HK40042919A

HK40042919A - Novel glp-1 receptor modulators

Info

Publication number: HK40042919A
Application number: HK42021031319.3A
Authority: HK
Inventors: 马库斯·F·勃姆; 埃丝特·马丁伯勒; 玛妮莎·穆尔加尼; 淳子田宫; 黄黎明; 亚当·R·耶格尔; 埃努格尔斯伊·布拉哈马查理; 托马斯·福勒; 安德鲁·诺瓦克; 普拉姆基·玛格哈尼; 迈克尔·科奈格斯
Original assignee: 赛尔基因第二国际有限公司
Priority date: 2014-07-25
Filing date: 2021-05-18
Publication date: 2021-09-10

Description

Novel GLP-1 receptor modulators

The present application is a divisional application of chinese patent application No. 201580046095.3 entitled "new GLP-1 receptor modulator" filed on 24/7/2015.

Technical Field

The present invention relates to compounds that bind to the glucagon-like peptide 1(GLP-1) receptor, methods for their synthesis, and methods for their therapeutic and/or prophylactic use. The present invention relates to compounds suitable for use as modulators of the GLP-1 receptor, and compounds suitable for use as potentiators of incretin peptides and oxyntomodulin, such as GLP-1(7-36), GLP-1(9-36), and peptide-based therapies, such as exenatide and liraglutide.

Background

The glucagon-like peptide 1 receptor (GLP-1R) belongs to the B1 family of seven transmembrane G-protein coupled receptors, and its natural agonist ligand is the peptide hormone glucagon-like peptide-1 (GLP-1). GLP-1 is a peptide hormone produced by its selective enzymatic cleavage from glucagon (the prohormone precursor of GLP-1), which is highly expressed in enteroendocrine cells of the intestine, alpha cells of the endocrine pancreas (islets of Langerhans) and in the brain (Kieffer T.J. and Habener, J.F. endocrine. Rev.20:876-913 (1999); Drucker, D.J., endocrine 142:521-7 (2001); Holst, J.J., Diabetes metal. Res. Rev.18:430-41 (2002)). The initial action of GLP-1 observed is on the insulin producing cells of the islets of Langerhans, where it stimulates glucose-dependent insulin secretion. Subsequently, a number of additional antidiabetic effects of GLP-1 have been discovered, including stimulating the growth of pancreatic beta cells and inhibiting their apoptosis (Drucker, D.J., Endocrinology 144:5145-8 (2003); Holz, G.G., and Chepurny O.G., curr. Med.Chem.10:2471-83 (2003); List, J.F. and Habener, J.F., am.J.Physiol.Endocrinol.Metab.286: E875-81 (2004)).

Like GLP-1, oxyntomodulin is also produced from L-cell derived pro-glucagon by selective proteolysis. Oxyntomodulin is equivalent to glucagon plus an additional 8 amino acid carboxy-terminal extension (Bataille D. et al, Peptides 2 suppls: 41-4 (1981)). Oxyntomodulin is a dual agonist of both the GLP-1 receptor and the glucagon receptor. Oxyntomodulin induces glucose-dependent insulin secretion from pancreatic beta cells (Maida, a. et al, Endocrinology 149:5670-8(2008), and in vivo, oxyntomodulin regulates food intake (Dakin, c.l. et al, Endocrinology 142:4244-50(2001)) and is significantly appetite suppressive (Baggio, l.l. et al, Gastroenterology127:46-58 (2004)).

Upon activation, the GLP-1 receptor couples to the α -subunit of the G protein, with subsequent activation of adenylate cyclase and elevation of cAMP levels, thereby enhancing glucose-stimulated insulin secretion. Thus, GLP-1 is an attractive therapeutic target for lowering blood glucose and protecting the beta cells of the pancreas of diabetic patients. Glucagon has been used in the medical practice for diabetes for decades and several glucagon-like peptides are under development for a variety of therapeutic indications. For the treatment of patients with diabetes, analogues and derivatives of GLP-1 are being developed.

Summary of The Invention

The present invention relates to compounds suitable for use as potentiators or modulators of the GLP-1 receptor; methods for their preparation, and methods for their use in, for example, the treatment of malignant conditions mediated by activation of the GLP-1 receptor or when modulation or enhancement of the GLP-1 receptor is medically indicated.

Certain embodiments of the present invention comprise compounds having the structure of formula I-R or formula I-S, or a pharmaceutically acceptable isomer, enantiomer, racemate, salt, isotope, prodrug, hydrate or solvate thereof:

wherein

A is pyrimidinyl, pyridinyl, pyridazinyl or pyrazinyl, each of which may be substituted by one or more R₄Optionally substituted;

b is phenyl or heterocycle;

c is a non-aromatic carbocyclic group or a non-aromatic carbocyclic alkyl group;

each R is₁Independently is H or C_1-4An alkyl group;

R₂is-OH, -O-R₈、-N(R₁)-SO₂-R₇、-NR₄₁R₄₂、–N(R₁)-(CR_aR_b)_m-COOR₈、-N(R₁)-(CR_aR_b)_m-CO-N(R₁)(R₄₀)、-N(R₁)-(CR_aR_b)_m-N(R₁)C(O)O(R₈)、-N(R₁)-(CR_aR_b)_m-N(R₁)(R₄₀)、-N(R₁)-(CR_aR_b)_m-CO-N(R₁) -heterocyclyl or-N (R)₁)-(CR_aR_b)_m-heterocyclyl, which may be substituted by R₇Optionally (mono or poly) substituted;

each R is₃And R₄Independently H, halogen, alkyl, by R₃₁(mono-or poly-) substituted alkyl, alkoxy, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, aryl, heteroCyclyl, -OH, -OR₇、-CN、-NO₂、-NR₁R₇、-C(O)R₇、-(O)NR₁R₇、-NR₁C(O)R₇、-SR₇、-S(O)R₇、-S(O)₂R₇、-OS(O)₂R₇、-S(O)₂NR₁R₇、-NR₁S(O)₂R₇、-(CR_aR_b)_mNR₁R₇、-(CR_aR_b)_mO(CR_aR_b)_mR₇、-(CR_aR_b)_mNR₁(CR_aR_b)_mR₇Or- (CR)_aR_b)_mNR₁(CR_aR_b)_mCOOR₈(ii) a Or any two R on the same carbon atom₃Or R₄The groups together form oxo;

R₅is R₇、-(CR_aR_b)_m-(CR_aR_b)_m-R₇Or- (-L)₃-(CR_aR_b)_r-L₃-R₇Any two of them being adjacent- (CR)_aR_b)_mOr (CR)_aR_b)_rThe carbon atoms of the radicals may together form a double bond (- (C (R)_a)＝(C(R_a) -) or a triple bond (-C.ident.C-);

R₆is H, alkyl, aryl, heteroaryl, heterocyclyl, heterocycloalkyl, any of which may be substituted by R₇Or- (CR)_aR_b)_m-L₂-(CR_aR_b)_m-R₇Optionally (mono or poly) substituted;

each R is₇Independently is R₁₀(ii) a A ring moiety selected from cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl wherein such ring moiety is represented by R₁₀Optionally (mono or poly) substituted; or when the carbon atom has two R₇When it is a radical, the two R₇The groups together form oxo or thioxo, or (when attached to the same or different carbon atoms) form a groupA ring portion selected from cycloalkyl, aryl, heterocyclyl or heterocyclylalkyl wherein such ring portion is substituted with R₁₀Optionally mono-or poly-substituted;

each R is₈Independently is H, alkyl, haloalkyl, aryl, - (CR)_aR_b)_m-L₂-(CR_aR_b)_m-R₁Or- (-L)₃-(CR_aR_b)_r-)_s-L₃-R₁；

Each R is₁₀Independently is H, halogen, alkyl, haloalkyl, halohydrocarbonoxy, perhaloalkyl, perhalohydrocarbonoxy, - (CR)_aR_b)_mOH、-(CR_aR_b)_mOR₈、-(CR_aR_b)_mCN、-(CR_aR_b)_mNH(C＝NH)NH₂、-(CR_aR_b)_mNR₁R₈、-(CR_aR_b)_mO(CR_aR_b)_mR₈、-(CR_aR_b)_mNR₁(CR_aR_b)_mR₈、-(CR_aR_b)_mC(O)R₈、-(CR_aR_b)_mC(O)OR₈、-(CR_aR_b)_mC(O)NR₁R₈、-(CR_aR_b)_mNR₁(CR_aR_b)_mC(O)OR₈、-(CR_aR_b)_mNR₁C(O)R₈、-(CR_aR_b)_mC(O)NR₁S(O)₂R₈、-(CR_aR_b)_mSR₈、-(CR_aR_b)_mS(O)R₈、-(CR_aR_b)_mS(O)₂R₈、-(CR_aR_b)_mS(O)₂NR₁R₈Or- (CR)_aR_b)_mNR₁S(O)₂R₈；

Each R is₃₁Independent of each otherIs H, halogen, hydroxy, -NR₄₁R₄₂Or an alkoxy group;

each R is₄₀Independently H, R₇Can be substituted by R₇Optionally (mono or poly) substituted alkyl, or R₄₀And R₁Together with the N atom to which they are attached form a group which may be substituted by R₇An optionally (mono or poly) substituted 3-to 7-membered heterocyclyl;

each R is₄₁And R₄₂Independently is R₄₀、-(CHR₄₀)_n-C(O)O-R₄₀、-(CHR₄₀)_n-C(O)-R₄₀、-(CH₂)_n-N(R₁)(R₇) Aryl or heteroaryl, any of which may be substituted by R₇Optionally (mono or poly) substituted; or any two R₄₁And R₄₂Together with the N atom to which they are attached form a group which may be substituted by R₇An optionally (mono or poly) substituted 3-to 7-membered heterocyclyl;

each R is_aAnd R_bIndependently H, halogen, alkyl, alkoxy, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl (any of which may be substituted with R₇、-(CHR₄₀)_mC(O)OR₄₀、-(CHR₄₀)_mOR₄₀、-(CHR₄₀)_mSR₄₀、-(CHR₄₀)_mNR₄₁R₄₂、-(CHR₄₀)_mC(O)NR₄₁R₄₂、-(CHR₄₀)_mC(O)N(R₁)(CHR₄₀)_mNR₄₁R₄₂、-(CHR₄₀)_mC(O)N(R₁)(CHR₄₀)_mC(O)NR₄₁R₄₂、-(CHR₄₀)_mC(O)N(R₁)-(CHR₄₀)_mC(O)OR₄₀Or- (CHR)₄₀)_m-S-S-R₄₀Optionally (mono or poly) substituted); or any two R_aAnd R_bTogether with the carbon atom to which they are attached form R₇Optionally (mono or poly) substituted cycloalkyl or heterocyclyl; or R₁And R_aOr R_bAny of which, together with the atoms to which they are attached, form R₇Optionally (mono or poly) substituted heterocyclyl;

from the proximal end to the distal end of the structure of formula I-R or formula I-S, L₂Independently absent, -O-, -OC (O) -, -NR₁-、-C(O)NR₁-、-N(R₁)-C(O)-、-S(O₂) -, -S (O) -, -S-, -C (O) -or-S (O)₂)-N(R₁)-；

Each L₃Independently absent, -O-or-N (R)₁)-；

Each m is independently 0,1, 2,3,4,5, or 6;

each n is independently 0 or 1 or 2;

p is 0,1, 2 or 3;

q is 0,1, 2 or 3;

each r is independently 2,3 or 4; and

each s is independently 1,2,3 or 4.

In certain embodiments, there is provided a pharmaceutical composition comprising a compound of the present invention together with at least one pharmaceutically acceptable carrier, diluent or excipient.

In certain embodiments, methods of using the compounds of the invention are provided, including preparing a medicament.

In certain embodiments, the present invention provides a pharmaceutical combination comprising a compound of the present invention and a second agent. In various such embodiments, the second agent is an agonist or modulator of the glucagon receptor, the GIP receptor, the GLP-2 receptor, or the PTH receptor, or the glucagon-like peptide 1(GLP-1) receptor. In various such embodiments, the second drug is exenatide, liraglutide, tasaglutide, abiglutide, or lisiratide or other insulin modulating peptide. In various embodiments, the second medicament is medically desirable for treating type II diabetes. In various embodiments, the second drug is a biguanide, a sulfonylurea, meglitinide, a thiazolidinedione, an alpha-glucosidase inhibitor, a bile acid sequestrant, an SGLT inhibitor and/or a dopamine-2 agonist, and in more specific embodiments, the second drug is metformin (a biguanide), sitagliptin (a DPPIV inhibitor), or canagliflozin, dapagliflozin or empagliflozin (an SGLT inhibitor).

In certain embodiments, there is provided a method of activating, potentiating or agonizing a GLP-1 receptor comprising contacting the receptor with a compound, pharmaceutical composition or pharmaceutical combination of the present invention.

In certain embodiments, methods of treating a malignant condition in a subject in need of activation, potentiation or agonism of the GLP-1 receptor medically are provided, wherein such methods comprise administering to such subject a compound, pharmaceutical composition or pharmaceutical combination of the present invention. In various such embodiments, selective activation, potentiation or agonism of the GLP-1 receptor is medically indicated. In various such embodiments, the malignant condition comprises type I diabetes, type II diabetes, gestational diabetes, obesity, bulimia, insufficient satiety, or a metabolic disorder.

In certain embodiments, the present invention provides methods of synthesizing certain compounds, including compounds of the present invention. In certain other embodiments, the present invention provides certain intermediate compounds associated with such synthetic methods.

Detailed Description

Certain embodiments include compounds having a chiral structure (having chirality as indicated) of formula I-R or formula I-S, or a pharmaceutically acceptable isomer, enantiomer, racemate, salt, isotope, prodrug, hydrate or solvate thereof:

certain embodiments of the present invention include compounds having the structure of formula I-R or formula I-S, or a pharmaceutically acceptable isomer, enantiomer, racemate, salt, isotope, prodrug, hydrate or solvate thereof:

a, B, C, R therein₁、R₂、R₃、R₄、R₅N, p and q are as defined above.

In certain embodiments, the present invention provides compounds of formula I-R and/or formula I-S, wherein B is phenyl.

In certain embodiments, the present invention provides compounds of formula I-R and/or formula I-S, wherein B is a heterocycle.

In certain embodiments, the present invention provides compounds of formula I-R and/or formula I-S, wherein B is thienyl.

In certain embodiments, the present invention provides compounds of formula I-R and/or formula I-S, wherein B is pyrimidinyl.

In certain embodiments, the present invention provides compounds of formula I-R and/or formula I-S, wherein B is pyrazolyl.

In certain embodiments, the present invention provides compounds of formula I-R and/or formula I-S, wherein B is pyridinyl.

In certain embodiments, the present invention provides compounds of formula I-R and/or formula I-S, wherein B is indolyl.

wherein

b is phenyl or thienyl;

each R is₁Independently is H or C_1-4An alkyl group;

each R is₇Independently is R₁₀(ii) a A ring moiety selected from cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl wherein such ring moiety is represented by R₁₀Optionally (mono or poly) substituted; or when the carbon atom has two R₇When it is a radical, the two R₇The groups together form oxo or thioxo, or together form a ring moiety selected from cycloalkyl, aryl, heterocyclyl or heterocyclylalkyl wherein such ring moiety is substituted with R₁₀Optionally mono-or poly-substituted;

Each R is₃₁Independently H, halogen, hydroxy, -NR₄₁R₄₂Or an alkoxy group;

Each L₃Independently absent, -O-or-N (R)₁)-；

Each m is independently 0,1, 2,3,4,5, or 6;

each n is independently 0 or 1 or 2;

p is 0,1, 2 or 3;

q is 0,1, 2 or 3;

each r is independently 2,3 or 4; and

each s is independently 1,2,3 or 4.

In certain embodiments, the compounds have the structure of formula I-R or a pharmaceutically acceptable isomer, enantiomer, salt, isotope, prodrug, hydrate or solvate thereof. In other embodiments, the compounds have the structure of formula I-S or a pharmaceutically acceptable isomer, enantiomer, salt, isotope, prodrug, hydrate or solvate thereof.

In certain embodiments, the compounds may be substantially enantiomerically pure.

In certain embodiments, the present invention provides compounds of formula I-R and/or formula I-S, wherein A is substituted with one or more R₄Optionally substituted pyrimidinyl. Representative compounds of this embodiment include those of the structure (whereinRepresents one or both of the R and S forms of the compound):

in certain embodiments, the present invention provides compounds of formula I-R and/or formula I-S, wherein A is substituted with one or more R₄Optionally substituted pyridyl. Representative compounds of this embodiment include those of the structure (whereinRepresents one or both of the R and S forms of the compound):

in certain embodiments, the present invention provides compounds of formula I-R and/or formula I-S, wherein A is substituted with one or more R₄Optionally substituted pyridazinyl. Representative compounds of this embodiment include those of the structure (whereinRepresents one or both of the R and S forms of the compound):

in certain embodiments, the present invention provides compounds of formula I-R and/or formula I-S, wherein A is substituted with one or more R₄Optionally substituted pyrazinyl. Representative compounds of this embodiment include those of the structure (whereinRepresents one or both of the R and S forms of the compound):

in certain embodiments, the present invention provides compounds of each structure I-R/S (1) - (5) wherein B is pyrimidinyl, pyrazolyl, pyridinyl, or indolyl, and in other embodiments, the present invention provides compounds of each structure I-R/S (1) - (5) wherein the B group is:

in certain embodiments, the present invention provides compounds of each structure I-R/S (1) - (5) wherein the B group is phenyl. Representative compounds of this embodiment include those of the structure (whereinRepresents one or both of the R and S forms of the compound):

in certain embodiments, the present invention provides compounds of each structure I-R/S (7) - (9), wherein n is 0 or 1. Representative compounds of this embodiment include those of the structure (whereinRepresents one or both of the R and S forms of the compound):

in certain embodiments, the present invention provides compounds of each structure I-R/S (1) - (3) wherein the B group is thienyl. Representative compounds of this embodiment include those of the structure (whereinRepresents one or both of the R and S forms of the compound):

in certain embodiments, the present invention provides compounds of each structure I-R/S (13) - (15), wherein the B group is thiophen-2-yl. Representative compounds of this embodiment include those of the structure (whereinRepresents one or both of the R and S forms of the compound):

in certain embodiments, the present invention provides compounds of each of structures I-R/S (16) - (18), wherein n is 0 or 1. Representative compounds of this embodiment include those of the structure (whereinRepresents one or both of the R and S forms of the compound):

in certain embodiments, the present invention provides compounds of each of structures I-R/S (1) - (21), wherein the C group is a non-aromatic carbocyclic group.

In certain embodiments, the present invention provides compounds of each structure I-R/S (1) - (21) wherein the C group is cycloalkyl.

In certain embodiments, the present invention provides compounds of each structure I-R/S (1) - (21) wherein the C group is cycloalkenyl.

In certain embodiments, the present invention provides compounds of each structure I-R/S (1) - (21), wherein the C group is a non-aromatic carbocyclylalkyl.

In certain embodiments, the present invention provides compounds of each structure I-R/S (1) - (21) wherein the C group is cycloalkylalkyl.

In certain embodiments, the present invention provides compounds of each structure I-R/S (1) - (21) wherein the C group is cycloalkenylalkyl.

In certain embodiments, the present invention provides compounds of each structure I-R/S (1) - (21), wherein the C group is:

in certain embodiments, the present invention provides compounds of structures I-R/S (22) - (23):

in certain embodiments, the present invention provides compounds of each structure I-R/S (1) - (23), wherein R₁Is H.

In certain embodiments, the present invention provides compounds of each structure I-R/S (1) - (23), wherein R₄Is H.

In certain embodiments, the present invention provides compounds of each structure I-R/S (1) - (23), wherein q is 0.

In certain embodiments, the present invention provides compounds of each of structures I-R/S (1) - (23), wherein q is 1,2, or 3.

In certain embodiments, the present invention provides compounds of each structure I-R/S (1) - (23), wherein q is 1.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (23), wherein q is 1, and R is₅Is- (CR)_aR_b)_m-L₂-(CR_aR_b)_m-R₇Or- (-L)₃-(CR_aR_b)_r-)_s-L₃-R₇。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (23), wherein q is 1, and R is₅Is R₇。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (23), wherein q is 1 and R is₅Is R₇And R is₇Is halogen, alkyl, haloalkyl, perhaloalkyl, hydrocarbonoxy, - (CR)_aR_b)_mOH、-(CR_aR_b)_mOR₈、-(CR_aR_b)_mCN、-(CR_aR_b)_mNH(C＝NH)NH₂、-(CR_aR_b)_mNR₁R₈、-(CR_aR_b)_mO(CR_aR_b)_mR₈、-(CR_aR_b)_mNR₁(CR_aR_b)_mR₈、-(CR_aR_b)_mC(O)R₈、-(CR_aR_b)_mC(O)OR₈、-(CR_aR_b)_mC(O)NR₁R₈、-(CR_aR_b)_mNR₁(CR_aR_b)_mC(O)OR₈、--(CR_aR_b)_mNR₁C(O)R₈、-(CR_aR_b)_mC(O)NR₁R₈、-(CR_aR_b)_mSR₈、-(CR_aR_b)_mS(O)R₈、-(CR_aR_b)_mS(O)₂R₈、-(CR_aR_b)_mS(O)₂NR₁R₈、-(CR_aR_b)_mNR₁S(O)₂R₈。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (23), wherein q is 1 and R is₅Is R₇And R is₇Is a cyclic moiety selected from cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl wherein such cyclic moiety is optionally (mono or poly) substituted with halogen, -OH, -CN, alkyl, alkoxy, haloalkyl or perhaloalkyl.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (23), wherein q is 1 and R is₅Is R₇And R is₇Is a cyclic moiety selected from the group consisting of cyclic hydrocarbon radicals monosubstituted with alkyl radicals.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (23), wherein q is 1 and R is₅Is R₇And R is₇Is selected from linear chains C_3-6The ring portion of an alkyl monosubstituted cycloalkyl.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (23), wherein p is 1, and R is₃Is halogen, alkyl, or R₃₁Substituted alkyl, alkoxy, haloalkyl, perhaloalkyl, haloHydrocarbyloxy, perhalohydrocarbyloxy, aryl, heterocyclyl, -OH, -OR₇、-CN、-NO₂、-NR₁R₇、-C(O)R₇、-C(O)NR₁R₇、-NR₁C(O)R₇、-SR₇、-S(O)R₇、-S(O)₂R₇、-OS(O)₂R₇、-S(O)₂NR₁R₇、-NR₁S(O)₂R₇、-(CR_aR_b)_mNR₁R₇、-(CR_aR_b)_mO(CR_aR_b)_mR₇、-(CR_aR_b)_mNR₁(CR_aR_b)_mR₇Or- (CR)_aR_b)_mNR₁(CR_aR_b)_mCOOR₈。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (23), wherein p is 1, and R is₃Is an alkyl group.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (23), wherein p is 1, and R is₃Is a tert-butyl group.

In certain embodiments, the present invention provides compounds of structures I-R/S (24) - (25):

in certain embodiments, the present invention provides compounds of structures I-R/S (26) - (27):

in certain embodiments, the present invention provides compounds of structure I-R/S (24) - (27), wherein each described alkyl is a straight or branched alkyl, and in some embodiments, each described alkyl is C₁-C₈Straight-chain or branched alkyl radicals, e.g. methyl, ethylA radical, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl or tert-butyl.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-OH.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-N (R)₁)(CR_aR_b)_mCOOR₈。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-N (R)₁)SO₂R₇。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-NHCH₂COOH。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-NH (CHR)_b) COOH, wherein R_bIs as a quilt R₇Optionally substituted alkyl, - (CHR)₄₀)_mOR₄₀、-(CHR₄₀)_mSR₄₀、-(CHR₄₀)_mNR₄₁R₄₂、-(CHR₄₀)_mC(O)NR₄₁R₄₂、-(CHR₄₀)_mC(O)N(R₁)(CHR₄₀)_mNR₄₁R₄₂、-(CHR₄₀)_mC(O)N(R₁)(CHR₄₀)_mC(O)NR₄₁R₄₂、-(CHR₄₀)_mC(O)N(R₁)(CHR₄₀)_mC(O)OR₄₀Or- (CHR)₄₀)m-S-S-R₄₀。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-NH (CR)_aR_b)_mCOOH, wherein R_aAnd R_bIndependently is H, by R₇Optionally substituted alkyl, - (CHR)₄₀)_mOR₄₀、-(CHR₄₀)_mSR₄₀、-(CHR₄₀)_mNR₄₁R₄₂、-(CHR₄₀)_mC(O)NR₄₁R₄₂、-(CHR₄₀)_mC(O)N(R₁)(CHR₄₀)_m-NR₄₁R₄₂、-(CHR₄₀)_mC(O)N(R₁)-(CHR₄₀)_mC(O)NR₄₁R₄₂、-(CHR₄₀)_mC(O)N(R₁)(CHR₄₀)_mC(O)OR₄₀Or- (CHR)₄₀)m-S-S-R₄₀。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-NR₁(CHR_b)_mCOOH, wherein R₁And R_bTogether form a heterocyclic group.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-NR₁(CR_aR_b)_mCOOH, wherein R₁And R_bOne together form a heterocyclic group.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-NR₁(CR_aR_b)_mCOOH, wherein any two R_aAnd R_bTogether with the carbon to which they are attached form a cyclic hydrocarbon group.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-NH (CR)_aR_b)_mCOOH, wherein R_aAnd R_bOne is H, and R_aAnd R_bIs another one of R₇A substituted aryl group.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-NR₁(CR_aR_b)_mCOOH, m is 2, R₁For hydrogen, each occurrence of R_aAnd R_bIs hydrogen, and R₈Is hydrogen:

in certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-NR₁(CR_aR_b)_mCOOH, m is 1, and R₁、R_bAnd R₈Is hydrogen:

in certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-NR₁(CR_aR_b)_mCOOH, m is 2, one R_a(i.e., one of the two) is hydrogen, R being present at each occurrence_bIs hydrogen, and R₈Is hydrogen:

in certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs as a quilt R₇Optionally substituted alkyl, wherein alkyl includes straight or branched chain alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl) and cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl).

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs methyl.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs a heterocyclic or heterocyclic hydrocarbon radical, either of which may be substituted by R₇Optionally substituted.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs a heterocycle such as pyrazinyl, pyrimidinyl, pyridazinyl, thiadiazolyl, oxadiazolyl, imidazolinyl, hexahydropyrimidinyl, diazepanyl, triazinyl, imidazolyl, pyrrolidinyl, furanyl, tetrahydrofuryl, tetrahydro-2H-pyranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, thienyl, benzothienyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzoimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphtalenyl, purinyl, xanthine, adenine, guanine, quinolyl, isoquinolyl, Tetrahydroquinolyl, quinoxalyl and quinazolinyl, any of which may be substituted by R₇Optionally substituted.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs aryl or arylalkyl, any of which may be substituted by R₇Optionally substituted.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs an aryl or arylalkyl radical, such as phenyl or benzyl.

In certain embodiments, the present invention provides the structure I-R/S (1) -(27) Wherein R is₂Is (R)₂-b) or (R)₂-c) wherein R_aIs as a quilt R₇Substituted aryl or heteroaryl.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs phenyl or benzyl substituted by hydroxy.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_ais-CH (OH) C₆H₅。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs- (CHR)₄₀)_mC(O)OR₄₀。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs- (CH)₂)_mC(O)OH。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs- (CHR)₄₀)_mOR₄₀。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs- (CH)₂)_mOH。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_ais-CH₂OH。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs- (CHR)₄₀)_mSR₄₀。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs- (CH)₂)_mSR₄₀Wherein R is₄₀Is H or alkyl.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs- (CHR)₄₀)_mNR₄₁R₄₂。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs- (CH)₂)_mNR₄₁R₄₂。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs- (CHR)₄₀)_mC(O)NR₄₁R₄₂。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs- (CH)₂)_mC(O)NR₄₁R₄₂。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_ais-CH₂C(O)NH₂or-CH₂CH₂C(O)NH₂。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs- (CHR)₄₀)_mC(O)N(R₁)(CHR₄₀)_mNR₄₁R₄₂。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂B) or(R₂-c) wherein R_aIs- (CH)₂)_mC(O)N(R₁)(CH₂)_mNR₄₁R₄₂。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs- (CHR)₄₀)_mC(O)N(R₁)(CHR₄₀)_mC(O)NR₄₁R₄₂。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs- (CH)₂)_mC(O)N(R₁)(CH₂)_mC(O)NR₄₁R₄₂。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs- (CHR)₄₀)_mC(O)N(R₁)(CHR₄₀)_mC(O)OR₄₀。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs- (CH)₂)_mC(O)N(R₁)(CH₂)_mC(O)OR₄₀。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein R_aIs- (CHR)₄₀)_m-S-S-R₄₀。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein at R_aIn the radical, R₁、R₄₀、R₄₁And R₄₂Is hydrogen.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b)Or (R)₂-c) wherein at R_aIn the group, m is 1.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-b) or (R)₂-c) wherein at R_aIn the group, m is 2.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-N (R)₁)(CR_aR_b)_mCOOR₈Wherein m is 1, R₈Is hydrogen, R_bIs hydrogen, and R₁And R_aTogether with the atom to which they are attached form R₇Optionally (mono-or poly-) substituted heterocyclyl:

in certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-N (R)₁)(CR_aR_b)_mCOOR₈Wherein m is 2, R₈Is hydrogen, second (CR)_aR_b) R of the radical_bIs hydrogen, and R₁And second (CR)_aR_b) R of the radical_aTogether with the atom to which they are attached form R₇Optionally (mono-or poly-) substituted heterocyclyl:

in certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R2-d) or (R2-e), wherein R₁And R_aTogether with the atom to which they are attached form an azetidinyl, pyrrolidinyl or piperidinyl group, each of which is substituted with R₇Optionally (mono or poly) substituted. Representative compounds of this embodiment include compounds of structure I-R/S (1) - (27), wherein R₂Comprises the following steps:

in certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is N (R)₁)(R₄₂)：

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-f) wherein R₄₁And R₄₂Independently is R₄₀、-(CHR₄₀)_n-C(O)OR₄₀、-(CHR₄₀)_n-C(O)R₄₀、-(CH₂)_nN(R₁)(R₇) Aryl or heteroaryl, said aryl or heteroaryl being substituted by R₇Optionally (mono or poly) substituted.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-f) wherein R₄₁Is hydrogen, and R₄₂Is as a quilt R₇Optionally (mono-or poly-) substituted alkyl.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-f) wherein R₄₁Is hydrogen, and R₄₂Is- (CHR)₄₀)_nC(O)OR₄₀。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-f) wherein R₄₁Is hydrogen, and R₄₂Is- (CHR)₄₀)_nC(O)R₄₀。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-f) wherein R₄₁Is hydrogen, and R₄₂Is- (CH)₂)_nN(R₁)(R₇)。

In some instancesIn one embodiment, the present invention provides compounds of structures I-R/S (1) - (27), wherein R₂Is (R)₂-f) wherein R₄₁Is hydrogen, and R₄₂Is as a quilt R₇Optionally (mono or poly) substituted aryl.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-f) wherein R₄₁Is hydrogen, and R₄₂Is as a quilt R₇Optionally (mono-or poly-) substituted heteroaryl.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-f) wherein R₄₁And R₄₂Together with the N atom to which they are attached form R₇Optionally (mono or poly) substituted 3-to 7-membered heterocyclyl.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-f) wherein R₄₁And R₄₂Together with the N atom to which they are attached form pyrazinyl, pyrimidinyl, pyridazinyl, thiadiazolyl, oxadiazolyl, imidazolinyl, hexahydropyrimidyl, diazepanyl, triazinyl, imidazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl or pyridinyl, any of which may be substituted by R₇Optionally (mono or poly) substituted.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-N (R)₁)(CR_aR_b)_mCON(R₁)(R₄₀)。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-N (R)₁)(CR_aR_b)_mCON(R₁)(R₄₀) Wherein m is 1, R_bIs hydrogen, and R₁And R_aTogether with the atom to which they are attached form R₇Optionally (mono-or poly-) substituted heterocyclyl:

in certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-N (R)₁)(CR_aR_b)_mCON(R₁)(R₄₀) Wherein m is 2, second (CR)_aR_b) R of the radical_bIs hydrogen, and R₁And second (CR)_aR_b) R of the radical_aTogether with the atom to which they are attached form R₇Optionally (mono-or poly-) substituted heterocyclyl:

in certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂Is (R)₂-h) wherein R₁And R_aTogether with the atom to which they are attached form R₇Optionally (mono-or poly-) substituted azetidinyl, pyrrolidinyl, piperidinyl. Representative compounds of this embodiment include compounds of structure I-R/S (1) - (27), wherein R₂Comprises the following steps:

in certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-N (R)₁)(CR_aR_b)_mN(R₁)C(O)O(R₈)。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-N (R)₁)(CR_aR_b)_mN(R₁)(R₇)。

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-N (R)₁)(CR_aR_b)_mCON(R₁) A heterocyclic group.

In certain embodiments, the present invention provides compounds of structure I-R/S (1) - (27), wherein R₂is-N (R)₁)(CR_aR_b)_m-heterocyclyl, which may be substituted by R₇Optionally substituted.

