 (d, J = 11.6 Hz, 1H), 3.53 (t, J: 10.4 Hz, 1H), 1.97 (m, 1H), 1.68 (s, 1H).

H NMR (400 MHz, DMSO—d6) 8 9.17 (s, 1H), 7.82 (s, 1H), 7.68 (dd, J: 16.3, 1.9 Hz, 1H), 7.41 (d, J: 6.8 Hz, 53 1H), 7.01 (s, 1H), 6.20 (dd, J: 17.0, 10.2 Hz, 1H), 5.99 521 (d, J: 16.9 Hz, 1H), 5.51 (d, J: 10.2 Hz, 1H), 4.44 (s, 2H), 3.96 (s, 6H), 2.00 (m, 2H), 1.87 — 1.46 (m, 4H). 1H NMR (400 MHz, DMSO—d6) 8 9.22 (s, 1H), 8.10 (s, 1H), 7.72 (m, 2H), 7.53 (d, J: 7.1 Hz, 1H), 7.01 (s, 1H), 54 6.24 (dd, J: 17.1, 10.2 Hz, 1H), 6.02 (m, 1H), 5.55 (d, J: 523 .1 Hz, 1H), 4.75 (m, 2H), 4.16 (m, 1H), 4.04 (m, 1H), 3.96 (s, 6H), 3.80 — 3.65 (m, 2H).

H NMR (400 MHz, DMSO—d6) 8 9.16 (s, 1H), 8.05 (d, J : 8.2 Hz, 1H), 7.76 (s, 1H), 7.67 (s, 1H), 7.40 (d, J: 7.7 Hz, 1H), 7.02 (s, 1H), 6.21 (dd, J: 17.1, 10.2 Hz, 1H), 55 523 6.00 (dd, J: 17.1, 2.2 Hz, 1H), 5.53 (dd, J: 10.2, 2.2 Hz, 1H), 4.71 (m, 2H), 4.09 (m, 1H), 4.05 — 3.99 (m, 1H), 3.97 (s, 6H), 3.69 (m, 2H). 1H NMR (400 MHz, DMSO-d6) 8 9.17 (s, 1H), 8.17 (dd, J : 14.3, 7.6 Hz, 1H), 7.73 — 7.67 (m, 1H), 7.61 — 7.48 (m, 2H), 7.43 (t, J : 6.8 Hz, 1H), 7.00 (d, J : 1.4 Hz, 1H), 6.23 (dtd, J :18.7, 9.2, 8.5, 1.5 Hz, 1H), 6.04 (dt, J : 17.1, 1.9 56 530 Hz, 1H), 5.56 (dt, J :10.1, 1.9 Hz, 1H), 4.82 — 4.59 (m, 2H), 3.96 (8, 6H), 3.93 — 3.77 (m, 1H), 3.72 (m, 1H), 3.59 (m, 1H), 3.55 — 3.37 (m, 2H), 1.94 (dd, J : 3.6, 1.4 Hz, 3H). 1H NMR (400 MHz, DMSO-d6) 8 9.17 (s, 1H), 8.18 (dd, J = 13.2, 7.5 Hz, 1H), 7.69 (t, J =1.4 Hz, 1H), 7.59 — 7.48 (m, 2H), 7.44 (t, J = 7.1 Hz, 1H), 7.00 (s, 1H), 6.23 (ddd, J = 16.7, 10.1, 8.6 Hz, 1H), 6.04 (dd, J = 17.1, 2.2 Hz, 1H), 57 530 .56 (dd, J : 10.1, 2.2 Hz, 1H), 4.83 — 4.59 (m, 3H), 3.96 (s, 6H), 3.93 — 3.79 (m, 1H), 3.70 (m, 1H), 3.59 (m, 1H), 3.55 — 3.46 (m, 1H), 3.45 — 3.37 (m, 2H), 1.94 (d, J : 3.4 Hz, 3H). 58 530 1H NMR (400 MHz, DMSO-d6) 8 9.16 (s, 1H), 7.89 (d, J : 7.4 Hz, 1H), 7.67 (t, J : 1.4 Hz, 1H), 7.49 (s, 2H), 6.99 (s, 1H), 6.90 (s, 1H), 6.15 (dd, J : 17.0, 10.0 Hz, 1H), 6.03 59 531 (dd, J : 17.1, 2.4 Hz, 1H), 5.50 (dd, J : 10.0, 2.5 Hz, 1H), 4.34 (s, 2H), 3.80 (m, 2H), 1.87 (t, J : 13.0 Hz, 1H), 1.51 (d, J : 13.0 Hz, 1H), 1.25 (s, 3H), 1.23 (s, 3H). 1H NMR (400 MHz, DMSO—dé) 8 9.16 (s, 1H), 7.89 (br s, 1H), 7.67 (s, 1H), 7.48 (s, 2H), 6.99 (s, 1H), 6.91 (s, 1H), 6.15 (dd, J: 17.0, 10.0 Hz, 1H), 6.03 (dd, J: 17.0.2.5 60 531 Hz, 1H), 5.50 (dd, J: 10.0, 2.5 Hz, 1H), 4.34 (s, 2H), 3.96 (s, 6H), 3.78 (d, J: 11.7 Hz, 2H), 1.87 (t, J: 13.0 Hz, 1H), 1.51 (d, J: 13.0 Hz, 1H), 1.25 (s, 3H), 1.23 (s, 3H).

