Inhibition of alpha v beta 6 integrins

文档序号：554780 发布日期：2021-05-14 浏览：21次中文

阅读说明：本技术 抑制αvβ6整联蛋白 (Inhibition of alpha v beta 6 integrins ) 是由 B·A·哈里森 J·E·道林 A·I·格拉休托 M·G·伯萨维奇 D·M·特罗亚斯特 B· 于 2019-08-29 设计创作，主要内容包括：公开了αvβ6整联蛋白的小分子抑制剂以及使用所述小分子抑制剂治疗多种疾病和病状的方法。申请人已经发现了新颖的αvβ6整联蛋白抑制剂化合物并评价了此类化合物的代表性实例对于生化效力(例如,使用实例35的测定评价对化合物的αvβ6结合进行的荧光偏振测定)和体外渗透性特性(例如,使用实例36的测定评价MDCK渗透性)两者而言的占有性、性能和有用性。(Small molecule inhibitors of the α ν β 6 integrin are disclosed, as well as methods of using the small molecule inhibitors for the treatment of various diseases and conditions. Applicants have discovered novel α v β 6 integrin inhibitor compounds and evaluated representative examples of such compounds for their occupations, performance, and usefulness for both biochemical efficacy (e.g., using the assay of example 35 to evaluate fluorescence polarization assays for α v β 6 binding of compounds) and in vitro permeability characteristics (e.g., using the assay of example 36 to evaluate MDCK permeability).)

1. A compound of formula (I):

A-B-C (I)

wherein:

a isWherein R is₁All examples of (a) are H;

b is selected from the group consisting of:

q is 0, 1, 2 or 3; and p is 0, 1 or 2;

c isWherein n is 0; and is

R₂Is composed ofAnd R is₂N in (1) is 0 or 1;

R₄independently selected from alkyl, -C (F)₂)CH₃Cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkyl, -alkylene-O-cycloalkyl, and-alkylene-O-alkylene-cycloalkyl;

R₅is F;

R_ais H; and is

The absolute configuration at any stereocenter is R, S or mixtures thereof;

Or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein B is

3. The compound of claim 2, wherein q is 2.

4. The compound of claim 3, wherein A is

5. The compound of claim 4, wherein R₄Is a cycloalkyl group.

6. The compound of claim 4, wherein R₄Is a heterocycloalkyl group.

7. The compound of claim 4, wherein R₄is-O-alkylene-cycloalkyl.

8. The compound of claim 4, wherein R₄Is selected from

9. The compound of claim 4, wherein R₄Is selected from

10. The compound of claim 4, wherein R₂Is composed ofWherein R is₂N in (1).

11. The compound of claim 10, wherein R₄Is composed of

12. The compound of claim 10, wherein R₄Is composed of

13The compound of claim 10, wherein R₄Is composed of

14. The compound of claim 10, wherein R₄Is composed of

15. The compound of claim 1, having the formula:

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1, having the formula:

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1, having the formula:

Or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1, having the formula:

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1, having the formula:

or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition formulated for oral delivery of an α v β 6 integrin inhibitor, the composition comprising the α v β 6 integrin inhibitor compound of claim 1, or a pharmaceutically acceptable salt thereof, as an active compound and a pharmaceutically acceptable carrier formulated for oral therapeutic administration of the α v β 6 integrin inhibitor compound.

21. A compound of formula (I):

A-B-C (I)

wherein:

a isWherein R is₁All examples of (a) are H;

b is selected from the group consisting of:

q is 0, 1, 2 or 3; and p is 0, 1 or 2;

c isWherein n is 0; and is

R₂Is composed ofAnd R is₂N in (1) is 0;

R₄independently selected from alkyl, -C (F)₂)CH₃Cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkyl, -alkylene-O-cycloalkyl, and-alkylene-O-alkylene-cycloalkyl;

R_ais H; and is

The absolute configuration at any stereocenter is R, S or mixtures thereof;

or a pharmaceutically acceptable salt thereof.

22. The compound of claim 21, wherein:

a is

B isq is 2;

c isWherein n is 0; and is

R₄Is a heterocycloalkyl group;

R_ais H; and is

The absolute configuration at any stereocenter is R, S or mixtures thereof;

or a pharmaceutically acceptable salt thereof.

23. The compound of claim 22, having the formula:

or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition formulated for oral delivery of an α v β 6 integrin inhibitor, the composition comprising the α v β 6 integrin inhibitor compound of claim 21 as an active compound and a pharmaceutically acceptable carrier formulated for oral therapeutic administration of the α v β 6 integrin inhibitor compound.

25. A compound of formula (I):

A-B-C (I)

wherein:

a isWherein R is₁All examples of (a) are H;

b is selected from the group consisting of:

q is 0, 1, 2 or 3; and p is 0, 1 or 2;

c isWherein n is 0; and is

R₂Is composed ofAnd R is₂M in (1) is 0 or 1;

R₄independently selected from alkyl, -C (F)₂)CH₃Cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkyl, -alkylene-O-cycloalkyl, and-alkylene-O-alkylene-cycloalkyl;

R₅Is F;

R_ais H; and is

The absolute configuration at any stereocenter is R, S or mixtures thereof;

or a pharmaceutically acceptable salt thereof.

26. The compound of claim 25, wherein:

b isq is 2;

c isWherein n is 0, and

R₄is cycloalkyl;

R_ais H; and is

The absolute configuration at any stereocenter is R, S or mixtures thereof;

or a pharmaceutically acceptable salt thereof.

27. The compound of claim 25, having the formula:

or a pharmaceutically acceptable salt thereof.

28. The compound of claim 25, having the formula:

or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition formulated for oral delivery of an α v β 6 integrin inhibitor, the composition comprising the α v β 6 integrin inhibitor compound of claim 25 as an active compound and a pharmaceutically acceptable carrier formulated for oral therapeutic administration of the α v β 6 integrin inhibitor compound.

30. The compound of claim 1, wherein the compound is selected from the group consisting of:

Technical Field

The present disclosure relates to novel chemical compounds and methods for inhibiting α v β 6 integrins.

Background

The heterodimeric integrin receptor family modulates cell shape and cell adhesion to the extracellular matrix in response to external and intrinsic cues.

Integrin signaling controls cell survival, cell cycle progression, cell differentiation, and cell migration.

Integrin receptors can signal cells only bi-directionally ("inside-out" and "outside-in"). Thus, they mediate cell migration by transmitting forces from the extracellular matrix to the cytoskeleton, and modulate cytoskeletal tissue to achieve the shape changes required during cell migration. RGD binding integrins can bind to and activate TGF- β and have recently been implicated in fibrotic diseases.

Integrins are expressed on the surface of most human cells. Its pathology results in a wide variety of human diseases including platelet disorders, atherosclerosis, cancer, osteoporosis, fibrosis, diabetic neuropathy of the kidney, macular degeneration, and various autoimmune and chronic inflammatory diseases.

The role of integrins as Drug targets has long been recognized, and a total of six injectable integrin inhibitors have been approved by the united states Food and Drug Administration for the treatment of various therapeutic indications: inflammatory bowel diseaseMultiple sclerosisPsoriasis vulgarisAnd acute coronary syndromeOf the 24 known integrin heterodimers, at least half are associated with inflammation, fibrosis, oncology, and vascular disease.

A new class of integrin inhibitors is needed. Oral bioavailing integrin inhibitors clearly lack therapeutic success. Thus, there remains a need for small molecule integrin inhibitors of α v β 6 that are suitable for oral administration. For small molecule delivery, the oral route of administration is preferred because it allows administration of a wide range of doses, allows convenient patient self-administration, is suitable for varying dosage regimens, and does not require specialized equipment. Therefore, it is important to identify α ν β 6 integrin inhibitor compounds that are not only effective against the intended biological target, but also demonstrate other properties related to the ability of the compound to absorb in the body in a therapeutically effective manner (e.g., following oral administration). For example, an α v β 6 integrin inhibitor compound can be selected based on both potency and performance based on in vitro permeability assays (e.g., assessing the ability of a compound to traverse the Madin-Darby Canine Kidney (MDCK) cell layer from the apical side to the basolateral side (a- > B)).

Disclosure of Invention

Applicants have discovered novelIntegrin inhibitor compounds and representative examples of such compounds were evaluated for their occupations, performance and usefulness for both biochemical efficacy (e.g., fluorescence polarization assay for α v β 6 binding of compounds evaluated using the assay of example 35) and in vitro permeability characteristics (e.g., MDCK permeability evaluated using the assay of example 36).

In certain embodiments, the invention relates to compounds of formula I:

A-B-C (I)

wherein:

a is

B is alkylene, -alkylene- (heterocyclyl) -alkylene-, -cycloalkylene, -alkylene-O-, -cycloalkylene-O-or-alkylene-O-alkylene-;

c is

R₁Independently H, alkyl, halide, alkoxy, CF₃OH, alkylene-OH, NO₂-N (H) R or NH₂；

R₂Is composed of

R₃And R₅Independently selected from H, CN, halide, CF₃、C(H)F₂、C(F)H₂Alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxy and alkoxy;

R₄independently selected from alkyl, -C (F)₂)CH₃Cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -O-cycloalkyl, -O-alkyl, -alkylene-O-cycloalkyl and-alkylene-O-alkylene-cycloalkyl;

R_ais H, (C)₁-C₆) Alkyl, - (C)₁-C₆) alkylene-O- (C)₁-C₆) Alkyl or- (C)₁-C₆) alkylene-O-C (O) O (C)₁-C₆) An alkyl group;

n is independently 0, 1, 2, 3 or 4;

m is 0, 1, 2 or 3; and is

The absolute configuration at any stereocenter is R, S or mixtures thereof;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the invention relates to compounds of formula I:

A-B-C (I)

wherein:

a is

B is selected from the group consisting of:

wherein

q is 0, 1, 2 or 3; and p is 0, 1 or 2;

C is

R₁All examples of (a) are H;

R₂is composed of

R₃H, halide, Me, OMe or Ph.

R₄Independently selected from alkyl, -C (F)₂)CH₃Cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -O-cycloalkyl, -O-alkyl, -alkylene-O-cycloalkyl and-alkylene-O-alkylene-cycloalkyl;

R₅is F;

R_ais H;

n is independently 0 or 1;

m is 0 or 1; and is

The absolute configuration at any stereocenter is R, S or mixtures thereof;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the invention relates to compounds of formula I:

A-B-C(I)

wherein:

a is

B is selected from the group consisting of:

wherein

q is 0, 1, 2 or 3; and p is 0, 1 or 2;

c is

R₁All examples of (a) are H;

R₂is composed of

R₃H, halide, Me, OMe or Ph;

R₅is F;

R_ais H;

n is 0 or 1;

m is 0 or 1; and is

The absolute configuration at any stereocenter is R, S or mixtures thereof;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention relates to a method of treating a disease or condition selected from the group consisting of: idiopathic pulmonary fibrosis, diabetic nephropathy, focal segmental glomerulosclerosis, chronic kidney disease, non-alcoholic steatohepatitis, primary biliary cholangitis, primary sclerosing cholangitis, a solid tumor, a hematologic tumor, organ transplantation, Alport syndrome, interstitial lung disease, radiation-induced fibrosis, bleomycin (bleomycin) -induced fibrosis, asbestos-induced fibrosis, influenza-induced fibrosis, coagulation-induced fibrosis, vascular injury-induced fibrosis, aortic stenosis, and cardiac fibrosis, the method comprising the steps of: administering to a subject in need thereof a therapeutically effective amount of any one of the compounds described herein.

Drawings

Figure 1 is a table summarizing the inhibition of α v β 6 integrin by exemplary compounds as measured in fluorescence polarization assays.

Figure 2 is a table summarizing the inhibition of α v β 6 integrin by exemplary compounds as measured in fluorescence polarization assays.

Fig. 3 is a table summarizing the permeability properties of the exemplary compounds from fig. 1 measured in the MDCK in vitro assay of example 36.

Fig. 4 is a table summarizing the permeability properties of the exemplary compounds from fig. 2 measured in the MDCK in vitro assay of example 36.

Detailed Description

In certain embodiments, the invention relates to compounds that inhibit α v β 6 integrin. In certain embodiments, the compound is selective for α v β 6 integrin.

The compounds will be useful for the treatment of idiopathic pulmonary fibrosis, diabetic nephropathy, focal segmental glomerulosclerosis, chronic kidney disease, non-alcoholic steatohepatitis, primary biliary cholangitis, primary sclerosing cholangitis, a solid tumor, a hematologic tumor, organ transplantation, Alport syndrome, interstitial lung disease, radiation-induced fibrosis, bleomycin-induced fibrosis, asbestos-induced fibrosis, influenza-induced fibrosis, coagulation-induced fibrosis, vascular injury-induced fibrosis, aortic stenosis, or cardiac fibrosis.

Definition of

For convenience, before further description of the present invention, certain terms used in the specification, examples, and appended claims are collected here. These definitions should be understood in light of the remainder of this disclosure and as understood by those skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

To facilitate an understanding of the invention, certain terms and phrases are defined below and throughout this specification.

The articles "a" and "an" as used herein refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

As used herein in the specification, the phrase "and/or" should be understood to mean "either or both" of the elements so combined, i.e., the elements exist together in some cases and separately in other cases. Multiple elements listed with "and/or" should be understood in the same way, i.e., "one or more" of the elements so combined. Other elements may optionally be present in addition to the elements specifically identified by the "and/or" clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, when used in conjunction with open language such as "including", references to "a and/or B" may: in one embodiment, only a (optionally including elements other than B); in another embodiment, only B (optionally including elements other than a); in yet another embodiment, refers to both a and B (optionally including other elements); and so on.

As used herein in the specification and claims, "or" should be understood to have the same meaning as "and/or" as defined above. For example, when items in a list are separated, "or" and/or "should be interpreted as inclusive, i.e., including at least one element of a plurality or list of elements, but also including more than one element, and optionally additional unlisted items. It is only expressly intended that the opposite term, such as "only one of … …" or "exactly one of … …" or "consisting of … …" when used in a claim, shall mean that there is exactly one element in a plurality or list of elements. In general, the term "or" as used herein should be interpreted merely as indicating an exclusive substitute (i.e., "one or the other, rather than two") when preceded by an exclusive term such as "either," one of … …, "" only one of … …, "or" exactly one of … …. "consisting essentially of … …" when used in the claims shall have the ordinary meaning as used in the patent law.

As used in this specification and claims, the phrase "at least one" in reference to a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each element specifically listed within the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, "at least one of a and B" (or, equivalently, "at least one of a or B," or, equivalently "at least one of a and/or B") may: in one embodiment refers to at least one, optionally comprising more than one, a, with no B present (and optionally comprising elements other than B); in another embodiment to at least one B, optionally comprising more than one B, with no a present (and optionally comprising elements other than a); in yet another embodiment to at least one a, optionally comprising more than one a, and at least one B, optionally comprising more than one B (and optionally including other elements); and so on.

It will also be understood that, unless explicitly stated to the contrary, in any methods claimed herein that include more than one step or action, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are recited.

In the claims, as well as in the specification above, all transitional phrases such as "comprising," including, "" carrying, "" having, "" containing, "" involving, "" containing, "" consisting of … … and the like are to be understood to be open-ended, i.e., to mean including but not limited to. As described in united states patent office patent examination manual section 2111.03, only the transition phrases "consisting of … …" and "consisting essentially of … …" should be closed or semi-closed transition phrases, respectively.

Certain compounds contained in the compositions of the present invention may exist in specific geometric or stereoisomeric forms. In addition, the polymers of the present invention may also be optically active. The present invention encompasses all such compounds falling within the scope of the present invention, including cis and trans isomers, R-and S-enantiomers, diastereomers, (D) -isomers, (L) -isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in a substituent (e.g., alkyl). All such isomers and mixtures thereof are intended to be included in the present invention.

For example, if a particular enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, in the case of molecules containing basic functions (such as amino) or acidic functions (such as carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by fractional crystallization or chromatographic methods well known in the art to attribute the diastereomers thus formed and subsequent recovery of the pure enantiomers.

The structures described herein are also meant to include compounds that differ only by the presence of one or more isotopically enriched atoms. For example, by replacement of hydrogen or tritium by deuterium or tritium¹³C-or¹⁴Compounds produced by replacing carbon with C-rich carbon are within the scope of the invention.

As used herein, the term "prodrug" encompasses compounds that are converted to therapeutically active agents under physiological conditions. A common method for making prodrugs is to include selected moieties that hydrolyze under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by enzymatic activity of the host animal.