In certain embodiments, the present invention provides pharmaceutical compositions comprising a compound of the present invention together with at least one pharmaceutically acceptable carrier, diluent or excipient.

In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a second agent. In certain such embodiments, the second drug is a GLP-1 agonist or a DPPIV inhibitor.

In certain embodiments, the present invention provides methods of using the compounds of the present invention for the preparation of medicaments.

In certain embodiments, the present invention provides a pharmaceutical combination comprising a compound of the present invention and a second agent. In various such embodiments, the second agent is an agonist or modulator of the glucagon receptor, the GIP receptor, the GLP-2 receptor, or the PTH receptor, or the glucagon-like peptide 1(GLP-1) receptor. In various such embodiments, the second drug is exenatide, liraglutide, tasaglutide, abiglutide, or risperidone or other insulin modulating peptide. In various such embodiments, the second drug is a DPPIV inhibitor, such as sitagliptin. In various such embodiments, the second agent is medically desirable for treating type II diabetes. In various combinations, the second drug is a sodium-glucose co-transporter (SGLT) inhibitor, such as SGLT1 and/or SGLT2 inhibitors, including dapagliflozin, empagliflozin, and canagliflozin. In various such embodiments, the second drug is a biguanide, such as metformin; sulfonylureas, such as glibenclamide, glipizide, gliclazide, and glimepiride; meglitinides, such as repaglinide and nateglinide; thiazolidinediones such as pioglitazone and rosiglitazone; alpha-glucosidase inhibitors, such as acarbose and miglitol; bile acid sequestrants, such as colesevelam and/or dopamine-2 agonists, such as bromocriptine.

In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a second drug, wherein the second drug is metformin.

In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a second drug, wherein the second drug is sitagliptin.

In certain embodiments, there is provided a method of activating, enhancing or agonizing glucagon-like peptide 1 comprising contacting the receptor with an effective amount of a compound, pharmaceutical composition or pharmaceutical combination of the present invention.

In other embodiments, methods of providing activation or agonism of a GLP-1 receptor by contacting the receptor with an effective amount of a compound of the present invention and GLP-1 peptides GLP-1(9-36) and GLP-1(7-36), a pharmaceutical composition or a pharmaceutical combination, wherein the GLP-1 receptor is treated in a living mammal (disposed); in certain embodiments, wherein such mammal is a human.

In certain embodiments, methods are provided for treating a malignant condition in a subject in need of activation, potentiation or agonism of the GLP-1 receptor medically by administering to the subject an effective amount of a compound of the present invention at a frequency and for a duration sufficient to provide a beneficial effect to the patient. In other embodiments, methods are provided for treating a malignant condition in a patient in need of activation, potentiation or agonism of a GLP-1 receptor medically, by administering to the patient an effective amount of a compound of the present invention with a frequency and duration sufficient to provide a beneficial effect to the patient, wherein the malignant condition comprises type I diabetes, type II diabetes, gestational diabetes, obesity, bulimia, insufficient satiety or a metabolic disorder. In certain embodiments, the subject is a patient or a human. In certain embodiments, the human has or is at risk of developing a disease or condition selected from: type I diabetes, type II diabetes, gestational diabetes, obesity, bulimia, satiety deficiency, and metabolic disorders. In certain such embodiments, the disease is type I diabetes or type II diabetes.

In certain embodiments, the present invention provides methods of synthesizing certain compounds, including the compounds of the present invention, as more fully described herein. In certain other embodiments, the present invention provides certain intermediate compounds that are related to the synthetic methods described herein.

In certain embodiments, methods of using the compounds of the invention for the preparation of medicaments suitable for the treatment of disorders or malignant conditions in which activation or inhibition of the GLP-1 receptor is medically indicated are provided. In certain embodiments, the malignant condition includes type I diabetes, type II diabetes, gestational diabetes, obesity, bulimia, satiety deficiency, and metabolic disorders. Preferably, the disease is type I diabetes or type II diabetes.

In certain embodiments, the method further comprises administering to the subject a second drug selected from the group consisting of biguanides, peptidic GLP-1 agonists and DPPIV inhibitors, wherein such second drug is a pharmaceutical composition or a component of a second pharmaceutical composition. In certain such embodiments, the second drug may be metformin, exenatide or sitagliptin.

As used in the specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

The terms "comprising," "including," "having," and "consisting of" as used herein are open-ended terms and do not preclude the presence of additional elements or components. In a claimed element, use of the form "comprising," "including," "having," or "consisting of" means that the element, regardless of whether it is comprised, has, includes, or contains, is not necessarily the only element encompassed by the subject matter of the clause containing the word.

As used herein, "individual" (as the subject of treatment) means mammals and non-mammals. Mammals include, for example, humans; non-human primates, e.g., apes and monkeys; cattle; a horse; sheep; and goats. Non-mammals include, for example, fish and birds.

As is well known in the art, a "receptor" is a biological molecular entity, which typically comprises a protein that specifically binds to a class of structural ligands or to a single self (native) ligand in a living organism, and this binding causes the receptor to transduce the binding signal into another biological effect, such as signaling to a cell that a binding event has occurred, which causes the cell to somehow alter its function. An example of transduction is ligand binding to a receptor causing an alteration in the "G-protein" activity in the cytoplasm of living cells. Any naturally occurring or non-naturally occurring molecule that binds to a receptor and causes it to activate for signal transduction is referred to as an "agonist" or "activator". Any naturally occurring or non-naturally occurring molecule that binds to a receptor but does not cause signal transduction to occur and can block the binding of an agonist and its subsequent signal transduction is referred to as an "antagonist". Certain molecules bind to the receptor at locations other than the natural ligand binding site of the receptor, and such allosteric binding molecules may enhance, activate or agonize the receptor and may enhance the effect of the natural ligand or the co-administered ligand.

As used herein, the term "GLP-1 compound" or "GLP-1 agonist" or "GLP-1 activator" or "GLP-1 inhibitor" or "GLP-1 antagonist" or "GLP-1 potentiator" or "GLP-1 modulator" refers to a compound that interacts in some way with the GLP-1 receptor. They may be agonists, potentiators or activators, or they may be antagonists or inhibitors. The "GLP-1 compounds" of the present invention may be selective for the effects of the GLP-1 receptor family.

The term "substantially" as used herein means completely or almost completely; for example, a composition that is "substantially free" of a component does not contain that component or contains trace amounts of that component (the presence of such trace amounts does not affect any relevant functional properties of the composition), or the compound is "substantially pure" meaning that only negligible trace amounts of impurities are present.

By "substantially enantiomerically pure or diastereomerically pure" is meant that the enantiomeric or diastereomeric enrichment level of one enantiomer relative to the other is at least about 80%, and more preferably greater than 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, or 99.9%.

By "treating" is meant herein alleviating the symptoms associated with a disorder or disease, or inhibiting the further progression or worsening of those symptoms, or preventing the disease or disorder.

When used to describe the use of a compound of the invention in providing treatment to a patient having a GLP-1 mediated disorder or malignant condition, the expression "effective amount" refers to an amount of a compound of the invention that effectively binds to a GLP-1 receptor in a tissue of the subject, as an agonist or as an antagonist, wherein the GLP-1 is associated with the disorder, wherein such binding is to an extent sufficient to produce a beneficial therapeutic effect in the patient. Similarly, as used herein, an "effective amount" or "therapeutically effective amount" of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, the symptoms associated with the disorder or condition, or stops or slows further progression or worsening of those symptoms, or prevents the disorder or condition. In particular, a "therapeutically effective amount" refers to an amount effective, at dosages and for durations necessary, to achieve the desired therapeutic result by acting as an agonist of GLP-1 activity. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compounds of the present invention are outweighed by the beneficial therapeutic effects. For example, in the case of treating a malignant condition mediated by activation of the GLP-1 receptor, a therapeutically effective amount of a GLP-1 receptor agonist of the present invention is an amount sufficient to control the malignant condition, reduce the progression of the malignant condition, or alleviate symptoms of the malignant condition. Examples of malignant conditions that may be so treated include, but are not limited to, type II diabetes.

Unless a particular stereochemistry or isomeric form is specifically indicated, the present invention is intended to include all chiral, diastereomeric, racemic forms of the structure. The compounds used in the present invention may include optical isomers enriched or isolated at any or all asymmetric atoms, at any degree of enrichment as is apparent from the description. Mixtures of racemic and diastereomeric isomers may be synthesized, as well as the individual optical isomers synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and are within the scope of certain embodiments of the invention.

Isomers resulting from the presence of chiral centers include a pair of non-superimposable isomers known as "enantiomers". The single enantiomers of the pure compounds are optically active, i.e., they are capable of rotating the plane of plane polarized light. The single enantiomers are named according to the Cahn-Ingold-Prelog system. Once the order of preference among the four groups is determined, the molecules are oriented so that the lowest priority group points away from the viewer. Then, if the descending order of the other groups is made clockwise, the molecule is named as (R) configuration, and if the descending order of the other groups is made counterclockwise, the molecule is named as (S) configuration. In the example of scheme 14, Cahn-Ingold-Prelog has an ordering of A > B > C > D. The lowest ranked atom D is oriented away from the viewer.

"isolated optical isomers" means compounds that have been substantially purified from the corresponding optical isomers of the same formula. Preferably, the isolated isomer is at least about 80% pure by weight, preferably at least 80% pure by weight or even at least 85% pure by weight. In other embodiments, the isolated isomer is at least 90% pure by weight, or at least 98% pure by weight, or at least about 99% pure by weight.

Enantiomers are sometimes referred to as optical isomers because the pure enantiomers rotate plane-polarized light in specific directions. If the light is rotated clockwise, the enantiomers are labeled "(+)" or "d" to indicate right-handed, their counterparts rotate the light counterclockwise and are labeled "(-) -" or "l" to indicate left-handed.

The terms "racemate" and "racemic mixture" are often used interchangeably. The racemate is an equal mixture of the two enantiomers. The racemate is labeled "(±)" because it is optically inactive (i.e., does not rotate plane-polarized light in any direction because its constituent enantiomers cancel each other out).

It will be appreciated that due to the chemical nature of the restricted rotation around the amide bond (as shown below) (i.e., resonance imparts some double bond character to the C — N bond), it is possible to observe isolated rotamer species, and even in some cases isolate such species, as shown below. It is also understood that certain structural elements, including steric bulk or substituents on the amide nitrogen, may improve the stability of rotamers to the extent that the compound can be isolated as a single stable rotamer and exist for extended periods of time. Thus, the present invention includes any potentially stable rotamer of a compound of the invention which is biologically active in the treatment of type I diabetes, type II diabetes, gestational diabetes, obesity, bulimia, insufficient satiety or metabolic disorders.

All structures encompassed in the claims are "chemically feasible", which means that the structure shown by any combination or subcombination of the optional substituents recited in the claims can physically exist with at least some stability that can be determined by structural chemistry principles and experimentation. Chemically infeasible structures are not within the scope of the claimed collection of compounds. Furthermore, isotopes of the indicated atoms (e.g., deuterium and deuterium for hydrogen) are also contemplated as falling within the scope of the present invention. For example, it is to be understood that the description herein of a compound having one or more hydrogen atoms is intended to encompass compounds having such hydrogen atoms substituted at one or more positions with deuterium (or deuterium). Such "deuterated compounds," whether partially (i.e., not all hydrogen atoms are replaced by deuterium) or fully (i.e., all hydrogen atoms are replaced by deuterium) deuterated, are within the scope of the compounds of the present invention.

Typically, "substituted" refers to an organic group as defined herein,in the organic group, one or more bonds to hydrogen atoms contained therein are substituted with one or more bonds to non-hydrogen atoms such as, but not limited to, halogens (i.e., F, Cl, Br, and I); oxygen atoms in groups such as hydroxyl, hydrocarbyloxy, aryloxy, arenyloxy, oxo (carbonyl), carboxyl groups (including carboxylic acids, carboxylates, and carboxylates); sulfur atoms in groups such as mercapto groups, alkyl sulfides and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; nitrogen atoms in groups such as amines, hydroxylamines, nitriles, nitro, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that may be bonded to a substituted carbon (or other) atom include: F. cl, Br, I, OR ', OC (O) N (R')₂、CN、CF₃、OCF₃R ', O, S, C (O), S (O), methylenedioxy, ethylenedioxy, N (R')₂、SR’、SOR’、SO₂R’、SO₂N(R’)₂、SO₃R’、C(O)R’、C(O)C(O)R’、C(O)CH₂C(O)R’、C(S)R’、C(O)OR’、OC(O)R’、C(O)N(R’)₂、OC(O)N(R’)₂、C(S)N(R’)₂、(CH₂)_0-2NHC(O)R’、(CH₂)_0-2N(R’)N(R’)₂、N(R’)N(R’)C(O)R’、N(R’)N(R’)C(O)OR’、N(R’)N(R’)CON(R’)₂、N(R’)SO₂R’、N(R’)SO₂N(R’)₂、N(R’)C(O)OR’、N(R’)C(O)R’、N(R’)C(S)R’、N(R’)C(O)N(R’)₂、N(R’)C(S)N(R’)₂、N(COR’)COR’、N(OR’)R’、C(＝NH)N(R’)₂C (o) N (OR ') R ' OR C (═ NOR ') R ', wherein R ' may be hydrogen OR a carbon-based moiety, and wherein the carbon-based moiety itself may be further substituted.

Substituted alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl groups, as well as other substituted groups, also include groups in which one or more bonds to a hydrogen atom are substituted with one or more bonds (including double or triple bonds) to a carbon atom or to a heteroatom, including, but not limited to, carbonyl (oxo), carboxyl, ester, amide, imide, urethane and the oxygen in urea groups; and the nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.

Substituted cyclic groups include substituted aryl, heterocyclyl and heteroaryl groups. A substituted cyclic group may be substituted with one or more substituents at any available ring position. In some embodiments, two substituents on a substituted ring group can form a ring with the ring to which they are attached, such that the two rings are fused together. For example, benzodioxolyl is a fused ring system formed by two substituents together on a phenyl group.

Such substituted ring groups also include rings and fused ring systems in which the bond to a hydrogen atom is replaced by a bond to a carbon atom. Thus, substituted aryl, heterocyclyl and heteroaryl groups may also be substituted by alkyl, alkenyl, cycloalkyl, aryl, heteroaryl and alkynyl groups (which groups may themselves be further substituted) as defined herein.

As used herein, the term "heteroatom" refers to atoms other than carbon and hydrogen, which are capable of forming covalent bonds with carbon, without further limitation. Typical heteroatoms are N, O and S. When referring to sulfur (S), unless the oxidation state is indicated, it is understood that the sulfur may be in any oxidation state found, and thus includes sulfoxides (R-S (O) -R') and sulfones (R-S (O))₂-R'); thus, the term "sulfone" encompasses only the sulfone form of sulfur; the term "thioether" encompasses only the sulfur in the form of thioether (R-S-R'). When using a variable such as "heteroatom selected from O, NH, NR' and S" or "[ variable]As the words O, s.

"alkyl" includes straight and branched chain alkyl and cyclic hydrocarbon radicals containing from 1 to about 20 carbon atoms, and typically containing from 1 to 12 carbon atoms (C)₁-C₁₂Alkyl), or in some embodiments, containing 1 to 8 carbon atoms (C)₁-C₈Alkyl), or in some embodiments, containing 1 to 4 carbon atoms (C)₁-C₄Alkyl groups). In the case of cyclic hydrocarbon groups, such groups have from 3 to 20 carbon atoms. Examples of straight chain alkyl groupsExamples include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of branched alkyl groups include, but are not limited to: isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isoamyl and 2, 2-dimethylpropyl. Alkyl groups as used herein may optionally contain one or more additional substituents. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed above (e.g., amino, hydroxy, cyano, carboxy, nitro, thio, hydrocarbyloxy, and halo groups).

"alkenyl" includes straight and branched chain and cyclic alkyl groups as defined above except that there is at least one double bond between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbon atoms, or in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to, -CH ═ CH₂、-CH＝CH(CH₃)、-CH＝C(CH₃)₂、-C(CH₃)＝CH₂、-C(CH₃)＝CH(CH₃)、-C(CH₂CH₃)＝CH₂、-CH＝CHCH₂CH₃、-CH＝CH(CH₂)₂CH₃、-CH＝CH(CH₂)₃CH₃、-CH＝CH(CH₂)₄CH₃Vinyl, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, and the like.

"alkynyl" includes straight and branched chain alkyl groups except that there is at least one triple bond between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbon atoms, or in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to, -C ≡ CH, -C ≡ C (CH)₃)、-C≡C(CH₂CH₃)、-CH₂C≡CH、-CH₂C≡C(CH₃) and-CH₂C≡C(CH₂CH₃) And the like.

"cycloalkyl" is a hydrocarbon group that forms a ring structure, which may be substituted or unsubstituted, wherein the ring is fully saturated, partially unsaturated, or fully unsaturated, wherein if unsaturation is present, conjugation of pi electrons in the ring does not result in aromaticity. Examples of cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the cyclic hydrocarbyl groups have 3 to 8 ring members, while in other embodiments the number of ring carbon atoms is 3 to 5, 3 to 6, or 3 to 7. Cyclic hydrocarbon groups also include polycyclic cyclic hydrocarbon groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphene, isobornenyl, and carenyl groups, as well as fused rings such as, but not limited to, decahydronaphthyl (decalinyl), and the like. Cycloalkyl also includes rings substituted with straight chain alkyl or branched chain alkyl as defined above. Representative substituted cycloalkyl groups may be mono-or substituted one or more times with any of the groups listed above, such as, but not limited to, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halo groups.

"(cycloalkyl) alkyl", also known as "cycloalkylalkyl", is an alkyl group as defined above in which a hydrogen or carbon bond on the alkyl group is substituted by a bond to a cycloalkyl group as defined above.

The term "cycloalkenyl" alone or in combination denotes a cyclic alkenyl group wherein at least one double bond is present in the ring structure. Cycloalkenyl includes cyclic hydrocarbon groups having at least one double bond between two adjacent carbon atoms. Thus, for example, cycloalkenyl groups include, but are not limited to, cyclohexenyl, cyclopentenyl, and cyclohexadienyl, as well as multiple ring systems and/or bridged ring systems such as adamantane.

"(cycloalkenyl) alkyl", also known as "cycloalkylalkyl", is an alkyl group as defined above wherein a hydrogen or carbon bond on the alkyl group is replaced by a bond to a cycloalkenyl group as defined above.

The terms "carbocyclic" and "carbocyclyl" refer to a ring structure in which the atoms on the ring are carbon. In some embodiments, carbocyclyl has 3 to 8 ring members, while in other embodiments the number of ring carbon atoms is 4,5, 6, or 7. Carbocyclyl includes, for example, cyclic hydrocarbon groups and cycloalkenyl groups. Unless specifically stated to the contrary, carbocyclic rings may be substituted with up to N substituents (e.g., amino, hydroxy, cyano, carboxy, nitro, thio, hydrocarbyloxy, and halo groups), where N is the size of the carbocyclic ring.

"(carbocyclyl) alkyl", also known as "carbocyclylalkyl", is an alkyl group as defined above in which a hydrogen or carbon bond on the alkyl group is replaced with a bond to a carbocyclyl as defined above.

A "non-aromatic carbocyclyl" or "non-aromatic carbocyclylalkyl" is a group in which the carbocyclic ring of the carbocyclyl or carbocyclylalkyl is a fully saturated, partially unsaturated, or fully unsaturated carbocyclyl in which the conjugation of pi electrons in the carbocyclic ring, if unsaturation is present, does not result in aromaticity.

An "aryl" group is a cyclic aromatic hydrocarbon that does not contain heteroatoms. Thus, aryl groups include, but are not limited to: phenyl, azulenyl, heptenylenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl,Mesityl, biphenylene, anthracenyl and naphthyl. In some embodiments, the aryl group contains 6 to 14 carbons in the ring portion of the group. The term "aryl" includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like), and also includes substituted aryl groups having other groups including, but not limited to, alkyl, halogen, amino, hydroxyl, cyano, carboxyl, nitro, thio, or hydrocarbonoxy bonded to one of the ring atoms. Representative substituted aryl groups may be mono-substituted or more than once substituted, such as, but not limited to, 2,3,4,5, or 6 substituted phenyl or naphthyl, which may be substituted by groups including, but not limited to, those listed above.

An "aralkyl" group is an alkyl, alkenyl or alkynyl group as defined above in which the hydrogen atom of the alkyl, alkenyl or alkynyl group is substituted with an aryl group as defined above. Representative aromatic hydrocarbon radicals include benzyl (-CH)₂Phenyl), phenethyl (-CH)₂CH₂Phenyl) and styryl (-CH ═ CH phenyl), and examplesFused (cycloalkylaryl) alkyl groups such as 4-ethyl-indanyl. The aryl moiety or the alkyl, alkenyl or alkynyl moiety or both are optionally substituted with other groups including, but not limited to, alkyl, halogen, amino, hydroxy, cyano, carboxy, nitro, thio or hydrocarbyloxy.

"heterocyclyl" or "heterocyclic" groups include aromatic and non-aromatic ring moieties containing 3 or more ring members, one or more of which is a heteroatom, such as, but not limited to, N, O, S or P. In some embodiments, heterocyclyl includes 3 to 20 ring members, while other such groups have 3 to 15 ring members, including, for example, monocyclic systems containing 5, 6, or 7 ring members. At least one ring contains a heteroatom, but it is not necessary that each ring in a polycyclic ring system contains a heteroatom. For example, dioxolanyl rings and benzodioxolyl ring systems (methylenedioxyphenyl ring systems) are both heterocyclyl groups within the meaning of this document. Is named as C₂The heterocyclic group of the heterocyclic group may be a 5-membered ring having 2 carbon atoms and 3 hetero atoms, a 6-membered ring having 2 carbon atoms and 4 hetero atoms, or the like. Likewise, C₄The heterocyclic group may be a 5-membered ring having 1 heteroatom, a 6-membered ring having 2 heteroatoms, or the like. The sum of the number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms.

The term "heterocyclyl" includes those fused ring materials containing fused aromatic and non-aromatic groups. The term also includes polycyclic and/or bridged ring systems containing heteroatoms such as, but not limited to, quinuclidinyl and 7-azabicyclo [2.2.1] heptane, and also includes heterocyclic groups having substituents including, but not limited to, alkyl, halogen, amino, hydroxyl, cyano, carboxyl, nitro, thio, or hydrocarbonoxy bonded to one of the ring members. A heterocyclyl group, as defined herein, may be a heteroaryl group or a partially or fully saturated cyclic group including at least one ring heteroatom. Heterocyclyl groups include, but are not limited to, pyrazinyl, pyrimidinyl, pyridazinyl, thiadiazolyl, oxadiazolyl, imidazolinyl, hexahydropyrimidinyl, diazepanyl, triazinyl, imidazolyl, pyrrolidinyl, furanyl, tetrahydrofuryl, tetrahydro-2H-pyranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, thienyl, benzothienyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzoimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthyl, purinyl, xanthine, adenine, guanine, quinolyl, Isoquinolinyl, tetrahydroquinolyl, quinoxalinyl and quinazolinyl. The heterocyclic group may be substituted. Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, including, but not limited to, rings containing at least one heteroatom and being mono-, di-, tri-, tetra-, penta-, hexa-, or more substituted with substituents such as those listed above, including, but not limited to: alkyl, halogen, amino, hydroxy, cyano, carboxy, nitro, thio and hydrocarbonoxy, and in the case of two substituents on the same carbon atom of the heterocycle, oxo (═ O) and thio (═ S) are included.

"heteroaryl" is an aromatic ring moiety comprising 5 or more ring members, wherein one or more ring members are heteroatoms, such as, but not limited to N, O and S. Is named as C₂The heteroaryl group of the heteroaryl group may be a 5-membered ring having 2 carbon atoms and 3 heteroatoms, a 6-membered ring having 2 carbon atoms and 4 heteroatoms, or the like. Likewise, C₄The heteroaryl group may be a 5-membered ring having 1 heteroatom, a 6-membered ring having 2 heteroatoms, or the like. The sum of the number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as: pyrrolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrimidinyl, thiadiazolyl, imidazolyl, oxadiazolyl, thienyl, triazolyl, tetrazolyl, triazinyl, thiazolyl, thienyl, oxazolyl, isoxazolyl, benzothienyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazole, and the likeA group selected from the group consisting of an azabenzimidazolyl group, a benzoxazolyl group, a benzothiazolyl group, a benzothiadiazolyl group, an imidazopyridinyl group, an isoxazolopyridinyl group, a thianaphthyl group, a purinyl group, a xanthine group, an adenine group, a guanine group, a quinolyl group, an isoquinolyl group, a tetrahydroquinolyl group, a tetrahydroisoquinolyl group, a quinoxalyl group and a quinazolinyl group. The terms "heteroaryl" and "heteroaryl group" include fused ring compounds, for example, wherein at least one, but not necessarily all, of the rings are aromatic rings, including tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, and 2, 3-dihydroindolyl. The term also includes heteroaryl groups that contain other groups bonded to one of the ring members, including but not limited to: alkyl, halogen, amino, hydroxy, cyano, carboxy, nitro, thio or hydrocarbyloxy. Representative substituted heteroaryl groups may be substituted one or more times with groups such as those listed above.

Additional examples of aryl and heteroaryl groups include, but are not limited to, phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thienyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl (1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl), thiadiazolyl (1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl), isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindolyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), Pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2, 3-triazol-1-yl, 1,2, 3-triazol-2-yl, 1,2, 3-triazol-4-yl, 1,2, 4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, triazolyl, triazol-2-yl, triazol-4-yl, 1,2, 4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5, Pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), pyrazolo [1, 5-. alpha. ]]Pyridyl, quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl)Quinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo [ b]Furyl (2-benzo [ b ]]Furyl, 3-benzo [ b ]]Furyl, 4-benzo [ b ]]Furyl, 5-benzo [ b ]]Furyl, 6-benzo [ b ]]Furyl, 7-benzo [ b ]]Furyl), isobenzofuryl, 2, 3-dihydro-benzo [ b ]]Furyl (2- (2, 3-dihydro-benzo [ b ]]Furyl), 3- (2, 3-dihydro-benzo [ b ]]Furyl), 4- (2, 3-dihydro-benzo [ b ]]Furyl), 5- (2, 3-dihydro-benzo [ b ]]Furyl), 6- (2, 3-dihydro-benzo [ b ]]Furyl), 7- (2, 3-dihydro-benzo [ b ]]Furyl)), benzo [ b ]]Thienyl (2-benzo [ b ]]Thienyl, 3-benzo [ b ]]Thienyl, 4-benzo [ b ]]Thienyl, 5-benzo [ b ]]Thienyl, 6-benzo [ b ]]Thienyl, 7-benzo [ b ]]Thienyl), 2, 3-dihydro-benzo [ b ]]Thienyl (2- (2, 3-dihydro-benzo [ b ]]Thienyl), 3- (2, 3-dihydro-benzo [ b ]]Thienyl), 4- (2, 3-dihydro-benzo [ b ]]Thienyl), 5- (2, 3-dihydro-benzo [ b ]]Thienyl), 6- (2, 3-dihydro-benzo [ b ]]Thienyl), 7- (2, 3-dihydro-benzo [ b ]]Thienyl)), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), benzo [ d]Isoxazolyl, carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenzo [ b, f]Aza derivatives(5H-dibenzo [ b, f ]]Aza derivatives-1-yl, 5H-dibenzo [ b, f ]]Aza derivatives2-yl, 5H-dibenzo [ b, f ]]Aza derivatives3-yl, 5H-dibenzo [ b, f ]]Aza derivatives-4-yl, 5H-dibenzo [ b, f ]]Aza derivatives-5-yl), 10, 11-dihydro-5H-dibenzo [ b, f)]Aza derivatives(10, 11-dihydro-5H-dibenzo [ b, f)]Aza derivatives-1-yl, 10, 11-dihydro-5H-dibenzo [ b, f]Aza derivatives-2-yl, 10, 11-dihydro-5H-dibenzo [ b, f]Aza derivatives3-yl, 10, 11-dihydro-5H-dibenzo [ b, f ]]Aza derivatives-4-yl, 10, 11-dihydro-5H-dibenzo [ b, f]Aza derivatives-5-yl), and the like.

A heterocyclyl hydrocarbyl is an alkyl, alkenyl or alkynyl group as defined above in which a hydrogen or carbon bond of the alkyl, alkenyl or alkynyl group is substituted by a bond to a heterocyclyl group as defined above. Representative heterocyclylalkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-2-ylmethyl (. alpha. -picolyl), pyridin-3-ylmethyl (. beta. -picolyl), pyridin-4-ylmethyl (. gamma. -picolyl), tetrahydrofuran-2-ylethyl, and indol-2-ylpropyl. The heterocyclyl hydrocarbon group may be substituted on the heterocyclyl moiety, as well as the alkyl, alkenyl or alkynyl moiety, or both.

The term "ring system" as used herein means a moiety comprising 1,2,3 or more rings, which may be substituted by an acyclic group or by other ring systems or by both, which may be fully saturated, partially unsaturated, fully unsaturated or aromatic, and when the ring system comprises more than a single ring, the rings may be fused, bridged or spiro. As is well known in the art, "spiro" means a class of structures in which two rings are fused on a single tetrahedral carbon atom.

The term "monocyclic, bicyclic or polycyclic aromatic or partially aromatic ring" as used herein is meant to include unsaturated rings having 4n +2 pi electrons or partially reduced (hydrogenated) forms thereof. The aromatic ring or partially aromatic ring may comprise additional fused, bridged or spiro rings that are not aromatic or partially aromatic in nature. For example, naphthalene and tetrahydronaphthalene are both "monocyclic, bicyclic or polycyclic aromatic or partially aromatic rings" as referred to herein. Furthermore, for example, benzo- [2.2.2] -bicyclooctane is also referred to herein as a "monocyclic, bicyclic or polycyclic aromatic or partially aromatic ring" and comprises a benzene ring fused to a bridged bicyclic ring system. A fully saturated ring has no double bonds and is carbocyclic or heterocyclic depending on the presence or absence of heteroatoms as referred to herein.

When two "R" groups are said to be linked together or to form a ring, it is meant that they may form a ring system with the carbon or non-carbon atom (e.g., nitrogen atom) to which they are bonded. Typically, they are bonded to each other to form a 3-to 7-membered ring, or a 5-to 7-membered ring. Non-limiting specific examples are cyclopentyl, cyclohexyl, cycloheptyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolyl, pyridinyl.

The term "hydrocarbyloxy" refers to an oxygen atom attached to a hydrocarbyl group (including cycloalkyl) as defined above. Examples of linear hydrocarbyloxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexoxy, n-heptoxy, n-octoxy, n-nonoxy, and the like. Examples of branched hydrocarbyloxy groups include, but are not limited to: isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic hydrocarbyloxy groups include, but are not limited to: cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.

The terms "aryloxy" and "arylalkoxy" refer to aryl groups bonded to oxygen atoms and arylalkyl groups bonded to oxygen atoms in the hydrocarbyl portion, respectively. Examples thereof include, but are not limited to, phenoxy, naphthoxy and benzyloxy.

The term "acyl" as used herein refers to a group comprising a carbonyl moiety, wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom, which may be part of an alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group, or the like. In the particular case where the carbonyl carbon atom is bonded to hydrogen, the group is a "formyl group," which is an acyl group as that term is defined herein. The acyl group can include from 0 to about 12-20 additional carbon atoms bonded to the carbonyl group. The acyl group referred to herein may contain a double bond or a triple bond. Acryloyl is an example of acyl. Acyl groups as referred to herein may also contain heteroatoms. Nicotinoyl (pyridyl-3-carbonyl) groups are examples of acyl groups referred to herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, acryloyl, and the like. When a group containing a carbon atom bonded to a carbonyl carbon atom contains a halogen, the group is referred to as a "haloacyl" group. An example is trifluoroacetyl.

The term "amine" includes compounds having, for example, the formula N (radical)₃Wherein each group may independently be H or non-hydrogen, such as alkyl, aryl, and the like. Amines include, but are not limited to: R-NH₂For example, alkylamines, arylamines, alkylarylamines; r₂NH, wherein each R is independently selected from the group consisting of dialkylamine, diarylamine, arylhydrocarbylamine, heterocyclylamine, and the like; and R₃N, wherein each R is independently selected from, for example, trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term "amineAlso included are ammonium ions as used herein.

"amino" is-NH₂、-NHR、-NR₂、-NR₃ ⁺The substituents of the forms (wherein each R is independently selected) and their respective protonated forms. Thus, any compound substituted with an amino group can be considered an amine.

The "ammonium" ion includes unsubstituted ammonium NH₄ ⁺But it also includes any protonated or quaternized form of the amine, unless otherwise indicated. Thus, trimethylamine hydrochloride and tetramethylammonium chloride are both ammonium ions and amines as referred to herein.

The term "amide" (or "amide group") includes C-and N-amide groups, respectively, i.e., -C (O) NR₂and-NRC (O) R groups. Thus, amide groups include, but are not limited to: carbamoyl (-C (O) NH)₂) And a carboxamide group (-NHC (O) H). The "amide (carboxamido)" group is of the formula C (O) NR₂Wherein R may be H, alkyl, aryl, and the like.