.I6 531 1H NMR (400 MHz, DMso—d6) 8 9.17 (s, 1H), 7.80 (s, 1H), 7.50 (s, 1H), 7.43 (d, J : 11.4 Hz, 1H), 7.33 (s, 1H), 7.00 (s, 1H), 6.19 (dd, J : 17.0, 10.0 Hz, 1H), 5.98 (d, J : 62 532 17.0 Hz, 1H), 5.50 (d, J : 10.2 Hz, 1H), 4.53 — 4.33 (m, 3H), 3.96 (s, 6H), 2.11 — 1.89 (m, 2H), 1.81 — 1.43 (m, 3H). 1H NMR (300 MHz, DMSO—d6) 8 8.73 (d, J : 13.2 Hz, 1H), 8.05 — 7.73 (m, 2H), 7.03 (s, 1H), 6.13 (dd, J :17.0, .0 Hz, 1H), 5.99 — 5.85 (m, 1H), 5.52 — 5.38 (m, 1H), 63 533 4.37 (dd, J : 26.9, 6.6 Hz, 2H), 4.32 — 4.15 (m, 1H), 3.97 (s, 6H), 1.83 (d, J : 19.8 Hz, 4H), 1.61 (d, J : 27.5 Hz, 2H), 1.22 (t, J : 6.8 Hz, 3H), 0.96 — 0.77 (m, 1H). 64 533 1H NMR (400 MHz, Chloroform—d) 8 9.18 (s, 1H), 7.77 (d, J : 8.6 Hz, 1H), 7.73 — 7.60 (m, 2H), 7.43 (d, J : 7.5 Hz, 1H), 7.30 (s, 1H), 7.15 (s, 1H), 6.66 (s, 1H), 5.95 — 65 533 .82 (m, 1H), 5.14 — 4.95 (m, 1H), 3.99 (s, 7H), 3.42 — 3.32 (m, 0H), 3.24 — 3.10 (m, 1H), 2.68 (d, J : 13.4 Hz, 1H), 0.93 — 0.78 (m, 3H).

H NMR (400 MHz, DMSO—dé) 8 9.18 (s, 1H), 7.68 (d, J : 1.9 Hz, 1H), 7.58 — 7.46 (m, 2H), 7.18 (d, J : 7.1 Hz, 1H), 7.01 (s, 1H), 6.95 (d, J: 7.8 Hz, 1H), 6.50 (dd, J: 16.5, 9.9 Hz, 1H), 5.84 (d, J: 16.5 Hz, 1H), 5.51 (d, J: 537 9.9 Hz, 1H), 4.13 (s, 1H), 3.62 (s, 1H), 3.38 (m, 1H), 1.78 (m, 1H), 1.62 (m, 3H), 1.38 (m, 1H), 1.18 (t, J: 7.1Hz, 1H), 1.09 (t, J: 7.0 Hz, 1H).