As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or part of the body to another organ or another part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, non-injurious to the patient, and substantially pyrogen-free. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc powder; (8) excipients, such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution (Ringer's solution); (19) ethanol; (20) a phosphate buffer solution; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, the pharmaceutical composition of the present invention is pyrogen-free, i.e., does not induce a significant temperature increase, when administered to a patient.

The term "pharmaceutically acceptable salts" refers to the relatively non-toxic inorganic and organic acid addition salts of one or more compounds. These salts may be prepared in situ during the final isolation and purification of the compound or compounds, or by separately reacting the purified compound or compounds in their free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, metasilicate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, and lauryl sulfonate, and the like. (see, e.g., Berge et al, (1977) "Pharmaceutical Salts", journal of Pharmaceutical sciences (J.pharm.Sci.66:1-19.)

In other cases, compounds useful in the methods of the invention may contain one or more acidic functional groups and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic inorganic and organic base addition salts of one or more compounds. These salts can likewise be prepared in situ during the final isolation and purification of one or more compounds, or by separately reacting one or more purified compounds in their free acid form with a suitable base (such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation), with ammonia or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, e.g., Berge et al, supra).

Reference to a "therapeutically effective amount" (or "effective amount") of a compound for use in therapy refers to the amount of the compound in a formulation that, when administered (to a mammal, preferably a human) as part of a desired dosage regimen, alleviates a symptom, ameliorates a condition, or slows the onset of a disease condition according to clinically acceptable standards (e.g., at a reasonable benefit/risk ratio applicable to any medical treatment) for the disorder or condition to be treated or for cosmetic purposes.

The term "prophylactic or therapeutic" treatment is art-recognized and encompasses administration of one or more of the subject compositions to a host. If the treatment is administered prior to clinical manifestation of the undesired condition (e.g., disease or other undesired state of the host animal), it is prophylactic (i.e., it protects the host from developing the undesired condition), whereas if the treatment is administered after manifestation of the undesired condition, it is therapeutic (i.e., it is intended to alleviate, ameliorate or stabilize the existing undesired condition or side effects thereof).

The term "patient" refers to a mammal in need of a particular treatment. In certain embodiments, the patient is a primate, dog, cat, or horse. In certain embodiments, the patient is a human.

Aliphatic chains include several classes of alkyl, alkenyl and alkynyl groups as defined below. The linear aliphatic chain is limited to the unbranched carbon chain portion. As used herein, the term "aliphatic group" refers to a straight, branched, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as alkyl, alkenyl, or alkynyl groups.

"alkyl" means a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the indicated number of carbon atoms or, if not specified, up to 30 carbon atoms. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, as well as those moieties that are positional isomers of such moieties. Alkyl of 10 to 30 carbon atoms containing decaneUndecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl. In certain embodiments, the linear or branched alkyl group has 30 or fewer carbon atoms in its backbone (e.g., C for linear chain)₁-C₃₀For the side chain is C ₃-C₃₀) And more preferably 20 or less carbon atoms. Alkyl groups may be substituted or unsubstituted.

As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbons (e.g., 2 to 12 carbon atoms) that contains two points of attachment to the remainder of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene- (CH)₂) -, ethylene- (CH)₂CH₂) -, n-propylene- (CH)₂CH₂CH₂) -, isopropylidene- (CH)₂CH(CH₃) Etc. -. The alkylene group may be a cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents.

"cycloalkyl" means a monocyclic or bicyclic or bridged or spiro or polycyclic saturated carbocyclic ring each having 3 to 12 carbon atoms. Also, preferred cycloalkyl groups have 3 to 10 carbon atoms in their ring structure, and more preferably 3 to 6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted.

As used herein, "lower alkyl" means an alkyl group as defined above but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl, unless the number of carbons is otherwise specified. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout this application, preferred alkyl groups are lower alkyl groups. In certain embodiments, the substituents designated herein as alkyl are lower alkyl.

"alkenyl" means any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the indicated number of carbon atoms or, if no limitation on the number of carbon atoms is indicated, up to 26 carbon atoms; and has one or more double bonds in the moiety. Alkenyl of 6 to 26 carbon atoms is exemplified by the following in their various isomeric forms: hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosenyl, docosenyl, tricosenyl, and tetracosenyl, wherein one or more unsaturated bonds may be located anywhere in the moiety and may have either (Z) or (E) configuration with respect to one or more double bonds.

"alkynyl" refers to a hydrocarbyl moiety within the scope of an alkenyl group but having one or more triple bonds in the moiety.

The term "alkylthio" refers to an alkyl group as defined above having a sulfur moiety attached thereto. In certain embodiments, an "alkylthio" moiety is substituted with- (S) -alkyl, - (S) -alkenyl, - (S) -alkynyl, and- (S) - (CH)₂)_m-R¹One of which is represented by the formula, wherein m and R ¹The definition is as follows. Representative alkylthio groups include methylthio, ethylthio, and the like. As used herein, the term "alkoxy" or "alkoxy" refers to an alkyl group having an oxygen moiety attached thereto as defined below. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like. An "ether" is two hydrocarbons covalently linked by oxygen. Thus, the substituent for an alkyl group which renders the alkyl group an ether is or resembles an alkoxy group, e.g. may be substituted by-O-alkyl, -O-alkenyl, -O-alkynyl, -O- (CH)₂)_m-R₁₀One of which is represented by the formula, wherein m and R₁₀As described below.

The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, such as moieties that can be represented by the formula:

wherein R is₁₁、R₁₂And R₁₃Each independently represents hydrogen, alkyl, alkenyl, - (CH)₂)_m-R₁₀Or R is₁₁And R₁₂And R₁₁And R₁₂The attached N atoms together complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; r₁₀Represents alkenyl, aryl, cycloalkyl, cycloalkenyl, heterocyclyl or polycyclyl; and m is zero or an integer in the range of 1 to 8. In certain embodiments, R₁₁Or R₁₂Only one of which may be carbonyl, e.g. R₁₁、R₁₂Together with the nitrogen, no imide is formed. In even more certain embodiments, R ₁₁And R₁₂(and optionally R₁₃) Each independently represents hydrogen, alkyl, alkenyl or- (CH)₂)_m-R₁₀. Thus, as used herein, the term "alkylamine" means having attached thereto a substituted or unsubstituted alkyl group (i.e., R) as defined above₁₁And R₁₂At least one of which is an alkyl group). In certain embodiments, the amino or alkylamine is basic, meaning that it has a pK_aConjugate acids of > 7.00, i.e., pK of protonated forms of these functional groups_aAbove about 7.00 relative to water.

As used herein, the term "amide" refers to a group

Wherein R is₁₄Independently represent hydrogen or a hydrocarbyl group, or two R₁₄And two R₁₄The N atoms attached thereto together complete a heterocyclic ring having from 4 to 8 atoms in the ring structure.

As used herein, the term "aryl" includes 3 to 12-membered substituted or unsubstituted monocyclic aromatic groups, wherein each atom of the ring is carbon (i.e., carbocyclic aryl) or wherein one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, the aryl group comprises a 5 to 12 membered ring, more preferably a 6 to 10 membered ring. The term "aryl" also embraces compounds havingA multicyclic ring system of two or more cyclic rings in which two or more carbons are common to two adjoining rings, wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Heteroaryl groups comprise substituted or unsubstituted aromatic 3 to 12 membered ring structures, more preferably 5 to 12 membered rings, more preferably 5 to 10 membered rings, the ring structures of which comprise one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. The aryl and heteroaryl groups may be monocyclic, bicyclic or polycyclic. Each instance of an aryl group can be independently optionally substituted with one or more substituents, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl"); for example, 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or only 1 substituent. The aromatic ring may be substituted at one or more ring positions with one or more substituents (e.g., halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, mercapto, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (e.g., trifluoromethyl), cyano, and the like). For example, in certain embodiments, aryl may be unsubstituted C ₅-C₁₂Aryl, and in certain embodiments, aryl may be substituted C₅-C₁₀And (4) an aryl group.

As used herein, the term "halo," "halide," or "halogen" means halogen and includes, for example, but is not limited to, fluorine, chlorine, bromine, iodine, and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro and bromo.

The term "heterocyclyl" or "heterocyclyl" refers to a 3 to 12 membered ring structure, more preferably 5 to 12 membered ringA ring, more preferably a 5 to 10 membered ring, whose ring structure contains one to four heteroatoms. The heterocycle may be monocyclic, bicyclic, spiro or polycyclic. Heterocyclic groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, benzopyran, xanthene, oxathianthrene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiacyclopentane, oxazole, piperidine, piperazine, morpholine, lactone, lactam (such as azetidinone and pyrrolidone), sultam, sultone, and the like. The heterocyclic ring may be substituted at one or more positions with such substituents as described above (e.g., halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, nitro, mercapto, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxy, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF ₃CN, -CN, etc.).

The term "carbonyl" is art-recognized and encompasses such moieties which may be represented by the formula:

wherein X' is a bond or represents oxygen or sulfur, and R₁₅Represents hydrogen, alkyl, alkenyl, - (CH)₂)_m-R₁₀Or a pharmaceutically acceptable salt, R₁₆Represents hydrogen, alkyl, alkenyl or- (CH)₂)_m-R₁₀Wherein m and R₁₀As defined above. In which X' is oxygen and R₁₅Or R₁₆In the case where it is not hydrogen, the formula represents an "ester". In which X' is oxygen and R₁₅When defined as above, moieties are referred to herein as carboxy, and specifically when R is₁₅When hydrogen, the formula represents a "carboxylic acid". In which X' is oxygen and R₁₆When hydrogen, the formula represents a "formate". Typically, when the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiocarbonyl" group. In X' is sulfur and R₁₅Or R₁₆In the case where it is not hydrogen, the formula represents a "thioester" group. In X' is sulfur and R₁₅In the case of hydrogen, the formula represents a "thiocarboxylic" group. In X' is sulfur and R₁₆In the case of hydrogen, the formula represents a "thioformate" group. On the other hand, where X' is a bond and R₁₅In the case where it is not hydrogen, the formula represents a "ketone" group. At X' is a bond and R₁₅In the case of hydrogen, the above formula represents an "aldehyde" group.

As used herein, the term "substituted" is contemplated to encompass all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described above. For suitable organic compounds, the permissible substituents can be one or more and the same or different. For the purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatom. The present invention is not intended to be limited in any way by the permissible substituents of organic compounds. It is understood that "substituted" or "substituted with … …" includes the implied condition that such substitution is according to the allowed valences of the substituted atom and substituent, and that the substitution results in a stable compound that, for example, does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, and the like.

As used herein, the term "nitro" means-NO ₂(ii) a The term "halogen" means-F, -Cl, -Br, or-I; the term "mercapto" means-SH; the term "hydroxy" means-OH; the term "sulfonyl" means-SO₂-; the term "azido" means-N₃(ii) a The term "cyano" means-CN; the term "isocyanato" means-NCO; the term "thiocyano" means-SCN; the term "isothiocyanato" means-NCS; and the term "cyanato" means-OCN.

The term "sulfamoyl" is art-recognized and includes moieties that can be represented by the formula:

wherein R is₁₁And R₁₂As defined above.

The term "sulfate" is art recognized and includes a moiety that can be represented by the formula:

wherein R is₁₅As defined above.

The term "sulfonamide" is art recognized and includes a moiety that can be represented by the formula:

wherein R is₁₁And R₁₆As defined above.

The term "sulfonate" is art recognized and includes a moiety that can be represented by the formula:

wherein R is₅₄Is an electron pair, hydrogen, alkyl, cycloalkyl or aryl.

As used herein, the term "sulfoxide" or "sulfinyl" refers to a moiety that can be represented by the formula:

wherein R is₁₇Selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl or aryl.

The term "urea" is art-recognized and may be represented by the general formula

Wherein each R₁₈Independently represent hydrogen or a hydrocarbyl group, such as alkyl, or any occurrence of R₁₈With another R₁₈Together with one or more intervening atoms complete a heterocyclic ring having from 4 to 8 atoms in the ring structure.

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

The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It is understood that "substituted" or "substituted with … …" includes the implied condition that such substitution is according to the allowed valences of the substituted atom and substituent, and that the substitution results in a stable compound that, for example, does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is contemplated to encompass all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For suitable organic compounds, the permissible substituents can be one or more and the same or different. For the purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatom. The substituents may comprise any of the substituents described herein, For example, a halogen, a hydroxyl group, a carbonyl group (such as a carboxyl, alkoxycarbonyl, formyl or acyl group), a thiocarbonyl group (such as a thioester, thioacetate or thioformate), an alkoxy group, a phosphoryl group, a phosphate ester, a phosphonate ester, a phosphinate ester, an amino group, an amido group, an amidine, an imine, a cyano group, a nitro group, an azido group, a mercapto group, an alkylthio group, a sulfate ester, a sulfonate ester, a sulfamoyl group, a sulfonamido group, a sulfonyl group, a heterocyclic group, an aralkyl group, or an aromatic or. In a more preferred embodiment, the substituents on the substituted alkyl group are selected from C_1-6Alkyl radical, C_3-6Cycloalkyl, halogen, carbonyl, cyano or hydroxy. In a more preferred embodiment, the substituents on the substituted alkyl group are selected from fluoro, carbonyl, cyano or hydroxy. It will be appreciated by those skilled in the art that the substituents themselves may be substituted if appropriate. Unless specifically stated as "unsubstituted," references herein to chemical moieties are understood to encompass substituted variants. For example, reference to an "aryl" group or moiety implicitly encompasses both substituted and unsubstituted variants.

For the purposes of the present invention, chemical Elements are identified according to the Periodic Table of the Elements (CAS edition, Handbook of Chemistry and Physics), 67 th edition, 1986-87, pages.

Exemplary compounds of the invention:

in certain embodiments, the invention relates to compounds of formula I:

A-B-C (I)

wherein:

a is

B is alkylene, -alkylene- (heterocyclyl) -alkylene-, -cycloalkylene, -alkylene-O-, -cycloalkylene-O-or-alkylene-O-alkylene-;

c is

R₁Independently H, alkyl, halide, alkoxy, CF₃OH, alkylene-OH, NO₂-N (H) R or NH₂；

R₂Is composed of

R₃And R₅Independently selected from H, halide, CF₃、C(H)F₂、C(F)H₂Alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxy and alkoxy;

R_ais H, (C)₁-C₆) Alkyl, - (C)₁-C₆) alkylene-O- (C)₁-C₆) Alkyl or- (C)₁-C₆) alkylene-O-C (O) O (C)₁-C₆) An alkyl group;

n is independently 0, 1, 2, 3 or 4;

m is 0, 1, 2 or 3; and is

The absolute configuration at any stereocenter is R, S or mixtures thereof;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the invention relates to compounds of formula I:

A-B-C (I)

wherein:

a is

B is alkylene, -alkylene- (heterocyclyl) -alkylene-, -cycloalkylene, -alkylene-O-, -cycloalkylene-O-or-alkylene-O-alkylene-;

C is

R₁Is H or alkoxy;

R₂is composed of

R₃And R₅Independently selected from H, halide, CF₃、C(H)F₂、C(F)H₂Alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxy and alkoxy;

R_ais H, (C)₁-C₆) Alkyl, - (C)₁-C₆) alkylene-O- (C)₁-C₆) Alkyl or- (C)₁-C₆) alkylene-O-C (O) O (C)₁-C₆) An alkyl group;

n is independently 0, 1, 2, 3 or 4;

m is 0, 1, 2 or 3; and is

The absolute configuration at any stereocenter is R, S or mixtures thereof;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the invention relates to compounds of formula I:

A-B-C (I)

wherein:

a is

B is alkylene, -alkylene-O-or-alkylene-O-alkylene-;

c is

R₁Is H;

R₂is composed of

R₃And R₅Independently selected from H, halide, CF₃、C(H)F₂、C(F)H₂Alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxy and alkoxy;

R_aIs H, (C)₁-C₆) Alkyl, - (C)₁-C₆) alkylene-O- (C)₁-C₆) Alkyl or- (C)₁-C₆) alkylene-O-C (O) O (C)₁-C₆) An alkyl group;

n is independently 0, 1, 2, 3 or 4;

m is 0, 1, 2 or 3; and is

The absolute configuration at any stereocenter is R, S or mixtures thereof;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the invention relates to compounds of formula I:

A-B-C (I)

wherein:

a is

B is alkylene or-alkylene-O-;

c is

R₁Is H;

R₂is composed of

R₅Independently selected from H, halide, CF₃、C(H)F₂、C(F)H₂Alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxy and alkoxy;

R_ais H;

n is 0;

m is 0, 1, 2 or 3; and is

The absolute configuration at any stereocenter is R, S or mixtures thereof;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the invention relates to compounds of formula I:

A-B-C (I)

wherein:

a is

B isWherein q is 0, 1, 2 or 3;

c is

R₁Independently H, alkyl, halide, alkoxy, CF₃OH, alkylene-OH, NO₂-N (H) R or NH ₂；

R₂Is composed of

R₅Independently selected from H, halide, CF₃、C(H)F₂、C(F)H₂Alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxy and alkoxy;

R_ais H, (C)₁-C₆) Alkyl, - (C)₁-C₆) alkylene-O- (C)₁-C₆) Alkyl or- (C)₁-C₆) alkylene-O-C (O) O (C)₁-C₆) An alkyl group;

n is 0;

m is 0, 1, 2 or 3; and is

The absolute configuration at any stereocenter is R, S or mixtures thereof;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein a isIn certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein a is

In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein B is alkylene. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein B is-alkylene- (heterocyclyl) -alkylene-. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein B is- (heterocyclyl) -alkylene-. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein B is-cycloalkylene. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein B is-alkylene-O-. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein B is-cycloalkylene-O-. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein B is-alkylene-O-alkylene-. In some embodiments, -alkylene-O-alkylene-is-methylene-O-propylene, -ethylene-O-ethylene, or-propylene-O-methylene. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein B is selected from the group consisting of:

q is 0, 1, 2 or 3; and p is 0, 1 or 2.