The term "carbonyl" refers to the group-C (O) -.

"halo", "halogen" and "halide" include fluorine, chlorine, bromine and iodine.

The term "perhaloalkyl" refers to an alkyl group in which all hydrogen atoms are replaced with halogen atoms. Perhaloalkyl groups include, but are not limited to: -CF₃and-C (CF)₃)₃. The term "haloalkyl" refers to an alkyl group in which some, but not necessarily all, of the hydrogen atoms are replaced with halogen atoms. Haloalkyl groups include, but are not limited to: -CHF₂and-CH₂F。

The term "perhalohydrocarbyloxy" refers to a hydrocarbyloxy group wherein all hydrogen atoms are replaced by halogen atoms. Perhalohydrocarbyloxy groups include, but are not limited to: -OCF₃and-OC (CF)₃)₃. The term "halohydrocarbyloxy" refers to a hydrocarbyloxy group wherein some, but not necessarily all, of the hydrogen atoms are replaced by halogen atoms. Halohydrocarbyloxy groups include, but are not limited to: -OCHF₂and-OCH₂F。

As is well known in the art, "salts" include organic compounds, for exampleCarboxylic acids, sulfonic acids or amines in ionic form in combination with a counter ion. For example, the acid in anionic form can be reacted with a cation such as, a metal cation, e.g., sodium, potassium, and the like; with ammonium salts, e.g. NH4⁺Or cations of various amines, including tetraalkylammonium salts such as tetramethylammonium; or other cations such as trimethylsulfonium and the like. A "pharmaceutically acceptable" or "pharmacologically acceptable" salt is a salt formed from ions that have been approved for human consumption and are generally non-toxic, e.g., the chloride or sodium salt. A "zwitterion" is an internal salt, such as may be formed within a molecule having at least two ionizable groups (one forming an anion and the other forming a cation, which serve to balance each other). For example, an amino acid (e.g., glycine) can be present in zwitterionic form. "zwitterions" are referred to herein as salts. The compounds of the present invention may take the form of salts. The term "salt" includes addition salts which are the free acids or the free bases of the compounds of the present invention. The salt may be a "pharmaceutically acceptable salt". The term "pharmaceutically acceptable salt" refers to salts having toxicity characteristics within a range that provides utility for pharmaceutical applications. However, pharmaceutically unacceptable salts may possess properties such as high crystallinity which are useful in the practice of the invention, e.g., in the synthesis, purification, or formulation of the compounds of the invention.

Suitable pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids may be selected from aliphatic, alicyclic, aromatic, araliphatic (araliphatic), heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, methylenepamoic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylsulfamic, stearic, alginic, beta-hydroxybutyric, salicylic, galactaric and galacturonic. Examples of pharmaceutically unacceptable acid addition salts include, for example, perchlorate and tetrafluoroborate.

Suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include, for example, metal salts, including alkali metal salts, alkaline earth metal salts, and transition metal salts, for example, calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts prepared from basic amines, such as N, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanates. Although pharmaceutically unacceptable salts are generally not suitable for use as pharmaceuticals, such salts may be used, for example, as intermediates in the synthesis of the compounds of formula I, for example, during their purification by recrystallization. All of these salts can be prepared in a conventional manner from the corresponding compounds of formula I by reacting, for example, an appropriate acid or base with the compounds of formula I. The term "pharmaceutically acceptable salts" refers to non-toxic inorganic or organic acid and/or base addition salts, see, e.g., Lit et al, Salt Selection for Basic Drugs (1986), Int J.Pharm.,33,201-217, which are incorporated herein by reference.

A "hydrate" is a compound that exists in combination with a water molecule. The composition may include a stoichiometric amount of water, such as a monohydrate or a dihydrate, or may include any amount of water. The term "hydrate" as used herein refers to a solid form, i.e., a hydrate of a compound in aqueous solution, although it may be hydrated, which is not a term as used herein.

"solvates" are similar compositions except that solvents other than water are used in place of water. For example, methanol or ethanol may form "alcoholates", which may also be stoichiometric or non-stoichiometric. The term "solvate" as used herein refers to a solid form, i.e., a compound in solution in a solvent, although it may be solvated, is not a solvate as the term is used herein.

As is well known in the art, a "prodrug" is a substance that can be administered to a patient, where the substance is converted in vivo to an active pharmaceutical ingredient by the action of a biochemical substance (e.g., an enzyme) in the patient's body. Examples of prodrugs include esters of carboxylic acid groups, which can be hydrolyzed by endogenous esterases, such as found in the blood of humans and other mammals.

"isotope" is well known in the art and refers to atoms having the same number of protons but different numbers of neutrons. For example, carbon 12 (the most common form of carbon) has 6 protons and 6 neutrons, while carbon 14 has 6 protons and 8 neutrons.

In addition, while features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. For example, if X is described as being selected from the group consisting of bromine, chlorine, and iodine, then the claims that X is bromine and chlorine are fully described. Furthermore, where features and aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. Thus, for example, if X is described as being selected from bromine, chlorine, and iodine, and Y is described as being selected from methyl, ethyl, and propyl, then the claims where X is bromine and Y is methyl are fully described.

The GLP-1 compounds, pharmaceutically acceptable salts or hydrolysable esters thereof of the present invention can be combined with a pharmaceutically acceptable carrier to provide pharmaceutical compositions suitable for use in the treatment of the biological conditions or disorders mentioned herein in mammalian species (and more preferably in humans). The specific carrier employed in these pharmaceutical compositions may vary depending upon the type of administration desired (e.g., intravenous, oral, topical, suppository, or parenteral).

In the preparation of compositions in oral liquid dosage form (e.g., suspensions, elixirs or solutions), typical pharmaceutical media can be employed such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like. Similarly, when preparing oral solid dosage forms (e.g., powders, tablets, or capsules), carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be employed.

Another aspect of an embodiment of the present invention provides a composition of a compound of the present invention, wherein the compound of the present invention is present alone, or in combination with another GLP-1 agonist, or in combination with another type of therapeutic agent or a second drug, or both. Non-limiting examples of GLP-1 receptor agonists include exenatide, liraglutide, tasaglutide, abiglutide, lixisenatide, and mixtures thereof.

In one embodiment, the GLP-1 agonist is exenatideOr ByettaExenatide is described, for example, in U.S. Pat. nos. 5,424,286; 6,902,744 No; 7,297,761 et al, the contents of each of which are incorporated herein by reference in their entirety.

In one embodiment, the GLP-1 agonist is liraglutide(also known as NN-2211 and [ Arg34, Lys 26)]- (N- ε - (γ -Glu (N- α -hexadecanoyl)) -GLP-1(7-37)), including sequence HAEGTFTSDVSSYLEGQAAKEFIAWKVRGRG, and available from Novo Nordisk (Denmark) or Scios (Ferrimon, Calif., USA). See, e.g., Elbrond et al, 2002, Diabetes Care.8; 25(8) 1398404; agerso et al, 2002, Diabetolomia.2 months; 45(2):195-202).

In one embodiment, the GLP-1 agonist is taselutide (CAS registry number 275371-94-3) and is available from Hoffman La-Roche. See, for example, U.S. patent No. 7,368,427, the contents of which are incorporated herein by reference in their entirety.

In one implementationIn this embodiment, the GLP-1 agonist is albiglutide (from GlaxoSmithKline))。

In another embodiment, the GLP-1 agonist is lixisenatide (from Sanofi-Aventis/Zealand Pharma))。

Non-limiting examples of the second medicament are disclosed above. In various such embodiments, the second drug is exenatide, liraglutide, tasaglutide, abiglutide, or lisiratide or other insulin modulating peptide. In various such embodiments, the second drug is a DPPIV inhibitor. In various such embodiments, the second agent is medically desirable for treating type II diabetes. In various such embodiments, the second agent is a biguanide, a sulfonylurea, meglitinide, a thiazolidinedione, an alpha-glucosidase inhibitor, a bile acid sequestrant, and/or a dopamine-2 agonist.

In another embodiment, the second drug is metformin.

In another embodiment, the second drug is sitagliptin.

As described herein, the compounds of the present invention include stereoisomers, tautomers, solvates, hydrates, salts (including pharmaceutically acceptable salts), and mixtures thereof. Compositions comprising the compounds of the present invention may be prepared by conventional techniques, for example, as described in Remington: the Science and Practice of Pharmacy, 19 th edition, 1995, which is incorporated herein by reference. The composition may be presented in conventional forms such as capsules, tablets, aerosols, solutions, suspensions or topical applications.

Typical compositions comprise a compound of the invention and a pharmaceutically acceptable excipient, which may be a carrier or diluent. For example, the active compound is typically admixed with, or diluted by, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper or other package. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound may be adsorbed onto a particulate solid support, for example, contained in sachets. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugars, cyclodextrins, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyethylene oxide, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, for example, glyceryl monostearate or glyceryl distearate alone or with a wax.

The formulations may be mixed with adjuvants which do not adversely react with the active compounds. Such additives may include wetting agents, emulsifying and suspending agents, salts for influencing osmotic pressure, buffering agents and/or coloring substances, preservatives, sweeteners or flavorings. The composition may also be sterilized, if desired.

The route of administration can be any route which effectively transports the active compounds of the invention to the appropriate or desired site of action, for example, oral, nasal, pulmonary, buccal, subcutaneous (subdermal), intradermal, transdermal or parenteral, e.g., rectal, depot (depot), subcutaneous (subeutaneous), intravenous, intraurethral, intramuscular, intranasal, ophthalmic solutions or ointments, preferably the oral route.

For parenteral administration, the carrier will typically include sterile water, although it may also contain other ingredients that aid solubility or act as preservatives. In addition, injectable suspensions may be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.

For topical application, the compounds of the present invention may be formulated using a mild, moisturizing base (e.g., an ointment or cream).

If a solid carrier is used for oral administration, the formulation may be tableted, placed in a hard gelatin capsule in powder form or in pellet form, or it may be in the form of a tablet or lozenge. If a liquid carrier is used, the formulation can be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid (e.g., aqueous or non-aqueous liquid suspension or solution).

Injectable dosage forms generally include aqueous or oily suspensions, which may be prepared using suitable dispersing or wetting agents and suspending agents. The injectable form may be in the form of a solution phase or suspension prepared using a solvent or diluent. Acceptable solvents or vehicles include sterile water, ringer's solution, or isotonic saline solution. Alternatively, sterile oils may be employed as a solvent or suspending agent. Preferably, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di-or triglycerides.

For injection, the formulation may also be a powder suitable for reconstitution with a suitable solution as described above. Examples of these include, but are not limited to: freeze-dried powder, spin-dried powder or spray-dried powder, amorphous powder, granules, precipitates or microgranules. For injection, the formulation may optionally include stabilizers, pH modifiers, surfactants, bioavailability modifiers, and combinations thereof. These compounds may be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). The unit dosage forms for injection may be in ampoules or in multi-dose containers.

The formulations of the present invention may be designed to provide rapid, sustained or delayed release of the active ingredient after administration to a patient by using procedures well known in the art. Thus, the formulation may also be formulated for controlled release or for sustained release.

Compositions encompassed by the present invention may include, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a long term storage and/or delivery effect. Thus, the formulation can be compressed into a pill or cylinder and implanted intramuscularly or subcutaneously as a long acting injection. Such implants may employ known inert materials such as silicone and biodegradable polymers, for example, polylactide-polyglycolide. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides).

For nasal administration, the formulations may comprise a compound of the invention dissolved or suspended in a liquid carrier, preferably an aqueous carrier, for aerosol applications. The carrier may contain additives such as solubilisers, for example propylene glycol, surfactants, absorption promoters such as lecithin (phosphatidylcholine) or cyclodextrins or preservatives such as parabens.

For parenteral use, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

The dosage form may be administered daily or multiple times a day (e.g., twice or three times a day). Alternatively, if the prescribing physician can make recommendations, the dosage form can be administered less frequently than once a day, e.g., every two days, or weekly. Dosage regimens include, for example, escalation of the dose to the extent necessary or useful for the indication being treated, thereby accommodating treatment to the patient's body, and/or minimizing or avoiding undesirable side effects associated with treatment. Other dosage forms include extended release forms or controlled release forms. Suitable dosage regimens and/or dosage forms include, for example, those set forth in the latest version of the Physicians' Desk Reference, which is incorporated herein by Reference.

Embodiments of the present invention also encompass prodrugs of the compounds of the present invention which undergo chemical transformation, by metabolic or other physiological processes, and then become pharmacologically active substances after administration. Transformation by metabolic or other physiological processes includes, but is not limited to: enzymatic (e.g., specific enzymatic) and non-enzymatic (e.g., general or specific acid or base induced) chemical conversion of a prodrug to a pharmacologically active substance. Typically, such prodrugs are functional derivatives of the compounds of the present invention which are readily converted in vivo to the compounds of the present invention. Conventional procedures for selecting and preparing suitable prodrug derivatives are described, for example, in Design of produgs, eds h.

In another embodiment, there is provided a method of preparing a composition of compounds described herein, comprising formulating a compound of the invention with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the method may further comprise the step of formulating the composition into a tablet or capsule. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the method further comprises the step of lyophilizing the composition to form a lyophilized formulation.

The compounds of the present invention may be used therapeutically in combination with i) one or more other GLP-1 modulator and/or ii) one or more other type of therapeutic agent or second drug, which may be administered orally in the same dosage form, in different oral dosage forms (e.g., continuously or discontinuously), or by co-injection or separate injection (e.g., continuously or discontinuously). Examples of combination therapies include metformin, sitagliptin (MK-0431, Januvia) -an oral antihyperglycemic agent (antidiabetic agent) in the class of dipeptidyl peptidase-4 (DPP-4) inhibitors and exenatide (Byetta) -an incretin mimetic. In other embodiments, the second drug is a biguanide such as metformin; sulfonylureas such as glibenclamide, glipizide, gliclazide, and glimepiride; meglitinide such as repaglinide and nateglinide; thiazolidinediones such as pioglitazone and rosiglitazone; alpha-glucosidase inhibitors such as acarbose and miglitol; bile acid sequestrants such as colesevelam; and/or dopamine-2 agonists such as bromocriptine.

The combination of the invention comprises a mixture of compounds from i) and ii) in a single formulation, as well as compounds from i) and ii) as separate formulations. Some combinations of the invention may be packaged as separate formulations in a kit. In some embodiments, two or more compounds from ii) are formulated together, while the compounds of the invention are formulated separately.

Dosages and formulations of other agents to be employed (where appropriate) are set forth in the latest version of the Physicians' Desk Reference, which is incorporated herein by Reference.

In certain embodiments, the invention encompasses compounds that bind to the GLP-1 receptor with high affinity and high specificity, either as agonists or as activators or potentiators. In certain embodiments, the compounds of the present invention are useful as positive allosteric modulators of the GLP-1 receptor.

In certain embodiments, the invention provides methods of activating, potentiating or agonizing (i.e., having an agonistic effect, for use as an agonist) a GLP-1 receptor using a compound of the invention. The method involves contacting the receptor with a suitable concentration of a compound of the invention to cause activation of the receptor. Such contacting can occur in vitro, for example, when a compound of the invention undergoing a relevant experiment submitted to a regulatory approval application is assayed to determine its GLP-1 receptor activating activity.

In certain embodiments, the method of activating a GLP-1 receptor may also be performed in vivo, i.e., in vivo in a mammal, such as a human patient or a test animal. The compounds of the invention may be provided to a living organism via one of the routes described above (e.g. orally) or may be provided locally in body tissue. In the presence of the compounds of the invention, activation of the receptor occurs and its effect can be studied.

Embodiments of the present invention provide methods of treating a malignant condition in a patient in need of GLP-1 receptor activation medically, wherein a compound of the present invention is administered to the patient at a dose, frequency, and duration that produces a beneficial effect to the patient. The compounds of the invention may be administered by any suitable means, examples of which are described above.

In certain embodiments, the present invention relates to compounds suitable for use as modulators or potentiators of class B GPCRs. These compounds may be active per se or in the presence of a receptor ligand. Receptors include incretins, which include GLP-1(7-36) and GLP-1 (9-36).

The therapeutic methods provided by the present invention include administering a compound of the invention alone, or in combination with another pharmacologically active agent or a second drug, to a subject or patient having a malignant condition in which activation, potentiation or agonism of a glucagon-like peptide 1 receptor is medically indicated, such as type I diabetes, type II diabetes, gestational diabetes, obesity, bulimia, insufficient satiety, or metabolic disorder.

In another embodiment, the treatment methods provided herein comprise administering a compound of the invention for the treatment of nonalcoholic fatty liver disease (NAFLD) and/or nonalcoholic steatohepatitis (NASH). NAFLD is thought to be caused by disruption of hepatic lipid homeostasis, and at least a proportion of patients may develop NASH. NAFLD is associated with insulin resistance in type 2 diabetes, GLP1 increases insulin sensitivity and aids glucose metabolism. In this context, the compounds of the invention are useful by being used to increase the oxidation of fatty acids, reduce adipogenesis and/or improve the glucose metabolism of the liver (for the results of using liraglutide in phase II experiments, see, e.g., Lee et al, Diabetes metals. J.36:262-267, 2012; Trevaskis et al, am. J.Physiol.Gastrointest. Liver Physiol.302: G762-G772,2012; Kim et al, Korean J.Physiol.Pharmacol.18:333-339, 2014; and see: Armstrong et al, Journal of Hepatology 62: S187-S212,2015).

The application also comprises the following technical scheme:

1. a compound having the structure of formula I-R or formula I-S or a pharmaceutically acceptable isomer, enantiomer, racemate, salt, ester, prodrug, hydrate or solvate thereof:

wherein

b is phenyl or heterocycle;

c is a non-aromatic carbocyclic group or a non-aromatic carbocyclic alkyl group:

each R is₁Independently is H or C_1-4An alkyl group;

R₂is-OH, -O-R₈、-N(R₁)-SO₂-R₇、-NR₄₁R₄₂、-N(R₁)-(CR_aR_b)_m-COOR₈、-N(R₁)-(CR_aR_b)_m-CO-N(R₁)(R₄₀)、-N(R₁)-(CR_aR_b)_m-N(R₁)C(O)O(R₈)、-N(R₁)-(CR_aR_b)_m-N(R₁)(R₄₀)、-N(R₁)-(CR_aR_b)_m-CO-N(R₁) -heterocyclyl or-N (R)₁)-(CR_aR_b)_m-heterocyclyl, which may be substituted by R₇Optionally (mono or poly) substituted;

each R is₃And R₄Independently H, halogen, alkyl, by R₃₁(mono-OR poly-) substituted alkyl, alkoxy, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, aryl, heterocyclyl, -OH, -OR₇、-CN、-NO₂、-NR₁R₇、-C(O)R₇、-(O)NR₁R₇、-NR₁C(O)R₇、-SR₇、-S(O)R₇、-S(O)₂R₇、-OS(O)₂R₇、-(O)₂NR₁R₇、-NR₁S(O)₂R₇、-(CR_aR_b)_mNR₁R₇、-(CR_aR_b)_mO(CR_aR_b)_mR₇、-(CR_aR_b)_mNR₁(CR_aR_b)_mR₇Or- (CR)_aR_b)_mNR₁(CR_aR_b)_mCOOR₈(ii) a Or any two R on the same carbon atom₃Or R₄The groups together form oxo;

each R is₄₁And R₄₂Independently is R₄₀、-(CHR₄₀)_n-C(O)O-R₄₀、-(CHR₄₀)_n-C(O)-R₄₀、-(CH₂)_n-N(R₁)(R₇) Aryl or heteroaryl, any of which may be substituted by R₇Optional(mono or poly) substitution; or any two R₄₁And R₄₂Together with the N atom to which they are attached form a group which may be substituted by R₇An optionally (mono or poly) substituted 3-to 7-membered heterocyclyl;

Each L₃Independently absent, -O-or-N (R)₁)-；

Each m is independently 0,1, 2,3,4,5, or 6;

each n is independently 0 or 1 or 2;

p is 0,1, 2 or 3;

q is 0,1, 2 or 3;

each r is independently 2,3 or 4; and

each s is independently 1,2,3 or 4.

2. The compound of embodiment 1, having the structure:

3. the compound of embodiment 1, having the structure:

4. the compound of embodiment 1, having the structure:

5. the compound of embodiment 1, having the structure:

6. the compound of embodiment 1, having the structure:

7. the compound of embodiment 1, having the structure:

8. the compound of embodiment 1, having the structure:

9. the compound of embodiment 1, having the structure:

10. the compound of embodiment 1, having the structure:

11. the compound of embodiment 1, having the structure:

12. the compound of embodiment 1, having the structure:

13. the compound of embodiment 1, having the structure:

14. the compound of embodiment 1, having the structure:

15. the compound of embodiment 1, having the structure:

16. the compound of embodiment 1, having the structure:

17. a compound of embodiment 1 wherein B is pyrimidinyl.

18. A compound of embodiment 1 wherein B is pyrazolyl.

19. A compound of embodiment 1 wherein B is pyridyl.

20. A compound of embodiment 1 wherein B is indolyl.

21. The compound of any one of embodiments 1 to 20, wherein C is a non-aromatic carbocyclic group.

22. A compound of embodiment 21 wherein the non-aromatic carbocyclic group is a cyclic hydrocarbon group.

23. A compound of embodiment 21, wherein the non-aromatic carbocyclic group is cycloalkenyl.

24. The compound of any one of embodiments 1 to 20, wherein C is selected from:

25. the compound of embodiment 1, having the structure:

26. the compound of embodiment 1, having the structure:

27. the compound of any one of embodiments 1 to 26, wherein R₁Is H.

28. The compound of any one of embodiments 1 to 26, wherein R₄Is H.

29. The compound of any one of embodiments 1 to 26 wherein q is 1.

30. The compound of embodiment 29 wherein R₅Is an alkyl group.

31. The compound of any one of embodiments 1 to 26 wherein p is 1.

32. The compound of embodiment 31, wherein R₃Is an alkyl group.

33. A compound of embodiment 32 wherein alkyl is straight or branched chain alkyl.

34. A compound of embodiment 32 wherein alkyl is cycloalkyl.

35. The compound of embodiment 1, having the structure:

36. the compound of embodiment 1, having the structure:

37. the compound of embodiment 1, having the structure:

38. the compound of embodiment 1, having the structure:

39. the compound of any one of embodiments 35 to 38, wherein each alkyl is independently C₁-C₈Straight chain alkyl or branched alkyl.

40. The compound of any one of embodiments 35 to 38, wherein each alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

41. The compound of any one of embodiments 1 to 40, wherein R₂is-N (R)₁)(CR_aR_b)_mCOOR₈。

42. The compound of embodiment 39 wherein m is 2 and R₁For hydrogen, each occurrence of R_aAnd R_bIs hydrogen, and R₈Is hydrogen.

43. The compound of embodiment 41 wherein m is 1, R₁、R_bAnd R₈Is hydrogen, and R_aAs defined in embodiment 1.

44. The compound of embodiment 41 wherein m is 2, one R_aIs hydrogen and the other R is_aAs defined in embodiment 1, each occurrence of R_bIs hydrogen, and R₁And R₈Is hydrogen.

45. The compound of any one of embodiments 43 to 44, wherein the other R_aIs as a quilt R₇Optionally substituted alkyl.

46. The compound of embodiment 45, wherein the other R_aIs a straight-chain or branched alkyl group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

47. The compound of embodiment 46 wherein another R_aIs methyl.

48. Examples 43 to44, wherein another R_aIs a cycloalkyl group selected from isopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

49. The compound of any one of embodiments 43 to 44, wherein the other R_aIs as a quilt R₇Optionally substituted heterocyclyl or by R₇Optionally substituted heterocyclylalkyl.

50. The compound of any one of embodiments 43 to 44, wherein the other R_aIs as a quilt R₇Optionally substituted aryl or by R₇Optionally substituted aromatic hydrocarbon groups.

51. The compound of any one of embodiments 43 to 44, wherein the other R_aIs- (CHR)₄₀)_mC(O)OR₄₀、-(CHR₄₀)_mOR₄₀、-(CHR₄₀)_mSR₄₀、-(CHR₄₀)_mNR₄₁R₄₂、-(CHR₄₀)_mC(O)NR₄₁R₄₂、-(CHR₄₀)_mC(O)N(R₁)(CHR₄₀)_m-NR₄₁R₄₂、-(CHR₄₀)_mC(O)N(R₁)(CHR₄₀)_m-C(O)NR₄₁R₄₂、-(CHR₄₀)_mC(O)N(R₁)(CHR₄₀)_m-C(O)OR₄₀Or- (CHR)₄₀)_m-S-S-R₄₀。

52. The compound of embodiment 41 wherein m is 1, R_bIs hydrogen, and R₁And R_aTogether with the atom to which they are attached form R₇Optionally substituted heterocyclyl.

53. The compound of embodiment 41 wherein m is 2, second (CR)_aR_b) R of the radical_bIs hydrogen, and R₁And second (CR)_aR_b) R of the radical_aTogether with the atom to which they are attached form R₇Optionally substituted heterocyclyl.

54. The compound of any one of embodiments 1 to 40, wherein R₂is-OH.

55.The compound of any one of embodiments 1 to 40, wherein R₂is-N (R)₁)-SO₂-R₈。

56. The compound of any one of embodiments 1 to 40, wherein R₂is-N (R)₁)(R₄₂)。

57. The compound of embodiment 56 wherein R₄₁And R₄₂Independently is R₄₀、-(CHR₄₀)_n-C(O)OR₄₀、-(CHR₄₀)_n-C(O)R₄₀、-(CH₂)_nN(R₁)(R₇) Quilt R₇Optionally substituted aryl or by R₇Optionally substituted heteroaryl.

58. The compound of embodiment 56 wherein R₄₁Is hydrogen, and R₄₂Is as a quilt R₇Optionally substituted alkyl.

59. The compound of embodiment 56 wherein R₄₁Is hydrogen, and R₄₂Is- (CHR)₄₀)_nC(O)OR₄₀、-(CHR₄₀)_nC(O)R₄₀、-(CH₂)_nN(R₁)(R₇) Quilt R₇Optionally substituted aryl or by R₇Optionally substituted heteroaryl.

60. The compound of embodiment 56 wherein R₄₁And R₄₂Together with the N atom to which they are attached form R₇An optionally substituted 3-to 7-membered heterocyclyl.

61. The compound of any one of embodiments 1 to 40, wherein R₂is-N (R)₁)(CR_aR_b)_mCON(R₁)(R₄₀)。

62. The compound of embodiment 61 wherein m is 1 and R_bIs hydrogen, and R₁And R_aTogether with the atom to which they are attached form R₇Optionally substituted heterocyclyl.

63. The compound of embodiment 61 wherein m is 2, second (CR)_aR_b) R of the radical_bIs hydrogen, and R₁And a firstTwo (CR)_aR_b) R of the radical_aTogether with the atom to which they are attached form R₇Optionally substituted heterocyclyl.

64. The compound of any one of embodiments 1 to 40, wherein R₂is-N (R)₁)(CR_aR_b)_mN(R₁)C(O)OR₈、-N(R₁)(CR_aR_b)_mN(R₁)(R₇)、-N(R₁)(CR_aR_b)_mCON(R₁) -heterocyclyl or- (CR)_aR_b)_mN(R₁) A heterocyclic group.

65. The compound of embodiment 1, wherein the compound has the structure of any one of the compounds of table 1 or a pharmaceutically acceptable isomer, enantiomer, racemate, salt, ester, prodrug, hydrate or solvate thereof.

66. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 65 and at least one pharmaceutically acceptable carrier, diluent or excipient.

67. A pharmaceutical combination comprising a compound according to any one of embodiments 1 to 65 and a second drug.

68. The pharmaceutical combination of embodiment 67, wherein the second agent is an agonist or modulator of a glucagon receptor, a GIP receptor, a GLP-2 receptor, or a PTH receptor, or a glucagon-like peptide 1(GLP-1) receptor.

69. The pharmaceutical combination of embodiment 67, wherein the second drug is exenatide, liraglutide, tasaglutide, abiglutide, or lisiratide.

70. The pharmaceutical combination of embodiment 67, wherein the second drug is a DPPIV inhibitor.

71. The pharmaceutical combination of embodiment 67, wherein the second drug is sitagliptin.

72. The pharmaceutical combination of embodiment 67, wherein the second drug is a biguanide, a sulfonylurea, meglitinide, a thiazolidinedione, an alpha-glucosidase inhibitor, an SGLT2 inhibitor, a bile acid sequestrant and/or a dopamine-2 agonist.

73. The pharmaceutical combination of embodiment 67, wherein the second drug is metformin.

74. The pharmaceutical combination of embodiment 67, wherein the second drug is dapagliflozin, empagliflozin, or canagliflozin.

75. A method of activating, enhancing, modulating or agonizing a glucagon-like peptide 1 receptor comprising contacting the receptor with an effective amount of a compound of any one of embodiments 1 to 65 or a pharmaceutical composition of embodiment 66 or a pharmaceutical combination of embodiment 67.

76. A method of treating a malignant condition in a patient in medical need of activation, enhancement, modulation or agonism of a glucagon-like peptide 1 receptor comprising administering to the patient an effective amount of a compound of any one of embodiments 1 to 65 at a frequency and for a duration sufficient to provide a beneficial effect to the patient.

77. The method of embodiment 76, wherein the malignant condition is type I diabetes, type II diabetes, gestational diabetes, obesity, bulimia, insufficient satiety, a metabolic disorder, a non-alcoholic fatty liver disease, or non-alcoholic steatohepatitis.

78. The method of embodiment 76, wherein the malignant condition is type II diabetes.

General synthetic methods for preparing Compounds

Molecular embodiments of the invention can be synthesized using standard synthetic techniques known to those skilled in the art. The compounds of the present invention can be synthesized using the general synthetic procedures described in schemes 1-9.

Scheme 1:

reagent: PG is a protecting group, and X_AAnd X_BIs CR₄Or N; (i) when Z ═ CO, then coupling with an acid chloride to an amide: DIEA. DCM, or coupling with acid to amide: EDC, HOBt, DMF or HATU, DMF; z is SO₂Then, coupled with sulfonyl chloride: DIEA or NEt₃DCM or dmf (ii) DIEA, 1,1, 1-trifluoro-N-phenyl-N- ((trifluoromethyl) sulfonyl) methanesulfonamide, DCM; (iii) KOAc, bis-pinacolborane, PdCl₂(dppf) or Pd (dppf) Cl₂、Na₂CO₃THF, ACN, water; (iv) pd (dppf) Cl₂、Na₂CO₃THF, ACN, water; (v) pd (dppf) Cl₂、Na₂CO₃THF, ACN, water; (vi) deprotection, e.g. methyl ester deprotection: NaOH, MeOH, water.

Other enantiomers and/or diastereomers may be prepared in a similar manner using scheme 1.

Scheme 2:

reagent: PG is a protecting group, and X_AAnd X_BIs CR₄Or N; (i) pd (dppf) Cl₂、Na₂CO₃THF, ACN, water; (ii) pd (dppf) Cl₂、Na₂CO₃THF, ACN, water; (iii) deprotection, e.g. methyl ester deprotection: NaOH, MeOH, water.

Other enantiomers and/or diastereomers can be prepared in a similar manner using scheme 2.

Scheme 3:

reagent: PG (Picture experts group)₁And PG₂Is a protecting group; (i) DIEA, 1,1, 1-trifluoro-N-phenyl-N- ((trifluoromethyl) sulfonyl) methanesulfonamide, DCM; (ii) KOAc, bis-pinacolborane, PdCl₂(dppf)；(iii)Pd(dppf)Cl₂、Na₂CO₃THF, ACN, water; (iv) pd (dppf) Cl₂、Na₂CO₃THF, ACN, water; (v) PG (Picture experts group)₂Deprotection of (e.g. CBZ): Pd/C, H₂EA; (vi) if Z ═ CO, coupling with acid chloride to amide: DIEA, DCM, or coupling with acid to amide: EDC, HOBt, DMF or HATU, DMF; if Z is SO₂Then coupling with sulfonyl chloride: DIEA or NEt₃DCM or DMF; (vii) PG (Picture experts group)₁Deprotection of e.g. tert-butyl ester: DCM, TFA.

Other enantiomers and/or diastereomers may be prepared in a similar manner using scheme 3.

Scheme 4:

reagent: PG (Picture experts group)₁And PG₂Is a protecting group, and X_AAnd X_BIs CR₄Or N; (i) pd (dppf) Cl₂、Na₂CO₃THF, ACN, water; (ii) PG (Picture experts group)₂Deprotection of (e.g. CBZ): Pd/C, H₂EA; (iii) if Z ═ CO, coupling with acid chloride to amide: DIEA, DCM, or coupling with acid to amide: EDC, HOBt, DMF or HATU, DMF; if Z is SO₂Then coupling with sulfonyl chloride: DIEA or NEt₃DCM or DMF; (iv) PG (Picture experts group)₁Deprotection of e.g. tert-butyl ester: DCM, TFA.

Other enantiomers and/or diastereomers can be prepared in a similar manner using scheme 4.