H NMR (400 MHz, 6) 8 9.22 (s, 1H), 8.00 (d, J : 7.7 Hz, 1H), 7.70 (m, 1H), 7.44 — 7.29 (m, 1H), 7.01 (s, 1H), 6.24 (dd, J: 17.0, 10.2 Hz, 1H), 6.05 (dd, J: 17.1, 67 537 2.2 Hz, 1H), 5.55 (dd, J: 10.2, 2.2 Hz, 1H), 4.35 (m, 2H), 3.96 (s, 6H), 3.85 (m, 2H), 3.67 (m, 1H), 3.54 (m, 1H), 1.98 (m, 1H), 1.68 (m, 1H). 68 1H NMR (400 MHz, DMSO—d6) 8 8.52 (d, J = 8.1 Hz, 543 1H), 8.37 (s, 1H), 7.63 (s, 1H), 6.97 (s, 1H), 6.73 (d, J = 8.2 Hz, 1H), 6.51 (s, 1H), 4.27 (m, 1H), 4.15 — 4.06 (m, 3H), 3.95 (s, 6H), 2.69 (s, 1H), 1.73 (m, 3H), 1.59 (m, 3H), 1.38 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H). 1H NMR (400 MHz, DMSO—dé) 8 9.17 (d, J: 23.3 Hz, 1H), 8.01 (dd, J : 22.5, 7.8 Hz, 1H), 7.73 — 7.63 (m, 1H), 7.61 _ 7.44 (m, 2H), 7.16 (dd, J: 19.0, 7.3 Hz, 1H), 7.00 (d, J: 1.? Hz, 1H), 6.26 (ddd, J: 16.9, 10.1, 6.6 Hz, 1H), 69 544 6.12 — 6.01 (m, 1H), 5.56 (ddd, J: 23.8, 10.1, 2.2 Hz, 1H), 4.26 (m, 2H), 4.16 — 3.99 (m, 1H), 3.96 (s, 6H), 3.90 (m, 1H), 3.63 (m, 1H), 3.14 (m, 1H), 1.99 — 1.85 (m, 1H), 1.81 (s, 3H), 1.66 (m, 1H).

H NMR (400 MHz, DMSO-d6) 5 9.17 (d, J : 23.3 Hz, 1H), 8.01 (dd, J : 22.4, 7.8 Hz, 1H), 7.74 _ 7.63 (m, 1H), 7.61 — 7.45 (m, 2H), 7.22 — 7.10 (m, 1H), 7.00 (d, J: 1.7 Hz, 1H), 6.26 (ddd, J: 17.0, 10.2, 6.7 Hz, 1H), 6.12 — 70 544 6.01 (m, 1H), 5.56 (ddd, J: 23.8, 10.2, 2.2 Hz, 1H), 4.26 (d, J : 46.4 Hz, 2H), 4.16 — 4.04 (m, 1H), 3.96 (s, 6H), 3.63 (dd, J: 56.7, 14.0 Hz, 1H), 3.14 (s, 1H), 1.85 (d, J: 36.3 Hz, 3H), 1.66 (s, 1H). 1H NMR (400 MHz, DMSO—d6) 8 9.16 (s, 1H), 7.93 (d, J : 7.0 Hz, 1H), 7.68 (d, J: 2.1 Hz, 1H), 7.61 — 7.45 (m, 2H), 7.10 (d, J: 7.8 Hz, 1H), 7.00 (s, 1H), 6.39 (dd, J: 71 17.1, 10.2 Hz, 1H), 6.05 (dd, J: 17.1, 2.2 Hz, 1H), 5.58 544 (dd, J : 10.1, 2.3 Hz, 1H), 4.33 (m, 3H), 3.96 (s, 6H), 3.83 — 3.73 (m, 1H), 3.38 (m, 1H), 2.87 (m, 1H), 1.86 (s, 3H), 1.78 (m, 2H).