In some embodiments, B isIn some embodiments, B isIn some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₁Is H. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₁Is an alkyl group. In certain embodiments, R₁Is methyl. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₁Is a halide. In certain embodiments, the present invention relates to any one of the compounds mentioned above, whereinR₁Is an alkoxy group. In some embodiments, alkoxy is methoxy, ethoxy, isopropoxy, isobutoxy, or tert-butoxy. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is ₁Is CF₃. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₁Is OH. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₁Is alkylene-OH. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₁Is NO₂. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₁is-N (H) R_a. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₁Is NH₂. In some embodiments, R₁Is alkyl, halide, OMe, OH, alkylene-OH or NH₂. In some embodiments, R₁Is OMe. In some embodiments, R₁All examples of (c) are H.

In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₂Is composed ofIn certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₂Is composed ofIn certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is ₂Is composed ofIn certain embodiments, the present invention relates to the compounds mentioned aboveAny one of the compounds wherein R₂Is composed ofIn certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₂Is composed ofIn certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₂Is composed ofIn certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₂Is composed of

In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein n is 0. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein n is 1. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein n is 2. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein n is 3. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein n is 4.

In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein m is 0. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein m is 1. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein m is 2. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein m is 3.

In some embodimentsThe present invention relates to any one of the above-mentioned compounds, wherein R is₃Is H. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₃Is a halide. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₃Is CN. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₃Is CF₃. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₃Is C (H) F₂. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₃Is C (F) H₂. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₃Is an alkyl group. In some embodiments, the alkyl group is methyl, ethyl, isopropyl, or tert-butyl. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₃Is a cycloalkyl group. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is ₃Is an alkylene-alkoxy group. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₃Is an aryl group. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₃Is a hydroxyl group. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₃Is an alkoxy group. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₃H, halide, Me, OMe or Ph.

In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₄Is an alkyl group. In certain embodiments, the present inventionThe invention relates to any one of the compounds mentioned above, wherein R is₄is-C (F)₂)CH₃. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₄Is a cycloalkyl group. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₄Is a heterocycloalkyl group. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is ₄Is-alkylene-cycloalkyl. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₄is-O-alkylene-cycloalkyl. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₄is-O-cycloalkyl. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₄is-O-alkyl. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₄is-alkylene-O-alkyl. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₄is-alkylene-O-cycloalkyl. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₄is-alkylene-O-alkylene-cycloalkyl. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₄Selected from-alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -alkylene-O-alkyl, -alkylene-O-cycloalkyl and-alkylene-O-alkylene-cycloalkyl. In some embodiments, alkylene R ₄Is methylene or ethylene.

In certain embodiments, the present invention relates to any one of the compounds mentioned above, R₄Is selected from In certain embodiments, the present invention relates to any one of the compounds mentioned above, R₄Selected from optionally substitutedIn certain embodiments, the present invention relates to any one of the compounds mentioned above, R₄Is composed ofIn certain embodiments, the present invention relates to any one of the compounds mentioned above, R₄Is composed ofIn certain embodiments, the present invention relates to any one of the compounds mentioned above, R₄Is composed ofIn certain embodiments, the present invention relates to any one of the compounds mentioned above, R₄Is composed ofIn certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₄Is selected from

In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₅Is H. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₅Is a halide. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is ₅Is F. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₅Is CN. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₅Is CF₃. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₅Is C (H) F₂. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₅Is C (F) H₂. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₅Is an alkyl group. In some embodiments, the alkyl group is methyl, ethyl, isopropyl, or tert-butyl. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₅Is a cycloalkyl group. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₅Is an alkylene-alkoxy group. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is ₅Is an aryl group. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₅Is a hydroxyl group. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₅Is an alkoxy group. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein R is₅H, halide, Me, OMe or Ph.

In certain embodiments, the present invention relates to any one of the compounds mentioned above, R_aIs H. In certain embodiments, the present invention relates to any one of the compounds mentioned above, R_aIs (C)₁-C₆) An alkyl group. In some embodiments, (C)₁-C₆) Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In certain embodiments, the present invention relates to any one of the compounds mentioned above, R_aIs- (C)₁-C₆) alkylene-O- (C)₁-C₆) An alkyl group. In certain embodiments, the present invention relates to any one of the compounds mentioned above, R_aIs- (C)₁-C₆) alkylene-O-C (O) O (C)₁-C₆) An alkyl group.

In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein the absolute configuration at any stereocenter is R. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein the absolute configuration at any stereocenter is S. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein the absolute configuration at any stereocenter is a mixture of R and S.

In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein the compound is a pharmaceutically acceptable salt.

In certain embodiments, the present invention relates to a compound selected from the group consisting of:

in certain embodiments, the present invention relates to a compound selected from the group consisting of:

in certain embodiments, the present invention relates to compounds of the formula:

in certain embodiments, the present invention relates to a compound selected from the group consisting of:

In certain embodiments, the present invention relates to compounds of the formula:

in certain embodiments, the present invention relates to compounds of the formula:

in certain embodiments, the present invention relates to a compound selected from the group consisting of:

in certain embodiments, the present invention relates to compounds of the formula:

in certain embodiments, the present invention relates to a compound selected from the group consisting of:

In certain embodiments, the present invention relates to a compound selected from the group consisting of:

in certain embodiments, the present invention relates to a compound selected from the group consisting of:

in some embodiments, the present invention relates to a compound selected from the group consisting of:

exemplary pharmaceutical compositions

In certain embodiments, the present invention relates to a pharmaceutical composition comprising any one of the compounds mentioned above and a pharmaceutically acceptable carrier.

Patients, including but not limited to humans, may be treated by administering to the patient an effective amount of the active compound, or a pharmaceutically acceptable prodrug or salt thereof, in the presence of a pharmaceutically acceptable carrier or diluent. The active material may be administered in liquid or solid form by any suitable route (e.g., oral, parenteral, intravenous, intradermal, subcutaneous, or topical).

The concentration of the active compound in the pharmaceutical composition will depend on the absorption, inactivation, and excretion rates of the drug, as well as other factors known to those skilled in the art. It should be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosing regimens should be adjusted over time according to the individual need and the professional judgment of the person administering the composition or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope and practice of the claimed compositions. The active ingredient may be administered at one time, or may be divided into a number of smaller doses to be administered at different time intervals.

In certain embodiments, the mode of administration of the active compound is oral. Oral compositions will generally comprise an inert diluent or an edible carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compounds can be incorporated with excipients and used in the form of tablets, lozenges or capsules. Pharmaceutically compatible binders and/or adjuvant materials may be included as part of the composition.

Tablets, pills, capsules, lozenges, and the like may contain any of the following ingredients or compounds of similar properties: a binder, such as microcrystalline cellulose, gum tragacanth or gelatin; excipients, such as starch or lactose; dispersing agents, such as alginic acid, primary gel (Primogel) or corn starch; lubricants, such as magnesium stearate or hydrogenated vegetable oils (Sterotes); glidants, such as colloidal silicon dioxide; sweetening agents, such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. In addition, the dosage unit form may contain various other materials which modify the physical form of the dosage unit, such as coatings of sugar, shellac, or other enteric agents.

The compounds may be administered as components of elixirs, suspensions, syrups, wafers, chewing gums and the like. Syrups may contain, in addition to one or more active compounds, sucrose or a sweetener as a sweetening agent and certain preservatives, dyes and colorings and flavors.

The compound or pharmaceutically acceptable prodrug or salt thereof may also be mixed with other active materials that do not impair the desired effect or with materials that complement the desired effect (such as antibiotics, antifungal agents, anti-inflammatory agents, or other antiviral agents, including but not limited to nucleoside compounds). Solutions or suspensions for parenteral, intradermal, subcutaneous or topical application may comprise the following components: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for adjusting tonicity such as sodium chloride or dextrose. The parenteral formulations can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

If administered intravenously, the vehicle comprises physiological saline and Phosphate Buffered Saline (PBS).

In certain embodiments, the active compound is prepared with a carrier that will protect the compound from rapid elimination from the body (such as a controlled release formulation, including but not limited to implants and microencapsulated delivery systems). Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid may be used. For example, enteric coated compounds may be used to protect against cleavage by gastric acid. Methods for preparing such formulations will be apparent to those skilled in the art. Suitable materials are also commercially available.

Liposomal suspensions (including but not limited to liposomes targeted to infected cells with monoclonal antibodies to viral antigens) are also preferred as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example as described in U.S. Pat. No. 4,522,811 (incorporated by reference). For example, a liposome formulation can be prepared by dissolving the appropriate lipid or lipids (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachidoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving a thin film of dry lipid on the surface of the container. Then, an aqueous solution of the active compound is introduced into the container. The container is then rotated by hand to release the lipid material from the sides of the container and disperse the lipid aggregates, thereby forming a liposome suspension.

Exemplary methods of the invention:

in certain embodiments, the present invention relates to a method of treating a disease or condition selected from the group consisting of: idiopathic pulmonary fibrosis, diabetic nephropathy, focal segmental glomerulosclerosis, chronic kidney disease, non-alcoholic steatohepatitis, primary biliary cholangitis, primary sclerosing cholangitis, a solid tumor, a hematologic tumor, organ transplantation, Alport syndrome, interstitial lung disease, radiation-induced fibrosis, bleomycin (bleomycin) -induced fibrosis, asbestos-induced fibrosis, influenza-induced fibrosis, coagulation-induced fibrosis, vascular injury-induced fibrosis, aortic stenosis, and cardiac fibrosis, the method comprising the steps of: administering to a subject in need thereof a therapeutically effective amount of any one of the compounds mentioned above.

In certain embodiments, the present invention relates to any one of the above-mentioned methods, wherein the disease or condition is a solid tumor (sarcoma, carcinoma, and lymphoma). Exemplary tumors that can be treated according to the invention include, for example, Ewing's sarcoma, rhabdomyosarcoma, osteosarcoma, myeloid sarcoma, chondrosarcoma, liposarcoma, leiomyosarcoma, soft tissue sarcoma, non-small cell lung cancer, bronchial cancer, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colon cancer (colon cancer), rectal cancer, colon cancer (colon carcinoma), colorectal adenoma, thyroid cancer, liver cancer, intrahepatic bile duct cancer, hepatocellular carcinoma, adrenal cancer, gastric cancer (stomach cancer), gastric cancer (gastic cancer), glioma (e.g., adult, pediatric brain stem glioma, pediatric brain astrocytoma, pediatric visual pathway and hypothalamic glioma), glioblastoma, endometrial cancer, melanoma, renal cancer, urinary bladder cancer, uterine body, uterine cervical cancer, renal carcinoma, bladder cancer, uterine cervix cancer, and the like, Vaginal cancer, ovarian cancer, multiple myeloma, esophageal cancer, brain cancer (e.g., brain stem glioma, cerebellar astrocytoma, brain astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma), lip and oral and pharyngeal cancers, larynx, small intestine, melanoma, villous colon adenoma, neoplasia, epithelial neoplasia, lymphoma (e.g., AIDS-related lymphoma, Burkitt's lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma and primary central nervous system lymphoma), breast cancer, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, neoplastic diseases (including solid tumors, head and neck tumors), polycythemia vera, polycythemia, and neuroblastoma, Essential thrombocytosis, myelofibrotic and myeloid metaplasia, Waldenstrom's macroglobinemia, adrenocortical carcinoma, AIDS-related cancer, childhood cerebellar astrocytoma, basal cell carcinoma, extrahepatic bile duct carcinoma, malignant fibrous histiocytoma, bone cancer, bronchial adenoma/benign tumor, carcinoid tumor, gastrointestinal carcinoid tumor, primary central nervous system, cerebellar astrocytoma, childhood cancer, ependymoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, intraocular melanoma eye cancer, retinoblastoma eye cancer, gallbladder cancer, gastrointestinal carcinoid tumor, germ cell tumor (e.g., extracranial germ cell tumor, extragonadal germ cell tumor, and ovarian germ cell tumor), gestational trophoblastic tumor, hepatocellular carcinoma, hypopharynx cancer, hypothalamic and visual pathway glioma, thalamocytoma, and neuroblastoma of the renal pathway, Pancreatic islet cell carcinoma (endocrine pancreas), laryngeal carcinoma, malignant fibrous histiocytoma of bone/osteosarcoma, medulloblastoma, mesothelioma, primary occult metastatic squamous neck cancer, multiple endocrine neoplasia syndrome, multiple myeloma/plasma cell neoplasm, mycosis fungoides, nasal cavity and sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, epithelial ovarian cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic islet cell carcinoma, parathyroid cancer, pheochromocytoma, pinealoblastoma, pituitary tumor, pleural pneumocblastoma, transitional cell carcinoma of ureter, retinoblastoma, rhabdomyosarcoma, salivary gland carcinoma, Sezary syndrome (Sezadrosyndrome), non-melanoma skin cancer, Merkel cell carcinoma (Merkel cell carcinoma), squamous cell carcinoma, testicular cancer, neuroblastoma, cervical cancer, cervical, Thymoma, gestational trophoblastic tumors, and Wilms' tumor.

In certain embodiments, the present invention relates to any one of the above-mentioned methods, wherein the disease is a disease or condition is a hematological tumor. Exemplary hematological tumors that can be treated according to the present invention include, for example, acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hodgkin's lymphoma, non-hodgkin's lymphoma, and multiple myeloma.

In certain embodiments, the present invention relates to any one of the above-mentioned methods, wherein the disease or condition is selected from the group consisting of: idiopathic pulmonary fibrosis, interstitial lung disease associated with systemic sclerosis, interstitial lung disease associated with myositis, interstitial lung disease associated with systemic lupus erythematosus, rheumatoid arthritis, and related interstitial lung diseases.

In certain embodiments, the present invention relates to any one of the above-mentioned methods, wherein the disease or condition is selected from the group consisting of: diabetic nephropathy, focal segmental glomerulosclerosis and chronic kidney disease.

In certain embodiments, the present invention relates to any one of the above-mentioned methods, wherein the disease or condition is selected from the group consisting of: non-alcoholic steatohepatitis, primary biliary cholangitis, and primary sclerosing cholangitis.

In certain embodiments, the present invention relates to any one of the above-mentioned methods, wherein the subject is a mammal. In certain embodiments, the present invention relates to any one of the compounds mentioned above, wherein the subject is a human.