Scheme 5:

reagent: PG is a protecting group; (i) (a) when R is₂Is NR₁-(CR_aR_b)_m-COOH: NHR₁-(CR_aR_b)_m-COOPG, HATU, DMF, followed by deprotection, e.g.Deprotection of tert-butyl ester: DCM, TFA; (b) when R is₂Is NH-SO₂-R₈The method comprises the following steps: r₈SO₂NH₂DCC, DMAP, DCM; (c) when R is₂Is NR₄₁R₄₂The method comprises the following steps: HNR₄₁R₄₂HATU, DMF, then deprotected, e.g. tert-butyl ester deprotected: DCM, TFA; (d) when R is₂Is N (R)₁)-(CR_aR_b)m-CO-N(R₁) -heterocyclyl group(s): HN (R)₁)-(CR_aR_b)m-CO-N(R₁) Heterocyclyl, HATU, DMF, followed by deprotection, for example of tert-butyl ester: DCM, TFA; (e) when R is₂is-N (R)₁)-(CR_aR_b)_m-CO-N(R₁)(R₇) The method comprises the following steps: NH (NH)₂-(CR_aR_b)_m-COOPG, HATU, DMF, followed by deprotection, e.g. of tert-butyl ester: DCM, TFA; then HN (R)₁)(R₇) HATU, DMAP, DCM; (f) when R is₂Is N (R)₁)-(CR_aR_b)_m-heterocyclyl group(s): HN (R)₁)-(CR_aR_b)_mHeterocyclyl, HATU, DMF, followed by deprotection, for example of tert-butyl ester: DCM, TFA.

Other enantiomers and/or diastereomers can be prepared in a similar manner using scheme 5.

Scheme 6:

reagent: PG (Picture experts group)₁And PG₂Is a protecting group, and X_AAnd X_BIs CR₄Or N; (i) PG (Picture experts group)₁Deprotection of e.g. tert-butyl ester: DCM, TFA; (ii) HATU, DIEA, DMF.

Other enantiomers and/or diastereomers can be prepared in a similar manner using scheme 6.

Scheme 7:

reagent: PG (Picture experts group)₁And PG₂Is a protecting group, and X_AAnd X_BIs CR₄Or N; (i) pd (dppf) Cl₂、Na₂CO₃THF, ACN, water; (ii) PG (Picture experts group)₂Deprotection of e.g. tert-butyl ester: DCM, TFA.

Other enantiomers and/or diastereomers can be prepared in a similar manner using scheme 7.

Scheme 8:

reagent: PG (Picture experts group)₁And PG₂Is a protecting group, and X_AAnd X_BIs CR₄Or N; (i) tosylhydrazine, LiOtBu, XPhos, Pd₂(dba)₃Dioxane (dioxane), 100 ℃. (ii) PG (Picture experts group)₂Deprotection of e.g. tert-butyl ester: DCM, TFA.

Other enantiomers and/or diastereomers can be prepared in a similar manner using scheme 8.

Scheme 9:

reagent: PG (Picture experts group)₁、PG₂And PG₃Is a protecting group; (i) PG (Picture experts group)₁Deprotection of e.g. tert-butyl ester: DCM, TFA; (ii) (a) when R is₂Is NR₁-(CR_aR_b)_m-COOH: NHR₁-(CR_aR_b)_m-COOPG₃HATU, DMF; (b) when R is₂Is NH-SO₂-R₈The method comprises the following steps: r₈SO₂NH₂DCC, DMAP, DCM; (c) when R is₂Is NR₄₁R₄₂The method comprises the following steps: HNR₄₁R₄₂HATU, DMF; (d) when R is₂Is N (R)₁)-(CR_aR_b)m-CO-N(R₁) -heterocyclyl group(s): HN (R)₁)-(CR_aR_b)m-CO-N(R₁) -heterocyclyl, HATU, DMF; (e) when R is₂is-N (R)₁)-(CR_aR_b)_m-CO-N(R₁)(R₇) The method comprises the following steps: NH (NH)₂-(CR_aR_b)_m-COOPG₃HATU, DMF, then deprotected, e.g. tert-butyl ester deprotected: DCM, TFA, then HN (R)₁)(R₇) HATU, DMAP, DCM; (f) when R is₂Is N (R)₁) -heterocyclyl group(s): HN (R)₁) -heterocyclyl, HATU; (iii) PG (Picture experts group)₂Deprotection of (e.g. CBZ): Pd/C, H₂EA; (iv) if Z ═ CO, coupling with acid chloride to amide: DIEA, DCM, or coupling with acid to amide: EDC, HOBt, DMF or HATU, DMF; if Z is SO₂Then coupling with sulfonyl chloride: DIEA or NEt₃DCM or DMF; (v) PG (Picture experts group)₃Deprotection of e.g. tert-butyl ester: DCM, TFA.

Other enantiomers and/or diastereomers can be prepared in a similar manner using scheme 9.

Scheme 10:

reagent: PG (Picture experts group)₁And PG₂Is a protecting group, and X_AAnd X_BIs CR₄Or N; (i) pd (dppf) Cl₂、KOAc、Na₂CO₃THF, ACN, water; (ii) pd (dppf) Cl₂、Na₂CO₃THF, ACN, water.

Other enantiomers and/or diastereomers can be prepared in a similar manner using scheme 10.

Scheme 11:

reagent: PG (Picture experts group)₁、PG₂And PG₃Is a protecting group; (i) PG (Picture experts group)₂Deprotection of e.g. Boc deprotection: 6N HCl in isopropanol, DCM; (ii) if Z ═ CO, coupling with acid chloride to amide: DIEA, DCM, or coupling with acid to amide: EDC, HOBt, DMF or HATU, DMF; if Z is SO₂Then coupling with sulfonyl chloride: DIEA or NEt₃DCM or DMF; (iii) PG (Picture experts group)₁Deprotection of e.g. tert-butyl ester: DCM, TFA; (iv) (a) when R is₂Is NH- (CR)_aR_b)_m-COOH: NH (NH)₂-(CR_aR_b)_m-COOPG₃HATU, DMF, then deprotected, e.g. tert-butyl ester deprotected: DCM, TFA; (b) when R is₂Is NH-SO₂-R₈The method comprises the following steps: r₈SO₂NH₂DCC, DMAP, DCM; (c) when R is₂Is NR₄₁R₄₂The method comprises the following steps: HNR₄₁R₄₂HATU, DMF, then deprotected, e.g. tert-butyl ester deprotected: DCM, TFA; (d) when R is₂Is N (R)₁)-(CR_aR_b)_m-CO-N(R₁) -heterocyclyl group(s): HN (R)₁)-(CR_aR_b)_m-CO-N(R₁) Heterocyclyl, HATU, DMF, followed by deprotection, for example of tert-butyl ester: DCM, TFA; (e) when R is₂is-N (R)₁)-(CR_aR_b)_m-CO-N(R₁)(R₇) The method comprises the following steps: NH (NH)₂-(CR_aR_b)_m-COOPG₃HATU, DMF, then deprotected, e.g. tert-butyl ester deprotected: DCM, TFA, then HN (R)₁)(R₇) HATU, DMAP, DCM; (f) when R is₂Is N (R)₁) -heterocyclyl group(s): HN (R)₁) Heterocyclyl, HATU, DMF, followed by deprotection, for example of tert-butyl ester: DCM, TFA; (v) pd (dppf) Cl₂、Na₂CO₃THF, ACN, water.

Other enantiomers and/or diastereomers can be prepared in a similar manner using scheme 11.

Examples

The invention is further illustrated in the following examples. The following examples are non-limiting and merely represent various aspects of the present invention.

Solid and dashed line wedges within the structures disclosed herein show relative stereochemistry, with absolute stereochemistry depicted only when explicitly shown or depicted.

General procedure

NMR spectra

¹H NMR (400MHz) and¹³c NMR (100MHz) in deuterated chloroform (CDCl)₃) Or dimethyl sulfoxide (d)₆-DMSO). The NMR spectra were processed using MestReNova6.0.3-5604.

LCMS data

Mass Spectra (LCMS) were obtained using one of 6 systems. The system 1 a: an Agilent1100/6110HPLC system equipped with A Thompson ODS-A,100A,5 μ (50X4.6mM) column, using water containing 0.1% formic acid as mobile phase A, acetonitrile containing 0.1% formic acid as mobile phase B, water containing 5mM ammonium acetate as mobile phase C, and acetonitrile containing 5mM ammonium acetate as mobile phase D, at A mobile phase flow rate of 1 mL/min. The method comprises the following steps: 20-100% mobile phase B (80-0% A) over 2.5 min; then held at 100% B for 2.5 min. The method 2 comprises the following steps: 5% mobile phase B (95% a) over 1 min; 5-95% of B, over 9 min; then held at 95% B for 5min. The method 3 comprises the following steps: 20-100% mobile phase B (80-0% A) over 2.5 min; then held at 100% B for 4.5 min. The method 12 comprises the following steps: 5% D (95% C) over 1 min; then 5-95% of D, over 9 min; and maintained at 95% D for 5min. System 1 b: an Agilent1100/6110HPLC system equipped with an Agilent Poroshell 120EC-C8,2.7 μ (50X3mM) column, using water containing 5mM ammonium acetate as mobile phase C and acetonitrile containing 5mM ammonium acetate as mobile phase D, the flow rate of the mobile phase being 1 mL/min. Method 13: 5% D (95% C) to 95% D over 12 min; then kept at 95% D for 2.8 min; then to 5% D over 0.2 min. System 1 c: an Agilent1100/6110HPLC system equipped with an Agilent Poroshell 120EC-C18,2.7 μ (50X3mM) column, using water containing 5mM ammonium acetate as mobile phase C and acetonitrile containing 5mM ammonium acetate as mobile phase D, the flow rate of the mobile phase being 1 mL/min. The method 14 comprises the following steps: 5% D (95% C) to 95% D over 12 min; then kept at 95% D for 2.8 min; then to 5% D over 0.2 min. The method 15 comprises the following steps: 20% D (80% C) to 95% D over 3 min; then held at 95% D for 1.8 min; then to 20% D over 0.2 min. The method 16 comprises the following steps: 20% D (80% C) to 95% D over 3.0 min; and kept at 95% D for 3.8 min; then 20% of D over 0.2 min. System 1 d: an Agilent1100/6110HPLC system equipped with an Agilent Poroshell 120EC-C8,2.7 μ (50X3mM) column, using water containing 5mM ammonium acetate as mobile phase C and acetonitrile containing 5mM ammonium acetate as mobile phase D, at a mobile phase flow rate of 1 mL/min. The method 18 comprises the following steps: 20% D (80% C) to 95% D over 3 min; and kept at 95% D for 1.8 min; then to 20% D over 0.2 min. Method 19: 20% D (80% C) to 95% D over 3.0 min; and kept at 95% D for 3.8 min; then 20% of D over 0.2 min. The method 20 comprises the following steps: 5% D (95% C) to 95% D over 12 min; then kept at 95% D for 2.8 min; then to 5% D over 0.2 min. System 1 e: an Agilent1100/6110HPLC system equipped with a Waters X-Bridge C-8, 3.5. mu. column (50X4.6mM) using water containing 5mM ammonium acetate as mobile phase C and acetonitrile containing 5mM ammonium acetate as mobile phase D, at a mobile phase flow rate of 1 mL/min. The method 25 comprises the following steps: 20% D (80% C) to 95% D over 3 min; then kept at 95% D for 3.8 min; then to 5% D over 0.2 min. The method 26 comprises the following steps: 20% D (80% C) to 95% D over 3 min; and kept at 95% D for 1.8 min; then to 20% D over 0.2 min. The method 28: 20% D (80% C) to 95% D over 12.0 min; and kept at 95% D for 2.8 min; then 20% of D over 0.2 min. And (3) system 2: agilent 1200LCMS equipped with Agilent Zorbax extended RRHT 1.8 μm (4.6x30mm) column using water containing 0.1% formic acid as mobile phase a and acetonitrile containing 0.1% formic acid as mobile phase B. The method 4 comprises the following steps: 5-95% of mobile phase B, 3.0min, flow rate of 2.5 mL/min; then held at 95% for 0.5min at a flow rate of 4.5 mL/min. The method 5 comprises the following steps: 5-95% of mobile phase B, at a flow rate of 2.5mL/min over 14 min; then held at 95% for 0.5min at a flow rate of 4.5 mL/min. And (3) system: a Waters Fractionlynx LCMS system equipped with an Agilent Zorbax extended RRHT 1.8 μm, (4.6X30mm) column, using water containing 0.1% formic acid as mobile phase A and acetonitrile containing 0.1% formic acid as mobile phase B. The method 6 comprises the following steps: 5-95% of mobile phase B, 3.0min, flow rate of 2.5 mL/min; then, it was kept at 95% for 0.5min at a flow rate of 4.5 mL/min. The method 7 comprises the following steps: 5-95% of mobile phase B, at a flow rate of 2.5mL/min over 14 min; then, it was kept at 95% for 0.5min at a flow rate of 4.5 mL/min. And (4) system: agilent 1260LCMS equipped with Agilent Zorbax extended RRHT 1.8 μm (4.6x30mm) column using water with 0.1% formic acid as mobile phase a and acetonitrile with 0.1% formic acid as mobile phase B. The method 8 comprises the following steps: 5-95% of mobile phase B, 3.0min, flow rate of 2.5 mL/min; then, it was kept at 95% for 0.5min at a flow rate of 4.5 mL/min. The method 9: 5-95% of mobile phase B, at a flow rate of 2.5mL/min over 14 min; then, it was kept at 95% for 0.5min at a flow rate of 4.5 mL/min. And (5) the system: agilent 1260LCMS equipped with a Waters XSelect CSH C183.5 μm (4.6X50mm) column using water with 0.1% formic acid as mobile phase A and acetonitrile with 0.1% formic acid as mobile phase B. The method 10 comprises the following steps: mobile phase B with a gradient of 5-95% over 13.0min at a flow rate of 2.5 mL/min; then, it was kept at 95% for 1.0min at a flow rate of 4.5 mL/min. The method 11 comprises the following steps: gradient 5-95% mobile phase B over 3.0min, flow rate 2.5 mL/min; then, it was kept at 95% for 0.6min at a flow rate of 4.5 mL/min. And (6) the system: a Waters acquisition UPLC system equipped with an acquisition UPLC BEH C18,1.7 μm (2.1X50mM) column or a Phenomenex Kinetex C18,1.7 μm (2.1X50mM) column, using water containing 10mM ammonium formate as mobile phase A and acetonitrile as mobile phase B at a flow rate of 0.5 mL/min. The method 17: 10% mobile phase B (90% a) for 0.5 min; 10-95% of B over 3min, then held at 95% of B for 1.1 min; 95-10% B over 0.1min, then held for 0.3min, and the total run time was 5min. The method 23 comprises the following steps: 20% mobile phase B (80% a) for 0.5 min; 20-95% of B, over 3 min; then keeping the temperature at 95% of B for 1.1 min; 95-20% of B, over 0.1 min; then hold for 0.3min and total run time 5min. The method 24 comprises the following steps: 30% mobile phase B (70% a) for 0.5 min; 30-95% of B, over 2.2 min; then keeping the temperature at 95% of B for 1.9 min; 95-30% B over 0.1min, then held for 0.3min and a total run time of 5min. The method 27 comprises the following steps: 40% mobile phase B (60% a) for 0.5 min; 40-95% of B, over 1.9 min; then keeping at 95% B for 2.2 min; 95-40% B over 0.1min, then held for 0.3min and total run time 5min. The method 21 comprises the following steps: 20% mobile phase B (80% a) for 0.5 min; 20-95% of B, over 2.7 min; then keeping at 95% B for 1.4 min; 95-20% of B, over 0.1 min; then hold for 0.3min and total run time 5min. The method 22 comprises the following steps: 40% mobile phase B (60% a) for 0.5 min; 40-95% of B, over 1.6 min; then keeping at 95% B for 2.5 min; 95-40% of B, over 0.1 min; then hold for 0.3min and total run time 5min.

Hydrogenation

Hydrogenation reactions were carried out using either a Thales Nanotechnology H-Cube reactor equipped with the indicated CatCart or using standard laboratory techniques.

Reaction conditions and abbreviations

Pyridine, Dichloromethane (DCM), Tetrahydrofuran (THF) and toluene used in the procedure were obtained from Aldrich Sure-Seal bottles or Acros Acrosseal dry solvents and placed under nitrogen (N)₂) And (5) storing. All reactions were stirred magnetically and the temperature was the ambient reaction temperature. The following abbreviations are used: ethyl Acetate (EA), 1-methyl-2-pyrrolidone (NMP), Triethylamine (TEA), N-hydroxybenzotriazole (HOBt), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), N-Dimethylformamide (DMF), Dimethylacetamide (DMA), di-tert-butyl dicarbonate (Boc)₂O), N, N-Diisopropylethylamine (DIEA), acetic acid (AcOH), hydrochloric acid (HCl), O- (7-azabenzotriazol-1-yl-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), 4-dimethyluronium Hexafluorophosphate (HATU)Aminopyridine (DMAP), t-butanol (t-BuOH), sodium hydride (NaH), sodium triacetoxyborohydride (Na (OAc)₃BH), ethanol (EtOH), methanol (MeOH), Acetonitrile (ACN).

Purification of

Use is made of silica gel (SiO) provided with redisep (Teledyne isco), Telos (Kinesis) or GraceResolv (Grace Davison Discovery sciences)₂) Chromatography was performed in a Combiflash Rf rapid purification system (Teledyne Isco) column. Preparative HPLC purification was performed using one of two systems. The system 1: a Varian ProStar/PrepStar system equipped with a Waters SunFire Prep C18 OBD,5 μm (19x150mm) column, using water containing 0.05% trifluoroacetic acid as mobile phase a and acetonitrile containing 0.05% trifluoroacetic acid as mobile phase B. Mobile phase B with gradient 40-95% over 10 min; keeping at 95% for 5-10 min; then returned to 40% over 2min at a flow rate of 18 mL/min. Fractions were collected by UV detection at 254nm using a Varian Prostar fraction collector and concentrated by evaporation using a Savant speedVac Plus vacuum pump or Genevac EZ-2. And (3) system 2: a Waters Fractionlynx system equipped with an Agilent Prep-C18,5 μm (21.2X50mm) column, using water containing 0.1% formic acid as mobile phase A and acetonitrile containing 0.1% formic acid as mobile phase B. Mobile phase B with gradient 45-95% over 7.5 min; keeping at 95% for 1 min; then returned to 45% over 1.5min at a flow rate of 28 mL/min. Fractions were collected by UV detection at 254nm or by weight and concentrated by evaporation using Genevac EZ-2.

Chiral process

Chiral process 1: this method was used to detect enantiomeric excess of a tyrosine chiral center (but not other stereocenters) within exemplary compounds. Enantiomeric excess was determined by integrating the peaks separated on a 5 μm particle size Diacel Chiralpak IA,4.6X250mm column. The solvent used is "solvent a": 4:1 (0.2% TFA in hexanes), DCM and "solvent B": EtOH. The flow rate was maintained at 1.0mL/min, with the following gradient: raising solvent B from 2% to 10% over 30 min; solvent B was kept at 10% for 15 min.

Chiral process 2: enantiomeric excess was determined by integrating the peak separated on a 5 μm particle size Daicel Chiralpak IC,4.6X250mm column run with an isocratic mixture of 76% (isohexane with 0.2% TFA), 19% DCM and 5% EtOH at a flow rate of 1.5 mL/min.

Chiral preparative HPLC: chiral preparative HPLC was performed using a Gilson preparative HPLC system equipped with a Daicel Chiralpak IC column (20 × 250mm column, 5 μm particle size) running an isocratic mixture of mobile phase a (60% (isohexane with 0.2% TFA) and 40% DCM) at a flow rate of 15mL/min and diluted on the column with mobile phase b etoh at 1.5 mL/min. Fractions were collected by UV detection at 254nm and concentrated by evaporation using Genevac EZ-2.

General procedure

General procedure 4: the ester is hydrolyzed to the acid.

To a stirred solution of the ester (1 eq) in THF or dioxane and water was added NaOH or LiOH (1-3 eq). The reaction mixture was stirred up to 60 ℃ for up to 18 h. The reaction mixture is neutralized with AcOH or HCl and diluted with water or concentrated. If the reaction mixture is diluted with water, HCl is added to acidify the reaction mixture to a pH of about 2. The resulting precipitate was isolated by filtration to yield the product, which can be purified by chromatography, preparative HPLC, or used without purification. If the reaction mixture is concentrated, the crude material is diluted with DCM or EA and washed with brine. The organic layer was concentrated and purified by chromatography or preparative HPLC to give the final product. Alternatively, the crude material may be used without further purification.

General procedure 7: amides were prepared via peptide coupling.

A solution of amine (1.0 equiv.) and base (DIEA, TEA or NMM) (0-3.0 equiv.) in DCM or DMF (0.08-0.10M) was treated with the appropriate carboxylic acid (1.0-1.5 equiv.). A coupling agent is added to the mixture. The coupling agent may be HATU (1.05-2.5 equivalents) optionally containing DMAP (0.01-1 equivalent), EDC (1.5 equivalents) containing HOBt (1.5 equivalents) or DMAP (0.01-1 equivalents), DCC (1.1 equivalents) containing HOBt (1.1 equivalents) or DCC (1.5 equivalents) containing DMAP (2.0 equivalents). Stirring deviceThe reaction mixture was stirred until the reaction was complete. The reaction was diluted with EA and saturated NaHCO₃And (4) washing with an aqueous solution. The organic layer was purified over MgSO₄Dried and concentrated. The product was purified by chromatography or the product could be carried on to the next step without further purification.

General procedure 8: deprotection of esters to acids, Boc-amines, and/or protodesilication of protected alcohols (protodesilylation)

A solution of tert-butyl ester or Boc-amine (1.00 equiv.) in DCM (0.06M) was treated with ether or dioxane (10.0-20.0 equiv.) containing TFA (0.16-0.33M) or 1-4N HCl. The reaction mixture was stirred at room temperature or 30 ℃ until the reaction was complete. The solvent is removed and the product is purified by chromatography or preparative HPLC. This procedure is also applicable to protodesilylation of tert-butyl, dimethylsilyl-protected alcohols. A solution of methyl ester (1.00 equiv.) in dioxane (0.04-0.08M) was treated with 1-6N aqueous HCl (10-00 equiv.). The reaction mixture was stirred at room temperature or 30 ℃ until the reaction was complete. The solvent is removed and the product is purified by chromatography or preparative HPLC.

General procedure 9: triflate formation

A solution of phenol (1.0 eq) in DCM (0.25M) was treated with 1, 1-trifluoro-N-phenyl-N- ((trifluoromethyl) sulfonyl) methanesulfonamide (1.1 eq). The reaction mixture was stirred at room temperature until the reaction was complete. With water and saturated NaHCO₃The aqueous solution stirred the reaction. The organic layer was dried and concentrated. The material was purified by chromatography or used without purification.

General procedure 10: palladium catalyzed coupling reactions

Boric acid or boric acid ester (1.0-1.3 equivalent), halide (1.0-1.3 equivalent), sodium bicarbonate or sodium carbonate decahydrate (2.0-2.5 equivalent) and dichloro [1, 1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) or Pd (dppf) Cl₂The solutions of (a) were combined in THF, acetonitrile or dioxane (0.1-0.2M) and water (0.25-0.50M). The reaction was heated at 80 to 100 ℃ until the reaction was complete. The reaction was diluted with EA and saturated NaHCO₃Dissolving in waterAnd (4) washing the solution. The organic layer was purified over MgSO₄Dried and concentrated. The product can be purified by chromatography, preparative HPLC, or carried on to the next step without further purification.

General procedure 13: formation of sulfonates or sulfonamides

To a solution of alcohol or amine in DCM (0.02M) was added sulfonyl chloride (2 equivalents) and triethylamine (3 equivalents). The reaction was stirred at room temperature until completion. The reaction was diluted with DCM and saturated NaHCO₃And (4) washing with an aqueous solution. The organic layer was purified over MgSO₄Dried and concentrated. The product can be purified by chromatography, preparative HPLC, or carried on to the next step without further purification.

To a solution of the acid in DCM (0.02M) was added sulfonamide (2 equiv.), EDC (2 equiv.) and DMAP (2 equiv.) at 0 ℃. The reaction mixture was stirred and allowed to stir at room temperature until the reaction was complete. The reaction was diluted with DCM and saturated NaHCO₃Aqueous solution, water, and then brine washes. The organic layer was dried over MgSO4 and concentrated. The product can be purified by chromatography or preparative HPLC.

General procedure 18: deprotection of Cbz to give amine or benzyl ester and deprotection to give acid

Conventional hydrogenation: to a stirred solution of Cbz-protected amine or benzyl-protected ester (1.0 eq) in EA, THF, EtOH or MeOH (0.01-0.05M) was added Pd/C and the reaction was stirred under hydrogen until the reaction was complete. The catalyst was filtered and the solvent was removed. The product was purified by chromatography or it could be carried on to the next step without further purification.

Hydrogenation using H-cube: a solution of Cbz-protected amine or benzyl-protected ester (1.0 equiv.) in dioxane or THF (0.01-0.03M) was passed through a 10% Pd/C CatCart in a Thales Nanotechnology H-Cube reactor at 1 mL/min. The solvent was distilled off and the product was carried on to the next step without further purification.

General procedure 37: ketone coupling

To a stirred solution of aryl bromide (1 equivalent) in dioxane (0.06M) was added ketone (1-2 equivalents), tosylhydrazine (R) ((R))1-2 equiv.), lithium tert-butoxide (3-5.5 equiv.), Pd₂dba₃(2 mol%) and Xphos (8 mol%). The mixture was heated to 100 ℃ for 16h, then quenched with aqueous acetic acid and extracted with DCM. The combined organic extracts were dried over MgSO₄Dried and the solvent evaporated. The product is isolated by column chromatography or preparative HPLC.

Synthesis of representative Compounds

(S) -tert-butyl 2- (((benzyloxy) carbonyl) amino) -3- (4- (((trifluoromethyl) sulfonyl) oxy) -phenyl) Propionate (INT-5)

Prepared using general procedure 9: with MgSO₄A stirred solution of (S) -tert-butyl 2- (((benzyloxy) carbonyl) amino) -3- (4-hydroxyphenyl) propionate hydrate (25g,64.2mmol) in DCM (100mL) was treated (4.01g,33.7 mmol). After 15min, the mixture was filtered and washed with DCM (2 × 20 mL). The organics were treated with N-ethyl-N-isopropylpropan-2-amine (17.41g,134.7mmol) and stirred. The solution was treated with 1,1, 1-trifluoro-N-phenyl-N- ((trifluoromethyl) sulfonyl) methanesulfonamide (26.44g,74.01mmol) and the mixture was allowed to stir at room temperature overnight. The mixture was washed with water (50mL) and saturated NaHCO₃Aqueous solution (20mL) and stirred vigorously for 10 min. The layers were separated and the organic layer was washed with saturated NaHCO₃Aqueous solution (2 × 50mL), water (50mL) and saturated NaHCO₃The aqueous solution (50mL) was further washed and concentrated. The compound was purified by chromatography (EA/hexane) to afford 26.85g (79%) of (S) -tert-butyl 2- (((benzyloxy) carbonyl) amino) -3- (4- (((trifluoromethyl) sulfonyl) oxy) phenyl) propanoate INT-5. C₂₂H₂₄F₃NO₇LCMS-ESI (m/z) calculation of S: 503.1; found 526.1[ M + Na]⁺，t_R4.12min (method 3).

(S) -tert-butyl 2- (((benzyloxy) carbonyl) amino) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxan) Pentaborane-2-yl) Phenyl) propanoate (INT-6)

A solution of (S) -tert-butyl 2- (((benzyloxy) carbonyl) amino) -3- (4- (((trifluoromethyl) sulfonyl) oxy) phenyl) propionate INT-5(26.85g,53.4mmol), potassium acetate (15.71g,160.1mmol), bis-pinacolborane (27.1g,106.7mmol), and DMSO (100mL) was degassed with a steady stream of nitrogen for 5 minutes. To this solution PdCl was added₂(dppf) (1.95g,2.67mmol), the solution was further degassed and kept under nitrogen. The mixture was heated at 100 ℃ for 18h, then cooled to room temperature, diluted with EA (50mL), and saturated NaHCO₃Aqueous solution (20mL), water (3X30mL) and over MgSO₄Dried, filtered and the solvent removed under reduced pressure. The compound was purified by column chromatography to give 11.10g (41%) of (S) -tert-butyl 2- (((benzyloxy) carbonyl) amino) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propanoate INT-6 as an oil. C₂₇H₃₆BNO₆Calculated LCMS-ESI (m/z): 481.3, respectively; found 504.3[ M + Na]⁺，t_R4.21min (method 3).¹H NMR(400MHz,DMSO)δ7.72(d,J＝8.3Hz,1H),7.60(d,J＝8.0Hz,2H),7.42–7.11(m,6H),4.98(s,2H),4.22–4.08(m,1H),3.03(dd,J＝13.7,5.2Hz,1H),2.85(dd,J＝13.6,10.1Hz,1H),1.36(s,6H),1.30(s,9H),1.22–1.13(m,6H)。

(S) -tert-butyl 2- (((benzyloxy) carbonyl) amino) -3- (4- (5-bromopyrimidin-2-yl) phenyl) propanoate (INT- 7)

Prepared using general procedure 10: (S) -tert-butyl 2- (((benzyloxy) carbonyl) amino) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propanoate INT-6(21.7g,45.0mmol) and 5-bromo-2-iodopyrimidine (15.4g,54.0mmol) in dioxane (400mL) and sodium carbonate decahydrateA stirred mixture of compound (25.7g,90mmol) in water (100mL) was degassed. Addition of PdCl₂(dppf) (0.99g,1.4mmol) and the mixture was further degassed and then heated at reflux for 5 h. The mixture was allowed to cool while stirring overnight. The mixture was poured onto water (1L) and EA (300mL) and stirred for 30 min. The mixture was filtered and the layers were separated. The aqueous layer was further extracted with EA (2x200mL) and the combined organic layers were washed with water (2x100mL) and then brine (50mL), MgSO₄Dried and concentrated. Column chromatography (EA/hexanes) gave 14.84g (63%) of (S) -tert-butyl 2- (((benzyloxy) carbonyl) amino) -3- (4- (5-bromopyrimidin-2-yl) phenyl) propionate INT-7. C₂₅H₂₆BrN₃O₄Calculated LCMS-ESI (m/z): 511.1, respectively; found 534.0[ M + Na]⁺，t_R2.97min (method 11).