H NMR (400 MHz, DMSO-d6) 5 9.15 (s, 1H), 7.90 (d, J : 8.0 Hz, 1H), 7.66 (br s, 1H), 7.55 — 7.42 (m, 2H), 7.19 — 7.11 (m, 1H), 7.00 (m, 2H), 6.70 (s, 1H), 6.17 (dd, J: 72 17.0, 10.1 Hz, 1H), 6.02 (dd, J: 17.0, 2.3 Hz, 1H), 5.50 544 (dd, J: 10.1, 2.3 Hz, 1H), 4.47 (m, 1H), 4.00 (m, 1H), 3.96 (s, 6H), 2.49 (m, 1H), 2.13 (s, 1H), 1.81 (m, 2H), 1.65 (m, 2H), 1.51 (m, 1H). 1H NMR (400 MHz, 6) 8 9.13 (s, 1H), 7.86 (d, J : 8.3 Hz, 1H), 7.65 (s, 1H), 7.50 (q, J : 9.2 Hz, 1H), 7.00 (d, J : 7.1 Hz, 1H), 6.15 (dd, J : 17.1, 10.1 Hz, 1H), 5.98 (d, J : 15.1 Hz, 0H), 5.60 — 5.47 (m, 1H), 4.52 (s, 1H), 73 545 4.40 (s, 1H), 3.97 (d, J : 10.8 Hz, 6H), 3.61 (d, J : 11.6 Hz, 2H), 3.26 (s, 3H), 3.03 — 2.87 (m, 1H), 2.29 (d, J : .3 Hz, 1H), 2.10 — 1.90 (m, 2H), 1.25 — 1.08 (m, 1H), 0.88 (dd, J : 41.1, 7.4 Hz, 1H). 74 545 1H NMR (400 MHz, DMSO'd6) 5 9.17 (s, 1H), 8.16 (dd, J 75 = 12.1, 7.6 Hz, 1H), 7.69 (br s, 1H), 7.60 — 7.47 (m, 2H), 546 7.44 (d, J: 6.6 Hz, 1H), 7.00 (s, 1H), 6.21 (ddd, J: 16.8, .2, 6.5 Hz, 1H), 6.08 — 6.00 (m, 1H), 5.56 (dt, J: 10.2, 2.1 Hz, 1H), 4.84 — 4.54 (m, 3H), 4.00 (m, 2H), 3.96 (s, 6H), 3.86 — 3.71 (m, 2H), 3.52 — 3.37 (m, 2H).

H NMR (400 MHz, DMSO—d6) 8 9.17 (s, 1H), 8.17 (dd, J : 12.3, 7.7 Hz, 1H), 7.69 (br s, 1H), 7.61 — 7.47 (m, 2H), 7.45 (d, J: 7.5 Hz, 1H), 7.00 (s, 1H), 6.21 (ddd, J : 16.9, 76 546 .1, 6.6 Hz, 1H), 6.08 — 5.99 (m, 1H), 5.56 (dt, J: 10.1, 2.1 Hz, 1H), 4.84 — 4.62 (m, 3H), 4.00 (m, 2H), 3.96 (s, 6H), 3.86 — 3.62 (m, 2H), 3.52 — 3.38 (m, 2H).