Further numerical examples

1. A compound of formula (I):

A-B-C (I)

wherein:

a is

B is alkylene, -alkylene- (heterocyclyl) -alkylene-, -cycloalkylene, -alkylene-O-, -cycloalkylene-O-or-alkylene-O-alkylene-;

c is

R₁Independently H, alkyl, halide, alkoxy, CF₃OH, alkylene-OH, NO₂or-N (H) R_a；

R₂Is composed of

R₃And R₅Independently selected from H, -CN, halide, CF₃、C(H)F₂、C(F)H₂Alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxy and alkoxy;

R₄independently selected from alkyl, -C (F)₂)CH₃Cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, -O-alkyl, -alkylene-O-cycloalkyl, and-alkylene-O-alkylene-cycloalkyl;

R_ais H, (C)₁-C₆) Alkyl, - (C)₁-C₆) alkylene-O- (C)₁-C₆) Alkyl or- (C)₁-C₆) alkylene-O-C (O) O (C)₁-C₆) An alkyl group;

n is independently 0, 1, 2, 3 or 4;

m is 0, 1, 2 or 3; and is

The absolute configuration at any stereocenter is R, S or mixtures thereof;

or a pharmaceutically acceptable salt thereof.

2. The compound of embodiment 1, wherein B is selected from the group consisting of:

q is 0, 1, 2 or 3; and is

p is 0, 1 or 2.

3. A compound according to embodiment 1 wherein B is-alkylene-O-alkylene-.

4. A compound according to embodiment 3 wherein-alkylene-O-alkylene-is-methylene-O-propylene, -ethylene-O-ethylene or-propylene-O-methylene.

5. A compound according to any one of embodiments 1 to 4, wherein R₁Is alkyl, halide, OMe, OH, alkylene-OH or NH₂。

6. A compound according to embodiment 5, wherein R₁Is by OMe.

7. A compound according to any one of embodiments 1 to 4, wherein R₁Is H.

8. A compound according to any one of embodiments 1 to 7, wherein R₂Is composed of

9. A compound according to embodiment 8, wherein R₂N in (1) is 0.

10. A compound according to embodiment 8, wherein R₂N in (1).

11. A compound according to any one of embodiments 1 to 7, wherein R ₂Is composed of

12. A compound according to embodiment 11, wherein R₂M in (1) is 0.

13. A compound according to embodiment 11, wherein R₂M in (1).

14. A compound according to embodiment 1, 8, 10, 11 or 13 wherein R₅Is F.

15. A compound according to embodiment 1, 8, 10, 11 or 13 wherein R₅Is CN.

16. A compound according to any one of embodiments 1 to 7, wherein R₂Is composed of

17. A compound according to any one of embodiments 1 to 16, wherein cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

18. A compound according to any one of embodiments 1 to 16 wherein alkyl is methyl, ethyl, isopropyl or tert-butyl.

19. A compound according to any one of embodiments 1 to 18, wherein R₃H, halide, Me, OMe or Ph.

20. A compound according to any one of embodiments 1 to 19, wherein R₄Independently selected from-alkylene-cycloalkyl, -O-alkylene-cycloalkyl; -alkylene-O-alkyl, -alkylene-O-cycloalkyl and-alkylene-O-alkylene-cycloalkyl.

21. A compound according to embodiment 20, wherein R₄The alkylene group in (1) is a methylene group or an ethylene group.

22. A compound according to any one of embodiments 1 to 19, wherein R ₄Is selected from

23. A compound according to any one of embodiments 1 to 19, wherein R₄Is selected from

24. According to example 1The compound of any one of to 23, wherein R_aIs H.

Example

The invention as generally described herein will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the invention, and are not intended to be limiting of the invention.

General schemes and procedures for preparing the Compounds of the invention

Moiety R₁And R₂Represents a suitable substituent; l represents a suitable linker and X represents a suitable halogen (such as Br, Cl or I) or another leaving group (such as methanesulfonate or toluenesulfonate).

Represents a suitable optionally substituted pyrrolidine.

Represents a suitable optionally substituted tetrahydronaphthyridine.

Represents a suitable optionally substituted naphthyridine.

General protocol for the synthesis of α v β 6 inhibitors

General procedure:

9-BBN and Suzuki reaction

The alkene intermediate can be cross-coupled with a 2-halonaphthyridine or tetrahydronaphthyridine by the following procedure. To a solution of the olefin (1 eq) in dry THF (2-10mL/mmol) was added 9-BBN (0.5M solution in THF, 1-2 eq.) under Ar. The reaction was stirred at 40-80 ℃ for 1-4 hours and then cooled to room temperature. This solution was added to a mixture of 2-halonaphthyridine or Boc protected 2-halotetrahydronaphthyridine (1-1.5 equiv.), cesium carbonate (2-5 equiv.), and Pd (PPh3)4 or another suitable Pd/ligand combination (0.05 to 0.1 equiv.) in 1, 4-dioxane (2-10 mL/mmol). The reaction is stirred at 80-100 ℃ for 12-24 hours. The solvent was removed in vacuo and the residue was purified through a silica gel column to yield the alkyl-linked naphthyridine product.

Cyclic structure of ring

Naphthyridine can also be prepared from methyl ketone by the following procedure. A mixture of methyl ketone (1 equivalent), 2-aminonicotinaldehyde (1-2 equivalents) and a secondary amine such as pyrrolidine or L-proline (1-2 equivalents) in DMF or EtOH (1-10mL/mmol) is stirred at 70-100 deg.C for 2-10 hours. The solvent was removed in vacuo and the residue was purified through a silica gel column to yield the desired naphthyridine product.

Naphthyridine reduction

Naphthyridine can be reduced to tetrahydronaphthyridine by the following procedure. At H₂A mixture of the appropriate naphthyridine (1 eq.) and Pd/C (5-20 weight percent Pd, 0.05 to 0.2 eq.) in ethyl acetate or another appropriate solvent (2-10mL/mmol) was stirred under a balloon at room temperature to 50 deg.C for 2-20 hours. The reaction was filtered and concentrated in vacuo to yield the desired tetrahydronaphthyridine product.

Deprotection of Boc

The Boc protected amine (1 eq) was treated with 1, 4-dioxane (1-50mL/mmol amine) containing HCl (4-100 eq) at room temperature to 50 ℃ for 1-4 hours. The reaction was concentrated in vacuo and the amine product was used either crude or after purification through a silica gel column. The amine may be used crude as the dihydrochloride salt, or may be prepared by dissolving in a suitable solvent and using aqueous NaHCO₃Washed and converted to the free base.

Amine alkylation:

an amine (1 equivalent), an alkylating agent (1-1.5 equivalents) and K₂CO₃Or a mixture of N, N-diisopropylethylamine (2-10 equivalents) in MeCN or DMF (3-10mL/mmole amine) is stirred at room temperature to 80 ℃ for 4-16 hours. The reaction was concentrated in vacuo and the residue was purified through a silica gel column to give the desired aminoacetate. The amine used may be a free base or a salt, such as the hydrochloride or dihydrochloride. If the reaction is carried out with a salt of an amine, additional equivalents of base may be required.

Saponification:

for certain esters, e.g. R₁Me or ethyl, the ester may be saponified under alkaline conditions. The ester (1 equivalent) is treated with a solution containing LiOH-H₂O (3-5 equiv.) MeOH (3-10mL/mmol ester) and water (3-10mL/mmol ester) at room temperature to 50 deg.C for 1-16 h. The reaction was concentrated in vacuo and the residue was purified by preparative HPLC to yield the desired carboxylic acid product.

For certain esters, e.g. R₁The ester may be saponified under acidic conditions. The ester (1 equiv.) was treated with 4N HCl (4-100 equiv.) in 1, 4-dioxane (1-25mL/mmol ester) at room temperature to 50 ℃ for 1-16 hours. The reaction was concentrated in vacuo and the residue was purified by preparative HPLC to give the desired product The carboxylic acid product of (a).

Petasis reaction:

as an alternative to the amine alkylation/saponification sequence, the Petasis reaction may be used to prepare certain aryl analogs: a mixture of amine (1 equivalent), arylboronic acid or arylboronic acid ester (1-1.5 equivalents) and 2-oxoacetic acid (1.5-2 equivalents) in MeCN or DMF (2-10mL/mmole amine) was stirred at 50-80 deg.C for 2-16 hours. The reaction was concentrated in vacuo and the residue was purified by preparative HPLC to yield the desired glycine.

Analytical method

Preparative HPLC method

The crude sample was dissolved in MeOH and purified by preparative HPLC using a Gilson 215 instrument, detecting a wavelength of 214 nm:

preparative HPLC a: column: XBridge C18, 21.2 × 250mm, 10 μm; mobile phase: water (10mM ammonium bicarbonate), B CH₃CN; gradient elution as in text; flow rate: 20 ml/min.

Preparative HPLC B: column: XBridge C18, 21.2 × 250mm, 10 μm; mobile phase: water (10mM formic acid), B CH₃CN; gradient elution as in text; flow rate: 20 ml/min.

Preparative HPLC C: column: XBridge OBD C18, 19 × 100mm, 5 μm; mobile phase: water, B CH₃CN; gradient elution as in text; flow rate: 20 ml/min.

Preparation type chiral SFC method

The racemic product was separated into the individual enantiomers by chiral preparative SFC using an SFC-80(Thar, Waters) instrument, with a detection wavelength of 214 nm:

preparative chiral SFC a: column: (R, R) -Whelk-O1, 20X 250mm, 5 μm (Dailco, Decial)), column temperature: 35 ℃, mobile phase: CO 2₂Methanol (0.2% methanolic ammonia) ═ 60/40, flow rate: 80 gPer minute, back pressure: 100 bar.

Preparative chiral SFC B: column: AD 20X 250mm, 10 μm (Dailco corporation), column temperature: at a temperature of 35 c,

mobile phase: CO 2₂Methanol (0.2% methanolic ammonia) ═ 60/40, flow rate: 80 g/min, back pressure: 100 bar.

Preparative chiral SFC: column: AS 20X 250mm, 10 μm (Dailk Co.), column temperature: at a temperature of 35 c,

mobile phase: CO 2₂Methanol (0.2% methanolic ammonia) ═ 60/40, flow rate: 80 g/min, back pressure: 100 bar.

Preparative chiral SFC D: column: OD 20X 250mm, 10 μm (Dailn Co.), column temperature: at a temperature of 35 c,

mobile phase: CO 2₂Methanol (0.2% methanolic ammonia) ═ 60/40, flow rate: 80 g/min, back pressure: 100 bar.

Preparative chiral SFC E: column: cellulose-SC 20X 250mm, 10 μm (Dailco corporation), column temperature: 35 ℃, mobile phase: CO 2 ₂Methanol (0.2% methanolic ammonia) ═ 60/40, flow rate: 80 g/min, back pressure: 100 bar.

Preparative chiral SFC F: column: OZ 20 × 250mm, 10 μm (Dailn Co.), column temperature: 35 ℃, mobile phase: CO 2₂Methanol (0.2% methanolic ammonia) ═ 60/40, flow rate: 80 g/min, back pressure: 100 bar.

Preparative chiral SFC G: column: IC 20X 250mm, 10 μm (Dailn Co.), column temperature: 35 ℃, mobile phase: CO 2₂Methanol (0.2% methanolic ammonia) ═ 60/40, flow rate: 80 g/min, back pressure: 100 bar.

Preparative chiral SFC H: column: (S, S) -Whelk-O1, 20X 250mm, 5 μm (Dailco, Decial)), column temperature: 35 ℃, mobile phase: CO 2₂Methanol (0.2% methanolic ammonia) ═ 60/40, flow rate: 80 g/min, back pressure: 100 bar.

Method for analyzing chiral SFC

The chiral product was analyzed by chiral SFC using an SFC-80 (rear, Watts Corp.) instrument, detecting the wavelength 214 nm:

chiral SFC A: column: (R, R) -Whelk-O1, 4.6X 100mm, 5 μm (Dailco Co.), column temperature: 40 ℃, mobile phase: CO 2₂Methanol (0.2% methanolic ammonia), isocratic elution as in the text, flow rate: 4 g/min, back pressure: 120 bar.

Chiral SFC B: column: AD 4.6 × 100mm, 5 μm (xylonite corporation), column temperature: at a temperature of 40 c,

Mobile phase: CO2₂Methanol (0.2% methanolic ammonia), isocratic elution as in the text, flow rate: 4 g/min, back pressure: 120 bar.

Chiral SFC C: column: AS 4.6X 100mm, 5 μm (Dailco corporation), column temperature: at a temperature of 40 c,

mobile phase: CO2₂Methanol (0.2% methanolic ammonia), isocratic elution as in the text, flow rate: 4 g/min, back pressure: 120 bar.

Chiral SFC D: column: OD 4.6X 100mm, 5 μm (Dailuo Co.), column temperature: 40 ℃, mobile phase: CO2₂Methanol (0.2% methanolic ammonia), isocratic elution as in the text, flow rate: 4 g/min, back pressure: 120 bar.

Chiral SFC E: column: cellulose-SC 4.6X 100mm, 5 μm (Dailco Co.), column temperature: 40 ℃, mobile phase: CO 2/methanol (0.2% methanolic ammonia), isocratic elution as in the text, flow rate: 4 g/min, back pressure: 120 bar.

Chiral SFC F: column: OZ 4.6X 100mm, 5 μm (Dailuo Co.), column temperature: at a temperature of 40 c,

mobile phase: CO2₂Methanol (0.2% methanolic ammonia), isocratic elution as in the text, flow rate: 4 g/min, back pressure: 120 bar.

Chiral SFC G: column: IC 4.6X 100mm, 5 μm (Dailuo Co.), column temperature: at a temperature of 40 c,

mobile phase: CO2 ₂Methanol (0.2% methanolic ammonia), isocratic elution as in the text, flow rate: 4 g/min, back pressure: 120 bar.

Chiral SFC H: column: (S, S) -Whelk-O1, 4.6X 100mm, 5 μm (Dailco Co.), column temperature: 40 ℃, mobile phase: CO 2₂Methanol (0.2% methanolic ammonia), isocratic elution as in the text, flow rateRate: 4 g/min, back pressure: 120 bar.

Chiral SFC I: column: IC 4.6X 250mm, 5 μm (Shimadzu), column temperature: 40 ℃;

mobile phase: n-hexane (0.1% DEA): EtOH (0.1% DEA), isocratic elution as in the text, flow rate: 1 ml/min.

Chiral SFC J: column: (S, S) -Whelk-O14.6X 250mm, 5 μm (Shimadzu corporation), column temperature: 40 ℃, mobile phase: n-hexane (0.1% DEA): EtOH (0.1% DEA), isocratic elution as in the text, flow rate: 1 ml/min.

Chiral SFC K: column: OZ-H4.6X 250mm, 5 μm (Shimadzu corporation), column temperature: 40 ℃, mobile phase: n-hexane (0.1% DEA): EtOH (0.1% DEA), isocratic elution as in the text, flow rate: 1 ml/min.

Chiral SFC L: column: chiral PAK IG 4.6X 250mm, 5 μm (Shimadzu corporation), column temperature: 35 ℃, mobile phase: n-hexane (0.1% DEA): EtOH (0.1% DEA), isocratic elution as in the text, flow rate: 1 ml/min.

Chiral SFC M: column: EnantioPak OJ 4.6X 250mm, 5 μm (Dailol corporation), column temperature: 40 ℃, mobile phase: n-hexane (0.1% DEA): EtOH (0.1% DEA), isocratic elution as in the text, flow rate: 1 ml/min.