(4- (tert-butyl) benzoyl) -L-tyrosine tert-butyl ester

Prepared using general procedure 7: to a solution of 4- (tert-butyl) benzoic acid (8.3g,46.4mmol) in DMF (100mL) was added HATU (19.2g,50.6mmol), TEA (17.6mL,126.4mmol) and (S) -tert-butyl 2-amino-3- (4-hydroxyphenyl) propionate (10.0g,42.1 mmol). After 5h, the reaction mixture was diluted with EA and saturated NaHCO₃The aqueous solution and brine are washed and then dried (Na)₂SO₄) Concentration and purification by chromatography (EA/hexane) afforded 12.9g (69%) (4- (tert-butyl) benzoyl) -L-tyrosine tert-butyl ester. C₂₄H₃₁NO₄Calculated LCMS-ESI (m/z): 397.5, respectively; no observed m/z, t_R3.59min (method 1).¹H NMR(400MHz,CDCl₃)δ7.71–7.65(m,2H),7.47–7.39(m,2H),7.04(t,J＝5.7Hz,2H),6.78–6.70(m,2H),6.59(d,J＝7.5Hz,1H),4.91(dt,J＝7.5,5.6Hz,1H),3.15(qd,J＝14.0,5.6Hz,2H),1.45(s,9H),1.33(s,9H)。

(S) -2- (4- (tert-butyl) benzoylamino) -3- (4- (((trifluoromethyl) sulfonyl) oxy) phenylpropanoic acid tert-butyl Butyl ester (INT-12)

Prepared using general procedure 9: to a solution of tert-butyl (4- (tert-butyl) benzoyl) -L-tyrosine (8.0g,17.9mmol) was added DIEA (3.7mL,1.2mmol) and N-phenyl bis (trifluoromethanesulfonylimide) (7.0g,19.7 mmol). After stirring for 36h, the reaction mixture was diluted with DCM, then diluted with 10% aqueous citric acid and saturated NaHCO₃And (4) washing with an aqueous solution. Subjecting the organic layer to Na₂SO₄Dried and concentrated to afford 9.5g (100%) of tert-butyl (S) -2- (4- (tert-butyl) benzoylamino) -3- (4- (((trifluoromethyl) sulfonyl) oxy) phenyl) propanoate INT-12, which was used without further purification. C₂₅H₃₀F₃NO₆LCMS-ESI (m/z) calculation of S: 529.6; no observed m/z, t_R4.42min (method 1).¹H NMR(400MHz,CDCl₃)δ7.71–7.65(m,2H),7.49–7.43(m,2H),7.32–7.26(m,2H),7.22–7.16(m,2H),6.69(d,J＝7.0Hz,1H),4.94(dt,J＝6.9,5.9Hz,1H),3.24(t,J＝7.1Hz,2H),1.41(s,9H),1.33(s,9H)。

(S) -2- (4- (tert-butyl) benzoylamino) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborole) Alk-2-yl) phenyl) propionic acid tert-butyl ester (INT-13)

To a degassed solution of (S) -2- (4- (tert-butyl) benzoylamino) -3- (4- (((trifluoromethyl) sulfonyl) oxy) phenyl) propionate INT-12(9.5g,24mmol), KOAc (7.0g,72mmol) and bis-pinacolborane (9.1g,36mmol) in DMSO (20mL) was added Pd (dppf) Cl₂(0.87g,1 mmol). In N₂The reaction mixture was heated at 100 ℃ for 12h under an atmosphere. The reaction mixture was diluted with EA and then saturated NaHCO₃Aqueous solution and H₂And O washing. Subjecting the organic layer to Na₂SO₄Drying, concentration and purification by chromatography (EA/hexane) afforded 7.2g (60%) (S) -2- (4- (tert-butyl) benzoylamino) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -propionic acid tert-butyl ester INT-13. C₃₀H₄₂BNO₅Calculated LCMS-ESI (m/z): 507.5, respectively; no observed m/z, t_R4.53min (method 1).¹H NMR(400MHz,CDCl₃)δ7.74(d,J＝8.0Hz,2H),7.72–7.67(m,2H),7.48–7.43(m,2H),7.21(d,J＝8.0Hz,2H),6.59(d,J＝7.4Hz,1H),5.05–4.92(m,1H),3.27(qd,J＝13.7,5.4Hz,2H),1.47(s,9H),1.36(m,21H)。

(S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (4- (tert-butyl) benzoylamino) -propionic acid tert-butyl ester (INT-14)

Prepared using general procedure 10: to (S) -2- (4- (tert-butyl) benzoylamino) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -propionate INT-13(1.0g,2.0mmol), NaHCO₃(420mg,3.9mmol) and 5-bromo-2-iodopyrimidine (615mg,2.2mmol) in 2/2/1ACN/THF/H₂Degassing in O solution Pd (dppf) Cl is added₂(140mg,0.2 mmol). In a microwave reactor, the reaction mixture was heated at 110 ℃ for 1 h. The reaction mixture was concentrated, dissolved in DCM and washed with H₂And O washing. Subjecting the organic layer to Na₂SO₄Dried, concentrated, and purified by chromatography (EA/hexanes) to provide 630mg (58%) of tert-butyl (S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (4- (tert-butyl) benzamido) propionate INT-14. C₂₈H₃₂BrN₄O₃Calculated LCMS-ESI (m/z): 538.5; no observed m/z, t_R4.66min (method 1).¹H NMR(400MHz,CDCl₃)δ8.84–8.78(s,2H),8.31(t,J＝7.0Hz,2H),7.75–7.64(m,2H),7.46–7.38(m,2H),7.30(dd,J＝12.9,7.1Hz,2H),6.65(d,J＝7.2Hz,1H),5.10–4.94(m,1H),3.43–3.20(m,2H),1.45(s,9H),1.32(s,9H)。

(5-(tert-butyl) thiophene-2-carbonyl) -L-tyrosine tert-butyl ester

Prepared using general procedure 7: to a solution of 5- (tert-butyl) thiophene-2-carboxylic acid (1.93g,10.0mmol) in DMF (20mL) was added HATU (4.56g,12.0mmol) and TEA (4.18mL,30.0 mmol). The mixture was stirred at room temperature for 30min, and (S) -tert-butyl 2-amino-3- (4-hydroxyphenyl) propionate (2.37g,10.0mmol) was added. After 1h, the reaction mixture was poured into 400mL of ice water and the solid was filtered. The solid was dissolved in DCM and EA over MgSO₄Drying, concentration, and purification by chromatography (EA/hexane) provided 3.6g (89%) (5- (tert-butyl) thiophene-2-carbonyl) -L-tyrosine tert-butyl ester. C₂₂H₂₉NO₄LCMS-ESI (m/z) calculation of S: 403.2; measured value: 426.1[ M + Na ]]⁺，t_R9.07min (method 2).

(S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (((trifluoromethyl) sulfonyl) oxy) phenyl) Propionic acid tert-butyl ester (INT-15)

Prepared using general procedure 9: to a solution of tert-butyl (5- (tert-butyl) thiophene-2-carbonyl) -L-tyrosine (3.52g,8.72mmol) was added DIEA (4.56mL,26.17mmol) and N-phenyl bis (trifluoromethanesulfonylimide) (3.27g,9.16 mmol). After stirring for 18h, the reaction mixture was diluted with DCM and then with saturated NaHCO₃And (4) washing with an aqueous solution. The organic layer was purified over MgSO₄Dried and concentrated. The crude product was purified by chromatography to afford 4.10g (87.6%) of (S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (((trifluoromethyl) sulfonyl) oxy) phenyl) -propionic acid tert-butyl ester INT-15. C₂₃H₂₈F₃NO₆S₂Calculated LCMS-ESI (m/z): 535.1; no observed m/z, t_R4.22min (method)3)。

(S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxan Pentaborane-2-yl) phenyl) propionic acid tert-butyl ester (INT-16)

To a degassed solution of (S) -tert-butyl 2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (((trifluoromethyl) sulfonyl) oxy) phenyl) propionate INT-15(3.89g,7.26mmol), KOAc (2.14g,21.79mmol) and bis-pinacolborane (2.40g,9.44mmol) in DMSO (50mL) was added Pd (dppf) Cl₂(0.27g,0.36 mmol). In N₂The reaction mixture was heated at 100 ℃ for 18h under an atmosphere. The reaction mixture was poured into 600mL of ice water, and the solid was filtered. The precipitate was diluted with EA over MgSO₄Drying, concentration and purification by chromatography (EA/hexane) afforded 3.68g (99%) (S) -tert-butyl 2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propanoate INT-16. C₂₈H₄₀BNO₅LCMS-ESI (m/z) calculation of S: 513.3; no observed m/z, t_R4.51min (method 3).

(S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionic acid tert-butyl ester (INT-17)

Prepared using general procedure 10: to a mixture of (S) -tert-butyl 2- (5- (tert-butyl) thiophene-2-carboxamide) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propanoate INT-16(510mg,1.0mmol) and 5-bromo-2-iodopyrimidine (570mg,2.0mmol) in 2/2/1 ACN/THF/saturated NaHCO 2₃Degassed solution of aqueous solution (10mL) was supplemented with Pd (dppf) Cl₂(30mg,0.4 mmol). In a microwave reactor, the reaction mixture was heated at 120 ℃ for 1 h. The reaction mixture is taken up in waterDiluted (100mL) and EA (50mL) and filtered through Celite (Celite). The aqueous layer was extracted with EA (3 × 30mL) and the combined organic layers were over MgSO₄Dried, concentrated, and purified by chromatography (EA/hexanes) to provide 342mg (63%) of tert-butyl (S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionate INT-17. C₂₆H₃₀BrN₃O₃LCMS-ESI (m/z) calculation of S: 543.1, respectively; measured value: 488.0[ M-tBu + H]⁺，t_R10.95min (method 2).

(S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (4- (tert-butyl) benzoylamino) propionic acid (INT-27)

Prepared using general procedure 8 and INT-14: c₂₄H₂₄BrN₃O₃Calculated LCMS-ESI (m/z): 482.3, respectively; found 481.1[ M-H ]]⁺，t_R2.6min (method 15), and 98.7% e.e. (chiral method 1, isocratic elution with 2% solvent a, 98% solvent B).¹H NMR(400MHz,CDCl₃)δ8.87(s,2H),8.32(d,J＝8.3Hz,2H),7.64(d,J＝8.5Hz,2H),7.45(d,J＝8.5Hz,2H),7.36(d,J＝8.3Hz,2H),6.64(d,J＝6.9Hz,1H),5.16(dd,J＝12.7,5.7Hz,1H),3.42(ddd,J＝38.8,14.0,5.7Hz,2H),1.32(s,9H)。

((S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (4- (tert-butyl) benzoylamino) -propionyl) -D-propane Alanine tert-butyl ester (INT-32)

Prepared using general procedure 7: to a stirred solution of (S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (4- (tert-butyl) benzoylamino) propionic acid INT-27(1.50g,3.10mmol) in DMF (15mL) was added tert-butyl D-alanine (680.0mg,3.73mmol) and Et₃N (802.3mg,6.2 mmol). The reaction was stirred for 1 hour at 0 deg.CThen, 2mL of DMF containing HATU (877.5mg,3.37mmol) was added. The reaction was stirred at 0 ℃ for 1 hour, then warmed to room temperature while stirring for 18 hours. With NaHCO₃The reaction solution was extracted with aqueous solution (3 × 20 mL). The combined organics were dried over MgSO₄Dried and evaporated. The crude product was purified by column chromatography (50% EA in hexanes) to afford ((S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (4- (tert-butyl) benzamido) -propionyl) -D-alanine tert-butyl ester INT-32 as a solid powder, 1.44g (76%). C₃₁H₃₇BrN₄O₄Calculated LCMS-ESI (m/z): 609.6; found 610.2[ M + H]⁺，t_R4.05min (method 16).¹H NMR(400MHz,DMSO)δ9.03(s,2H),8.49(d,J＝8.7Hz,1H),8.41(d,J＝7.2Hz,1H),8.24(d,J＝8.2Hz,2H),7.73(t,J＝7.4Hz,2H),7.54–7.37(m,4H),4.85(td,J＝10.1,4.6Hz,1H),4.16(t,J＝7.2Hz,1H),3.24–2.97(m,2H),1.50–1.29(m,9H),1.32–1.17(m,12H)。

(S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) -propionic acid

Prepared using general procedure 8: a stirred solution of tert-butyl (S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionate INT-17(15.7g,28.8mmol) in DCM (30mL) was treated with TFA (30.0g,263.1 mmol). The reaction mixture was stirred at room temperature for 18 hours until the reaction was complete. The solvent was evaporated and then co-evaporated with toluene (3x20mL) to remove traces of TFA. The compound was dried in vacuo overnight to afford 13.7g (97%) of (S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionic acid as a powder. C₂₂H₂₂BrN₃O₃LCMS-ESI (m/z) calculation of S: 487.1, respectively; found 488.1[ M + H]⁺，t_R2.55min. (method 16).¹H NMR(400MHz,DMSO)δ9.05(d,J＝5.0Hz,2H),8.64(d,J＝8.4Hz,1H),8.25(d,J＝8.1Hz,2H),7.62(d,J＝3.8Hz,1H),7.45(d,J＝8.2Hz,2H),6.92(d,J＝3.8Hz,2H),4.64(td,J＝10.5,4.5Hz,1H),3.26(dd,J＝13.8,4.4Hz,1H),3.11(dd,J＝13.7,10.7Hz,1H),1.32(s,9H)。

(S) -1- ((S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propane Acyl) pyrrolidine-3-carboxylic acid methyl ester (INT-35)

Prepared using general procedure 7: to a stirred solution of (S) -pyrrolidine-3-carboxylic acid methyl ester (357.0mg,2.16mmol) in DMF (10mL) was added DIEA (465.26mg,3.60mmol) and (S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionic acid (700.0mg,1.44 mmol). The solution was cooled to 0 ℃ in an ice bath, and then a solution of HATU (677.55mg,2.88mmol) in 2mL of DMF was added slowly. The reaction was stirred at 0 ℃ for 1 hour, then warmed to room temperature while stirring for 2 hours. With DCM (3X20mL) and NaHCO₃The reaction solution was extracted with aqueous solution (3 × 10 mL). The combined organics were dried over MgSO₄Dried and evaporated. The final compound was purified by column chromatography (40% DCM in hexanes) to afford 501.0mg (58%) of (S) -1- ((S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionyl) pyrrolidine-3-carboxylic acid methyl ester INT-35 as a powder. C₂₈H₃₁BrN₄O₄LCMS-ESI (m/z) calculation of S: 598.1, respectively; found 599.3[ M + H]⁺，t_R3.553min (method 16).¹H NMR(400MHz,DMSO)δ9.05(d,J＝1.1Hz,2H),8.77(dd,J＝11.5,8.3Hz,1H),8.25(d,J＝7.7Hz,2H),7.72(d,J＝3.5Hz,1H),7.46(d,J＝8.3Hz,2H),6.92(d,J＝3.8Hz,1H),4.98–4.73(m,1H),3.88(dd,J＝10.3,8.0Hz,1H),3.71(dd,J＝15.5,7.5Hz,1H),3.50(ddd,J＝18.3,12.2,5.4Hz,2H),3.38(dd,J＝17.3,7.6Hz,1H),3.23(ddd,J＝28.0,15.0,8.7Hz,1H),3.18–2.85(m,3H),2.17–1.96(m,2H),1.87(td,J＝15.2,7.4Hz,1H),1.32(s,9H)。

(S) -1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionyl) Azetidine-3-carboxylic acid tert-butyl esterEsters (INT-38)

Prepared using general procedure 7: to a stirred solution of azetidine-3-carboxylic acid tert-butyl ester (64.55mg,0.41mmol) in DMF (1mL) was added DIEA (169.6mg,1.31mmol) and (S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionic acid (100.0mg,0.21 mmol). The solution was cooled to 0 ℃ in an ice bath, then a solution of HATU (74.11mg,1.31mmol) in 1mL DMF was added slowly. The reaction was stirred at 0 ℃ for 1 hour, then warmed to room temperature while stirring for 2 hours. With DCM (3X10mL) and NaHCO₃The reaction solution was extracted with aqueous solution (3 × 10 mL). The combined organics were dried over MgSO₄Dried and evaporated to afford 117.6mg (85%) of (S) -tert-butyl 1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionyl) azetidine-3-carboxylate INT-38 as a solid powder, which was used in the next step without further purification. C₃₀H₃₅BrN₄O₄LCMS-ESI (m/z) calculation of S: 626.2, respectively; found value of 627.2[ M + H]⁺，t_R3.884min (method 16).¹H NMR(400MHz,DMSO)δ9.03(d,J＝1.0Hz,2H),8.66(dd,J＝30.6,8.1Hz,1H),8.25(dd,J＝8.1,6.1Hz,2H),7.82-7.60(m,1H),7.44(dd,J＝8.2,4.5Hz,2H),6.91(dd,J＝3.8,1.2Hz,1H),4.77-4.49(m,1H),4.36(t,J＝8.9Hz,0.5H),4.31-4.24(m,0.5H),4.20(t,J＝8.8Hz,0.5H),4.06-3.94(m,1H),3.93-3.83(m,1H),3.78(dd,J＝9.6,6.1Hz,0.5H),3.44-3.30(m,1H),3.06(tdd,J＝13.6,11.5,5.4Hz,2H),1.40(d,J＝5.7Hz,4H),1.35-1.27(m,14H)。

(S) -tert-butyl 1- ((S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamide Yl) propionyl) pyrrolidine-2-carboxylate (INT-54)

Preparation using general procedure 7: to a stirred solution of (S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionic acid (1.0g,2.05mmol) in DMF (5mL) at 0 deg.C was added DIPEA (2.14mL,12.28mmol) followed by L-proline tert-butyl ester hydrochloride (0.468g,2.25 mmol). HATU (0.856g,2.25mmol) dissolved in DMF (1.5mL) was added to the mixture in portions over 10 min. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was diluted with saturated sodium bicarbonate solution and extracted with DCM (3 × 30 mL). Over MgSO₄The combined organic layers were dried and the solvent was evaporated. The crude product was purified by column chromatography (0-40% EtOAc/hexanes) to afford 1.06g (81%) of (S) -tert-butyl 1- ((S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionyl) pyrrolidine-2-carboxylate (INT-54). C₃₁H₃₇BrN₄O₄LCMS-ESI (m/z) calculation of S: 640.2, respectively; found 641.3[ M + H ]]⁺，t_R10.63min (method 14).¹H NMR(400MHz,DMSO-d6)δ9.03(s,2H),8.70(d,J＝8.4Hz,1H),8.23(d,J＝9.1Hz,2H),7.68(d,J＝3.9Hz,1H),7.52(d,J＝8.3Hz,2H),6.90(d,J＝3.8Hz,1H),4.97–4.84(m,1H),4.23(m,1H),3.83-3.62(m,2H),3.09(m,2H),2.18(m,1H),1.96(m,2H),1.82(m,1H),1.39-1.28(m,18H)。

((S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propanoyl) D-alanine tert-butyl ester

Prepared using general procedure 7: to a stirred solution of D-alanine tert-butyl ester (5.60g,30.80mmol) in DMF (50mL) was added DIEA (8.29g,64.18mmol) and (S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) -propionic acid (12.5g,25.67 mmol). The solution was cooled to 0 ℃ in an ice bath, then a solution of HATU (9.06g,38.50mmol) in 15mL of DMF was slowly added. The reaction was stirred at 0 ℃ for 1 hour, then warmed to room temperature while stirring for 2 hours. With DCM (3X50mL) and NaHCO₃The reaction solution was extracted with aqueous solution (3 × 30 mL). Combining the organic matterOver MgSO₄Dried and evaporated. The final compound was purified by column chromatography (40% DCM in hexanes) to afford 14.7g (94%) of tert-butyl ((S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propanoyl) -D-alanine as a solid powder. C₂₉H₃₅BrN₄O₄LCMS-ESI (m/z) calculation of S: 614.2, respectively; found 615.3[ M + H]⁺，t_R3.914min (method 16).¹H NMR(400MHz,CDCl₃)δ8.83(d,J＝3.6Hz,2H),8.36(d,J＝8.2Hz,2H),7.39(d,J＝8.2Hz,2H),7.34(d,J＝3.8Hz,1H),6.81(d,J＝3.8Hz,1H),6.66(d,J＝7.6Hz,1H),6.34(d,J＝7.2Hz,1H),4.88(d,J＝5.9Hz,1H),4.41(t,J＝7.2Hz,1H),3.31(dd,J＝13.6,5.8Hz,1H),3.20(dd,J＝13.6,7.8Hz,1H),1.51–1.32(m,18H),1.27(d,J＝7.1Hz,3H)。¹³C NMR(101MHz,DMSO)δ172.02,171.31,162.28,162.13,161.42,158.55,142.27,136.34,134.66,130.20,128.82,127.92,123.07,118.63,80.90,54.45,48.86,39.59,39.38,32.39,28.04,17.68。

(2R) -tert-butyl 2- ((2S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (5- (4' -propyl- [1, 1' -bis (cyclohexyl)]-3-en-4-yl) pyrimidin-2-yl) phenyl) propionamido) propionate

Prepared using general procedure 10: (R) -tert-butyl 2- ((S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propanamido) propionate (0.15g,0.244mmol) and (4 '-propyl- [1, 1' -bis (cyclohexyl)]A stirred solution of-3-en-4-yl) boronic acid (0.061g,0.244mmol) in dioxane (12mL) was treated with sodium bicarbonate (0.54mL of 0.9M aqueous solution, 0.487mmol), warmed to 40 ℃ and degassed. Adding PdCl₂dppf (7.13mg, 9.75. mu. mol), the mixture was degassed and then heated at reflux for 3 h. The reaction was cooled to room temperature, poured into water (50mL) and extracted with EA (3 × 50 mL). The combined organic extracts are passed over Na₂SO₄Dried and evaporated. Column chromatography (EA/isohexane) gave 142mg (78%) of (2) as an off-white solidR) -tert-butyl 2- ((2S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (5- (4 '-propyl- [1, 1' -bis (cyclohexyl)]A mixture of diastereomers of (E) -3-en-4-yl) pyrimidin-2-yl) phenyl) propionamido) propionate. C₄₄H₆₀N₄O₄LCMS-ESI (m/z) calculation of S: 741.1, respectively; no observed m/z, t_R3.49min (method 11).

(S) -2- (((benzyloxy) carbonyl) amino) -3- (4- (5-bromopyrimidin-2-yl) phenyl) propionic acid

Prepared using general procedure 8: a stirred solution of tert-butyl (S) -2- (((benzyloxy) carbonyl) amino) -3- (4- (5-bromopyrimidin-2-yl) phenyl) propionate INT-7(3.0g,5.8mmol) in DCM (20mL) was treated with TFA (10 mL). The reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated and then co-evaporated with toluene (3x20mL) to remove residual TFA. The compound was dried in vacuo overnight to afford 13.7g (97%) of (S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionic acid as a powder. C₂₁H₁₈BrN₃O₄Calculated LCMS-ESI (m/z): 456.30, respectively; found 457.43[ M + H]⁺，t_R2.21min (method 16).

(S) -1- (2- (((benzyloxy) carbonyl) amino) -3- (4- (5-bromopyrimidin-2-yl) phenyl) propanoyl) azacyclic ring Butane-3-carboxylic acid tert-butyl ester

Prepared using general procedure 7: to a stirred solution of (S) -2- (((benzyloxy) carbonyl) amino) -3- (4- (5-bromopyrimidin-2-yl) phenyl) propionic acid (6.0g,12.2mmol) in DMF (20mL) at 0 ℃ was added DIPEA (15.8g,122mmol) followed by azetidine-3-carboxylic acid tert-butyl ester hydrochloride (2.85g,14.7 mmol). HATU (14g,36mmol) was added slowly in three portions to the mixture, whereWith 30 minutes intervals. The reaction was stirred at 0 ℃ for 2h and then warmed to room temperature over 2 h. The reaction mixture was then diluted with saturated sodium bicarbonate solution (25mL), water (25mL) and EA (100 mL). The layers were separated and the aqueous layer was extracted with EA (2x100 mL). The combined organic layers were washed with water, brine and then MgSO₄Dried and concentrated. The crude product was purified by column chromatography (0-40% EA/hexane) to afford 4.6g (60%) of tert-butyl (S) -1- (2- (((benzyloxy) carbonyl) amino) -3- (4- (5-bromopyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylate. C₂₉H₃₁BrN₄O₅Calculated LCMS-ESI (m/z): 595.5, respectively; found 596.6[ M + H]⁺，t_R3.59min (method 16).

1- ((2S) -2- (((benzyloxy) carbonyl) amino) -3- (4- (5- (4 '-propyl- [1, 1' -bis (cyclohexyl)]-3-ene- 4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid tert-butyl ester

Prepared using general procedure 10: treatment of tert-butyl (S) -1- (2- (((benzyloxy) carbonyl) amino) -3- (4- (5-bromopyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylate (1.5g,2.52mmol) and (4 '-propyl- [1, 1' -bis (cyclohexyl) with sodium carbonate (0.30g,5.0mmol)]A stirred solution of-3-en-4-yl) boronic acid (0.76g,3.02mmol) in a mixture of 3:1 dioxane and water (20mL) and the mixture degassed for 5min. Adding PdCl₂dppf (0.18g,0.25mmol), the mixture was degassed again for 2min and then heated at 70 ℃ for 7 h. The reaction mixture was cooled to room temperature and then diluted with EA (20mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with EA (3 × 50 mL). The combined organic extracts were dried over MgSO₄The solvent was dried and evaporated. Column chromatography of the crude product (0-60% EA/hexanes) yielded 1.56g (85%) of 1- ((2S) -2- (((benzyloxy) carbonyl) amino) -3- (4- (5- (4 '-propyl- [1, 1' -bis (cyclohexane)) as an off-white solid]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid tert-butyl ester. C₄₄H₅₆N₄O₅Calculated LCMS-ESI (m/z): 720.95, respectively; found 721.63[ M + H]⁺，t_R7.02min (method 16).

1- ((2S) -2-amino-3- (4- (5- (4 '-propyl- [1, 1' -di (cyclohexyl))]-3-en-4-yl) pyrimidin-2-yl) Phenyl) propionyl) azetidine-3-carboxylic acid tert-butyl ester (INT-64)

Prepared using general procedure 18. To 1- ((2S) -2- (((benzyloxy) carbonyl) amino) -3- (4- (5- (4 '-propyl- [1, 1' -di (cyclohexane)]A stirred solution of a mixture of diastereomers of (1.0g,1.38mmol) tert-butyl (3-en-4-yl) pyrimidin-2-yl) phenyl) propionyl) azetidine-3-carboxylate (1.0g,1.38mmol) in EA (40mL) was added Pd/C (0.1g,0.1mmol) and hydrogen was bubbled through the reaction three times. The reaction mixture was stirred under a hydrogen atmosphere for 36 hours, the mixture was filtered through celite, and then concentrated to give 0.75g (92%) of 1- ((2S) -2-amino-3- (4- (5- (4 '-propyl- [1, 1' -bis (cyclohexane)) as a gray solid]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid tert-butyl ester (INT-64). The material was used without further purification. C₃₆H₅₀N₄O₃Calculated LCMS-ESI (m/z): 586.8, respectively; found 587.4[ M + H]⁺，t_R5.82min (method 16). The material contains 10% of the by-product of the olefin reduction (bi-product) (S) -1- (2-amino-3- (4- (5- (4 '-propyl- [1, 1' -di (cyclohexane))]-4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid tert-butyl ester and could not be isolated by column chromatography. C₃₆H₅₂N₄O₃Calculated LCMS-ESI (m/z): 588.82, respectively; found 589.4[ M + H]⁺，t_R5.58min (method 16).

(S) -1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionyl) Azetidine-3-carboxylic acid methyl ester

Prepared using general procedure 7: a stirred solution of (S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionic acid (3.85g,7.90mmol) in DMF (50mL) was treated with azetidine-3-carboxylic acid methyl ester hydrochloride (3.59g,23.69mmol) and cooled to-5 deg.C whereupon DIEA (8.75mL,47.4mmol) was added. When a clear solution was observed, HATU (7.51g,19.74mmol) was added in portions to maintain the internal temperature at 0 to-5 ℃. After 15min, additional HATU (0.75g,1.97mmol) was added. After an additional 30min, the mixture was quenched with water (2mL) and warmed to room temperature. The mixture was diluted with water (. about.30 mL) and acidified with AcOH. The precipitate was collected by filtration, washed successively with water (3x30mL) followed by ACN (2x5mL) to afford 4.25g (92%) of methyl (S) -1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propanoyl) azetidine-3-carboxylate. C₂₇H₂₉BrN₄O₄LCMS-ESI (m/z) calculation of S: 584.1; found 585.0[ M + H]⁺，t_R2.55min (method 11).

(S) -1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionyl) Azetidine-3-carboxylic acid (INT-71)

To a stirred mixture of water (140mL) and AcOH (140mL) was added sulfuric acid (53.2mL,993mmol) and the mixture was cooled to room temperature. This was then added to a stirred solution of (S) -methyl 1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propanoyl) azetidine-3-carboxylate (19.39g,33.1mmol) in dioxane (225 mL). After 20h, the mixture was diluted with ice water (500mL) and extracted with DCM (2 × 350 mL). The combined organic extracts were washed with water (2 × 500mL) over MgSO₄Drying and evaporatingA solvent. Column chromatography (DCM/EA/AcOH) gave 12.96g (69%) of (S) -1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propanoyl) azetidine-3-carboxylic acid INT-71. C₂₆H₂₇BrN₄O₄LCMS-ESI (m/z) calculation of S: 570.1, respectively; found 571.0[ M + H]⁺，t_R2.36min (method 11).

((S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propanoyl) D-alanine (INT-72)

Prepared using general procedure 8: to a stirred solution of (R) -tert-butyl 2- ((S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionamido) propionate (4.8g,7.80mmol) in DCM (150mL) was added TFA (18 mL). After 16h, the reaction was diluted with toluene (100mL) and the solvent was evaporated to afford 4.36g (100%) ((S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propanoyl) -D-alanine INT-72. C₂₅H₂₇BrN₄O₄LCMS-ESI (m/z) calculation of S: 558.1; no observed m/z, t_R2.43min (method 11).

((2S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (5- (4 '-propyl- [1, 1' -bis (cyclohexyl)]- 3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) -D-alanine (compound 1)

Prepared using general procedure 8: to (2R) -tert-butyl 2- ((2S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (5- (4 '-propyl- [1, 1' -bis (cyclohexyl)]A stirred solution of a diastereomeric mixture of (E) -3-en-4-yl) pyrimidin-2-yl) phenyl) propionamido) propionate (136mg,0.184mmol) in DCM (10mL) was added TFA (1.7mL,22 mmol).After 16h, the reaction was diluted with toluene (10mL) and the solvent was evaporated. The mixture was further coevaporated with toluene (2 × 10mL) to give a light brown glass. Column chromatography (EA/AcOH/DCM/isohexane) gave 94mg (75%) of (2R) -2- ((2S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (5- (4 '-propyl- [1, 1' -bis (cyclohexane) as a cream solid]-3-en-4-yl) pyrimidin-2-yl) phenyl) propionamido) propionic acid (compound 1). C₄₀H₅₂N₄O₄LCMS-ESI (m/z) calculation of S: 684.4, respectively; no observed m/z, t_R12.15min (method 10). Chiral analysis showed a d.e.t. of 92.8%_R21.00min (chiral method 1).¹H NMR(400MHz,DMSO-d6)δ12.60(s,1H),8.90(s,2H),8.51(d,J＝8.7Hz,1H),8.44(d,J＝7.4Hz,1H),8.31–8.20(m,2H),7.67–7.65(m,1H),7.51–7.44(m,2H),6.91(dd,J＝3.9,2.0Hz,1H),6.44(br s,1H),4.80(td,J＝9.5,4.4Hz,1H),4.25(p,J＝7.1Hz,1H),3.17–2.95(m,2H),2.47–2.18(m,2H),1.99–1.92(m,2H),1.83-1.75(m,4H),1.44–0.78(m,28H)。

Compound 2 was prepared from (R) -tert-butyl 2- ((S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionamide) propionate using general procedure 10 followed by general procedure 8.

Compound 3 was prepared from INT-35 using general procedure 10, followed by general procedure 4.

1- ((2S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (5- (4 '-pentyl- [1, 1' -di (cyclo) Chinese character Ji)]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid (compound 4)

Prepared using general procedures 10 and 8: mixing (4 '-pentyl- [1, 1' -di (cyclohexyl)]-3-en-4-yl) boronic acid (200.3mg,0.72mmol), sodium carbonate decahydrate (57.6mg,0.96mmol), (S) -1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionyl) azetidine-3-carboxylic acid tert-butyl ester INT-38(300.0mg,0.48mmol) and Pd (dppf) Cl₂A stirred solution of (35.1mg,0.048mmol) in dioxane (9mL) and water (3mL) was degassed by nitrogen and heated to 60 ℃ for 2 hours. The reaction solution was evaporated under reduced pressure and then diluted with DCM (20 mL). With NaHCO₃Aqueous solution (3 × 20mL) extracted the crude material. The combined organics were dried over MgSO₄Dried and the solvent evaporated. The crude product was purified by column chromatography (50% EA in hexanes) to provide 302.5mg (80.8%) of 1- ((2S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (5- (4 '-pentyl- [1, 1' -bis (cyclohexyl))]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid tert-butyl ester as an intermediate. The intermediate was dissolved in DCM (10mL), treated with 5.0mL TFA and stirred at rt for 18 h. The product is reacted with CH₃CN (5X10mL) coevaporation to provide 268.2mg (77%) of 1- ((2S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (5- (4 '-pentyl- [1, 1' -bis (cyclohexyl)) as a solid powder]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid (compound 4). C₄₃H₅₆N₄O₄LCMS-ESI (m/z) calculation of S: 724.4, respectively; found 725.3[ M + H]⁺，t_R12.55min. (method 14);¹H NMR(400MHz,DMSO)δ8.90(d,J＝1.0Hz,2H),8.70(d,J＝8.1Hz,1H),8.27(dd,J＝8.1,4.6Hz,2H),7.69(d,J＝3.9Hz,1H),7.43(d,J＝8.0Hz,2H),6.92(d,J＝3.8Hz,1H),6.42(s,1H),4.76-4.54(m,3H),4.43(t,J＝8.8Hz,1H),4.37-4.23(m,1H),4.17(dd,J＝18.4,7.7Hz,1H),4.11-3.96(m,2H),3.95-3.77(m,1H),3.38(d,J＝44.3Hz,1H),3.18-2.94(m,2H),2.40(s,1H),2.27(d,J＝18.8Hz,1H),1.97(d,J＝18.0Hz,2H),1.86-1.63(m,4H),1.46-1.19(m,16H),1.15(s,4H),0.98(dd,J＝24.6,11.9Hz,2H),0.8–0.95(m,J＝7.0Hz,4H)。¹³C NMR(101MHz,DMSO)δ173.44,170.43,162.00,161.32,160.81,153.27,140.57,135.44,135.27,131.62,130.53,129.53,129.49,128.47,127.22,122.66,52.60,50.29,50.17,41.77,39.52,39.31,39.10,38.89,38.02,37.25,34.36,32.94,31.88,31.56,29.54,29.32,29.28,26.30,25.97,25.68,22.04,13.86。

compounds 5 and 8 were prepared from INT-54 using general procedure 10, followed by general procedure 8.