H NMR (400 MHz, DMSO-d6) 8 8.63 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.63 (m, 2H), 6.96 (s, 1H), 6.31 (m, 1H), 77 6.00 (m, 1H), 5.51 (m, 1H), 4.40 — 4.13 (m, 4H), 3.94 (s, 546 6H), 1.85 — 1.49 (m, 6H), 1.40 (s, 2H), 1.19 (t, J: 7.1 Hz, 3H). 1H NMR (400 MHz, DMSO—d6) 8 8.72 (s, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.81 (d, J: 8.3 Hz, 1H), 7.75 (d, J: 8.0 Hz, 1H), 7.02 (s, 1H), 6.42 — 6.22 (m, 1H), 5.99 (m, 1H), 78 547 .52 (m, 1H), 4.26 (m, 4H), 3.96 (s, 6H), 1.63 (m, 6H), 1.40 (m, 2H), 1.22 (t, J: 7.3 Hz, 3H). 1H NMR (400 MHz, DMSO—dg) 8 9.18 (s, 1H), 8.16 (d, J : 9.2 Hz, 1H), 7.70 (s, 1H), 7.64 — 7.41 (m, 3H), 7.00 (s, 79 1H), 6.28 (dd, J: 17.1, 10.2 Hz, 1H), 6.06 (dd, J: 17.1, 551 2.2 Hz, 1H), 5.60 (dd, J: 102,22 Hz, 1H), 4.69 (m, 2H), 3.96 (s, 6H), 3.45 (m, 3H), 3.15 (m, 1H), 2.12 (s, 2H). 1H NMR (400 MHz, DMSO—d6) 8 9.18 (s, 1H), 8.27 — 8.14 (m, 1H), 7.69 (dq, J = 2.4, 1.2 Hz, 1H), 7.62 — 7.48 (m, 2H), 7.44 (dd, J = 10.7, 7.1 Hz, 1H), 7.00 (s, 1H), 6.32 80 — 6.18 (m, 1H), 6.05 (dq, J =17.1, 1.7 Hz, 1H), 5.62 — 5.52 556 (m, 1H), 4.73 (m, 2H), 4.16 — 4.07 (m, 1H), 3.96 (s, 6H), 3.79 — 3.58 (m, 2H), 3.45 (m, 1H), 1.74 (m, 1H), 0.80 — 0.66 (m, 4H). 1H NMR (400 MHz, DMSO—d6) 8 9.12 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.50 (q, J = 8.7 Hz, 2H), 7.17 (d, J = 7.9 Hz, 1H), 6.99 (s, 1H), 6.18 (dd, J = 17.0, 10.1 81 Hz, 1H), 6.00 (dd, J = 17.0, 2.3 Hz, 1H), 5.51 (dd, J = 558 .1, 2.3 Hz, 1H), 4.55 (s, 1H), 4.44 (s, 1H), 3.95 (s, 6H), 3.28 — 3.14 (m, 3H), 2.99 (s, 2H), 2.84 (s, 2H), 2.18 — 1.81 (m, 3H), 1.27 — 1.15 (m, 1H). 1H NMR (400 MHz, DMSO-d6) 8 9.10 (s, 1H), 7.93 (d, J = 8.3 , 7.64 (d, J = 1.5 Hz,1H), 7.47 (d, J = 3.1 Hz, 2H), 7.13 (d, J = 8.3 Hz, 1H), 6.99 (s, 1H), 6.08 (dd, J 82 217.1, 10.0 Hz,1H), 5.96 (dd, J 217.1, 2.4 Hz,1H), 5.47 558 (dd, J = 10.0, 2.4 Hz, 1H), 4.65 — 4.47 (m, 1H), 4.46 — 4.24 (m, 1H), 3.95 (s, 6H), 3.61 (td, J = 6.6, 3.9 Hz, 1H), 3.04 (s, 3H), 2.86 (s, 3H), 2.23 (s, 2H), 1.82 (ddt, J = 33.1, 14.2, 7.2 Hz, 2H).

H NMR (400 MHz, fi) 5 9.18 (s, 1H), 8.15 (d, J = 7.6 Hz, 1H), 7.69 (s, 1H), 7.61 — 7.47 (m, 2H), 7.31 (d, J = 7.2 Hz, 1H), 7.00 (s, 1H), 6.26 (dd, J: 17.1, 10.2 Hz, 1H), 6.17 (t, J: 5.6 Hz, 1H), 6.05 (dd, J=17.1, 2.2 Hz, 83 559 1H), 5.58 (dd, J: 10.1, 2.2 Hz, 1H), 4.75 — 4.55 (m, 2H), 3.96 (s, 6H), 3.69 (t, J: 8.6 Hz, 1H), 3.57 (dd, J: 10.8, 6.1 Hz, 1H), 3.41 — 3.32 (m, 2H), 3.03 (p, J: 6.8 Hz, 2H), 1.00 (t, J: 7.1 Hz, 3H). 84 560 H NMR (400 MHz, DMSO-d6) 8 9.17 (s, 1H), 8.16 (dd, J = 11.6, 7.7 Hz, 1H), 7.69 (br s, 1H), 7.59 — 7.48 (m, 2H), 7.44 (dd, J: 7.7, 3.1 Hz, 1H), 7.00 (s, 1H), 6.22 (ddd, J: 85 16.9, 10.2, 6.7 Hz, 1H), 6.04 (dt, J: 17.1, 2.2 Hz, 1H), 560 .56 (dt, J: 10.1, 2.5 Hz, 1H), 4.82 — 4.59 (m, 2H), 4.04 — 3.98 (m, 2H), 3.96 (S, 6H), 3.87 — 3.62 (m, 2H), 3.45 (m, 2H), 3.31 (s, 3H). 1H NMR (400 MHz, DMSO—d6) 8 9.17 (s, 1H), 8.16 (dd, J : 11.8, 7.6 Hz, 1H), 7.72 — 7.66 (m, 1H), 7.61 — 7.49 (m, 2H), 7.44 (dd, J : 7.5, 3.1 Hz, 1H), 7.00 (s, 1H), 6.22 (ddd, 86 J : 16.9, 10.2, 6.7 Hz, 1H), 6.04 (dt, J : 17.2, 2.2 Hz, 1H), 560 .56 (dt, J : 10.2, 2.5 Hz, 1H), 4.81 — 4.58 (m, 2H), 4.00 (s, 1H), 3.96 (s, 6H), 3.88 — 3.71 (m, 2H), 3.65 (m, 1H), 3.51 — 3.41 (m, 2H), 3.30 (s, 3H).