Synthesis of intermediates

The following intermediates were prepared according to the following procedure for the synthesis of examples:

preparation of (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride

Step 1: (R) -3- (4- (2-methyl-1, 3-dioxolan-2-yl) butoxy) pyrrolidine-1-carboxylic acid tert-butyl ester

3-hydroxypyrrolidine-1-carboxylic acid (R) -tert-butyl ester (1.09g, 5.41mmol), 2- (4-bromobutyl) -2-methyl-1, 3-dioxolane (1.2g, 5.41mmol) anda mixture of sodium hydride (260mg, 10.82mmol) in DMF (5mL) was stirred at 100 ℃ for 6 h. The solvent was removed in vacuo, and the residue was purified by silica gel column (petroleum ether: EtOAc 10:1) to give the desired product, 3- (4- (2-methyl-1, 3-dioxolan-2-yl) butoxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester (380mg) as a colorless oil. Yield 21% (ESI 330.2(M + H)⁺)。

Step 2: 3- (5-Oxohexyloxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester

(R) -tert-butyl 3- (4- (2-methyl-1, 3-dioxolan-2-yl) butoxy) pyrrolidine-1-carboxylate (1.3g, 3.95mmol) was treated with a solution of HCl/dioxane (4.0M, 10mL) at room temperature for 2 hours. The solvent was removed in vacuo, and the residue was taken up in acetone (10mL) and H ₂Dilution with O (1 mL). Potassium carbonate was added to adjust the pH to 8-9, followed by Boc addition₂O (1.24g, 5.69 mmol). The reaction was stirred at room temperature for 3, then filtered and concentrated in vacuo. The residue was purified by column on silica gel (petroleum ether: EtOAc 15:1) to give the desired product (R) -tert-butyl 3- (5-oxohexyloxy) pyrrolidine-1-carboxylate (820mg) as a colorless oil. Yield 73% (ESI 186(M-100)⁺,230(M-56)⁺)。

And step 3: 3- (4- (1, 8-Naphthyridin-2-yl) butoxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester

A mixture of (R) -tert-butyl 3- (5-oxohexyloxy) pyrrolidine-1-carboxylate (820mg, 2.88mmol), 2-aminonicotinaldehyde (456mg, 3.77mmol) and pyrrolidine (265mg, 3.77mmol) in DMF (5mL) was stirred at 85 ℃ for 4 h. The solvent was removed in vacuo, and the residue was purified by column of silica gel (DCM: MeOH 15:1) to give the desired product 3- (4- (1, 8-naphthyridin-2-yl) butoxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester as a colorless oil (750 mg). Yield of70％(ESI 372.2(M+H)⁺)。

And 4, step 4: (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride

A mixture of (R) -tert-butyl 3- (4- (1, 8-naphthyridin-2-yl) butoxy) pyrrolidine-1-carboxylate (750mg, 2.02mmol), Pd/C (10%, 500mg) in EtOAc (10mL) was stirred at 60 ℃ under hydrogen for 6 h. The reaction was filtered and concentrated in vacuo. The residue was treated with a solution of HCl in dioxane (4.0M, 4mL) at room temperature for 2 hours, and the solvent was removed in vacuo to yield the desired product (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride (600mg) as a white solid. Yield 96% (ESI 276.2(M + H) +).

Preparation of (R) -5-methoxy-7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride

Step 1: 3- (4-Bromobutoxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester

To a solution of (R) -3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (500mg, 2.67mmol) in n-heptane (10mL) were added water (5mL, 31.2mmol) containing 50% sodium hydroxide solution, tetrabutylammonium bromide (43.0mg, 0.13mmol) and 1, 4-dibromobutane (1.595mL, 13.35 mmol). The mixture was stirred at 80 ℃ C for 2 hours, then cooled to room temperature, diluted with water (10mL), and extracted with diethyl ether (3X 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified through a silica gel column (petroleum ether: EtOAc ═ 4:1) to give the desired product 3- (4-bromobutoxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester (686mg) as a colorless oil. Yield 80% (ESI 314(M + H-Boc) +).

Step 2: 3- (but-3-Enyloxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester

To a solution of tert-butyl (R) -3- (4-bromobutoxy) pyrrolidine-1-carboxylate (512mg, 1.58mmol) in THF (10mL) at 0 deg.C was added t-BuOK (446mg, 3.97 mmol). The reaction was stirred at room temperature for 1 hour, then diluted with water (20mL) and extracted with diethyl ether (3X 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the desired product (R) -tert-butyl 3- (but-3-enyloxy) pyrrolidine-1-carboxylate (355mg) as a colorless oil. Yield 90% (ESI 186(M + H-Boc) +).

And step 3: 3- (4- (4-chloro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester

To a solution of tert-butyl 3- (but-3-enyloxy) pyrrolidine-1-carboxylate (R) -tert-butyl ester (486mg, 1.8mmol) in THF (dry, 2mL) under Ar was added 9-BBN (THF containing 0.5M solution, 7.2mL, 3.6 mmol). The reaction was stirred at 50 ℃ for 2 hours and then cooled to room temperature. This solution was added to a mixture of 2, 4-dichloro-1, 8-naphthyridine (360mg, 1.8mmol), cesium carbonate (1730mg, 5.4mmol), and Pd (PPh3)4(208mg, 0.18mmol) in 1, 4-dioxane (7 mL). The reaction was stirred at 90 ℃ for 1.5 hours. The solvent was removed in vacuo, and the residue was purified by silica gel column (petroleum ether: EtOAc 1:1 to 1:10) to give the desired product 3- (4- (4-chloro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester as a yellow oil (300 mg). Yield 41% (ESI 406(M + H) +).

And 4, step 4: 3- (4- (4-methoxy-1, 8-naphthyridin-2-yl) butoxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester

To a solution of (R) -tert-butyl 3- (4- (4-chloro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidine-1-carboxylate (76mg, 0.13mmol) in MeOH (5mL) was added NaOMe (45mg, 0.26 mmol). The reaction was stirred at reflux overnight, then concentrated in vacuo, diluted with ethyl acetate (30mL), washed with water (2 × 20mL), dried over MgSO4, filtered and concentrated in vacuo to give the desired product, 3- (4- (4-methoxy-1, 8-naphthyridin-2-yl) butoxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester (60mg) as a colourless oil. Yield 80% (ESI 402(M + H) +).

And 5: (R) -5-methoxy-7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride

A mixture of (R) -tert-butyl 3- (4- (4-methoxy-1, 8-naphthyridin-2-yl) butoxy) pyrrolidine-1-carboxylate (60mg, 0.15mmol) and Pd/C (10%, 30mg) in EtOAc (10mL) was stirred under a balloon of hydrogen at 30 ℃ for 17 h. The mixture was filtered and concentrated in vacuo. The residue was treated with 4M HCl in dioxane (3mL, 12mmol) at room temperature for 2 hours. The solvent was removed in vacuo to give the desired product (R) -5-methoxy-7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride (45mg) as a colorless oil. Yield 88% (ESI 306(M + H)⁺)。

Preparation of (R) -7- (5- (pyrrolidin-3-yl) pentyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride

Step 1: 3- (iodomethyl) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester

A solution of PPh3(5.11g, 19.5mmol) and 1H-imidazole (1.33g, 19.5mmol) in DCM (50mL) was cooled to 0 deg.C and then treated with I₂(4.95g, 19.5mmol) was treated slowly. After stirring at 0 ℃ for 30 min, a solution of 3- (hydroxymethyl) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester in DCM (10mL) was added and the reaction was allowed to proceedStir at room temperature overnight. The reaction was diluted with water (50mL) and extracted with DCM (30 mL. times.3). The combined organic layers were passed over Na ₂SO₄Dried, filtered and removed in vacuo. The residue was purified by column on silica gel (petroleum ether: EtOAc 10:1) to give the desired product (R) -tert-butyl 3- (iodomethyl) pyrrolidine-1-carboxylate (3.7g) as a colorless oil. The yield was 80%. (ESI 256(M + H-56) +).

Step 2: (R) - ((1- (tert-butoxycarbonyl) pyrrolidin-3-yl) methyl) triphenylphosphonium

A solution of (R) -tert-butyl 3- (iodomethyl) pyrrolidine-1-carboxylate (3.7g, 12mmol) and PPh3(4.1g, 15.5mmol) in DMF (50mL) was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH 10:1) to give the crude product. Diethyl ether (30mL) was added to the crude product and stirred at room temperature for 30 min, filtered. The filter cake was dried under vacuum to give the desired product (R) - ((1- (tert-butoxycarbonyl) pyrrolidin-3-yl) methyl) triphenylphosphonium (5.6g) as a white solid. The yield was 84%. (ESI N/A).

And step 3: 4- (2-methyl-1, 3-dioxolan-2-yl) butanoic acid ethyl ester

A solution of ethyl 5-oxohexanoate (2g, 13.9mmol), ethylene glycol (2.6g, 42mmol) and p-toluenesulfonic acid (478mg, 2.78mmol) in toluene (50mL) was stirred at reflux to remove water through a Dean-Stark trap (Dean-stark trap) for 6 hours. The solvent was removed in vacuo and the residue was purified by silica gel column (petroleum ether: EtOAc 10:1) to give the desired product ethyl 4- (2-methyl-1, 3-dioxolan-2-yl) butyrate (1.4g, 50% yield) as a colorless oil. (ESI 203(M + H) +).

And 4, step 4: 4- (2-methyl-1, 3-dioxolan-2-yl) butanal

DIBAL-H (1M, 3.7mL, 3.7mmol) was added slowly to a solution of ethyl 4- (2-methyl-1, 3-dioxolan-2-yl) butanoate (500mg, 2.48mmol) in DCM (10mL) at-78 deg.C under Ar. The reaction was stirred at-78 ℃ for 30 minutes, then 20mL of water was added, warmed to room temperature, and extracted with DCM (20 mL. times.3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column on silica gel (petroleum ether: EtOAc 2:1) to give the desired product 4- (2-methyl-1, 3-dioxolan-2-yl) butanal as a colorless oil (220 mg). The yield was 56%. (ESI 159(M + H) +).

And 5: (S) -3- (5- (2-methyl-1, 3-dioxolan-2-yl) pent-1-enyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of (R) - ((1- (tert-butoxycarbonyl) pyrrolidin-3-yl) methyl) triphenylphosphonium (2.0g, 3.6mmol) in DCM (30mL) at 0 deg.C under N2 was added LiHMDS (1M, 5.4mL, 5.4 mmol). The mixture was stirred at 0 ℃ for 30 minutes, then 4- (2-methyl-1, 3-dioxolan-2-yl) butyraldehyde (565mg, 3.6mmol) was added. The reaction was stirred at room temperature for 4 hours, then MeOH (20mL) was added. The solvent was removed in vacuo and the residue was purified by column on silica gel (petroleum ether: EtOAc 3:1) to give the desired product (S) -tert-butyl 3- (5- (2-methyl-1, 3-dioxolan-2-yl) pent-1-enyl) pyrrolidine-1-carboxylate (500mg) as a yellow oil. The yield was 43%. (ESI 226(M + H-100) +).

Step 6: 3- (6-Oxoheptyl) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester

To a solution of tert-butyl (S) -3- (5- (2-methyl-1, 3-dioxolan-2-yl) pent-1-enyl) pyrrolidine-1-carboxylate (500mg, 1.54mmol) in EtOAc (20mL) was added Pd/C (10%, 50mg), and the mixture was stirred at 40 ℃ under H2 overnight. The reaction was filtered and the filtrate was concentrated in vacuo. The residue was treated with TsOH (264mg, 1.54mmol) in acetone (5 mL). The mixture was stirred at room temperature for 6 h, then EtOAc (20mL) was added, washed with saturated NaHCO3 solution (20mL) and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the desired product (R) -tert-butyl 3- (6-oxoheptyl) pyrrolidine-1-carboxylate (200mg) as a yellow oil. Yield was 46% (ESI 184(M + H-100) +).

And 7: 3- (5- (1, 8-naphthyridin-2-yl) pentyl) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester

To a solution of (R) -tert-butyl 3- (6-oxoheptyl) pyrrolidine-1-carboxylate (300mg, 1.06mmol) in EtOH (10mL) was added 2-aminonicotinaldehyde (155mg, 1.27mmol) and pyrrolidine (90mg, 1.27 mmol). The reaction was heated to reflux overnight. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH ═ 20:1) to give the desired product 3- (5- (1, 8-naphthyridin-2-yl) pentyl) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester as a yellow oil (220 mg). The yield was 56%. (ESI 370(M + H) +).

And 8: (R) -7- (5- (pyrrolidin-3-yl) pentyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride

To a solution of (R) -tert-butyl 3- (5- (1, 8-naphthyridin-2-yl) pentyl) pyrrolidine-1-carboxylate (220mg, 0.60mmol) in EtOAc (10mL) was added Pd/C (10%, 30 mg). The mixture was stirred at 40 ℃ under H2 overnight. The reaction was filtered and the filtrate was concentrated in vacuo. The residue was treated with a solution of HCl in dioxane (4.0M, 5mL) at room temperature for 2 hours, then the solvent was removed in vacuo to yield the desired product (R) -7- (5- (pyrrolidin-3-yl) pentyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride (160mg) as a yellow oil. The yield was 86%. (ESI 274(M + H) +).

Preparation of (R) -7- (3- (pyrrolidin-3-yloxy) propyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride

Step 1: 2- (3-bromopropyl) -2-methyl-1, 3-dioxolane

In a flame-dried round-bottom flask equipped with a magnetic stir bar and a dean-Stark trap, in N₂Next, a solution of 5-bromopentane-2-one (2.0g, 12.12mmol) in toluene (40mL) was treated with ethylene glycol (6.93g, 111.7mmol) and TsOH (384mg, 0.22 mmol). The reaction mixture was heated to reflux for 1 hour, allowed to cool to room temperature, and saturated aqueous NaHCO was used ₃Diluted (60mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (2 × 100mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 4:1) to give the desired product as a colorless oil (1.5 g). The yield was 59%.

Step 2: 3- (3- (2-methyl-1, 3-dioxolan-2-yl) propoxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester

A mixture of (R) -tert-butyl 3-hydroxypyrrolidine-1-carboxylate (894mg, 4.78mmol) and NaH (287mg, 7.18mmol) in DMF (10mL) was stirred at 0 deg.C for 1 h. A solution of 2- (3-bromopropyl) -2-methyl-1, 3-dioxolane (1g, 4.78mmol) in DMF (5mL) was added dropwise at 0 deg.C and the reaction mixture was stirred at 100 deg.C overnight. The solvent was removed in vacuo and the residue was purified through a silica gel column (petroleum ether: EtOAc 1:1) to give the desired product as a colorless oil (500 mg). Yield 33% (ESI 216(M + H-100)⁺)。

And step 3: 3- (4-Oxopentyloxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester

A mixture of (R) -tert-butyl 3- (3- (2-methyl-1, 3-dioxolan-2-yl) propoxy) pyrrolidine-1-carboxylate (500mg, 1.59mmol) and p-toluenesulfonic acid monohydrate (151mg, 0.79mmol) in acetone (10mL) and H2O (5mL) was stirred at room temperature for 4 hours. The reaction was diluted with H2O (10mL) and extracted with EtOAc (3X 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to yield the desired product as a colorless oil (380 mg). Yield 88% (ESI 172(M + H-100) ⁺)。

And 4, step 4: 3- (3- (1, 8-Naphthyridin-2-yl) propoxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester

A mixture of 3- (4-oxopentyloxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester (380mg, 1.40mmol), 2-aminonicotinaldehyde (171mg, 1.40mmol) and pyrrolidine (99mg, 1.40mmol) in ethanol (8mL) was refluxed overnight. The solvent was removed in vacuo, and the residue was purified by silica gel column (DCM: MeOH 40:1) to give the desired product as a colorless oil (310 mg). Yield 62% (ESI 358(M + H) +).

And 5: (R) -7- (3- (pyrrolidin-3-yloxy) propyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride

A mixture of 3- (3- (1, 8-naphthyridin-2-yl) propoxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester (310mg, 0.87mmol) and Pd/C (10%, 30mg) in EtOAc (30mL) was stirred under a balloon of hydrogen at room temperature for 16 h. The mixture was filtered and concentrated in vacuo. The residue was treated with 1, 4-dioxane containing HCl (4M, 5mL) at 25 ℃ for 2 hours. The solvent was removed in vacuo to give (R) -7- (3- (pyrrolidin-3-yloxy) propyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride as a colorless oil (240 mg). Yield 83% (ESI 262(M + H) +).

Preparation of (R) -7- (5- (pyrrolidin-3-yloxy) pentyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride

Step 1: 2- (5-Bromopentyl) -2-methyl-1, 3-dioxolane

To a solution of 7-bromoheptane-2-one (14g, 73mmol) in toluene (150mL) in a three-necked flask equipped with a dean-Stark trap was added ethane-1, 2-diol (15g, 255mmol) and p-toluenesulfonic acid (251mg, 1.46 mmol). The reaction mixture was stirred at reflux for 20 hours. The reaction mixture was cooled to room temperature and saturated NaHCO was used₃The solution, water and brine were washed. The organic phase was concentrated and the residue was separated by column on silica gel (7% EtOAc in petroleum ether) to give 2- (5-bromopentyl) -2-methyl-1, 3-dioxolane (16g, 92%).