1- ((2S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (5- (4 '-propyl- [1, 1' -di (cyclo) Chinese character Ji)]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid (compound 6)

Prepared using general procedures 10 and 8: to (4 '-propyl- [1, 1' -di (cyclohexyl)]-3-en-4-yl) boronic acid (31.9mg,0.13mmol), sodium carbonate decahydrate (7.8mg,0.13mmol), (S) -1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionyl) -azetidine-3-carboxylic acid tert-butyl ester INT-38(40.0mg,0.064mmol) and pd (dppf) Cl₂(46.8mg,0.048mmol) in dioxane (3mL) and water (1.0 mL). The reaction solution was degassed by nitrogen and heated to 60 ℃ for 2 hours. The reaction solvent was evaporated under reduced pressure and then diluted in DCM (10 mL). With NaHCO₃Aqueous solution (2 × 3mL) extracted the crude material. The combined organics were dried over MgSO₄Dried and the solvent evaporated. To 1mL of DCM containing the crude material was added 0.1mL of TFA and stirred at room temperature for 18 h. The final product was purified by HPLC to give 1.14mg (2.6%) of 1- ((2S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (5- (4 '-propyl- [1, 1' -bis (cyclohexyl) as a solid]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid (compound 6). C₄₁H₅₂N₄O₄LCMS-ESI (m/z) calculation of S: 696.4, respectively; measured value: 697.4[ M + H]⁺，t_R11.38min. (method 14). Chiral analysis showed 97.2% d.e.t_R21.01min (chiral method 1);¹H NMR(400MHz,DMSO)δ12.59(s,1H),8.90(d,J＝1.5Hz,2H),8.68(dd,J＝8.2,2.6Hz,0.9H),8.56(d,J＝8.0Hz,0.1H),8.26(dd,J＝8.1,4.5Hz,2H),7.68(d,J＝3.9Hz,0.8H),7.61(d,J＝3.8Hz,0.2H),7.42(d,J＝7.9Hz,2H),6.91(d,J＝3.8Hz,1H),6.42(s,1H),4.64(dd,J＝11.5,6.3Hz,1H),4.43-4.2(m,0.5H),4.33-4.22(m,0.5H),4.23-4.09(m,1H),4.09-3.95(m,1H),3.96-3.79(m,1H),3.47-3.37(m,1H),3.07-3.08(m,2H),2.53-2.52(m,0.5H),2.32(dd,J＝45.3,16.2Hz,2.5H),1.97(d,J＝18.6Hz,2H),1.86-1.65(m,4H),1.43-1.20(m,13H),1.21-1.07(m,4H),0.99(dt,J＝24.4,12.2Hz,2H),0.92-0.77(m,5H)。¹³C NMR(101MHz,DMSO)δ173.44,172.90,170.44,162.00,161.31,160.82,153.25,140.56,135.48,135.28,135.25,131.60,130.52,129.53,129.48,129.35,128.47,127.23,127.19,127.14,122.65,53.65,52.61,50.30,50.17,41.78,38.02,36.96,36.31,36.19,32.90,31.88,31.58,29.53,29.31,29.28,28.96,26.31,25.68,19.42,14.20。

similar procedure was used to prepare 1- ((2R) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (5- (4 '-propyl- [1, 1' -bis (cyclohexyl)]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid (compound 81). Chiral analysis at the tyrosine chiral center showed 97.3% e.e. t is t_R14.84min (chiral method 1).

(3S) -1- ((2S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (5- (4 '-propyl- [1, 1' -di) (Cyclohexanaphthalene)]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) pyrrolidine-3-carboxylic acid (compound 7)

Prepared using general procedures 10 and 4. To (4 '-propyl- [1, 1' -di (cyclohexyl)]-3-en-4-yl) boronic acid (31.9mg,0.13mmol), sodium carbonate decahydrate (7.8mg,0.13mmol), (S) -1- ((S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionyl) -pyrrolidine-3-carboxylic acid methyl ester INT-35(38.9mg,0.064mmol) and pd (dppf) Cl₂(46.8mg,0.048mmol) in dioxane (3mL) and water (1.0 mL). The reaction solution was degassed by nitrogen and heated to 60 ℃ for 2 hours. The reaction solvent was evaporated under reduced pressure and then diluted in DCM (5 mL). With NaHCO₃Aqueous solution (2 × 1mL) extracted the crude material. The combined organics were dried over MgSO₄Dried and the solvent evaporated. The crude material was dissolved in 1mL MeOH and 0.1mL 1N aqueous NaOH and stirred at room temperature for 18 h. The final product was purified by HPLCPurification afforded 0.52mg (1.1%) of (3S) -1- ((2S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (5- (4 '-propyl- [1, 1' -bis (cyclohexane) as a solid]-3-en-4-yl) pyrimidin-2-yl) phenyl) -propionyl) pyrrolidine-3-carboxylic acid (compound 7). C₄₂H₅₄N₄O₄LCMS-ESI (m/z) calculation of S: 710.4, respectively; measured value: 711.4[ M + H]⁺，t_R11.84min. (method 14).¹H NMR(400MHz,DMSO)δ12.47(s,1H),8.90(s,2H),8.70(d,J＝7.9Hz,1H),8.26(d,J＝7.9Hz,2H),7.71(s,1H),7.56-7.12(m,2H),6.91(d,J＝3.8Hz,1H),6.42(s,1H),5.06-4.68(m,1H),3.69(d,J＝7.6Hz,0.5H),3.63-3.50(m,1.5H),3.43(dd,J＝17.0,10.2Hz,1H),3.05(ddd,J＝23.8,16.8,8.0Hz,4H),2.42-2.17(m,2H),1.97(dd,J＝28.0,9.5Hz,4H),1.86-1.61(m,4H),1.50-1.21(m,13H),1.21-1.09(m,4H),1.00(dt,J＝24.7,12.2Hz,3H),0.92-0.78(m,5H)。

Compound 9 was prepared from INT-17 using general procedure 10, then general procedure 8.

Compound 10 was prepared from INT-17 using general procedures 10, 7, then general procedure 8.

Compound 11 was prepared from INT-38 using general procedure 10, then general procedure 8.

Compounds 13, 15, 17, 19, 21-24, 26, 27, 29, 30, 32, 33, 34, and 35 were prepared from INT-64 using general procedure 7, followed by general procedure 8.

1- ((S) -2- (4- (tert-butyl) benzoylamino) -3- (4- (5- ((1RS,1 ' S,4 ' RS) -4 ' -propyl- [1, 1' -bis (cyclohexyl)]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid (compound 14)

Prepared using general procedure 10: to (S) -1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (4- (tert-butyl) benzamido) propanoyl) azetidine-3-carboxylic acid (prepared from INT-27 using general procedure 7, followed by general procedure 4) (2)1.3g,37.7mmol) and racemic (1RS, 1's, 4' RS) -4 '-propyl- [1, 1' -bis (cyclohexyl)]A stirred solution of-3-en-4-yl) boronic acid (11.66g,45.2mmol) in dioxane (500mL) was added sodium bicarbonate solution (105mL, 0.9M aqueous solution, 94 mmol). The mixture was warmed to 40 ℃ and degassed. Addition of PdCl₂dppf (1.230g,1.51mmol) and the mixture was heated at 95 ℃ for 1.5 h. The mixture was cooled, then diluted with 1M HCl (400mL) and extracted with EA (2 × 500 mL). The combined organic extracts were evaporated. The residue was purified by column chromatography (THF/AcOH/isohexane/DCM) and reslurried with ACN to provide 16.42g (63%) of 1- ((S) -2- (4- (tert-butyl) benzoylamino) -3- (4- (5- ((1RS,1 'S, 4' RS) -4 '-propyl- [1, 1' -bis (cyclohexyl)]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid. C₄₃H₅₄N₄O₄Calculated LCMS-ESI (m/z): 690.4, respectively; no observed m/z, t_R3.46min (method 11). Chiral analysis (chiral method 1) shows>95% of a single peak.¹H NMR(400MHz,DMSO-d₆)δ12.71(s,1H),8.91(s,2H),8.74–8.68(m,1H),8.30–8.24(m,2H),7.76(d,J＝8.4Hz,2H),7.49–7.41(m,4H),6.43(s,1H),4.74–4.65(m,1H),4.45(app t,J＝8.6Hz,0.5H),4.34–4.27(m,0.5H),4.25–4.13(m,1H),4.10–3.98(m,1H),3.96–3.85(m,1H),3.48–3.40(m,1H),3.17–3.02(m,2H),2.45–2.21(m,2H),2.02–1.87(m,2H),1.85–1.69(m,4H),1.42–0.78(m,25H)。

1- ((S) -2- (5-ethylthiophene-2-carboxamido) -3- (4- (5- ((1RS,1 ' S,4 ' RS) -4 ' -propyl- [1, 1' -bis (cyclohexyl)]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid (compound 31)

Prepared using general procedure 10: (S) -1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5-ethylthiophene-2-carboxamido) propanoyl) azetidine-3-carboxylic acid (4.4g,8.10mmol) (prepared from INT-73 using general procedure 8) and racemic (1RS,1 'S, 4'RS) -4 '-propyl- [1, 1' -bis (cyclohexyl)]-3-en-4-yl) boronic acid (2.228g,8.91mmol) in dioxane (100mL) and NaHCO₃The stirred solution in (27.0mL,0.9M aqueous solution, 24.29mmol) was warmed to 40 ℃ and degassed. Adding PdCl₂dppf (0.178g,0.24mmol) and the mixture was heated to reflux. After 6h, the mixture was diluted with water (200mL) and acidified with acetic acid (3.41mL,48.6 mmol). After stirring for 1h, the precipitate was collected by filtration, washed with water (2 × 30mL) and then MeOH (20 mL). The residue was purified by column chromatography (AcOH/EtOAc/DCM) and reslurried with MeOH (100mL) to afford 4.1g (76%) of 1- ((S) -2- (5-ethylthiophene-2-carboxamido) -3- (4- (5- ((1RS,1 'S, 4' RS) -4 '-propyl- [1, 1' -bis (cyclohexyl)]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid. C₃₉H₄₈N₄O₄LCMS-ESI (m/z) calculation of S: 688.3, respectively; no observed m/z, t_R11.44min (method 10). Chiral analysis (chiral method 1) shows>95% of a single peak.¹H NMR(400MHz,DMSO-d₆)δ12.70(s,1H),8.91(app d,J＝1.7Hz,2H),8.73(app dd,J＝8.3,2.2Hz,1H),8.40–8.20(m,2H),7.70(d,J＝3.7Hz,1H),7.43(app dd,J＝8.3,1.4Hz,2H),6.87(app dd,J＝3.7,1.2Hz,1H),6.54–6.35(m,1H),4.67–4.60(m,1H),4.45(t,J＝8.0Hz,0.5H),4.31–4.27(m,0.5H),4.25–4.10(m,1H),4.08–3.98(m,1H),3.93–3.85(m,1H),3.47–3.39(m,0.5H),3.33–3.27(m,0.5H),3.18–2.95(m,2H),2.79(q,J＝7.5Hz,2H),2.55–2.26(m,3H),2.00–1.92(m,2H),1.83–1.74(m,4H),1.35–1.11(m,11H),1.11–0.95(m,2H),0.91–0.84(t,J＝7.3Hz,5H)。

Compounds 12, 16, 18, 20, 25 and 28 were prepared from tert-butyl (S) -1- (2-amino-3- (4- (5- (4 '-propyl- [1, 1' -di (cyclohexyl) ] -4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylate using general procedure 7 followed by general procedure 8.

Compounds 36-40 and 77 were prepared from INT-71 using general procedure 10.

Compound 41 was prepared from INT-71 using general procedures 10 and 18, in sequence.

Compounds 43, 45-47 and 48 were prepared from INT-71 using general procedure 37.

1- ((S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (5- ((1RS,1 ' r,4 ' RS) -4 ' -methyl-) [1, 1' -bis (cyclohexyl)]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid (compound 44)

Prepared using general procedure 10: to (S) -1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionyl) azetidine-3-carboxylic acid INT-71(3.14g,5.50mmol) and racemic 4,4,5, 5-tetramethyl-2- ((1RS,1 'r, 4' RS) -4 '-methyl- [1, 1' -bis (cyclohexyl)]A stirred solution of (E) -3-en-4-yl) -1,3, 2-dioxaborolan (1.84g,6.05mmol) in dioxane (110mL) was added NaHCO₃(18.3mL,0.9M aqueous, 16.49 mmol). The mixture was degassed and treated with PdCl₂(dppf) (0.201g,0.28mmol) and then heated to reflux for 4 h. The mixture was cooled, then diluted with 1M HCl (100mL) and extracted with EA (3 × 150 mL). The combined organic extracts were dried over MgSO₄The solvent was dried and evaporated. Column chromatography (AcOH/EA/DCM/isohexane) followed by reslurrying with ACN followed by reslurrying with DCM/isohexane yielded 2.78g (76%) of 1- ((S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (5- ((1RS,1 'r, 4' RS) -4 '-methyl- [1, 1' -bis (cyclohexane)]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid. C₃₉H₄₈N₄O₄LCMS-ESI (m/z) calculation of S: 688.3, respectively; no observed m/z, t_R11.03min (method 10). Chiral analysis (chiral method 1) shows>95% of a single peak.¹H NMR(400MHz,DMSO-d₆)δ12.74(s,1H),8.91(d,J＝1.9Hz,2H),8.75(dd,J＝8.5,2.9Hz,1H),8.32–8.18(m,2H),7.69(d,J＝3.9Hz,1H),7.43(d,J＝8.0Hz,2H),6.92(dd,J＝3.9,1.6Hz,1H),6.51–6.36(m,1H),4.79–4.55(m,1H),4.52–3.77(m,4H),3.49–3.37(m,0.5H),3.34–3.31(m,0.5H),3.17–2.95(m,2H),2.59–2.19(m,3H),2.10–1.85(m,2H),1.86–1.58(m,4H),1.45–1.20(m,12H),1.17–0.71(m,8H)。

Compounds 49-66 and 69 were prepared from INT-72 using general procedure 10.

Compound 67 was prepared from INT-72 using general procedures 10 and 18, in sequence.

Compound 70 was prepared from INT-72 using general procedure 37.

Compounds 71, 73, 74 and 75 were prepared from compound 9 using general procedure 7, then general procedure 8.

1- ((S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (5- ((1RS,1 ' r,4 ' RS) -4 ' -ethyl-) [1, 1' -bis (cyclohexyl)]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid (compound 76)

Prepared using general procedure 10: to (S) -1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionyl) azetidine-3-carboxylic acid INT-71(5.5g,9.62mmol) and racemic 2- ((1RS,1 'r, 4' RS) -4 '-ethyl- [1, 1' -bis (cyclohexyl)]A stirred solution of (E) -3-en-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (3.37g,10.59mmol) in dioxane (100mL) was added NaHCO₃(2.021g,24.06mmol) in water (100mL) and the mixture was degassed. Addition of PdCl₂(dppf) (0.352g,0.48mmol) and the mixture was heated to reflux for 1 h. The mixture was cooled, then diluted with water (200mL), acidified with AcOH and extracted with EA (2 × 150 mL). The combined organic extracts were evaporated and the residue was purified by column chromatography (AcOH/EA/DCM/isohexane) and reslurried with ACN to afford 5.7g (87%) of 1- ((S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (5- ((1RS,1 'r, 4' RS) -4 '-ethyl- [1, 1' -bis (cyclohexane)]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid. C₄₀H₅₀N₄O₄LCMS-ESI (m/z) calculation of S: 682.4, respectively; found 683.4[ M + H ]]⁺，t_R＝3.41min (method 11). Chiral analysis (chiral method 1) shows>95% of a single peak.¹H NMR(400MHz,DMSO-d₆)δ12.68(s,1H),8.90(app d,J＝1.8Hz,2H),8.74(app dd,J＝8.3,2.9Hz,1H),8.32–8.20(m,2H),7.68(d,J＝3.9Hz,1H),7.42(d,J＝8.0Hz,2H),6.91(app dd,J＝3.9,1.5Hz,1H),6.51–6.30(m,1H),4.64(tt,J＝9.4,4.5Hz,1H),4.42(t,J＝8.0Hz,0.5H),4.29(dd,J＝8.7,6.1Hz,0.5H),4.24–4.10(m,1H),4.07–3.98(m,1H),3.94–3.85(m,1H),3.42(ddd,J＝15.2,9.2,6.0Hz,0.5H),3.31–3.27(m,0.5H),3.13–2.99(m,2H),2.53–2.24(m,3H),1.98–1.91(m,2H),1.82–1.75(m,4H),1.36–1.29(m,10H),1.23–0.78(m,12H)。

Compound 72 was prepared from compound 9 using general procedures 7, 4, then general procedure 8.

Compounds 78 and 80 were prepared from compound 9 using general procedure 7, followed by general procedure 4.

Compound 79 was prepared from compound 9 using general procedure 13.

Compound 82 was prepared from (S) -tert-butyl 3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionate INT-17 using general procedures 8, 10, 7 and 8 in sequence.

(1s,4s) -4- (1, 4-dioxaspiro [4.5]]Dec-8-yl) cyclohexan-1-ol

To a stirred solution of L-selectaide (7.24mL, 1.0M in THF, 7.24mmol) was added 4- (1, 4-dioxaspiro [4.5] spiro]Decyl-8-yl) cyclohexanone (1.15g,4.83mmol) in THF (10 mL). The resulting reaction mixture was stirred for 3 h. The reaction mixture was quenched with water (1mL) and EtOH (4 mL). After stirring for 5min, 2M NaOH (9mL) was added followed by slow addition of 30% H₂O₂Aqueous solution (4 mL). After 5min, saturated Na was added₂CO₃Aqueous solution (10 mL). The mixture was washed with Et₂O (3X10mL) extraction over MgSO₄Dry, filter and evaporate the solvent. The residue was purified by column chromatography (EA/isohexane) to obtain748mg (65%) of (1s,4s) -4- (1, 4-dioxaspiro [4.5] spiro as a white solid was supplied]Decan-8-yl) cyclohexan-1-ol.

8- ((1s,4s) -4-ethoxycyclohexyl) -1, 4-dioxaspiro [ 4.5%]Decane

At 0 deg.C to (1s,4s) -4- (1, 4-dioxaspiro [4.5]]Decyl-8-yl) cyclohexanol (748mg,3.11mmol) in THF (6mL) was stirred and sodium hydride (149mg, 60% dispersion in mineral oil, 3.73mmol) was added. The resulting reaction mixture was stirred at 0 ℃ for 10 min. Ethyl iodide (747 μ L,9.34mmol) was then added, and the mixture was stirred at room temperature overnight. Sodium hydride (75mg,1.89mmol) and iodoethane (375. mu.L, 4.69mmol) were added and the mixture was stirred at room temperature overnight. EA (20mL), water (5mL) and saturated NH were added₄Cl solution (10mL) and the layers were separated. The aqueous layer was extracted with EA (2 × 30 mL). The combined organic layers were washed with 1M HCl (10mL) over MgSO₄The solvent was dried and evaporated. The residue was purified by column chromatography (EA/isohexane) to give 345mg (39%) of 8- ((1s,4s) -4-ethoxycyclohexyl) -1, 4-dioxaspiro [4.5] as a colorless oil]Decane.

(1's, 4's) -4 '-ethoxy- [1, 1' -bis (cyclohexyl)]-4-ketones

To 8- ((1s,4s) -4-ethoxycyclohexyl) -1, 4-dioxaspiro [4.5]]A stirred solution of decane (345mg,1.29mmol) in a mixture of acetone (3mL) and water (1.5mL) was added TFA (2.4mL,31.2 mmol). The resulting reaction mixture was stirred at room temperature for 72 h. The solvent was evaporated and driven off with toluene. The residue was purified by column chromatography (EA/isohexane) to give 219mg (74%) of (1's, 4's) -4 '-ethoxy- [1, 1' -bis (cyclohexyl) as a pale yellow oil]-4-ketones. The molecular formula is as follows: c₁₄H₂₄O₂。¹H NMR (400MHz, chloroform-d) delta 3.56-3.49 (m,1H),3.44(q,J＝7.0Hz,2H),2.43–2.24(m,4H),2.10–2.02(m,2H),1.92–1.85(m,2H),1.64–1.54(m,1H),1.51–1.36(m,8H),1.29–1.22(m,1H),1.19(t,J＝7.0Hz,3H)。

compound 83 was prepared from (S) -1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propanoyl) azetidine-3-carboxylic acid INT-71 and (1 'S, 4' S) -4 '-ethoxy- [1, 1' -di (cyclohexyl) ] -4-one using general procedure 37.

(1r,4r) -4- (1, 4-dioxaspiro [4.5]]Dec-8-yl) cyclohexan-1-ol

To a stirred suspension of 4- (1, 4-dioxaspiro [4.5] dec-8-yl) cyclohexanone (1.18g,4.95mmol) in MeOH (10mL) at 0 deg.C was added sodium borohydride (375mg,9.90 mmol). The resulting reaction mixture was stirred for 3h and then quenched with water (50 mL). The aqueous layer was extracted with DCM (50mL), acidified with 1M HCl (10mL) and re-extracted with DCM (20 mL). The organic layers were combined and the solvent was evaporated. The residue was dissolved in toluene (20mL), heated to 60 ℃, and then allowed to cool slowly to room temperature. The precipitate was collected by filtration and washed with hexane to give 795mg (67%) of (1r,4r) -4- (1, 4-dioxaspiro [4.5] decan-8-yl) cyclohexanol as a white solid.

8- ((1r,4r) -4-ethoxycyclohexyl) -1, 4-dioxaspiro [ 4.5%]Decane

At 0 deg.C to (1r,4r) -4- (1, 4-dioxaspiro [4.5]]Decyl-8-yl) cyclohexanol (795mg,3.31mmol) in THF (12mL) was stirred and sodium hydride (159mg, 60% dispersion in mineral oil, 3.97mmol) was added. The resulting reaction mixture was stirred at 0 ℃ for 10 min. Ethyl iodide (794 μ L,9.92mmol) was then added and the mixture was stirred at room temperature overnight. Additional sodium hydride (80mg, 60% dispersion in mineral oil, 1.99 m) was addedmol) and iodoethane (400 μ L,4.99 mmol). The mixture was stirred at room temperature overnight. EA (20mL), water (5mL) and saturated NH were added₄Cl solution (10mL) and the layers were separated. The aqueous layer was extracted with EA (2 × 30 mL). The combined organic layers were washed with 1M HCl (10mL) over MgSO₄Dry, filter and evaporate the solvent. The residue was purified by column chromatography (EA/isohexane) to give 546mg (58%) of 8- ((1r,4r) -4-ethoxycyclohexyl) -1, 4-dioxaspiro [4.5] as a clear colorless oil]Decane.

(1 'r, 4' r) -4 '-ethoxy- [1, 1' -bis (cyclohexyl)]-4-ketones

To 8- ((1r,4r) -4-ethoxycyclohexyl) -1, 4-dioxaspiro [4.5]]A stirred solution of decane (546mg,2.03mmol) in a mixture of acetone (4mL) and water (2mL) was added TFA (3mL,38.9 mmol). The resulting reaction mixture was stirred at room temperature for 72 h. The reaction mixture was concentrated in vacuo and azeotroped with toluene. The residue was purified by column chromatography (EA/isohexane) to give 330mg (69%) of (1 'r, 4' r) -4 '-ethoxy- [1, 1' -bis (cyclohexyl) as a colorless oil]-4-ketones. The molecular formula is as follows: c₁₄H₂₄O₂。¹H NMR (400MHz, chloroform-d) δ 3.52(q, J ═ 7.0Hz,2H), 3.19-3.13 (m,1H), 2.41-2.26 (m,4H), 2.13-2.00 (m,4H), 1.80-1.76 (m,2H), 1.52-1.40 (m,3H), 1.27-1.15 (m,6H), 1.11-0.98 (m, 2H).

Compound 84 was prepared from (S) -1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propanoyl) azetidine-3-carboxylic acid INT-71 and (1 'r, 4' r) -4 '-ethoxy- [1, 1' -di (cyclohexyl) ] -4-one using general procedure 37.

2-methyl-4- (1, 4-dioxaspiro [4.5]]Dec-8-yl) cyclohex-1-one

At-78 deg.CTo a stirred solution of LDA (4.62mL, 2.0M THF/heptane/ethylbenzene solution, 9.23mmol) in THF (20mL) was slowly added a solution containing 4- (1, 4-dioxaspiro [4.5] spiro]Decan-8-yl) cyclohexanone (2.0g,8.39mmol) in THF (15 mL). The resulting reaction mixture was stirred at-78 ℃ for 1h and a solution of iodomethane (0.577mL,9.23mmol) in THF (10mL) was added. The reaction mixture was stirred at-78 ℃ for 1h, over 2h, warmed to room temperature, and saturated NH was added₄Aqueous Cl (40 mL). With Et₂The reaction mixture was extracted with O (100mL) and the organic layer was washed with water (100mL) and brine (100 mL). The organics were then washed over MgSO₄Dried and the solvent evaporated. The residue was purified by column chromatography (EA/isohexane) to give 1.30g (58%) of 2-methyl-4- (1, 4-dioxaspiro [4.5] as an off-white solid]Decan-8-yl) cyclohexanone.

(Z) -8- (3-methyl-4-propylidenecyclohexyl) -1, 4-dioxaspiro [4.5]]Decane

To a stirred solution of triphenyl (propyl) phosphine bromide (1.17g,3.04mmol) in THF (10mL) was added potassium tert-butoxide (341mg,3.04 mmol). The resulting reaction mixture was stirred at room temperature for 1h, then 2-methyl-4- (1, 4-dioxaspiro [4.5] spiro was added dropwise]Decyl-8-yl) cyclohexanone (590mg,2.34mmol) in THF (5 mL). The reaction mixture was stirred at rt for 16 h. The solvent was evaporated. The residue was taken up in Et₂Treated with O (50mL) and stirred for 1 h. The mixture was filtered and washed with additional Et₂O wash and evaporate the solvent. The residue was purified by column chromatography (EA/isohexane) to give 457mg (70%) of (Z) -8- (3-methyl-4-propylidenecyclohexyl) -1, 4-dioxaspiro [4.5] as a colorless oil]Decane.

8- (3-methyl-4-propylcyclohexyl) -1, 4-dioxaspiro [4.5]]Decane

To a stirred solution of 8- (3-methyl-4-propylidenecyclohexyl) -1, 4-dioxaspiro [4.5] decane (760mg,2.73mmol) in MeOH/THF (1:1,20mL) was added 10% Pd/C (76 mg). The resulting reaction mixture was hydrogenated at 50 ℃. The mixture was filtered and the solvent evaporated to afford 769mg (99%) of 8- (3-methyl-4-propylcyclohexyl) -1, 4-dioxaspiro [4.5] decane as a colorless oil.

3 ' -methyl-4 ' -propyl- [1,1 ' -bis (cyclohexyl)]-4-ketones

To 8- (3-methyl-4-propylcyclohexyl) -1, 4-dioxaspiro [4.5]]A stirred solution of decane (769mg,2.74mmol) in a mixture of acetone (5mL) and water (2.5mL) was added TFA (5mL,64.9 mmol). The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was added to EA (200mL) and H₂O (150 mL). The layers were separated. The organic layer was washed with brine (150mL) and saturated NaHCO₃Washed with aqueous solution (150mL) over MgSO₄Dry, filter and evaporate the solvent. The residue was purified by column chromatography (EA/isohexane) to give 580mg (89%) of 3 ' -methyl-4 ' -propyl- [1,1 ' -bis (cyclohexane) as a colorless oil]-4-ketones.

3 ' -methyl-4 ' -propyl- [1,1 ' -bis (cyclohexyl)]-3-en-4-yl trifluoromethanesulfonate

To a stirred solution of LDA (795. mu.L, 2.0M THF/heptane/ethylbenzene solution, 1.59mmol) in THF (4mL) at-78 deg.C was added a solution containing 3 ' -methyl-4 ' -propyl- [1,1 ' -bis (cyclohexane)]-4-ketone (289mg,1.22mmol) in THF (4 mL). The reaction mixture was stirred at-78 ℃ for 30min, then 1,1, 1-trifluoro-N-phenyl-N- ((trifluoromethyl) sulfonyl) methanesulfonamide (480mg,1.35mmol) in THF (4mL) was added. The reaction mixture was stirred at-78 ℃ for 30min and then at room temperature for 1 h. Saturated NaHCO₃Aqueous solution (20mL) was added to the reaction mixture and extracted with EA (2 × 20mL)And taking a water layer. The combined organic layers were dried over MgSO₄The solvent was dried and evaporated. The residue was purified by column chromatography (EA/isohexane) to give 270mg (59%) of 3 ' -methyl-4 ' -propyl- [1,1 ' -bis (cyclohexane) as a colorless oil]-3-en-4-yl trifluoromethanesulfonate.

4,4,5, 5-tetramethyl-2- (3 ' -methyl-4 ' -propyl- [1,1 ' -di (cyclohexyl)]-3-en-4-yl) -1,3, 2-bis Oxopentaneborane

To 3 ' -methyl-4 ' -propyl- [1,1 ' -bis (cyclohexyl)]A stirred solution of (E) -3-en-4-yl trifluoromethanesulfonate (335mg,0.91mmol) in dioxane (8mL) was added 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (231mg,0.91mmol) and potassium acetate (268mg,2.73 mmol). The resulting reaction mixture was heated at 40 ℃ and degassed. Addition of PdCl₂(dppf) (13.31mg,0.02 mmol). Over 3h, the reaction mixture was heated at 90 ℃. The reaction mixture was partitioned between EA (20mL) and water (20 mL). The aqueous layer was extracted with EA (20 mL). The combined organic layers were dried over MgSO₄The solvent was dried and evaporated. The residue was purified by column chromatography (EA/isohexane) to give 165mg (51%) of 4,4,5, 5-tetramethyl-2- (3 ' -methyl-4 ' -propyl- [1,1 ' -bis (cyclohexyl) as a colorless oil]-3-en-4-yl) -1,3, 2-dioxaborolan. The molecular formula is as follows: c₂₂H₃₉BO₂。¹H NMR(400MHz,DMSO-d₆)δ6.44(s,1H),2.20–2.00(m,2H),1.97–1.85(m,1H),1.83–0.95(m,27H),0.93–0.65(8H)。

Compound 85 was prepared from (S) -1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionyl) azetidine-3-carboxylic acid INT-71 and 4,4,5, 5-tetramethyl-2- (3 ' -methyl-4 ' -propyl- [1,1 ' -di (cyclohexyl) ] -3-en-4-yl) -1,3, 2-dioxaborolan using general procedure 10.

8- (4- (2-methylpropylidene) cyclohexyl) -1, 4-dioxaspiro [4.5]]Decane

To a stirred solution of isobutyltriphenylphosphine bromide (5.66g,14.18mmol) in THF (45mL) was added potassium tert-butoxide (1.591g,14.18mmol) dropwise. The resulting reaction mixture was stirred at room temperature for 1h, then 4- (1, 4-dioxaspiro [4.5] spiro was added in portions]Decan-8-yl) cyclohexanone (2.6g,10.91 mmol). The reaction mixture was stirred at rt for 72 h. The solvent was evaporated. The residue was taken up in Et₂Treated with O (60mL) and stirred for 1 h. The mixture was filtered and washed with additional Et₂O wash and evaporate filtrate. The residue was purified by column chromatography (EA/isohexane) to give 1.63g (51%) of 8- (4- (2-methylpropylidene) cyclohexyl) -1, 4-dioxaspiro [4.5] as a colorless oil]Decane.

8- (4-isobutylcyclohexyl) -1, 4-dioxaspiro [4.5]]Decane

To a stirred solution of 8- (4- (2-methylpropylidene) cyclohexyl) -1, 4-dioxaspiro [4.5] decane (1.97g,6.37mmol) in IPA (14mL) were added phenylsilane (0.786mL,6.37mmol) and a solution of t-butylhydroperoxide (1.74mL, 5-6M decane solution, 9.55 mmol). The resulting mixture was degassed then tris (2,2,6, 6-tetramethyl-3, 5-heptanedionato) manganese (III) (0.385g,0.65mmol) was added and the mixture was degassed for only 30 seconds. The reaction mixture was stirred at room temperature for 2h and the solvent was evaporated. The residue was purified by column chromatography (EA/isohexane) to give 680mg (38%) of 8- (4-isobutylcyclohexyl) -1, 4-dioxaspiro [4.5] decane as a white solid.

4 '-isobutyl- [1, 1' -bis (cyclohexyl)]-4-ketones

To 8- (4-isobutyl-cyclohexyl)Yl) -1, 4-dioxaspiro [4.5]]A stirred solution of decane (630mg,2.25mmol) in a mixture of acetone (4mL) and water (2mL) was added trifluoroacetic acid (3mL,38.9 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated. The reaction mixture was added to EA (200mL) and H₂O (150mL), and the layers were separated. The organic layer was washed with brine (150mL) and saturated NaHCO₃Washed with aqueous solution (150mL) over MgSO₄Dry, filter and evaporate the solvent. The residue was purified by column chromatography (EA/isohexane) to give 399mg (74%) of 4 '-isobutyl- [1, 1' -bis (cyclohexane) as a white solid]-4-ketones.