H NMR (400 MHz, DMSO—d6) 8 9.10 (s, 1H), 7.82 (d, J : 8.7 Hz, 1H), 7.64 (d, J: 1.7 Hz, 1H), 7.60 — 7.43 (m, 2H), 7.18 (d, J : 7.9 Hz, 1H), 6.99 (s, 1H), 6.40 (dd, J: 87 17.1, 10.2 Hz, 1H), 6.03 (dd, J: 17.1, 2.3 Hz, 1H), 5.58 572 (dd, J: 10.2, 2.3 Hz, 1H), 4.59 (s, 1H), 4.08 (s, 1H), 3.96 (s, 6H), 3.04 (m, 1H), 2.99 (s, 3H), 2.80 (s, 3H), 1.86 — 1.62 (m, 5H), 1.51 (m, 1H). 1H NMR (400 MHz, DMSO-d6) 8 9.17 (s, 1H), 8.15 (t, J: 8.1 Hz, 1H), 7.72 _ 7.66 (m, 1H), 7.59 — 7.47 (m, 2H), 7.41 (d, J: 7.4 Hz, 1H), 7.00 (s, 1H), 6.22 (ddd, J: 17.1, 88 10.1, 4.3 Hz, 1H), 6.04 (dt, J: 17.1, 2.1 Hz, 1H), 5.56 (dt, 573 J : 10.1, 2.8 Hz, 1H), 4.82 — 4.56 (m, 2H), 3.96 (s, 6H), 3.86 (m, 1H), 3.79 — 3.65 (m, 1H), 3.56 (m, 1H), 3.45 (m, 1H), 3.10 — 2.94 (m, 2H), 2.20 (s, 3H), 2.19 (s, 3H) 1H NMR (400 MHz, DMSO-d6) 8 9.20 (s, 1H), 8.16 (d, J : 7.4 Hz, 1H), 7.70 (d, J :1.7 Hz, 1H), 7.61 — 7.49 (m, 2H), 7.39 (d, J : 7.1 Hz, 1H), 7.00 (s, 1H), 6.26 (dd, J : 89 17.0, 10.2 Hz, 1H), 6.05 (dd, J =17.1,2.1Hz, 1H), 5.59 580 (dd, J : 102,21 Hz, 1H), 4.72 (m, 2H), 3.96 (s, 6H), 3.73 (m, 2H), 3.39 (ddd, J : 21.7, 10.1, 5.6 Hz, 2H), 3.15 (q, J : 7.4 Hz, 2H), 1.23 (t, J : 7.3 Hz, 3H). 90 588 1H NMR (400 MHz, DMSO-d6) 5 9.18 (s, 1H), 8.15 (t, J: 7.6 Hz, 1H), 7.69 (br s, 1H), 7.60 — 7.47 (m, 2H), 7.43 (d, J: 6.6 Hz, 1H), 7.00 (s, 1H), 6.22 (ddd, J: 17.2, 10.2, 7.1 91 4 Hz, 1H), 6.05 (ddd, J: 17.1, 3.8, 2.2 Hz, 1H), 5.57 (ddd, J 599 : 10.2, 4.9, 2.2 Hz, 1H), 4.68 (m, 2H), 3.96 (s, 6H), 3.92 — 3.70 (m, 2H), 3.69 — 3.51 (m, 2H), 3.45 (m, 3H), 2.67 (m, 3H), 1.71 (m, 4H). 92 3 602 Biochemical Activity Assessment In order to assess the activity of chemical compounds against the relevant kinase of interest, the Caliper iences electrophoretic ty shift technology platform is utilized.