Step 2: 3- (5- (2-methyl-1, 3-dioxolan-2-yl) pentyloxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester

To a solution of (R) -tert-butyl 3-hydroxypyrrolidine-1-carboxylate (3.5g, 18.7mmol) in DMF (25mL) at 0 deg.C was added NaH (830mg, 20.6mmol) in portions. The reaction mixture was stirred at 0 ℃ for 1 hour. 2- (5-Bromopentyl) -2-methyl-1, 3-dioxolane (4.9g, 20.6mmol) was added and the reaction mixture was stirred at 100 ℃ for 16 hours. The reaction mixture was poured into ice water and extracted with EtOAc (150mL × 3). The combined organic phases were washed with brine, over Na₂SO₄And (5) drying. The organic phase was concentrated and the residue was chromatographed on silica gel (20% EtOAc in petroleum ether) to give 3- (5- (2- Methyl-1, 3-dioxolan-2-yl) pentoxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester (3.7g, 57%); (ESI 344.3(M + H)⁺)。

And step 3: 3- (6-Oxoheptyloxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester

To a solution of (R) -tert-butyl 3- (5- (2-methyl-1, 3-dioxolan-2-yl) pentyloxy) pyrrolidine-1-carboxylate (3.7g, 10.8mmol) in acetone (70mL) and water (7mL) was added p-toluenesulfonic acid (927mg, 5.4 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with saturated aqueous NaHCO₃The solution was neutralized and concentrated under reduced pressure. The residue was extracted with EtOAc (100 mL. times.3). The combined organic phases were washed with brine, over Na₂SO₄Dried and concentrated to give the product (R) -tert-butyl 3- (6-oxoheptyloxy) pyrrolidine-1-carboxylate (2.99g, 92%) as a yellow oil; (ESI 300.1(M + H)⁺)。

And 4, step 4: 3- (5- (1, 8-naphthyridin-2-yl) pentyloxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester

To a solution of (R) -tert-butyl 3- (6-oxoheptyloxy) pyrrolidine-1-carboxylate (2.9g, 9.7mmol) in EtOH (40mL) was added 2-aminonicotinaldehyde (1.2g, 9.7mmol) and L-proline (558mg, 4.8 mmol). The reaction mixture was stirred at reflux for 16 hours. Then, the reaction mixture was concentrated and the residue was separated by silica gel column (5% MeOH in EtOAc) to give 3- (5- (1, 8-naphthyridin-2-yl) pentoxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester as a yellow oil (2.4g, 64%); (95% purity, UV ═ 214nm, ESI 386.0(M + H) ⁺)。

And 5: 3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyloxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester

To a solution of (R) -tert-butyl 3- (5- (1, 8-naphthyridin-2-yl) pentyloxy) pyrrolidine-1-carboxylate (2.4g, 6.2mmol) in EtOH (30mL) was added Pd/C (10%, 300 mg). Degassing the reaction mixture and reacting with H₂Purging 3 times and H at 45 ℃₂Stirred for 20 hours. The reaction mixture was filtered and the filtrate was concentrated to give (R) -tert-butyl 3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentoxy) pyrrolidine-1-carboxylate as a yellow oil (2.5g, 100%); (ESI 390.5(M + H)⁺)。

Step 6: (R) -7- (5- (pyrrolidin-3-yloxy) pentyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride

To a solution of (R) -tert-butyl 3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyloxy) pyrrolidine-1-carboxylate (2.4g, 6.2mmol) in DCM (10mL) was added HCl/1, 4-dioxane (4mol/L, 30 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give (R) -7- (5- (pyrrolidin-3-yloxy) pentyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride as a yellow oil (2.9g, 100%); (ESI 290.4(M-55)⁺)。

Preparation of 7- (5- (3-fluoropyrrolidin-3-yl) pentyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride

Step 1: 3- (4- (benzyloxy) butyl) -3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

To ((4-bromobutoxy) methyl) benzene (9.45g, 38.87mmol) and Mg (1.89g, 77.74mmol) in Et₂Mixture in O (20mL) addition of I₂(202mg, 1.09 mmol). The reaction mixture was stirred at 40 ℃ for 1 hour. After cooling to room temperature, the mixture was added to 3-oxopyrazine at 5 ℃Pyrrolidine-1-carboxylic acid tert-butyl ester (2.4g, 12.96mmol) in 30mL Et₂Solution in O. The reaction was stirred at room temperature overnight and then with aqueous NH₄Cl (10mL) was quenched and extracted with EtOAc (30 mL. times.3). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column on silica gel (petroleum ether: EtOAc 5:1-2:1) to give the desired product tert-butyl 3- (4- (benzyloxy) butyl) -3-hydroxypyrrolidine-1-carboxylate (1.7g) as a yellow oil. Yield 38% (ESI 294(M + H-56)⁺)。

Step 2: 3- (4- (benzyloxy) butyl) -3-fluoropyrrolidine-1-carboxylic acid tert-butyl ester

A mixture of tert-butyl 3- (4- (benzyloxy) butyl) -3-hydroxypyrrolidine-1-carboxylate (1.7g, 4.86mmol) and BAST (10.76g, 48.6mmol) in DCM (30mL) was stirred at 40 deg.C for 24 h. The reaction was diluted with MeOH (2mL), washed with water (20mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column on silica gel (petroleum ether: EtOAc 20:1-10:1) to give the desired product tert-butyl 3- (4- (benzyloxy) butyl) -3-fluoropyrrolidine-1-carboxylate (1.1g) as a pale yellow oil. Yield 64% (ESI 296(M + H-56) ⁺)。

And step 3: 3-fluoro-3- (4-hydroxybutyl) pyrrolidine-1-carboxylic acid tert-butyl ester

A mixture of tert-butyl 3- (4- (benzyloxy) butyl) -3-fluoropyrrolidine-1-carboxylate (1.1g, 3.13mmol) and Pd/C (5%, 1.1g) in EtOAc (100mL) was stirred under hydrogen at 45 ℃ overnight. The mixture was filtered and concentrated in vacuo to give the desired product tert-butyl 3-fluoro-3- (4-hydroxybutyl) pyrrolidine-1-carboxylate (780mg) as a pale yellow oil. Yield 95% (ESI 206(M + H-56)⁺)。

And 4, step 4: 3-fluoro-3- (4-iodobutyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of triphenylphosphine (1.58g, 6.04mmol) and imidazole (411mg, 6.04mmol) in DCM (40mL) at 5 deg.C was added I₂(835mg, 3.29 mmol). The reaction mixture was stirred at 5 ℃ for 15 minutes, and then a solution of tert-butyl 3-fluoro-3- (4-hydroxybutyl) pyrrolidine-1-carboxylate (780mg, 2.99mmol) in DCM (15mL) was added. The reaction mixture was stirred at 5 ℃ for 1 hour, then concentrated in vacuo at 15 ℃ and the residue was purified by column on silica gel (petroleum ether: EtOAc 20:1-10:1) to give the desired product tert-butyl 3-fluoro-3- (4-iodobutyl) pyrrolidine-1-carboxylate (700mg) as a pale yellow oil. Yield 63% (ESI 316(M + H-56)⁺)。

And 5: 3- (5- (1, 8-naphthyridin-2-yl) pentyl) -3-fluoropyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of (R) -tert-butyl 3- (1, 1-difluoro-4-iodobutyl) pyrrolidine-1-carboxylate (700mg, 1.88mmol) and 2-methyl-1, 8-naphthyridine (407mg, 2.82mmol) in THF (12mL) at 0 deg.C was added LiHMDS (2.82mL, 1M, 2.82 mmol). The reaction mixture was stirred at 0 ℃ for 3 h, then quenched with saturated ammonium chloride solution (6mL), diluted with water (15mL), and extracted with EtOAc (30 mL. times.2). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC to give the desired product tert-butyl 3- (5- (1, 8-naphthyridin-2-yl) pentyl) -3-fluoropyrrolidine-1-carboxylate (350mg) as a pale yellow solid. Yield 48% (ESI 388(M + H)⁺)。

Step 6: 7- (5- (3-fluoropyrrolidin-3-yl) pentyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride

A mixture of tert-butyl 3- (5- (1, 8-naphthyridin-2-yl) pentyl) -3-fluoropyrrolidine-1-carboxylate (200mg, 0.516mmol) and Pd/C (5%, 200mg) in EtOAc (20mL) was stirred under hydrogen at 45 ℃ overnight. The reaction mixture was filtered and concentrated in vacuo. To the residue were added 1, 4-dioxane (2mL) and HCl/dioxane (2mL, 4M) at room temperature. The reaction mixture was stirred at room temperature for 3 hours, then concentrated in vacuo to give the desired product 7- (5- (3-fluoropyrrolidin-3-yl) pentyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride (140mg) as a pale yellow solid. Yield 93% (ESI 292(M + H) ⁺)。

Preparation of 2- (4- (((R) -pyrrolidin-3-yl) oxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride

Step 1: (R) -3- (hex-5-en-1-yloxy) pyrrolidine-1-carboxylic acid tert-butyl ester

To a suspension of (R) -3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (12.8g, 68.4mmol), tetrabutylammonium bromide (1.102g, 3.42mmol) and 6-bromo-1-hexene (13.71mL, 103mmol) in heptane (256mL) was added sodium hydroxide (128mL, 68.4mmol, water containing 50 wt% solution). The mixture was stirred vigorously at 80 ℃ for 2 hours, then cooled to room temperature, diluted with water, and extracted with heptane and twice with diethyl ether/heptane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. By column chromatography (600g of silica, containing 5->14% ethyl acetate in heptane) gave the desired product (R) -tert-butyl 3- (hex-5-en-1-yloxy) pyrrolidine-1-carboxylate (14.93 g). The yield was 81%.¹H NMR (400MHz, chloroform-d) δ 5.87-5.74 (m,1H), 5.05-4.91 (m,2H), 4.04-3.95 (m,1H), 3.48-3.27 (m,6H),2.07(q, J ═ 7.2Hz,2H), 2.02-1.84 (m,2H), 1.60-1.51 (m,2H), 1.51-1.38 (m,11H).

Step 2: (R) -3- ((5-oxopentyl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl (R) -3- (hex-5-en-1-yloxy) pyrrolidine-1-carboxylate (14.93g, 55.4mmol) in THF (420mL) and water (140mL) was added sodium periodate (26.1g, 122mmol) and osmium tetroxide (1.5mL, 0.232mmol, water containing 4% solution). After 1 hour, additional sodium periodate (5g, 23.38mmol) was added. After 30 minutes, the mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to flash column chromatography (about 600g of silica, 20->50% ethyl acetate in heptane). This gave the desired product, tert-butyl (R) -3- ((5-oxopentyl) oxy) pyrrolidine-1-carboxylate (10.97 g). The yield was 72%.¹H NMR (400MHz, chloroform-d) δ 9.77(s,1H), 4.03-3.94 (m,1H), 3.50-3.27 (m,6H),2.47(t, J ═ 7.2Hz,2H), 2.02-1.84 (m,2H), 1.77-1.65 (m,2H), 1.65-1.54 (m,2H),1.46(s,9H).

And step 3: (3R) -3- ((5-hydroxyhept-6-en-1-yl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of (R) -3- ((5-oxopentyl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester (10.97g, 40.4mmol) in THF (70mL) at 0 deg.C was added vinyl magnesium bromide (66.4mL, 46.5mmol, THF as a 0.7M solution) dropwise. After 16 h, the mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated, and the residue was purified by flash column chromatography (20- >50% EtOAc in heptane) to yield the desired product tert-butyl (3R) -3- ((5-hydroxyhept-6-en-1-yl) oxy) pyrrolidine-1-carboxylate (7.68 g). The yield was 63%.¹H NMR (400MHz, chloroform-d) delta 5.93-5.80 (m,1H), 5.28-5.17 (m,1H), 5.15-5.06 (m,1H), 4.17-4.05 (m,1H),3.99(s,1H), 3.52-3.23 (m,6H), 2.03-1.83 (m,2H), 1.65-1.50 (m,5H), 1.50-1.33 (m,11H).

And 4, step 4: (R) -3- ((7- (2-Chloropyridin-3-yl) -5-oxoheptyl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester

Tert-butyl (3R) -3- ((5-hydroxyhept-6-en-1-yl) oxy) pyrrolidine-1-carboxylate (10.48g, 35.0mmol), 2-chloro-3-iodopyridine (4.19g, 17.50mmol), tetrabutylammonium chloride (0.486g, 1.750mmol) and sodium bicarbonate (3.68g, 43.8mmol) were dissolved/suspended in DMF (35mL) under argon and argon was bubbled through this mixture for 15 minutes. Palladium (II) acetate (0.393g, 1.750mmol) was added and the mixture was heated to 50 ℃ for 24 hours, then cooled to room temperature, diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed three times with brine, dried over sodium sulfate and concentrated, and the residue was purified by column chromatography (silica, 20->55% EtOAc in heptane) to give the desired product (R) -tert-butyl 3- ((7- (2-chloropyridin-3-yl) -5-oxoheptyl) oxy) pyrrolidine-1-carboxylate (3.05 g). The yield was 42%. ¹H NMR (400MHz, chloroform-d) δ 8.25(dd, J ═ 4.7,1.9Hz,1H),7.62(dd, J ═ 7.5,1.9Hz,1H),7.17(dd, J ═ 7.5,4.7Hz,1H), 4.04-3.93 (m,1H), 3.51-3.25 (m,6H),2.99(t, J ═ 7.3Hz,2H),2.79(t, J ═ 7.3Hz,2H),2.43(t, J ═ 7.2Hz,2H), 2.01-1.83 (m,2H), 1.72-1.48 (m,4H),1.30(s,9H).

And 5: (R) -3- ((5- (((R) -tert-butylsulfinyl) imino) -7- (2-chloropyridin-3-yl) heptyl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of (R) - (+) -2-methyl-2-propane sulfinamide (1.799g, 14.84mmol) and tert-butyl (R) -3- ((7- (2-chloropyridin-3-yl) -5-oxoheptyl) oxy) pyrrolidine-1-carboxylate (3.05g, 7.42mmol) in THF (30mL) was added titanium (IV) ethoxide (7.24mL, 22.27 mmol). The resulting mixture was heated to 50 ℃ for 20 hours, then poured over half-saturated aqueous sodium bicarbonate and stirredMix for 10 minutes, transfer to 2 centrifuge tubes, and centrifuge at 7800rpm for 5 minutes. The liquid was poured into a separatory funnel. The vial was then filled with ethyl acetate, shaken vigorously, and centrifuged again at 7800rpm for 5 minutes. The liquids were combined in a separatory funnel. The layers were separated and the aqueous phase was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated, and the residue was purified by flash column chromatography (300g silica, 35-65% EtOAc in heptane) to give the desired product tert-butyl (R) -3- ((5- (((R) -tert-butylsulfinyl) imino) -7- (2-chloropyridin-3-yl) heptyl) oxy) pyrrolidine-1-carboxylate (3.15 g). Yield 78% (ESI 514/516(M + H) +). ¹H NMR (400MHz, chloroform-d) δ 8.27(dd, J ═ 4.7,1.9Hz,1H),7.64(dd, J ═ 62.5,7.4Hz,1H),7.19(dd, J ═ 7.5,4.8Hz,1H),3.99(s,1H), 3.54-3.24 (m,6H), 3.16-2.87 (m,2H), 2.87-2.60 (m,2H), 2.60-2.35 (m,1H),1.94(s,2H), 1.77-1.53 (m,5H),1.45(s,9H), 1.35-1.11 (m,9H).

Step 6: (3R) -3- ((5- (((R) -tert-butylsulfinyl) amino) -7- (2-chloropyridin-3-yl) heptyl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl (R) -3- ((5- (((R) -tert-butylsulfinyl) imino) -7- (2-chloropyridin-3-yl) heptyl) oxy) pyrrolidine-1-carboxylate (3.15g, 6.13mmol) in methanol (20mL) was added sodium borohydride (0.278g, 7.35 mmol). After 2 hours, the mixture was quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated, and the residue was purified by flash column chromatography (50->100% EtOAc in heptane) to give the desired product tert-butyl (3R) -3- ((5- (((R) -tert-butylsulfinyl) amino) -7- (2-chloropyridin-3-yl) heptyl) oxy) pyrrolidine-1-carboxylate (3.05 g). The yield was 85%.¹H NMR (400MHz, chloroform-d) delta 8.28-8.22 (m,1H), 7.72-7.51 (m,1H), 7.22-7.15 (m,1H), 4.03-3.95 (m,1H), 3.49-3.22 (m,7H), 3.16-3.06 (m,1H), 2.96-2.64 (m,2H), 2.00-1.83 (m,1H) ,4H),1.80–1.70(m,1H),1.65–1.51(m,3H),1.51–1.37(m,11H),1.25(s,9H).