4 '-isobutyl- [1, 1' -bis (cyclohexyl)]-3-en-4-yl trifluoromethanesulfonate

To a stirred solution of LDA (495. mu.L, 2.0M THF/heptane/ethylbenzene solution, 0.99mmol) in THF (3mL) at-78 deg.C was added 4 '-isobutyl- [1, 1' -bis (cyclohexane)]-4-ketone (180mg,0.76mmol) in THF (3 mL). The reaction mixture was stirred at-78 ℃ for 30min, then a solution of N- (5-chloropyridin-2-yl) -1,1, 1-trifluoro-N- ((trifluoromethyl) sulfonyl) methanesulfonamide (359mg,0.91mmol) in THF (3mL) was added. The reaction mixture was stirred at-78 ℃ for 30min, then at room temperature for 30 min. Saturated NaHCO₃Solution (20mL) was added to the reaction mixture and the aqueous layer was extracted with EA (2 × 20 mL). The combined organic layers were dried over MgSO₄The solvent was dried and evaporated. The residue was purified by column chromatography (EA/isohexane) to give 163mg (58%) of 4 '-isobutyl- [1, 1' -bis (cyclohexyl) as a colorless oil]-3-en-4-yl trifluoromethanesulfonate.

2- (4 '-isobutyl- [1, 1' -bis (cyclohexyl)]-3-en-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxan Pentaneborane

To 4 '-isobutyl- [1, 1' -bis (cyclohexyl)]A stirred solution of (E) -3-en-4-yl trifluoromethanesulfonate (155mg,0.42mmol) in dioxane (4mL) was added 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (112mg,0.44mmol) and potassium acetate (124mg,1.26 mmol). The resulting reaction mixture was heated to 40 ℃ and degassed. Addition of PdCl₂(dppf) (6.16mg, 8.41. mu. mol) and the mixture was degassed again and then heated to 90 ℃ for 3 h. The reaction mixture was partitioned between EA (20mL) and water (20 mL). The aqueous layer was extracted once more with EA (20 mL). The combined organic layers were dried over MgSO₄Dry, filter and evaporate the solvent. The residue was purified by column chromatography (EA/isohexane) to give 78mg (51%) of 2- (4 '-isobutyl- [1, 1' -bis (cyclohexyl) as a colorless oil]-3-en-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan. The molecular formula is as follows: c₂₂H₃₉BO₂。¹H NMR(400MHz,DMSO-d₆)δ6.44(s,1H),2.16–2.04(m,2H),1.98–1.86(m,1H),1.79–0.90(m,27H),0.88–0.80(m,8H)。

Compound 86 was prepared from (S) -1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propanoyl) azetidine-3-carboxylic acid INT-71 and 2- (4 '-isobutyl- [1, 1' -di (cyclohexyl) ] -3-en-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan using general procedure 10.

(1RS, 1's, 4' RS) -3-methyl-4 '-propyl- [1, 1' -bis (cyclohexyl)]-4-ketones

To a stirred solution of LDA (5.67mL, 2.0M THF/heptane/ethylbenzene solution, 11.33mmol) in THF (20mL) at-78 deg.C was slowly added a solution containing trans-4 '-propyl- [1, 1' -bis (cyclohexane)]-4-ketone (2.1g,9.44mmol) in THF (15 mL). The reaction mixture was stirred at-78 ℃ for 1h, and a solution of iodomethane (0.709mL,11.33mmol) in THF (10mL) was added. The reaction mixture was stirred at-78 ℃ for 1h, warmed to room temperature over 2h, and saturated NH was added₄Aqueous Cl (40 mL). With Et₂Dilution with O (100mL)The reaction mixture was combined and the organic layer was washed with water (100mL) and brine (100 mL). The organics were then washed over MgSO₄Dry, filter and evaporate the solvent. The crude product was purified by column chromatography (EA/isohexane) to give 1.50g (67%) of (1RS, 1's, 4' RS) -3-methyl-4 '-propyl- [1, 1' -bis (cyclohexane) as a pale yellow oil]-4-ketones. The molecular formula is as follows: c₁₆H₂₈O。¹H NMR(400MHz,DMSO-d6)δ2.47–2.35(m,1H),2.25(app t,J＝6.7Hz,1H),2.20–2.06(m,1H),2.04–1.9(m,1H),1.97–1.60(m,6H),1.55–1.46(m,1H),1.40–1.23(m,3H),1.19–0.80(m,14H)。

Compound 87 was prepared from (S) -1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propanoyl) azetidine-3-carboxylic acid INT-71 and (1RS,1 'S, 4' RS) -3-methyl-4 '-propyl- [1, 1' -di (cyclohexyl) ] -4-one using general procedure 37.

8- (4- (methoxymethylene) cyclohexyl) -1, 4-dioxaspiro [4.5]Decane

To a stirred solution of (methoxymethyl) triphenylphosphine chloride (3.74g,10.91mmol) in THF (16mL) was added potassium tert-butoxide (1.224g,10.91mmol) portionwise. The solution was stirred at room temperature for 50min, then 4- (1, 4-dioxaspiro [4.5] spiro was added slowly]Solution of decan-8-yl) cyclohexanone (2g,8.39mmol) in THF (16 mL). The reaction mixture was stirred for 3.5 h. The solvent was removed in vacuo. The residue was taken up in Et₂Treated with O (44mL) and stirred for 1 h. The mixture was filtered and Et₂O (2 × 50mL) and the filtrate was evaporated. The crude product was purified by column chromatography (EA/isohexane) to give 1.8g (76%) of 8- (4- (methoxymethylene) cyclohexyl) -1, 4-dioxaspiro [4.5] as a colorless oil]Decane.

8- ((4- (methoxymethyl) cyclohexyl) -1, 4-dioxaspiro [4.5]]Decane

To a stirred solution of 8- (4- (methoxymethylene) cyclohexyl) -1, 4-dioxaspiro [4.5] decane (1.8g,6.76mmol) in EtOH (20mL) was added 5% palladium on activated carbon (Johnson and Matthey paste formulation 58,0.132g,1.24 mmol). The reaction was stirred at room temperature under 3bar of hydrogen pressure for 16 h. The mixture was filtered through celite and rinsed with EtOH (150 mL). The solvent was evaporated to give 1.8g (99%) of 8- ((1r,4r) -4- (methoxymethyl) cyclohexyl) -1, 4-dioxaspiro [4.5] decane as a colorless oil.

4 '- (methoxymethyl) - [1, 1' -bis (cyclohexyl)]-4-ketones

To a stirred solution of 8- (4- (methoxymethyl) cyclohexyl) -1, 4-dioxaspiro [4.5] decane (1.8g,6.71mmol) in a mixture of acetone (10mL) and water (5mL) was added TFA (7.23mL,94 mmol). The reaction mixture was stirred at rt for 2 h. The solvent was evaporated to afford 1.65g (97%) of 4 '- (methoxymethyl) - [1, 1' -di (cyclohexyl) ] -4-one as a colorless oil.

4 '- (methoxymethyl) - [1, 1' -bis (cyclohexyl)]-3-en-4-yl trifluoromethanesulfonate

To a solution of diisopropylamine (1.09mL,7.77mmol) in THF (10mL) at-20 deg.C was added n-BuLi (3.11mL,7.77 mmol). The mixture was cooled to-78 ℃. Slowly add 4 '- (methoxymethyl) - [1, 1' -bis (cyclohexyl)]-4-one (1.65g,6.47mmol) in THF (10mL) followed by the addition of 1,1, 1-trifluoro-N-phenyl-N- ((trifluoromethyl) sulfonyl) methanesulfonamide (2.43g,6.80 mmol). The resulting mixture was stirred at-78 ℃ for 1.75h, then at room temperature for 16 h. Saturated NaHCO₃Solution (20mL) was added to the reaction mixture and the aqueous layer was extracted with EA (2 × 30 mL). The organic layer was washed with brine (30mL) over MgSO₄Drying, filtration and evaporation of the solvent afforded 2.31g (100%) 4 '- (methoxymethyl) - [1, 1' -bis (cyclohexyl) as an orange oil]-3-en-4-yl trifluoromethanesulfonate.

2- (4 '- (methoxymethyl) - [1, 1' -bis (cyclohexyl)]-3-en-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-di Oxopentaneborane

To 4 '- (methoxymethyl) - [1, 1' -bis (cyclohexyl)]A stirred solution of (4.52g,6.47mmol) of (3-en-4-yl) trifluoromethanesulfonate in DMSO (10mL) was added with 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (1.642g,6.47mmol) and potassium acetate (1.904g,19.40 mmol). The resulting reaction mixture was warmed to 40 ℃ and degassed. Adding PdCl₂dppf (0.095g,0.13mmol) and the mixture was further degassed. The reaction mixture was heated to 100 ℃ for 8h and then at room temperature overnight. With Et₂The mixture was extracted with O (4x50 mL). The combined organics were washed with water (2 × 50mL), brine (50mL), and over MgSO₄Drying and evaporation afforded 1.70g (78%) 2- (4 '- (methoxymethyl) - [1, 1' -bis (cyclohexyl) as an orange oil]-3-en-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan. The molecular formula is as follows: c₂₀H₃₅BO₃。¹H NMR (400MHz, chloroform-d) δ 6.56(s,1H),3.30(s,3H),3.16(d, J ═ 6.5Hz,2H), 2.25-2.0 (m,3H), 1.85-0.81 (m, 26H).

Compound 88 was prepared from (S) -1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propanoyl) azetidine-3-carboxylic acid INT-71 and 2- (4 '- (methoxymethyl) - [1, 1' -di (cyclohexyl) ] -3-en-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan using general procedure 10.

Trimethyl (((1RS, 1's, 4' RS) -3-methyl-4 '-propyl- [1, 1' -bis (cyclohexyl)]-3-en-4-yl) oxy) Silane

To racemic (1RS, 1's, 4' RS) -3-methyl-4 '-propyl- [1, 1' -bis (cyclohexyl)]A stirred solution of-4-one (500mg,2.12mmol) in ACN (20mL) was added triethylamine (884. mu.L, 6.35mmol), trimethylchlorosilane (403. mu.L, 3.17mmol), and sodium iodide (476mg,3.17 mmol). The reaction mixture was stirred at rt for 16 h. Saturated NaHCO₃Solution (50mL) was added to the reaction mixture and the aqueous layer was extracted with isohexane (3 × 50 mL). The combined organic layers were washed with brine (100mL) and MgSO₄Drying, filtration and evaporation of the solvent gave 538mg (74%) of racemic trimethyl (((1RS, 1's, 4' RS) -3-methyl-4 '-propyl- [1, 1' -bis (cyclohexyl) as a yellow oil]-3-en-4-yl) oxy) silane.

(1RS, 1's, 4' RS) -3-methyl-4 '-propyl- [1, 1' -bis (cyclohexyl)]-3-en-4-yl trifluoromethanesulfonate

To racemic trimethyl (((1RS, 1's, 4' RS) -3-methyl-4 '-propyl- [1, 1' -bis (cyclohexyl) at 0 deg.C]A stirred solution of (3-en-4-yl) oxy) silane (484mg,1.41mmol) in THF (6mL) was added methyllithium (1147. mu.L, 1.6M Et₂Solution O, 1.84 mmol). After 30min, TMEDA (1065 μ L,7.06mmol) was added followed by a solution of 1,1, 1-trifluoro-N-phenyl-N- ((trifluoromethyl) sulfonyl) methanesulfonamide (656mg,1.84mmol) in THF (3 mL). The reaction was stirred at 0 ℃ for 1h and then warmed to room temperature. With saturated NaHCO₃The reaction mixture was quenched with aqueous solution (30mL) and the aqueous layer was extracted with EA (2 × 30 mL). The combined organic layers were dried over MgSO₄Dry, filter and evaporate the solvent. The crude product was purified by column chromatography (EA/isohexane) to give 224mg (43%) of racemic (1RS, 1's, 4' RS) -3-methyl-4 '-propyl- [1, 1' -bis (cyclohexane) as a colorless oil]-3-en-4-yl trifluoromethanesulfonate.

4,4,5, 5-tetramethyl-2- ((1RS, 1's, 4)' RS) -3-methyl-4 ' -propyl- [1,1 ' -bis (cyclohexyl)]-3-ene- 4-yl) -1,3, 2-dioxaborolane

To racemic (1RS, 1's, 4' RS) -3-methyl-4 '-propyl- [1, 1' -bis (cyclohexyl)]A stirred solution of (E) -3-en-4-yl trifluoromethanesulfonate (260mg,0.71mmol) in dioxane (5mL) was added 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (179mg,0.71mmol) and potassium acetate (208mg,2.12 mmol). The resulting reaction mixture was heated to 40 ℃ and degassed. Addition of PdCl₂(dppf) (10.33mg,0.014mmol) and the mixture was degassed again and then heated to 90 ℃ for 3 h. The reaction mixture was partitioned between EA (20mL) and water (20 mL). The aqueous layer was re-extracted with EA (20 mL). The combined organic layers were dried over MgSO₄The solvent was dried and evaporated. The crude product was purified by column chromatography (EA/isohexane) to give 146mg (57%) of racemic 4,4,5, 5-tetramethyl-2- ((1RS, 1's, 4' RS) -3-methyl-4 '-propyl- [1, 1' -bis (cyclohexane) as a white solid]-3-en-4-yl) -1,3, 2-dioxaborolan. The molecular formula is as follows: c₂₂H₃₉BO₂。¹H NMR (400MHz, chloroform-d) delta 2.28-2.19 (m,1H), 2.05-1.95 (m,2H),1.90(s,3H), 1.83-1.68 (m,6H), 1.35-1.21 (m,14H), 1.16-0.82 (m, 13H).

Compound 89 was prepared from (S) -1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionyl) azetidine-3-carboxylic acid INT-71 and 4,4,5, 5-tetramethyl-2- ((1RS,1 'S, 4' RS) -3-methyl-4 '-propyl- [1, 1' -di (cyclohexyl) ] -3-en-4-yl) -1,3, 2-dioxaborolan using general procedure 10.

1- (4- (benzyloxy) phenyl) -4, 4-dimethylcyclohexanol

At-60To a stirred suspension of magnesium (1.847g,76mmol) in THF (15mL) was added iodine (. about.20 mg). After 30min, a solution of 1- (benzyloxy) -4-bromobenzene (10g,38.0mmol) in THF (45mL) was added slowly to maintain a boundary reflux (. about.2 h addition). The mixture was stirred at-60 ℃ for a further 2h, then cooled to room temperature, then further cooled to-10 ℃, whereupon a solution of 4, 4-dimethylcyclohexanone (8.5mL,34.5mmol) in THF (15mL) was added to maintain the internal temperature at-5 ℃ to-10 ℃. After a further 1h, the mixture is taken up with NH₄Cl (100mL) was quenched and extracted with ether (2 × 100 mL). The combined organics were dried over MgSO₄Drying, filtration and evaporation afforded 10.7g (100%) 1- (4- (benzyloxy) phenyl) -4, 4-dimethylcyclohexanol as a yellow oil. C₂₁H₂₆O₂Calculated LCMS-ESI (m/z): 310.2 of the total weight of the mixture; found 293.2[ M + H-H₂O]⁺，t_R2.90min (method 11).

4 '- (benzyloxy) -4, 4-dimethyl-2, 3,4, 5-tetrahydro-1, 1' -biphenyl

To a stirred solution of 1- (4- (benzyloxy) phenyl) -4, 4-dimethylcyclohexanol (10.7g,34.5mmol) in MeOH (135mL) was added concentrated HCl (15 mL). The resulting reaction mixture was heated to 50 ℃ for 1 h. The reaction mixture was cooled and the product was collected by filtration and washed with MeOH to afford 4.32g (39%) of 4 '- (benzyloxy) -4, 4-dimethyl-2, 3,4, 5-tetrahydro-1, 1' -biphenyl as a yellow solid. LCMS-ESI (m/z) no ionization, t_R3.26min (method 11).

4 ', 4 ' -dimethyl- [1,1 ' -di (cyclohexyl)]-4-ketones

To a stirred solution of 4 '- (benzyloxy) -4, 4-dimethyl-2, 3,4, 5-tetrahydro-1, 1' -biphenyl (4.32g,14.77mmol) in xylene (55mL) was added 5% palladium on alumina (powder form 325; 1 g). The resulting reaction mixture was purged with nitrogen and hydrogen and then stirred overnight at 100 ℃ in hydrogen (5 bars). The reaction mixture was filtered through a glass microfiber filter and washed with EtOH. The solvent was evaporated. The crude product was purified by column chromatography (EA/isohexane) to give 1.55g (50%) of 4 ', 4 ' -dimethyl- [1,1 ' -di (cyclohexyl) ] -4-one as a colorless oil.

4 ', 4 ' -dimethyl- [1,1 ' -di (cyclohexyl)]-3-en-4-yl trifluoromethanesulfonate

To a stirred solution of diisopropylamine (1.251mL,8.93mmol) in THF (35mL) at-20 deg.C was added n-BuLi (3.57mL,8.93 mmol). The mixture was cooled to-78 ℃. Slowly adding the mixture containing 4 ', 4 ' -dimethyl- [1,1 ' -di (cyclohexyl)]-4-one (1.55g,7.44mmol) in THF (35mL) followed by addition of 1,1, 1-trifluoro-N-phenyl-N- ((trifluoromethyl) sulfonyl) methanesulfonamide (2.79g,7.81 mmol). The resulting mixture was stirred at-78 ℃ for 1h, then at room temperature for 16 h. Saturated NaHCO₃(80mL) solution was added to the reaction mixture and the aqueous layer was extracted with EA (2X120 mL). The organic layers were combined and MgSO₄Dried and the solvent evaporated. The crude product was purified by column chromatography (EA/isohexane) to give 807mg (32%) of 4 ', 4 ' -dimethyl- [1,1 ' -bis (cyclohexane) as a colorless oil]-3-en-4-yl trifluoromethanesulfonate.

2- (4 ', 4 ' -dimethyl- [1,1 ' -di (cyclohexyl)]-3-en-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxo Heterocyclopentylborane

To 4 ', 4 ' -dimethyl- [1,1 ' -di (cyclohexyl)]A stirred solution of (E) -3-en-4-yl trifluoromethanesulfonate (807mg,2.37mmol) in dioxane (15mL) was added 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (602mg,2.37mmol) and potassium acetate (698mg,7.11 mmol). The resulting reaction mixture was heated to 40 ℃ and degassed. Addition of PdCl₂(dppf) (34.7mg,0.047mmol) and the mixture was degassed again and then heated to 90 ℃ for 4 h. The reaction mixture was partitioned between EA (20mL) and water (20 mL). The aqueous layer was extracted with EA (3 × 20 mL). The combined organic layers were dried over MgSO4 and the solvent was evaporated. The crude product was purified by column chromatography (EA/isohexane) to give 450mg (57%) of 2- (4 ', 4 ' -dimethyl- [1,1 ' -bis (cyclohexane) as a yellow oil]-3-en-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan which crystallizes on standing. The molecular formula is as follows: c₂₀H₃₅BO₂。¹H NMR (400MHz, chloroform-d) delta 6.57(s,1H), 2.28-1.98 (m,3H), 1.89-1.73 (m,2H), 1.59-1.45 (m,3H), 1.41-1.30 (m,3H), 1.28-0.95 (m,17H),0.88(s,3H),0.85(s, 3H).

Compound 90 was prepared from (S) -1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionyl) azetidine-3-carboxylic acid INT-71 and 2- (4 ', 4 ' -dimethyl- [1,1 ' -di (cyclohexyl) ] -3-en-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan using general procedure 10.

(S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5-ethylthiophene-2-carboxamido) propionic acid

Prepared using general procedure 8: a stirred solution of tert-butyl (S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5-ethylthiophene-2-carboxamido) propionate (0.8g,1.5mmol) in DCM (10mL) was treated with TFA (4 mL). The reaction mixture was stirred at room temperature for 16 hours until the reaction was complete. The solvent was evaporated and then co-evaporated with toluene (3x20mL) to remove traces of TFA. The residue was suspended in acetonitrile (10mL) and the solid formed was filtered. The compound is inDrying in vacuo overnight afforded 0.46g (68%) of (S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5-ethylthiophene-2-carboxamido) propionic acid as a semi-white powder. C₂₀H₁₈BrN₃O₃LCMS-ESI (m/z) calculation of S: 460.3, respectively; found 462.3[ M + 2]]⁺，t_R2.76min (method 18).

(S) -1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5-ethylthiophene-2-carboxamido) propionyl) aza Cyclobutane-3-carboxylic acid tert-butyl ester (INT 73)

Prepared using general procedure 7: to a stirred solution of (S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5-ethylthiophene-2-carboxamido) propionic acid (0.43g,0.93mmol) in DMF (5mL) at 0 ℃ was added DIPEA (0.6g,4.6mmol) followed by azetidine-3-carboxylic acid tert-butyl ester hydrochloride (0.22g,1.1 mmol). HATU (0.88g,2.33mmol) was added to the mixture. The reaction was stirred at 0 ℃ for 2h, then warmed to room temperature for 16 h. The reaction mixture was then diluted with saturated sodium bicarbonate solution (5mL), water (5mL) and EA (10 mL). The layers were separated and the aqueous layer was extracted with EA (2 × 10 mL). The combined organic layers were washed with 1N hydrochloric acid, water, brine, then MgSO₄Dried and concentrated. The crude product was purified by column chromatography (0-40% EA/hexane) to afford 0.43g (76%) of tert-butyl (S) -1- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5-ethylthiophene-2-carboxamido) propanoyl) azetidine-3-carboxylate INT 73. C₂₈H₃₁BrN₄O₄LCMS-ESI (m/z) calculation of S: 599.5, respectively; found 601.3[ M + 2]]⁺，t_R4.22min (method 25).

(1RS,1 'r, 4' RS) -4 '-methyl- [1, 1' -di (cyclohexyl) ] -3-en-4-yl trifluoromethanesulfonate

At 0 ℃ to twoA stirred solution of isopropylamine (17.3mL,124mmol) in THF (350mL) was added butyllithium (41.9mL, 2.7M in hexane, 113 mmol). After 30min, the mixture was cooled to-78 ℃ and (1 'r, 4' r) -4 '-methyl- [1, 1' -bis (cyclohexyl) added over 1h]Treatment of a solution of-4-ketone (20g,103mmol) in THF (100 mL). After 30min, a solution of 1,1, 1-trifluoro-N-phenyl-N- ((trifluoromethyl) sulfonyl) methanesulfonamide (44.1g,124mmol) in THF (180mL) was added over 1 h. The resulting mixture was allowed to slowly warm to room temperature. The reaction mixture was washed with ice/NaHCO₃(200/250mL) was carefully quenched and extracted with EA (2X300 mL). The combined organics were dried over MgSO₄Dried and the solvent evaporated. Column chromatography (EA/isohexane) gave 30.7g (91%) of racemic (1RS,1 'r, 4' RS) -4 '-methyl- [1, 1' -bis (cyclohexyl)]-3-en-4-yl trifluoromethanesulfonate.

4,4,5, 5-tetramethyl-2- ((1RS,1 'r, 4' RS) -4 '-methyl- [1, 1' -bis (cyclohexyl)]-3-en-4-yl) - 1,3, 2-dioxaborolane

To racemic (1RS,1 'r, 4' RS) -4 '-methyl- [1, 1' -bis (cyclohexyl) at 40 deg.C]A stirred solution of (30.7g,94mmol) of (E) -3-en-4-yl trifluoromethanesulfonate and (E) -4,4, 4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (26.3g,103mmol) in dioxane (400mL) was added potassium acetate (27.7g,282mmol) and the mixture was degassed. Addition of PdCl₂(dppf) (1.377g,1.881mmol) and heated to 100 ℃ for 4 h. The mixture was allowed to cool then quenched with water (500mL) and extracted with EA (3x700 mL). The combined organic extracts were dried over MgSO₄Dried and the solvent evaporated. Column chromatography (EA/isohexane) gave 12.1g (42%) of racemic 4,4,5, 5-tetramethyl-2- ((1RS,1 'r, 4' RS) -4 '-methyl- [1, 1' -bis (cyclohexane)]-3-en-4-yl) -1,3, 2-dioxaborolan. The molecular formula is as follows: c₁₉H₃₃BO₂。¹H NMR (400MHz, chloroform-d) delta 6.60-6.57 (m,1H), 2.36-1.96 (m,3H), 1.95-1.67 (m,6H),1.40–0.78(m,23H)。

Compound 91 was prepared from INT-73 using general procedure 10 using racemic 4,4,5, 5-tetramethyl-2- ((1RS,1 'r, 4' RS) -4 '-methyl- [1, 1' -di (cyclohexyl) ] -3-en-4-yl) -1,3, 2-dioxaborolan followed by general procedure 8.

Compound 92 was prepared from INT-73 using general procedure 10 using 2- (4 ', 4 ' -dimethyl- [1,1 ' -di (cyclohexyl) ] -3-en-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan followed by general procedure 8.

(Z) -N ' - ((1RS,1 ' r,4 ' RS) -4 ' -ethyl- [1,1 ' -bis (cyclohexyl)]-4-ylidene) -4-toluenesulfonylhydrazide

A stirred mixture of (1 'r, 4' r) -4 '-ethyl- [1, 1' -di (cyclohexyl) ] -4-one (100g,470mmol) and 4-toluenesulfonylhydrazide (90g,470mmol) in EtOH (1700mL) was heated at 100 ℃ for 3 h. The reaction mixture was allowed to cool to room temperature. The precipitate was collected by filtration, washed with cold EtOH (100mL) and dried in a vacuum oven at 50 ℃ to provide 170g (94%) of racemic (Z) -N ' - ((1RS,1 ' r,4 ' RS) -4 ' -ethyl- [1,1 ' -di (cyclo-hexane) ] -4-ylidene) -4-toluenesulfonyl hydrazide as a white solid.

2- ((1RS,1 'r, 4' RS) -4 '-ethyl- [1, 1' -bis (cyclohexyl)]-3-en-4-yl) -4,4,5, 5-tetramethyl- 1,3, 2-dioxaborolane

Racemic (Z) -N ' - ((1RS,1 ' r,4 ' RS) -4 ' -ethyl- [1,1 ' -di (cyclohexyl)]A stirred mixture of-4-ylidene) -4-toluenesulfonylhydrazide (47g,125mmol) and N1, N1, N2, N2-tetramethylethane-1, 2-diamine (381mL,2496mmol) in isohexane (400mL) was cooled to-78 deg.C and, after 15min, treated with N-BuLi (200mL, 2.5M solution, 499 mmol). At 20mAfter in, the cooling bath was removed. After stirring for a further 2h, the mixture was cooled to-78 ℃ and 2-isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (105mL,499mmol) was added slowly. The reaction mixture was stirred at-78 ℃ and then warmed to room temperature overnight. By NH₄The reaction mixture was quenched with Cl (400 mL). The reaction mixture was washed with water (2.5L) and Et₂O (1.5L). The organic layer was purified over MgSO₄Dry, filter and evaporate the solvent. The residue was treated with MeOH (200mL) and cooled using an ice water bath. The solid formed was collected by filtration to give 23.78g (59%) of racemic 2- ((1RS,1 'r, 4' RS) -4 '-ethyl- [1, 1' -bis (cyclohexane) as an off-white solid]-3-en-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan. The molecular formula is as follows: c₂₀H₃₅BO₂。¹H NMR(400MHz,DMSO-d₆)δ6.43(s,1H),2.17–2.04(m,2H),1.98–1.86(m,1H),1.84–1.65(m,6H),1.31–0.77(m,25H)。

Compound 93 was prepared from INT-73 using general procedure 10 using racemic 2- ((1RS,1 'r, 4' RS) -4 '-ethyl- [1, 1' -di (cyclohexyl) ] -3-en-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan followed by general procedure 8.

1- ((S) -2- (((benzyloxy) carbonyl) amino) -3- (4- (5- ((1RS,1 ' r,4 ' RS) -4 ' -ethyl- [1, 1-) Two (cyclohexyl)]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid tert-butyl ester

Prepared using general procedure 10: to tert-butyl (S) -1- (2- (((benzyloxy) carbonyl) amino) -3- (4- (5-bromopyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylate (1.1g,1.9mmol) and racemic 2- ((1RS,1 'r, 4' RS) -4 '-ethyl- [1, 1' -bis (cyclohexyl)]-3-en-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (0.7g,2.2mmol) in 3:1 dioxane: h₂To a stirred solution in O (14mL) was added sodium carbonate decahydrate (1.1g,3.7 mmol). Mixing with nitrogen bubblingThe material is degassed and PdCl is added₂(dppf) (0.14g,0.2mmol) and the mixture was heated at 70 ℃. After 3h, the reaction mixture was diluted with DCM and washed with brine. The organic layer was dried (Na)₂SO₄) And purified by column chromatography (EA/hexane) to give 1.3g (99%) of 1- ((S) -2- (((benzyloxy) carbonyl) amino) -3- (4- (5- ((1RS,1 'r, 4' RS) -4 '-ethyl- [1, 1' -bis (cyclohexane)]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid tert-butyl ester. C₄₃H₅₄N₄O₅Calculated LCMS-ESI (m/z): 706.9, respectively; found 707.4[ M + H]⁺，t_R5.3min (method 25).

1- ((S) -2-amino-3- (4- (5- ((1RS,1 'r, 4' RS) -4 '-ethyl- [1, 1' -bis (cyclohexyl)]-3-ene-4- Yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid tert-butyl ester (INT-74)

Prepared using general procedure 18. To 1- ((S) -2- (((benzyloxy) carbonyl) amino) -3- (4- (5- ((1RS,1 'r, 4' RS) -4 '-ethyl- [1, 1' -bis (cyclohexane)]A stirred solution of a diastereomeric mixture of (100mg,0.14mmol) of tert-butyl (3-en-4-yl) pyrimidin-2-yl) phenyl) propionyl) azetidine-3-carboxylate in EA (6mL) was added Pd/C (10mg,0.01mmol) and hydrogen was bubbled through the reaction three times. The reaction mixture was stirred under a hydrogen atmosphere for 36 hours, then concentrated, dissolved in MeOH, filtered through celite, and concentrated again to provide 76mg (95%) of 1- ((S) -2-amino-3- (4- (5- ((1RS,1 'r, 4' RS) -4 '-ethyl- [1, 1' -bis (cyclohexane))]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) azetidine-3-carboxylic acid tert-butyl ester INT-74. C₃₅H₄₈N₄O₃Calculated LCMS-ESI (m/z): 572.8, respectively; found 573.4[ M + H]+，t_R5.02min (method 25).

Compounds 94-104 were prepared from INT-74 using general procedure 7, using the corresponding formic acid, followed by general procedure 8.

Compound 105-108 was prepared from compound 119 using general procedure 7, using the corresponding amine, followed by general procedure 8.

Prepared using general procedure 8: to a stirred solution of (S) -tert-butyl 2- (((benzyloxy) carbonyl) amino) -3- (4- (5-bromopyrimidin-2-yl) phenyl) propionate INT-7(12g,23.42mmol) in DCM (210mL) was added TFA (150 mL). After 3h, the mixture was diluted with DCM (100mL) and poured onto ice water (500 mL). The organic phase was separated, washed with water (2 × 100mL), over MgSO₄Drying and evaporation of the solvent gave 10.7g (100%) (S) -2- (((benzyloxy) carbonyl) amino) -3- (4- (5-bromopyrimidin-2-yl) phenyl) propanoic acid (12.16g,23.45mmol, 100% yield). C₂₁H₁₈BrN₃O₄Calculated LCMS-ESI (m/z): 455.1, respectively; found 456.1[ M + H]⁺，t_R6.08min (method 10).

(S) -benzyl (3- (4- (5-bromopyrimidin-2-yl) phenyl) -1- (methylsulfonylamino) -1-oxopropan-2-yl) amino Formic acid esters

Prepared using general procedure 7: to a stirred solution of (S) -2- (((benzyloxy) carbonyl) amino) -3- (4- (5-bromopyrimidin-2-yl) phenyl) propionic acid (12.16g,23.45mmol) in DCM (250mL) was added methanesulfonamide (22.31g,235mmol), DMAP (5.73g,46.9mmol) and DIEA (20.48mL,117mmol), followed by EDC (6.29g,32.8 mmol). The reaction mixture was stirred at room temperature for 3 days, then quenched in ice water (200mL), acidified with 1M HCl (250mL), and extracted with DCM (400 mL). The organic layer was washed with 0.1M HCl (3 × 200mL) over MgSO₄The mixture is dried and then is dried,filtration and evaporation of the solvent afforded 10.5g (84%) (S) -benzyl (3- (4- (5-bromopyrimidin-2-yl) phenyl) -1- (methylsulfonylamino) -1-oxoprop-2-yl) carbamate. C₂₂H₂₁BrN₄O₅LCMS-ESI (m/z) calculation of S: 532.0, respectively; found 533.0[ M + H]⁺，t_R2.34min (method 11).