Fluorescently labeled substrate peptide is incubated in the presence dosed levels of compounds, a set concentration of kinase and of ATP, so that a reflective proportion of the peptide is phosphorylated. At the end of the on, the mix of phosphorylated (product) and non— phosphorylated (substrate) peptides are passed through the microfluidic system of the Caliper LabChip® EZ Reader 11, under an applied potential difference. The presence of the ate group on the product peptide es a difference in mass and charge between the product peptide and the substrate peptide, resulting in a separation of the substrate and product pools in the sample. As the pools pass the LEDS within the instrument, these pools are detected and resolved as separate peaks. The ratio between these peaks therefore reflects the activity of the al matter at that concentration in that well, under those conditions.

FGFR—4 wild type assay at Km: In each well of a 384—well plate, 0.5 ng/ul of wild type FGFR—4 (Carna Biosciences, Inc.) was incubated in a total of 12.5 111 of buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 10 mM MgC12, lmM DTT) with 1 uM CSKtide (5—FAM— KKKKEEIYFFFG—NHZ) and 400 uM ATP at 25 C for 90 minutes in the presence or absence of a dosed concentration series of compound (1% DMSO final concentration). The reaction was stopped by the addition of 70 ul of Stop buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 35 mM EDTA and 0.2% of Coating Reagent 3 (Caliper Lifesciences)). The plate was then read on a Caliper LabChip® EZ Reader II (protocol gs: -1.9 psi, am voltage -700, downstream voltage —3000, post sample sip 35s).

Detection of pMAPK 1Thr202/Tyr2041 Using Alpha Elisa MDA—MB453 or DMS 114 cells were plated in l cell culture plates at a density of leOS cells or 3X104 cells, respectively. Cells were allowed to attach, and growth media was replaced with serum free media. Compounds were added at the indicated concentrations.

Following 1 hr tion in the presence of compound, cells were collected. For the DMS 114 cells, 100 ng/mL FGF2 was added for 10 min prior to cell collection. Cell s were prepared and processed according to manufacturer instruction (AlphaScreen® SureFireTM Phospho-ERK 1/2 Kit (Perkin Elmer).

The table below summarizes biochemical data for Compounds 1-92. In the table below, for FGFR4 and pERK alphaLISA: “A” means that the IC50 is less than 10 nM; “B” means the IC50 is greater than or equal to 10 and less than 100nM; “C” means that the IC50 is greater than or equal to 100 and less than 1000 nM; “D” means that the IC50 is greater than 1000 nM.

Compound INH- pERK Number FGFR4 alphaLISA Efficacy in an in vivo model The effects of nd 27 on tumor growth inhibition in Hep3B liver cancer cell subcutaneous xenograft model with different dosages were studied.

Female nude mice (Mus Musculus) age 6 to 8 weeks were used. Tumor cell culture and inoculation: Hep3B cells were cultured with EMEM medium (Invitrogen, USA) supplemented with 10% FBS (Gibco, Australia). The cells were harvested in 90% confluence, and the Viability was no less than 90%. Mice were implanted subcutaneously (s.c.) with 200 uL of 10 x 106 Hep3B cells in 50% Matrigel in the right flank at the beginning of the study.

Animal grouping and dosing schedule: Ten days after cell implantation, when tumors reached an average volume of 284 mm3, 36 mice were selected based on tumor volume and randomly assigned to 5 treatment groups (n=9). The day of randomization was denoted as day 0 and the ent was started from then on.

Tumor volume and body weight measurements: Tumor size was measured twice per week in two dimensions using a r, and the volume was expressed in mm3 using the formula: V = 0.5 a x b2 where a and b were the long and short diameters of the tumor, respectively. Body weight was measured at least twice .

Tumor volumes of Hep3B-bearing nude mice: Fig. 1 is a line graph depicting the growth inhibition of Compound 27—treated groups against Hep3B xenograft tumors in nude mice.

Statistically significant ion of tumor volumes was observed in 30 and 100 mg/kg PO BID cy groups when compared with vehicle group. Increasing dosage of Compound 27 enhanced the tumor inhibition efficiency. Tumors in the Compound 27—treated (100 mg/kg PO BID) group regressed.

Body weight change (%) of Hep3B—bearing nude mice: Fig. 2 is a line graph depicting the body weight change (%) during the entire study period. All the mice except for the mice in the Compound 27—treated (100 mg/kg PO BID) groups showed significant loss in bodyweight.