And 7: (3R) -3- (4- (1- ((R) -tert-butylsulfinyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl (3R) -3- ((5- (((R) -tert-butylsulfinyl) amino) -7- (2-chloropyridin-3-yl) heptyl) oxy) pyrrolidine-1-carboxylate (3.05g, 5.20mmol) in 1, 4-dioxane (25mL) was added xanthphos (0.602g, 1.040mmol) and cesium carbonate (3.39g, 10.40 mmol). The mixture was bubbled through with argon for 15 minutes. Palladium (II) acetate (0.117g, 0.520mmol) was added and the reaction bubbled through with argon for 1 minute and stirred at 100 ℃ for 16 hours, then cooled to room temperature, quenched with water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated, and the residue was purified by flash column chromatography (40->100% EtOAc in heptane) to yield the desired product tert-butyl (3R) -3- (4- (1- ((R) -tert-butylsulfinyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidine-1-carboxylate (928 mg). Yield 36% (ESI 480(M + H) +). The compounds were separated by chiral SFC to yield stereoisomer a and stereoisomer B. Equipment: vochtik 100SFC UV guidance system; vortex 2998 photodiode array (PDA) detectors; vortish 2767 sample manager; masslynx ^TMSoftware; FractionLynx^TMThe application manager, the acquisition method: cell-2_ f70_10_50_8mn _ SW _120bar, load: 50mg, column: phnomenex (Phenomenex) Lux cellulose-2 (250X 21.2mm, 5 μm), flow: 70 ml/min, column temperature: 35 ℃; ABPR: 120 bar; eluent A: CO 2₂And eluent B: methanol with 20mM ammonia, linear gradient: t-0 min 10% B, t-5 min 50% B, t-7.5 min 50% B, t-8 min 10% B. And (3) injection: sandwich 100 μ l methanol, assay PDA: 210 vs 320nm, collect: based on PDA TIC.

(3R)-3-(4-(1-(Tert-butyl (R) -tert-butylsulfinyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidine-1-carboxylic acid tert-butyl ester stereoisomer a: 0.58 g, LC/MS ESI 480(M + H) +.¹H NMR (400MHz, chloroform-d) Δ 8.06-7.98 (m,1H), 7.37-7.29 (m,1H), 6.73-6.63 (m,1H), 4.20-4.09 (m,1H), 4.03-3.93 (m,1H), 3.50-3.25 (m,6H), 2.94-2.79 (m,1H), 2.77-2.65 (m,1H), 2.20-2.08 (m,1H), 2.00-1.49 (m,7H),1.46(s,9H), 1.43-1.27 (m,2H),1.21(s,9H).

Tert-butyl (3R) -3- (4- (1- ((R) -tert-butylsulfinyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidine-1-carboxylate stereoisomer B: 0.45 g, LC/MS ESI 480(M + H) +.¹H NMR (400MHz, chloroform-d) Δ 8.20-8.09 (m,1H), 7.39-7.31 (m,1H), 6.90-6.80 (m,1H), 4.25-4.12 (m,1H), 4.04-3.92 (m,1H), 3.51-3.24 (m,6H), 2.87-2.62 (m,2H), 2.11-1.83 (m,3H), 1.76-1.49 (m,6H),1.46(s,9H), 1.40-1.27 (m,10H).

And 8: 2- (4- (((R) -pyrrolidin-3-yl) oxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine stereoisomer A dihydrochloride

To a solution of tert-butyl (3R) -3- (4- (1- ((R) -tert-butylsulfinyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidine-1-carboxylate stereoisomer a (0.58g, 1.209mmol) in methanol (5mL) was added hydrochloric acid (5mL, 20.00mmol, 4N solution in dioxane). The mixture was stirred at room temperature for 3 hours, then concentrated in vacuo and co-evaporated with methanol. Diethyl ether was added, which started slow crystallization of the product. After standing overnight, the crystallized material was scraped loose and the material was triturated with diethyl ether. After several hours, the solid was collected by filtration, rinsed with fresh diethyl ether, and dried under vacuum to give the desired product 2- (4- (((R) -pyrrolidin-3-yl) oxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine stereoisomer a dihydrochloride (438mg) as a beige solid. The yield was 100%. LC/MS ESI 276(M-2HCl + H) +.¹H NMR (400MHz, methanol-d 4) δ 7.75-7.66 (m,2H),6.80(t, J ═ 6.8Hz,1H), 4.30-4.23 (m,1H), 3.67-3.56 (c), (d), (m,1H), 3.56-3.44 (m,2H), 3.44-3.33 (m,3H),3.25(dd, J ═ 12.5,4.2Hz,1H), 2.96-2.78 (m,2H), 2.26-2.16 (m,1H), 2.13-1.99 (m,2H), 1.77-1.46 (m,7H), 1.23-1.12 (m,1H) specific optical rotation: 33.9 ℃ c ═ 0.5, MeOH, 22.7 ℃, 589 nm.

And step 9: 2- (4- (((R) -pyrrolidin-3-yl) oxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine stereoisomer B dihydrochloride

To a solution of tert-butyl (3R) -3- (4- (1- ((R) -tert-butylsulfinyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidine-1-carboxylate stereoisomer B (0.45g, 0.938mmol) in methanol (5mL) was added hydrochloric acid (5mL, 20.00mmol, 4N solution in dioxane). The mixture was stirred at room temperature for 3 hours, then concentrated in vacuo and co-evaporated with methanol. Diethyl ether was added, which started slow crystallization of the product. After standing overnight, the crystallized material was scraped loose and the material was triturated with diethyl ether. After a few hours, the solid was collected by filtration, rinsed with fresh diethyl ether and dried under vacuum to give the desired product 2- (4- (((R) -pyrrolidin-3-yl) oxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine stereoisomer B dihydrochloride (289mg) as a beige solid. The yield was 85%. LC/MS ESI 276(M-2HCl + H) +.¹H NMR (400MHz, methanol-d 4) δ 7.74-7.66 (m,2H),6.80(t, J ═ 6.8Hz,1H), 4.30-4.23 (m,1H), 3.66-3.57 (m,1H), 3.57-3.45 (m,2H), 3.45-3.33 (m,3H), 3.29-3.21 (m,1H), 2.96-2.78 (m,2H), 2.26-2.16 (m,1H), 2.13-1.97 (m,2H), 1.76-1.44 (m,7H) specific rotation: -48.3 ℃ c ═ 0.5, MeOH, 22.7 ℃, 589 nm.

Compounds 1-21 were prepared using the following method:

example 1: preparation of 2- (2-cyclopropylphenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compounds 1-E1 and 1-E2)

Step 1: 2- (2-Cyclopropylphenyl) acetic acid ethyl ester

Ethyl 2- (2-bromophenyl) acetate (5.0g, 20.57mmol), cyclopropylboronic acid (3.54g, 41.14mmol), Pd (OAc)₂A mixture of (922mg, 4.12mmol), tricyclohexylphosphine (1.73g, 6.17mmol) and tripotassium phosphate (15.3g, 72.01mmol) in toluene (60mL) and water (7.5mL) was stirred at 120 ℃ overnight. The solvent was removed in vacuo, and the residue was purified by silica gel column (petroleum ether: EtOAc 20:1) to give the desired product ethyl 2- (2-cyclopropylphenyl) acetate (4.0g) as a colorless oil. The yield was 95%.¹H NMR(400MHz,CDCl3)δ7.21-7.18(m,4H),4.18-4.16(q,2H),3.83(s,2H),1.52-1.48(m,1H),1.29-1.18(t,3H),0.94-0.64(m,4H).

Step 2: 2-bromo-2- (2-cyclopropylphenyl) acetic acid ethyl ester

To a solution of ethyl 2- (2-cyclopropylphenyl) acetate (1g, 4.9mmol) in THF (16mL) at-78 deg.C was added dropwise THF/hexane (6.2mL, 12.4mmol) containing a 2.0M solution of lithium diisopropylamide. The reaction was stirred at-78 ℃ for 30 minutes. Then, a solution of chlorotrimethylsilane (1.3g, 12.25mmol) in THF (5mL) was added and the reaction was stirred at-78 deg.C for an additional 30 minutes. Then, a solution of NBS (1.5g, 12.25mmol) in THF (10mL) was added and the reaction was stirred at-78 deg.C for 1 hour. The reaction was quenched with MeOH (2mL) and concentrated in vacuo, and the residue was purified through a silica gel column (petroleum ether: EtOAc 10:1) to give the desired product ethyl 2-bromo-2- (2-cyclopropylphenyl) acetate as a yellow oil (350 mg). The yield was 25%.

And step 3: 2- (2-Cyclopropylphenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid ethyl ester

Ethyl 2-bromo-2- (2-cyclopropylphenyl) acetate (350mg, 1.24mmol), (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (341mg, 1.24mmol) and K₂CO₃A mixture of (513mg, 3.72mmol) in acetonitrile (8mL) was stirred at 60 ℃ for 16 h. The solvent was removed in vacuo, and the residue was purified by silica gel column (DCM: MeOH 20:1) to give the desired product ethyl 2- (2-cyclopropylphenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate as a yellow oil (150 mg). Yield 25% (ESI 478(M + H) +).

And 4, step 4: 2- (2-Cyclopropylphenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compounds 1-E1 and 1-E2)

Ethyl 2- (2-cyclopropylphenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate (150mg, 0.31mmol) was treated with LiOH-H2O (52mg, 1.24mmol) in MeOH (4mL) and H2O (1mL) at 60 ℃ for 2H. The solvent was removed in vacuo and the residue was purified by preparative HPLC a (30-65% MeCN) to yield compound 1 as a white solid (110mg, 77% yield). The racemic product was isolated by preparative chiral SFC a to give the diastereomeric products compound 1-E1(25mg) and compound 1-E2(26mg) as white solids.

Compound 1-E1 LC/MS ESI 450.6(M + H) +. 1H NMR (400MHz, MeOD) δ 7.60(d, J ═ 7.6Hz,1H),7.28(m,2H),7.15(d, J ═ 7.3Hz,2H),6.37(d, J ═ 7.3Hz,1H),5.31(s,1H),4.21(s,1H), 3.72-3.32 (m,6H), 3.24-3.02 (m,2H),2.71(t, J ═ 6.3Hz,2H),2.54(t, J ═ 7.5Hz,2H), 2.31-1.95 (m,3H), 1.94-1.79 (m,2H), 1.77-1.66 (m,2H),1.58(m,2H), 1.05-0.87 (m,3H), 0.67-0.38 chiral MeOH (sfa): ee 98%, Rt 1.97 min

Compound 1-E2 LC/MS ESI 450.6(M + H) +. 1H NMR (400MHz, MeOD) δ 7.60(d, J ═ 7.6Hz,1H),7.28(m,2H),7.15(d, J ═ 7.3Hz,2H),6.37(d, J ═ 7.3Hz,1H),5.31(s,1H),4.21(s,1H), 3.72-3.32 (m,6H), 3.24-3.02 (m,2H),2.71(t, J ═ 6.3Hz,2H),2.54(t, J ═ 7.5Hz,2H), 2.31-1.95 (m,3H), 1.94-1.79 (m,2H), 1.77-1.66 (m,2H),1.58(m,2H), 1.05-0.87 (m,3H), 0.67-0.38 chiral MeOH (sfa): ee 98%, Rt 2.59 min

Example 2: preparation of 2- (2-Cyclopropoxyphenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compounds 2-E1 and 2-E2)

Step 1: 1-bromo-2-cyclopropoxybenzene

A mixture of 2-bromophenol (2.0g, 11.6mmol), bromocyclopropane (4.6g, 38.1mmol), and K2CO3(5.2g, 38.1mmol) in dry DMF (10mL) was sealed in a test tube and heated by microwave at 140 ℃ for 2 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with diethyl ether (3X 100 mL). The combined organic layers were washed with brine and concentrated in vacuo. The residue was purified by column on silica gel (eluted with 0-10% EtOAc in hexanes) to give the desired product as a colorless oil (400 mg). Yield 17% 1H NMR (400MHz, CDCL3) δ 7.52(d, J ═ 7.2Hz,1H),7.30-7.27(m,2H),6.88-6.84(m,1H),3.83-3.80(m,1H),0.90-0.82(m,4H).

Step 2: 2-Cyclopropoxyphenylboronic acid

To a solution of 1-bromo-2-cyclopropoxybenzene (800mg, 3.75mmol) in THF (20mL) was added n-BuLi (2.5M, 4.5mmol) dropwise. The reaction was stirred at-78 ℃ under Ar for 1 hour. A solution of trimethyl borate (779mg, 7.5mmol) in THF (5mL) was added dropwise and the reaction was stirred at-78 deg.C for an additional 1 hour, then slowly warmed to room temperature and stirred overnight. Aqueous HCl (1N, 20mL) was added and the reaction was stirred at room temperature for 30 min, then extracted with DCM (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified through a silica gel column (petroleum ether: EtOAc ═ 1:1) to give the desired product as a white solid (400 mg). Yield: 60% (ESI:178[ M-H ] -).

And step 3: 2- (2-Cyclopropoxyphenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compounds 2-E1 and 2-E2)

A mixture of 2-cyclopropoxyphenylboronic acid (400mg, 2.25mmol), (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (476mg, 1.73mmol) and 2-oxoacetic acid (304mg, 3.45mmol) in DCM (5mL) was stirred at room temperature for 8 hours. The solvent was removed in vacuo and the residue was purified by preparative HPLC a (30-65% MeCN) to yield compound 2 as a white solid (205mg, 26% yield). The racemic product was isolated by preparative chiral SFC a to give the diastereomeric products compound 2-E1(110mg) and compound 2-E2(79mg) as white solids.

Compound 2-E1 LC/MS ESI 466(M + H) + 1H NMR (400MHz, MeOD) δ 7.48(d, J ═ 7.6Hz,1H),7.41-7.40(M,2H),7.13(d, J ═ 7.6Hz,1H),7.04-7.00(M,1H),6.38(d, J ═ 7.6Hz,1H),4.92(s,1H),4.18-4.16(M,1H),3.90-3.85(M,1H),3.56-3.36(M,5H),3.27-3.01(M,3H),2.70(t, J ═ 6.0Hz,2H),2.56(t, J ═ 7.2Hz,2H), 2.09-1.55H (M, 8.55H), chiral MeOH (SFC, 4H), 4.85 (M, 40): ee 85.4%, Rt 2.39 min

Compound 2-E2 LC/MS ESI 466(M + H) + 1H NMR (400MHz, MeOD) δ 7.52(d, J ═ 7.6Hz,1H),7.41-7.40(M,2H),7.13(d, J ═ 7.2Hz,1H),7.03-6.99(M,1H),6.37(d, J ═ 7.2Hz,1H),4.86(s,1H),4.15-4.12(M,1H),3.92-3.75(M,1H),3.56-3.36(M,5H),3.27-3.14(M,3H),2.70(t, J ═ 6.0Hz,2H),2.53(t, J ═ 7.6Hz,2H),2.20-1.55(M,8H), chiral MeOH (M, 0.85) (SFC, 4% MeOH): ee 95.4%, Rt 3.27 min

Example 3: preparation of 2- (2-cyclopropylpyridin-3-yl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetic acid (compounds 3-E1 and 3-E2)

Step 1: 3-bromo-2-cyclopropylpyridine

To a solution of 2, 3-dibromopyridine (3g, 12.8mmol) and cyclopropylzinc (II) bromide (76mL, 0.5M in THF) in THF (30mL) was added Pd (PPh3)4(740mg, 0.64 mmol). The mixture was stirred at 70 ℃ under N2 for 4h, then diluted with water (50mL) and extracted with EtOAc (3X 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 10:1) to give the desired product 3-bromo-2-cyclopropylpyridine (1.2g) as a yellow oil. Yield 48% (ESI 198(M + H) +).

Step 2: 2- (2-Cyclopropylpyridin-3-yl) -2-Hydroxyacetic acid Ethyl ester

To a solution of EtMgBr (1M, 3.65mL, 3.65mmol) in THF (20mL) at 0 deg.C under N2 was added N-BuLi (2.9mL, 7.3 mmol). The solution was stirred at 0 ℃ for 30 minutes, then a solution of 3-bromo-2-cyclopropylpyridine (1.2g, 6.1mmol) in THF (5mL) was added at-10 ℃. The mixture was stirred at that temperature for 30 minutes and ethyl 2-oxoacetate (50% in toluene, 5g, 24.4mmol) was added. The reaction was stirred at 0 ℃ for 2 h, then quenched with saturated K2CO3 solution (20mL) and extracted with EtOAc (3X 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether: EtOAc 2:1) to give the desired product ethyl 2- (2-cyclopropylpyridin-3-yl) -2-hydroxyacetate (700mg) as a yellow oil. Yield 52% (ESI 222(M + H) +).