(S) -2-amino-3- (4- (5-bromopyrimidin-2-yl) phenyl) -N- (methylsulfonyl) propanamide

To a stirred hydrobromic acid (107mL, 33% AcOH solution, 591mmol) was added (S) -benzyl (3- (4- (5-bromopyrimidin-2-yl) phenyl) -1- (methylsulfonylamino) -1-oxoprop-2-yl) carbamate (10.5g,19.70 mmol). After 2h, diethyl ether (100mL) was added and the precipitate was collected by filtration and washed with isohexane (4x50mL) to give 9.5g (100%) of (S) -2-amino-3- (4- (5-bromopyrimidin-2-yl) phenyl) -N- (methylsulfonyl) propionamide as the HBr salt. C₁₄H₁₅BrN₄O₃LCMS-ESI (m/z) calculation of S: 398.0; found 399.1[ M + H]⁺，t_R1.21min (method 11).

(S) -N- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -1- (methylsulfonylamino) -1-oxopropan-2-yl) -5- (tert-butyl) amino Butyl) thiophene-2-carboxamide

Prepared using general procedure 7: to a stirred solution of 5- (tert-butyl) thiophene-2-carboxylic acid (4.56g,23.53mmol) and DIEA (21.72mL,118mmol) in DMF (95mL) was added HATU (8.95g,23.53mmol) in portions. After 30min, the yellow solution was added to a stirred solution of (S) -2-amino-3- (4- (5-bromopyrimidin-2-yl) phenyl) -N- (methylsulfonyl) propionamide, HBr (9.5g,19.61mmol) in DMF (190 mL). After 1.5h, ice water (190mL) was added. After 10min, acetic acid was added(8.97mL,157 mmol). After an additional 10min, more water (300mL) was added. The mixture was stirred at room temperature for 15 min. The precipitate was collected by filtration, washed successively with water (2x100mL), isohexane (2x100mL), water (2x100mL) and isohexane (2x100mL) to yield 11.1g (100%) (S) -N- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -1- (methylsulfonylamino) -1-oxoprop-2-yl) -5- (tert-butyl) thiophene-2-carboxamide. C₂₃H₂₅BrN₄O₄S₂Calculated LCMS-ESI (m/z): 564.1, respectively; found 565.1[ M + H ]]⁺，t_R2.58min (method 11).

5- (tert-butyl) -N- ((S) -3- (4- (5- ((1RS,1 'r, 4' RS) -4 '-ethyl- [1, 1' -bis (cyclohexyl)]-3- En-4-yl) pyrimidin-2-yl) phenyl) -1- (methylsulfonylamino) -1-oxoprop-2-yl) thiophene-2-carboxamide (compound 109)

Prepared using general procedure 10: to (S) -N- (3- (4- (5-bromopyrimidin-2-yl) phenyl) -1- (methylsulfonylamino) 1-oxopropan-2-yl) -5- (tert-butyl) thiophene-2-carboxamide (5.25g,9.28mmol) and racemic 2- ((1RS,1 'r, 4' RS) -4 '-ethyl- [1, 1' -bis (cyclohexyl)]A stirred solution of (E) -3-en-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (3.55g,11.14mmol) in dioxane (200mL) was added sodium bicarbonate (25.8mL, 0.9M aq. solution, 23.21 mmol). The mixture was warmed to 40 ℃, degassed, and then treated with PdCl₂dppf (0.303g,0.371mmol) was treated and then heated to reflux for 6 h. The mixture was allowed to cool, then poured onto 1M HCl (200mL) and extracted with EA (3 × 200 mL). The combined organic extracts were washed with brine (200mL) and over MgSO₄Dry, filter and evaporate the solvent. The residue was purified by column chromatography (AcOH/EA/DCM/isohexane) and reslurried with ACN. The residue was further purified by reverse phase column chromatography (RP Flash C18, ACN/water/formic acid) to give 4.25g (68%) of 5- (tert-butyl) -N- ((S) -3- (4- (5- ((1RS,1 'r, 4' RS) -4 '-ethyl- [1, 1' -bis (cyclohexane)]-3-en-4-yl) pyrimidin-2-yl) phenyl) -1- (methylsulfonylamino) -1-oxySubstituted prop-2-yl) thiophene-2-carboxamide diastereoisomeric mixtures. C₃₇H₄₈N₄O₄S₂Calculated LCMS-ESI (m/z): 676.3; found 677.3[ M + H]⁺，t_R3.39min (method 11). Chiral analysis (chiral method 1) shows>95% of a single peak.¹H NMR(400MHz,DMSO-d₆)δ12.18(s,1H),8.91(s,2H),8.70–8.68(m,1H),8.45–8.19(m,2H),7.67(d,J＝3.9Hz,1H),7.51(d,J＝8.3Hz,2H),6.93(d,J＝3.8Hz,1H),6.49–6.34(m,1H),4.75–4.69(m,1H),3.24–3.17(m,4H),3.06(dd,J＝13.6,10.8Hz,1H),2.49–2.19(m,3H),2.00–1.92(m,2H),1.87–1.70(m,4H),1.38-1.29(m,11H),1.23–0.95(m,6H),0.91–0.82(m,5H)。

(S) -1- ((S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propane Acyl) pyrrolidine-3-carboxylic acid

A solution of sulfuric acid (119mL,2228mmol) in acetic acid (300mL) and water (300mL) was prepared and allowed to cool to room temperature. This was added to a stirred solution of methyl 1- ((S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propanoyl) pyrrolidine-3-carboxylate INT-35(44.5g,74.3mmol) in dioxane (500 mL). After 16h, the mixture was poured into ice water (1L) and extracted with DCM (2 × 1L). The combined organic extracts were washed with water (2 × 1L) over MgSO₄The solvent was dried and evaporated. Column chromatography (AcOH/EA/DCM/isohexane) yielded clean product and mixed fractions. These combined fractions were further purified by column chromatography (AcOH/EA/DCM/isohexane), the clean products were combined and reslurried with ACN to afford 26.3g (60%) (S) -1- ((S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propanoyl) pyrrolidine-3-carboxylic acid. C₂₇H₂₉BrN₄O₄LCMS-ESI (m/z) calculation of S: 584.1; found 585.1[ M + H]⁺，t_R2.48min (method 11).

(S) -1- ((S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (5- ((1RS,1 'r, 4' RS) -4- Ethyl- [1, 1' -bis (cyclohexyl)]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) pyrrolidine-3-carboxylic acid (compound 110)

Prepared using general procedure 10: to (S) -1- ((S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propanoyl) pyrrolidine-3-carboxylic acid (5.7g,9.74mmol) and racemic 2- ((1RS,1 'r, 4' RS) -4 '-ethyl- [1, 1' -bis (cyclohexane)](iii) -3-En-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (3.41g,10.71mmol) in dioxane (150mL) with the addition of NaHCO₃(32.5mL, 0.9M aqueous solution, 29.2mmol) and the mixture degassed. Addition of PdCl₂(dppf) (0.356g,0.487mmol) and the mixture heated to reflux. After 3h, the mixture was cooled and then poured onto a mixture of ice water (75mL) and 1M HCl (125 mL). The precipitate was collected by filtration and washed with water (50 mL). The solid was reslurried with ACN (150mL) and then purified by column chromatography (AcOH/THF/DCM/isohexane). The product was reslurried with ACN (200mL) again to provide 4.74g (70%) (S) -1- ((S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (5- ((1RS,1 'r, 4' RS) -4 '-ethyl- [1, 1' -bis (cyclohexane)]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoyl) pyrrolidine-3-carboxylic acid. C₄₁H₅₂N₄O₄LCMS-ESI (m/z) calculation of S: 696.4, respectively; no observed m/z, t_R11.05min (method 10). Chiral analysis (chiral method 1) shows>95% of a single peak.¹H NMR(400MHz,DMSO-d₆)δ12.53(s,1H),8.91(d,J＝0.8Hz,2H),8.78(t,J＝8.2Hz,1H),8.27(d,J＝8.0Hz,2H),7.73(d,J＝3.9Hz,1H),7.44(dd,J＝8.5,2.3Hz,2H),6.92(dd,J＝3.9,0.9Hz,1H),6.51–6.37(m,1H),5.00–4.73(m,1H),3.88–3.83(m,0.5H),3.72–3.66(m,0.5H),3.62–3.36(m,2H),3.17–2.87(m,3H),2.49–2.19(m,3H),2.13–1.69(m,8H),1.36–1.32(m,11H),1.23–0.67(m,12H)。

Compounds 111-114 and 116 were prepared from compound 123 using general procedure 7, using the corresponding amines, followed by general procedure 8.

Compound 115 was prepared from compound 123 using general procedure 7.

(tert-Butoxycarbonyl) -L-tyrosine tert-butyl ester

To a stirred solution of sodium bicarbonate (37.4g,445mmol) in water (1L) was added (S) -tert-butyl 2-amino-3- (4-hydroxyphenyl) propionate (96g,405mmol) and acetone (850 mL). Then, over 2h, a solution of di-tert-butyl dicarbonate (97g,445mmol) in acetone (220mL) was slowly added. After an additional 16h, the mixture was treated with water (1.7L) and then with a slowly added solution of AcOH (30mL) in water (300 mL). The mixture was extracted with EA (1L) and the organics were purified over Na₂SO₄Dried and partially concentrated. The residue was reslurried with isohexane (1L). The precipitate was collected by filtration and washed with isohexane (100mL) to provide 128.4g (94%) (tert-butyloxycarbonyl) -L-tyrosine tert-butyl ester. C₁₈H₂₇NO₅Calculated LCMS-ESI (m/z): 337.2, respectively; found 360.2[ M + Na]⁺，t_R5.93min (method 10).

(S) -tert-butyl 2- ((tert-butoxycarbonyl) amino) -3- (4- (((trifluoromethyl) sulfonyl) oxy) phenyl) propanoate

To a stirred solution of tert-butyl (tert-butoxycarbonyl) -L-tyrosine (145g,429mmol) in DCM (1.5L) was added DIEA (95mL,514mmol) followed by 1,1, 1-trifluoro-N-phenyl-N- ((trifluoromethyl) sulfonyl) methanesulfonamide (7.66g,21.5 mmol). After 16h, additional 1,1, 1-trifluoro-N-phenyl-N- ((trifluoromethyl) sulfonyl) methane sulfonyl was addedAmine (7.66g,21.5 mmol). After an additional 3h, additional 1,1, 1-trifluoro-N-phenyl-N- ((trifluoromethyl) sulfonyl) methanesulfonamide (153.11g,429mmol) was added. After a further 20h, the mixture was washed successively with a solution of citric acid monohydrate (105g,500mmol) in water (1.5L) and then saturated aqueous sodium bicarbonate solution (1L). Subjecting the organic matter to Na₂SO₄Drying and evaporation of the solvent afforded an overweight of tert-butyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (4- (((trifluoromethyl) sulfonyl) oxy) phenyl) propanoate containing phenyltrifluoromethanesulfonimide (phenyltriflimide), and the crude was used in the next step. C₁₉H₂₆F₃NO₇LCMS-ESI (m/z) calculation of S: 469.1, respectively; found 492.2[ M + Na]⁺，t_R2.87min (method 11).

(S) -2- ((tert-butoxycarbonyl) amino) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-) Yl) phenyl) propionic acid tert-butyl ester

A stirred mixture of tert-butyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (4- (((trifluoromethyl) sulfonyl) oxy) phenyl) propanoate (crude from previous step, assumed 429mmol), potassium acetate (126g,1287mmol) and 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolane) (109g,429mmol) in DMSO (750mL) was warmed to 40 ℃ and degassed. Adding PdCl₂dppf (6.28g,8.58mmol), the mixture was degassed again and then heated to 100 ℃. After 2.5h, the mixture was cooled and then Et₂O (3 × 750 mL). The combined organics were washed with water (2x600mL, then 1x1L) and over Na₂The SO was dried and the solvent was evaporated to afford 188.9g (98%) of tert-butyl (S) -2- ((tert-butoxycarbonyl) amino) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propionate as a brown solid, which was used directly in the next step. C₂₄H₃₈BNO₆Calculated LCMS-ESI (m/z): 447.3 of the Chinese patent application; found value of 470.3M+Na]⁺，t_R2.99min (method 11).¹H NMR(400MHz,DMSO-d₆)δ7.63–7.55(m,2H),7.25(d,J＝7.8Hz,2H),7.15(d,J＝8.1Hz,1H),4.01(ddd,J＝9.7,8.1,5.5Hz,1H),3.05–2.78(m,2H),1.36(s,9H),1.34(s,9H),1.29(s,12H)。

(S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- ((tert-butoxycarbonyl) amino) propionic acid tert-butyl ester

A stirred solution of sodium carbonate decahydrate (242g,844mmol) in water (0.9L) was treated with dioxane (1.8L) containing (S) -tert-butyl 2- ((tert-butoxycarbonyl) amino) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propionate (188.9g,422mmol) and 5-bromo-2-iodopyrimidine (120g,422mmol), the resulting mixture was warmed to 40 deg.C and purified by filtration over N-hexane₂Degassing was performed by bubbling. Adding PdCl₂dppf (6.18g,8.44mmol) and the mixture was heated at gentle reflux for 6 h. The mixture was cooled to 40 ℃ and then treated with water (1.8L) and cooled to 20 ℃. The precipitate was collected by filtration. The reaction vessel was rinsed with acetone (250mL) and the solution was treated with water (300mL) to provide a second crop of precipitate, which was combined with most of the material. The precipitated solid was washed successively with water (2x500mL) and isohexane (2x500 mL). Then, it was slurried in EtOH (550mL) and heated to reflux for 30 min. The suspension was cooled to 20 ℃ and the precipitate was collected by filtration and washed with EtOH (200mL) to provide 146.8g (73%) of tert-butyl (S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- ((tert-butoxycarbonyl) amino) propionate as a beige fine powder. C₂₂H₂₈BrN₃O₄Calculated LCMS-ESI (m/z): 477.1, respectively; found 500.1[ M + Na]⁺，t_R2.18min (method 6).¹H NMR(400MHz,DMSO-d₆)δ9.00(s,2H),8.25–8.12(m,2H),7.34(d,J＝8.2Hz,2H),7.18(d,J＝8.0Hz,1H)4.05-3.94(m,1H),3.06–2.73(m,2H),1.28(m,18H)。

(S) -2-amino-3- (4- (5-bromopyrimidin-2-yl) benzeneYl) propionic acid tert-butyl ester (INT-79)

To a stirred solution of (S) -tert-butyl 3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- ((tert-butoxycarbonyl) amino) propionate (146.77g,307mmol) in DCM (500mL) was added hydrochloric acid (614mL, 5-6N IPA solution,. about.3.1 mol). After 1h, the product was collected by filtration, washed with IPA (100mL) then ether (2x100mL) to afford 122.3g (96%) (S) -2-amino-3- (4- (5-bromopyrimidin-2-yl) phenyl) propionic acid tert-butyl ester (hydrochloride salt). C₁₇H₂₀BrN₃O₂LCMS-ESI (m/z) calculated for HCl: 377.1; found 378.1[ M + H]⁺，t_R2.99min (method 10).¹H NMR(400MHz,DMSO-d₆)δ9.09(s,2H),8.61(br s,3H),8.39–8.25(m,2H),7.57–7.37(m,2H),4.21(br s,1H),3.42–3.19(m,1H),3.09(dd,J＝14.0,8.4Hz,1H),1.31(s,9H)。

The product was dissolved in CHCl₃In MeOH and washed with saturated aqueous sodium bicarbonate to afford the free base.

Compounds 117 and 118 were prepared from (S) -tert-butyl 2-amino-3- (4- (5-bromopyrimidin-2-yl) phenyl) propionate INT-79 using general procedures 7, 8, 7, 4, and 10, in that order.

Compound 119 was prepared from INT-17 using general procedure 10, then general procedure 8.

8-cyclohexyl-1, 4-dioxaspiro [4.5]]Decane

To 4- (1, 4-dioxaspiro [4.5]]A stirred solution of dec-8-yl cyclohexanone (1g,4.20mmol) in diethylene glycol (15mL) was added hydrazine (3.92mL,62.9mmol) and potassium hydroxide (2.354g,42.0 mmol). The reaction mixture was heated to 160 ℃ for 16h and then to 210 ℃ for 1 h. The reaction mixture was cooled to room temperature and diluted with NH₄Cl solutionSolution (120mL) was quenched. The aqueous layer was extracted with EA (3 × 80 mL). The combined organic layers were dried over MgSO₄Dry, filter and evaporate the solvent. The crude product was purified by column chromatography (EA/isohexane) to give 728mg (77%) of 8-cyclohexyl-1, 4-dioxaspiro [4.5] as a white solid]Decane.

[1, 1' -bis (cyclohexyl)]-4-ketones

To a stirred solution of 8-cyclohexyl-1, 4-dioxaspiro [4.5] decane (724mg,3.23mmol) in a mixture of acetone (4mL) and water (2mL) was added trifluoroacetic acid (3mL,38.9 mmol). The reaction mixture was stirred at rt for 4 h. The solvent was evaporated. The crude product was purified by column chromatography (EA/isohexane) to give 582mg (100%) of [1, 1' -bis (cyclohexyl) ] -4-one as a colorless oil.

[1, 1' -bis (cyclohexyl)]-3-en-4-yl trifluoromethanesulfonate

At-78 ℃ to [1, 1' -bis (cyclohexyl)]A stirred solution of-4-one (622mg,3.45mmol) in THF (10mL) was added 1,1, 1-trifluoro-N-phenyl-N- ((trifluoromethyl) sulfonyl) methanesulfonamide (1233mg,3.45mmol) and lithium bis (trimethylsilyl) amide (3.8mL, 1M in THF, 3.80 mmol). The solution was stirred at-78 ℃ for 2h, then at room temperature for 72 h. Saturated NaHCO₃Solution (20mL) was added to the reaction mixture and the aqueous layer was extracted with EA (3 × 30 mL). The organic layer was purified over MgSO₄Dried and the solvent evaporated. The crude product was purified by column chromatography (EA/isohexane) to give 519mg (48%) of [1, 1' -bis (cyclohexane) as a colorless oil]-3-en-4-yl trifluoromethanesulfonate.

2- ([1, 1' -bis (cyclohexyl)]-3-en-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan

Mixing [1, 1' -di (cyclohexyl)]A stirred solution of-3-en-4-yl trifluoromethanesulfonate (519mg,1.66mmol), 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (422mg,1.66mmol) and potassium acetate (489mg,4.98mmol) in dioxane (10mL) was heated to 40 ℃ and degassed. Addition of PdCl₂(dppf) (24.32mg,0.033mmol) and the mixture degassed again and then heated to 90 ℃ for 3 h. The reaction mixture was partitioned between EA (20mL) and water (20 mL). The aqueous layer was extracted once more with EA (20 mL). The combined organic layers were dried over MgSO4, filtered and the solvent was evaporated. The crude product was purified by column chromatography (EA/isohexane) to give 100mg (20%) of 2- ([1, 1' -bis (cyclohexane) as a colorless oil]-3-en-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan. The molecular formula is as follows: c₁₈H₃₁BO₂。¹H NMR(400MHz,DMSO-d₆)δ5.70(m,1H),1.43–1.27(m,2H),1.32–1.27(m,1H),1.08–0.81(m,7H),0.53–0.12(m,20H)。

Compound 120 was prepared from (S) -tert-butyl 3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionate INT-17 using general procedure 8 followed by general procedure 10 using 2- ([1, 1' -di (cyclohexyl) ] -3-en-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan.

8- (4-Propylphenyl) -1, 4-dioxaspiro [4.5]]Decan-8-ol

To 1, 4-dioxaspiro [4.5]]A stirred solution of decan-8-one (1g,6.40mmol) in THF (10mL) was added (4-propylphenyl) magnesium bromide (23mL, 0.5M in THF, 11.50 mmol). The reaction was heated to reflux for 5 h. The mixture was allowed to cool and then saturated NH₄Quenched in aqueous Cl and extracted with EA (2 × 40 mL). The combined organic extracts were dried over MgSO₄The solvent was dried and evaporated. Column chromatography (EA/isohexane) gave 1.38g(77%) 8- (4-Propylphenyl) -1, 4-dioxaspiro [4.5] as a white solid]Decan-8-ol.

8- (4-Propylphenyl) -1, 4-dioxaspiro [4.5]]Dec-7-ene

To a stirred solution of 8- (4-propylphenyl) -1, 4-dioxaspiro [4.5] decan-8-ol (1.38g,4.99mmol) in THF (24mL) was added Burgess reagent (2.38g,9.99 mmol). The mixture was heated at 50 ℃ for 3 h. The solvent was evaporated and the reaction mixture was partitioned between water (30mL) and DCM (50 mL). The solvent was evaporated and the residue was purified by column chromatography (EA/isohexane) to give 1.21g (93%) 8- (4-propylphenyl) -1, 4-dioxaspiro [4.5] dec-7-ene as a colorless oil (1.21g,4.64mmol, 93% yield).

8- (4-Propylphenyl) -1, 4-dioxaspiro [4.5]]Decane

To a stirred solution of 8- (4-propylphenyl) -1, 4-dioxaspiro [4.5] dec-7-ene (1.208g,4.68mmol) in EtOH (30mL) was added palladium on carbon (10% Johnson and Matthey paste formulation 39,200mg) and the mixture was hydrogenated at 5bar for 4 h. The mixture was filtered through celite and the solvent was evaporated to give 1.18g (96%) of 8- (4-propylphenyl) -1, 4-dioxaspiro [4.5] decane.

4- (4-propylphenyl) cyclohexanone

To a stirred solution of 8- (4-propylphenyl) -1, 4-dioxaspiro [4.5] decane (1.12g,4.30mmol) in acetone (6mL) and water (3mL) was added TFA (4.5mL,58.4 mmol). After 16h, the solvent was evaporated and the residue was purified by column chromatography (EA/isohexane) to afford the product and recovered starting material. The recovered starting material was re-subjected (re-submitted) to the above reaction conditions and the products were combined to provide 678mg (69%) of 4- (4-propylphenyl) cyclohexanone.

4 '-propyl-1, 2,3, 6-tetrahydro- [1, 1' -biphenyl]-4-yl trifluoromethanesulfonate

To a stirred solution of diisopropylamine (0.53mL,3.76mmol) in THF (15mL) at-20 deg.C was added butyllithium (1.5mL, 2.5M in hexane, 3.76 mmol). The mixture was cooled to-78 ℃ whereupon a solution of 4- (4-propylphenyl) cyclohexanone (678mg,3.13mmol) in THF (15mL) was slowly added followed by 1,1, 1-trifluoro-N-phenyl-N- ((trifluoromethyl) sulfonyl) methanesulfonamide (1176mg,3.29 mmol). After 1h, the mixture was allowed to warm to room temperature. The mixture is washed with NaHCO₃Quenched (40mL) and extracted with EA (3 × 50 mL). The combined organic extracts were dried over MgSO₄Dried and the solvent evaporated. Column chromatography (EA/isohexane) gave 506mg (46%) 4 '-propyl-1, 2,3, 6-tetrahydro- [1, 1' -biphenyl%]-4-yl trifluoromethanesulfonate.

4,4,5, 5-tetramethyl-2- (4 '-propyl-1, 2,3, 6-tetrahydro- [1, 1' -biphenylyl) benzene]-4-yl) -1,3, 2-dioxo Heterocyclopentylborane

To 4 '-propyl-1, 2,3, 6-tetrahydro- [1, 1' -biphenyl]A stirred solution of (E) -4-yl trifluoromethanesulfonate (506mg,1.452mmol) and 4,4,4 ', 4 ', 5,5,5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolan) (369mg,1.452mmol) in dioxane (8mL) was added potassium acetate (428mg,4.36 mmol). The mixture was heated to 40 ℃ and degassed, then with PdCl₂(dppf) (21mg,0.029mmol) and heated to 90 ℃ for 4 h. The mixture was allowed to cool, then diluted with water (20mL) and extracted with EA (4 × 20 mL). Will be provided withThe combined organic extracts were over MgSO₄The solvent was dried and evaporated. Column chromatography gave 146mg (31%) of 4,4,5, 5-tetramethyl-2- (4 '-propyl-1, 2,3, 6-tetrahydro- [1, 1' -biphenylyl ] amine]-4-yl) -1,3, 2-dioxaborolan. The molecular formula is as follows: c₂₁H₃₁BO₂。¹H NMR (400MHz, chloroform-d) δ 7.17-7.10 (m,4H), 6.76-6.57 (m,1H), 2.87-2.68 (m,1H), 2.61-2.54 (m,2H), 2.47-2.16 (m,3H),1.96(ddd, J ═ 10.2,5.2,2.7Hz,1H), 1.77-1.60 (m,3H), 1.30-1.24 (m,13H),0.96(t, J ═ 7.3Hz, 3H).

Compound 121 was prepared from (S) -tert-butyl 3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionate INT-17 using general procedure 8 followed by general procedure 10 using 4,4,5, 5-tetramethyl-2- (4 '-propyl-1, 2,3, 6-tetrahydro- [1, 1' -biphenyl ] -4-yl) -1,3, 2-dioxaborolan.

Compound 122 was prepared from (S) -tert-butyl 3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionate INT-17 using general procedure 8 followed by general procedure 10 using 2- (4 ', 4 ' -dimethyl- [1,1 ' -di (cyclohexyl) ] -3-en-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan.

(S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (5- ((1RS,1 ' r,4 ' RS) -4 ' -methyl- [1, 1' -bis (cyclohexyl)]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoic acid (compound 123)

Prepared using general procedure 10: to (S) -3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionic acid (6.13g,12.55mmol) and racemic 4,4,5, 5-tetramethyl-2- ((1RS,1 'r, 4' RS) -4 '-methyl- [1, 1' -bis (cyclohexyl)]A stirred solution of (E) -3-en-4-yl) -1,3, 2-dioxaborolan (4.20g,13.81mmol) in dioxane (100mL) was added NaHCO₃(3.16g,37.7mmol) in water (50 mL). The mixture was warmed to 40 ℃ and then degassed, and treated with PdCl₂dppf(0.276g,0.377mmol) of the raw materials. The mixture was heated at gentle reflux. After 3h, the mixture was cooled, diluted with water (100mL) and DCM (200mL), and then acidified with AcOH. The layers were separated and the aqueous layer was further extracted with DCM (2 × 100 mL). The solvent was evaporated and the residue was purified by column chromatography (AcOH/EA/THF/DCM/isohexane). The product was reslurried with MeOH to afford 4.57g (62%) (S) -2- (5- (tert-butyl) thiophene-2-carboxamido) -3- (4- (5- ((1RS,1 'r, 4' RS) -4 '-methyl- [1, 1' -bis (cyclohexane)]-3-en-4-yl) pyrimidin-2-yl) phenyl) propanoic acid. C₃₅H₄₃N₃O₃LCMS-ESI (m/z) calculation of S: 585.3, respectively; no observed m/z, t_R11.12min (method 10). Chiral analysis (chiral method 1) shows>95% of a single peak.¹H NMR(400MHz,DMSO-d₆)δ12.84(s,1H),8.91(s,2H),8.64(d,J＝8.3Hz,1H),8.27(d,J＝8.3Hz,2H),7.63(d,J＝3.9Hz,1H),7.43(d,J＝8.4Hz,2H),6.92(d,J＝3.9Hz,1H),6.44(s,1H),4.80–4.42(m,1H),3.25(dd,J＝13.9,4.5Hz,1H),3.10(dd,J＝13.9,10.5Hz,1H),2.55–2.51(m,2H),2.41–2.26(m,2H),2.00–1.92(m,2H),1.85–1.62(m,4H),1.39–1.28(m,11H),1.16–0.70(m,8H)。

Compound 124 was prepared from (S) -tert-butyl 3- (4- (5-bromopyrimidin-2-yl) phenyl) -2- (5- (tert-butyl) thiophene-2-carboxamido) propionate R-INT-17 using general procedures 8, 7, 4 and 4,4,5, 5-tetramethyl-2- (4 '-propyl-1, 2,3, 6-tetrahydro- [1, 1' -biphenyl ] -4-yl) -1,3, 2-dioxaborolan in step 10, sequentially.

Compound 125 was prepared from compound 76 using general procedure 18.

TABLE 1

Representative Compounds

Biological assay

Measurement procedure

GLP-1PAM converted cAMP assay: dose response of peptide ligands in the presence of a fixed concentration of compound.

GLP-1R expressing CRE-bla CHO-K1 cell line was purchased from Invitrogen. Cells were seeded at 5000 cells/well/20 μ L growth medium (DMEM-high glucose, 10% dialyzed FBS,0.1mM NEAA,25mM Hepes,100U/mL penicillin/100 μ g/mL streptomycin, 5 μ g/mL blasticidin, 600 μ g/mL hygromycin) in white 384 well flat-bottom plates at 37 ℃ at 5%CO₂And (4) incubating for 18 h. The growth medium was replaced with 12. mu.L of assay buffer (Hanks Balanced salt solution, 10mM Hepes, 0.1% BSA, pH 7.4). A5 × peptide dose response curve (12-point) was generated in assay buffer containing 1.5mM IBMX, 12.5% DMSO, and 50 μ M compound. The peptide ligand is GLP-1 (9-36). 5 × peptide dose response and compound mix (3 μ L) were added and cells were incubated at 37 deg.C for 30 min. Direct detection of cAMP was performed using the DiscoverX HitHunter cAMP kit according to the manufacturer's instructions and luminescence was read using a SpectraMax M5 plate reader. Luminescence was analyzed by nonlinear regression to determine EC₅₀And Emax. GLP-1(7-36) dose responses were included to determine maximal efficacy.

₂₀EC GLP-1(9-36) PAM cAMP assay: agents of compounds in the presence of a fixed concentration of GLP-1(9-36) And (4) responding by quantity.

GLP-1R CRE-bla CHO-K1 cells cultured in growth medium (DMEM-high glucose, 10% dialyzed FBS,0.1mM NEAA,25mM Hepes,100U/mL penicillin/100. mu.g/mL streptomycin, 5. mu.g/mL blasticidin, 600. mu.g/mL hygromycin) were trypsinized and suspended at 5000 cells/well in 12. mu.L assay buffer in a white 384 well flat plate (Hanks Balanced salt solution, 10mM Hepes, 0.1% BSA, pH 7.4). A 5x compound dose response curve (12-point) was generated in assay buffer containing 1.5mM IBMX, 4% DMSO. GLP-1(9-36) was diluted to 4.2. mu.M in assay buffer containing 1.5mM IBMX and 4% DMSO. 5X Compound dose response (3. mu.L) was added followed by 0.5. mu.L GLP-1(9-36) and cells were incubated at 37 ℃ for 30 min. Direct detection of cAMP was performed using the DiscoverX HitHunter cAMP kit according to the manufacturer's instructions and luminescence was read using a SpectraMax M5 plate reader. Luminescence was converted to total cAMP using cAMP standard curve and data was analyzed by non-linear regression to determine EC₅₀And Emax.

Peptide sequences

GLP-1(7-36)：HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH₂。GLP-1(9-36)：EGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH₂. GLP-1(7-36) was purchased from GenScript. GLP-1(9-36) was purchased from Biopeptide Co., Inc。

GLP-1 Activity

Activity data for representative GLP-1 modulators are shown in table 2. EC (EC)₂₀The GLP-1(9-36) PAM activity range is expressed as follows: + denotes an activity<0.5. mu.M, + represents an activity of 0.5 to 2.5. mu.M, + ++ represents an activity of 2.5 to 5. mu.M, and +++ represents an activity of 5 to 10. mu.M.

TABLE 2

GLP-1 Activity

The various embodiments described above can be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the application data sheet, are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary, to employ concepts of the various patents, applications and publications to provide yet further embodiments. These and other changes can be made to the embodiments in light of the above detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

wherein

b is phenyl or heterocycle;

each R is₁Independently is H or C_1-4An alkyl group;

each R is₄₀Independently H, R₇Can be substituted by R₇Optionally (mono or poly) substituted alkyl, or R₄₀And R₁Together with the N atom to which they are attached form a group which may be substituted by R₇Optionally (mono or poly) substituted 3-to 7-membered heterocyclic ringA group;

Each L₃Independently absent, -O-or-N (R)₁)-；

Each m is independently 0,1, 2,3,4,5, or 6;

each n is independently 0 or 1 or 2;

p is 0,1, 2 or 3;

q is 0,1, 2 or 3;

each r is independently 2,3 or 4; and

each s is independently 1,2,3 or 4.

2. The compound of claim 1, having the structure:

3. the compound of claim 1, having the structure:

4. the compound of claim 1, having the structure:

5. the compound of claim 1, having the structure:

6. the compound of claim 1, having the structure:

7. a pharmaceutical composition comprising a compound according to any one of claims 1 to 6 and at least one pharmaceutically acceptable carrier, diluent or excipient.

8. A pharmaceutical combination comprising a compound of any one of claims 1 to 6 and a second drug.

9. A method of activating, enhancing, modulating or agonizing a glucagon-like peptide 1 receptor comprising contacting the receptor with an effective amount of a compound of any one of claims 1 to 6 or a pharmaceutical composition of claim 7 or a pharmaceutical combination of claim 8.

10. A method of treating a malignant condition in a patient in medical need of activation, enhancement, modulation or agonism of a glucagon-like peptide 1 receptor comprising administering to the patient an effective amount of a compound of any one of claims 1 to 6 at a frequency and for a duration sufficient to provide a beneficial effect to the patient.