The body weight of mice in the vehicle group decreased by approximately 15% by Day 10 for the burden of tumor. This result indicated that Compound 27 was well tolerated at the current dosages and dosing schedule in nude mice, and that Compound 27 could alleviate body weight loss by inhibiting tumor growth.

Mice treated with nd 27 exhibited a significant reduction of tumor volume as compared with the vehicle group during the entire study. Increasing the dosage of Compound 27 from 10 mg/kg to 100 mg/kg enhanced the tumor tion efficiency. Tumors of mice in the Compound 27—treated (100 mg/kg PO BID) group regressed and almost disappeared. All mice except for those in the Compound 27-treated (100 mg/kg PO BID) groups lost bodyweight. The bodyweight of the mice in the vehicle group decreased by approximately 15% by Day 10 for the burden of tumor. These results indicated that nd 27 was well ted at the current dosages and at the dosing schedule in nude mice, and that Compound 27could ate body weight loss by inhibiting tumor growth.

Incorporation by Reference All publications and patents mentioned herein are hereby orated by reference in their ty as if each individual publication or patent was specifically and individually indicated to be incorporated by reference.

Eguivalents Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are ed to be encompassed by the following claims.

Claims (16)

What we claim is:

1. A compound of Formula I or a pharmaceutically able salt thereof, Formula I wherein: Warhead is a moiety capable of forming a covalent bond with a nucleophile; ring A is tetrahydrofuranyl or tetrahydropyranyl; each of R1 and R2 is independently selected from halo, cyano, C1-6 , hydroxy, oxo, amino, amido, alkyl urea, C1-6 alkyl, and heterocyclyl, wherein each of C1-6 alkoxy, C1-6 alkyl, and heterocyclyl is optionally substituted with 0-5 groups independently selected from halo, hydroxy, amino, cyano, and heterocyclyl; R3 is halo; m is 0-3; n is 0-4; and p is 0-2, wherein Warhead is selected from: ; ; ; ; O O ; ; and , wherein X is a g group; and each of Ra, Rb, and Rc is, ndently, H, C1-4 alkyl, C1-4 cycloalkyl, or cyano.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each of R1 and R2 is independently selected from halo, cyano, C1-6 alkoxy, hydroxy, oxo, amino, amido, alkyl urea, and C1-6 alkyl, wherein each of C1-6 alkoxy and C1-6 alkyl is optionally substituted with 0-5 groups independently ed from halo, hydroxy, amino, cyano, and heterocyclyl.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each of R1 and R2 is independently selected from halo, cyano, C1-6 alkoxy, hydroxy, oxo, amino, amido, alkyl urea, C1-6 alkyl, and heterocyclyl.

4. The compound of claim 1, or a pharmaceutically acceptable salt f, wherein each of R1 and R2 is independently selected from halo, cyano, C1-6 alkoxy, hydroxy, oxo, amino, amido, alkyl urea, and C1-6 alkyl.

5. The nd of any one of claims 1-4, or a pharmaceutically acceptable salt f, wherein the group Warhead, along with the adjacent N of Formula I, is selected from acrylamide and propargyl amide.

6. A compound according to claim 1 selected from Cl O HN HN Cl O O N , , , , , , , and , and pharmaceutically acceptable salts thereof.

7. The compound or pharmaceutically acceptable salt of claim 6, which is , or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a ceutically acceptable carrier and a compound or ceutically able salt according to any one of claims 1-7.

9. Use of a compound of any one of claims 1-7, in the manufacture of a medicament for treating a condition mediated by FGR-4.

10. Use of a compound of any one of claims 1-7, in the manufacture of a medicament for ng a condition characterized by overexpression of FGR-4.

11. Use of a compound of any one of claims 1-7, in the manufacture of a medicament for treating a condition characterized by amplified FGF-19.

12. Use of a compound of any one of claims 1-7, in the manufacture of a medicament for treating a condition characterized by overexpression of FGF-19.

13. Use of a compound of any one of claims 1-7, in the manufacture of a medicament for treating cancer, wherein the cancer is selected from the group consisting of liver cancer, breast cancer, lung cancer, n cancer, or a a.

14. Use of a compound of any one of claims 1-7, in the manufacture of a medicament for ng hepatocellular carcinoma.

15. Use of a compound of any one of claims 1-7, in the manufacture of a medicament for treating hyperlipidemia.

16. A compound which is or .