And step 3: 2- (2-Cyclopropylpyridin-3-yl) -2- (methylsulfonyloxy) acetic acid ethyl ester

To a solution of ethyl 2- (2-cyclopropylpyridin-3-yl) -2-hydroxyacetate (300mg, 1.36mmol) and triethylamine (411mg, 4.1mmol) in DCM (5mL) was added MsCl (232mg, 2mmol) at 0 ℃. The reaction was stirred at room temperature for 2 hours, then concentrated in vacuo and purified by silica gel column (petroleum ether: EtOAc 4:1) to give the desired product ethyl 2- (2-cyclopropylpyridin-3-yl) -2- (methylsulfonyloxy) acetate as a yellow oil (190 mg). Yield 47% (ESI 300(M + H) +).

And 4, step 4: 2- (2-Cyclopropylpyridin-3-yl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetic acid ethyl ester

A mixture of (R) -7- (5- (pyrrolidin-3-yl) pentyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine hydrochloride (300mg, 0.87mmol), ethyl 2- (2-cyclopropylpyridin-3-yl) -2- (methylsulfonyloxy) acetate (286mg, 0.96mmol) and diisopropylethylamine (337mg, 2.6mmol) in acetonitrile (10mL) was stirred at 50 ℃ overnight. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH 0% -20%) to give the desired product as a yellow oil (245 mg). Yield 54% (ESI 477(M + H) +).

Step 2: 2- (2-Cyclopropylpyridin-3-yl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetic acid (Compounds 3-E1 and 3-E2)

Ethyl 2- (2-cyclopropylpyridin-3-yl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetate (245mg, 0.51mmol) was diluted with LiOH-H₂O (210mg, 5.0mmol) in MeOH (4mL) and H₂O (1mL) was treated at room temperature for 2 hours. The solvent was removed in vacuo and the residue was purified by preparative HPLC a (30-60% MeCN) to yield a white solid Compound 3(110mg, 48% yield). The racemic product was separated by preparative chiral SFC H to give the diastereomeric products compound 3-E1(42mg) and compound 3-E2(45mg) as white solids.

Compound 3-E1 LC/MS ESI 449(M + H)⁺ ¹H NMR (400MHz, MeOD) δ 8.39(t, J ═ 6.1Hz,1H),7.98(d, J ═ 7.9Hz,1H),7.19 to 7.10(m,2H),6.35(d, J ═ 7.3Hz,1H),5.06(s,1H),3.40 to 3.31(m,3H),3.15 to 3.08(m,2H),2.84 to 2.81(m,1H),2.70 to 2.67(m,2H),2.59 to 2.56(m,1H),2.55 to 2.47(m,2H),2.36 to 2.26(m,1H),2.21 to 2.13(m,1H),1.90 to 1.84(m,2H),1.66 to 1.57(m,3H),1.44 to 1H (m,1H), chiral MeOH (m, 0.05 to 0.93) (sfh, 1H), 1H, 0% chiral MeOH: ee 92%, Rt 2.11 min

Compound 3-E2 LC/MS ESI 449(M + H)⁺ ¹H NMR (400MHz, MeOD) δ 8.36(t, J ═ 6.1Hz,1H),8.01(d, J ═ 7.9Hz,1H),7.20 to 7.11(m,2H),6.35(d, J ═ 8Hz,1H),4.91(s,1H),3.51 to 3.36(m,3H),3.20 to 2.91(m,2H),2.71 to 2.29(m,7H),2.14 to 2.09(m,1H),1.90 to 1.84(m,2H),1.64 to 1.57(m,3H),1.433 to 1.23(m,7H),1.06 to 1.01(m,2H),0.92 to 0.88(m,1H), SFC H (45% chiral MeOH): ee 100%, Rt 3.77 min

Example 4: preparation of 2- (2-cyclopropyl-5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compounds 4-E1 and 4-E2)

Step 1: 2-cyclopropyl-5-fluoroaniline

A mixture of 2-bromo-5-fluoroaniline (3.0g, 15.8mmol), cyclopropylboronic acid (2.7g, 31.4mmol), PCy3(440mg, 1.57mmol), Pd (OAc)2(352mg, 1.57mmol) and K3PO4(20g, 94.3mmol) in toluene (50mL) and H2O (10mL) was stirred at 100 ℃ for 4H. The reaction mixture was cooled to room temperature, diluted with H2O (10mL), and extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 2:1) to give the desired product as a colorless oil (1.8 g). Yield 75% (ESI:152[ M + H ] +).

Step 2: 1-cyclopropyl-4-fluoro-2-iodobenzene

2-cyclopropyl-5-fluoroaniline (1.8g, 11.9mmol) was added to a solution of p-toluenesulfonic acid monohydrate (6.8g, 35.8mmol) in acetonitrile (60 mL). The reaction was stirred at room temperature for 10 minutes and then cooled to 10 ℃. A solution of sodium nitrite (2.0g, 29.0mmol) and potassium iodide (4.0g, 24.1mmol) in water (20mL) was added dropwise over 30 minutes. The reaction mixture was stirred at room temperature for 4 hours, then basified with aqueous sodium bicarbonate to pH 9-10, then diluted with EtOAc (100mL) and 10% aqueous sodium metabisulfite (20 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2X 100 mL). The organics were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 10:1) to give the desired product as a colorless oil (1.3 g). Yield 42% (ESI: N/A).

And step 3: 2-cyclopropyl-5-fluorophenylboronic acid

To a solution of 1-cyclopropyl-4-fluoro-2-iodobenzene (1.3g, 4.96mmol) in THF (50mL) was added n-BuLi (2.5M, 2.2mL, 5.5mmol) dropwise. The reaction was stirred at-78 ℃ under Ar for 1 hour. A solution of trimethyl borate (1.0g, 9.62mmol) in THF (10mL) was added dropwise and the reaction was stirred at-78 deg.C for an additional 1 hour, then slowly warmed to room temperature and stirred overnight. Aqueous HCl (1N, 20mL) was added, and the mixture was stirred at room temperature for 30 min, then extracted with DCM (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified through a silica gel column (petroleum ether: EtOAc ═ 1:1) to give the desired product as a white solid (500 mg). Yield: 56% (ESI:179[ M-H ] -).

And 4, step 4: 2- (2-cyclopropyl-5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compounds 4-E1 and 4-E2)

A mixture of 2-cyclopropyl-5-fluorophenylboronic acid (200mg, 1.11mmol), (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (306mg, 1.11mmol) and 2-oxoacetic acid (123mg, 1.66mmol) in MeCN (5mL) was stirred at 60 ℃ for 15 hours. The solvent was removed in vacuo and the residue was purified by preparative HPLC a (30-65% MeCN) to yield compound 4 as a white solid (120mg, 23% yield). The racemic product was isolated by preparative chiral SFC a to give the diastereomeric products compound 4-E1(34mg) and compound 4-E2(41mg) as white solids.

Compound 4-E1 LC/MS ESI 468(M + H) + 1H NMR (400MHz, MeOD) δ 7.41(d, J ═ 10.0Hz,1H),7.20-7.01(M,3H),6.38(d, J ═ 7.2Hz,1H),5.28(s,1H),4.21(s,1H),3.55-3.05(M,8H),2.71(t, J ═ 6.4Hz,2H),2.55(t, J ═ 7.6Hz,2H),2.19-2.05(M,3H),1.92-1.55(M,6H),0.95-0.80(M,3H),0.55-0.50(M,1H), chiral SFC a (35% MeOH): ee 100%, Rt 2.69 min

Compound 4-E2 LC/MS ESI 468(M + H) + 1H NMR (400MHz, MeOD) δ 7.41(d, J ═ 10.0Hz,1H),7.20-7.01(M,3H),6.38(d, J ═ 7.2Hz,1H),5.19(s,1H),4.18(s,1H),3.54-3.19(M,8H),2.71(t, J ═ 6.0Hz,2H),2.59-2.53(M,2H),2.22-2.14(M,3H),1.92-1.55(M,6H),0.98-0.85(M,3H),0.55-0.50(M,1H), chiral SFC a (35% MeOH): ee 97%, Rt 3.26 min

Example 5: preparation of 2- (2-cyclopropylphenyl) -2- ((R) -3- (3- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propoxy) pyrrolidin-1-yl) acetic acid (compounds 5-E1 and 5-E2)

Step 1: 2- (2-Cyclopropylphenyl) -2- ((R) -3- (3- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propoxy) pyrrolidin-1-yl) acetic acid (Compounds 5-E1 and 5-E2)

A mixture of 2-cyclopropylphenylboronic acid (102mg, 0.63mmol), (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (140mg, 0.42mmol), and 2-oxoacetic acid (47mg, 0.63mmol) in DCM (5mL) was stirred at room temperature for 8 hours. The solvent was removed in vacuo and the residue was purified by preparative HPLC a (30-65% MeCN) to yield compound 5 as a white solid (95mg, 52% yield). The racemic product was separated by preparative chiral SFC H to give the diastereomeric products compound 5-E1(15mg) and compound 5-E2(9mg) as white solids.

Compound 5-E1 LC/MS ESI 436.4(M + H)⁺ ¹H NMR (400MHz, MeOD) δ 7.64(d, J ═ 7.6Hz,1H),7.33 to 7.12(m,4H),6.36(d, J ═ 7.2Hz,1H),5.26(s,1H),4.18(s,1H),3.55 to 3.22(m,8H),2.69(t, J ═ 6.4Hz,2H),2.60(t, J ═ 7.2Hz,2H),2.30 to 2.13(m,3H),1.92 to 1.84(m,4H),1.08 to 0.90(m,3H),0.65 to 0.55(m,1H), chiral SFC H (35% MeOH): ee 98%, Rt 2.74 min

Compound 5-E2 LC/MS ESI 436.4(M + H)⁺ ¹H NMR (400MHz, MeOD) δ 7.61(d, J ═ 7.6Hz,1H),7.32 to 7.12(m,4H),6.36(d, J ═ 7.2Hz,1H),5.33(s,1H),4.21(s,1H),3.55 to 3.09(m,8H),2.70(t, J ═ 6.4Hz,2H),2.60(t, J ═ 7.2Hz,2H),2.25 to 2.00(m,3H),1.93 to 1.84(m,4H),1.08 to 0.90(m,3H),0.65 to 0.55(m,1H), chiral SFC H (35% MeOH): ee 99%, Rt 3.55 min

Example 6: preparation of 2- (2, 6-dicyclopropylpyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compounds 6-E1 and 6-E2)

Step 1: 2, 6-dicyclopropylpyridin-3-amine

A mixture of 2, 6-dibromopyridine-3-ethylamine (6.0g, 23.8mmol), cyclopropylboronic acid (6.14g, 71.4mmol), Pd (OAc)2(267mg, 2.38mmol), tricyclohexylphosphine (668mg, 6.17mmol) and tripotassium phosphate (17.7g, 83.3mmol) in toluene (80mL) and water (10mL) was stirred at 120 ℃ overnight. The solvent was removed in vacuo and the residue was purified by silica gel column (petroleum ether: EtOAc 4:1) to give the desired product 2, 6-dicyclopropylpyridin-3-amine (3.0g) as a colorless oil. Yield 95% (ESI 175.0(M + H) +).

Step 2: 2, 6-dicyclopropylpyridin-3-amine

A mixture of 2, 6-dicyclopropylpyridine-3-ethylamine (3.0g, 17.2mmol), tert-butyl nitrite (2.66g, 25.8mmol) and cuprous bromide (17.7g, 25.8mmol) in acetonitrile (20mL) was stirred at 65 ℃ for 2 hours. The solvent was removed in vacuo and the residue was purified by silica gel column (petroleum ether: EtOAc 6:1) to give the desired product 3-bromo-2, 6-dicyclopropylpyridine (820mg) as a yellow oil. Yield 20% (ESI 239.0(M + H) +).

And step 3: 2- (2, 6-Dicyclopropylpyridin-3-yl) acetic acid tert-butyl ester

A mixture of 3-bromo-2, 6-dicyclopropylpyridine (800mg, 3.36mmol), 0.5M solution of (2-tert-butoxy-2-oxoethyl) zinc (II) bromide in THF (26.9mL, 13.44mmol), Pd2(dba)3(156mg, 0.17mmol), and Qphos (121mg, 0.17mmol) in THF (12mL) was stirred at 65 ℃ for 2 hours. The solvent was removed in vacuo, and the residue was purified by silica gel column (petroleum ether: EtOAc 4:1) to give the desired product tert-butyl 2- (2, 6-dicyclopropylpyridin-3-yl) acetate (550mg) as a yellow oil. Yield 60% (ESI 274.0(M + H) +).

And 4, step 4: 2-bromo-2- (2, 6-dicyclopropylpyridin-3-yl) acetic acid tert-butyl ester

To a solution of tert-butyl 2- (2, 6-dicyclopropylpyridin-3-yl) acetate (300mg, 1.1mmol) in THF (10mL) at-78 deg.C was added dropwise a solution of 2.0M lithium diisopropylamide in THF/hexane (1.4mL, 2.8 mmol). The reaction was stirred at-78 ℃ for 30 minutes, and then a solution of chlorotrimethylsilane (297mg, 2.75mmol) in THF (5mL) was added. The reaction was stirred at-78 ℃ for an additional 30 minutes. Then, a solution of NBS (325mg, 2.75mmol) in THF (5mL) was added and the reaction was stirred at-78 deg.C for 1 hour. The reaction was quenched with MeOH (2mL), concentrated in vacuo and purified by a silica gel column (petroleum ether: EtOAc 4:1) to give the desired product tert-butyl 2-bromo-2- (2, 6-dicyclopropylpyridin-3-yl) acetate (80mg) as a yellow oil. Yield 21% (ESI 353(M + H) +).

And 5: 2- (2, 6-Dicyclopropylpyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid tert-butyl ester

A mixture of tert-butyl 2-bromo-2- (2, 6-dicyclopropylphenyl-3-yl) acetate (80mg, 0.23mmol), (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (64mg, 0.23mmol) and K2CO3(96mg, 0.69mmol) in acetonitrile (8mL) was stirred at 60 ℃ for 16 h. The solvent was removed in vacuo and the residue was purified by column of silica gel (DCM: MeOH 20:1) to give the desired product tert-butyl 2- (2, 6-dicyclopropylpyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate as a yellow oil (90 mg). Yield 72% (ESI 547(M + H) +).

Step 6: 2- (2, 6-Dicyclopropylpyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compounds 6-E1 and 6-E2)

Tert-butyl 2- (2, 6-dicyclopropylpyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate (90mg, 0.16mmol) was treated with 1, 4-dioxane containing HCl (4M, 4mL) at 25 ℃ for 2 hours. The solvent was removed in vacuo and the residue was purified by preparative HPLC a (30-65% MeCN) to give the diastereomeric products compound 6-E1(11mg) and compound 6-E2(38mg) as white solids.

Compound 6-E1 LC/MS ESI 491.6(M + H) +. 1H NMR (400MHz, MeOD) δ 8.52(s,1H),7.77(d, J ═ 7.9Hz,1H), 7.67-7.44 (m,1H),7.03(d, J ═ 7.9Hz,1H),6.53(d, J ═ 7.3Hz,1H),5.18(s,1H),4.22(s,1H), 3.76-3.40 (m,6H),3.31-3.28(m,2H),2.79-2.66(m,4H),2.39(d, J ═ 5.6Hz,1H),2.19(s,2H),1.98-1.93(m,3H),1.76-1.74(m,2H),1.64-1.62(m,2H), 1.25-1.14 (m,1H), 1.06-0.06 (m, 72H).

Compound 6-E2 LC/MS ESI 491.6(M + H) +. 1H NMR (400MHz, MeOD) δ 8.52(s,1H),7.77(d, J ═ 7.9Hz,1H), 7.67-7.44 (m,1H),7.03(d, J ═ 7.9Hz,1H),6.53(d, J ═ 7.3Hz,1H),5.27(s,1H),4.23(s,1H), 3.76-3.40 (m,6H),3.31-3.28(m,2H),2.79-2.66(m,4H),2.39(d, J ═ 5.6Hz,1H),2.19(s,2H),1.98-1.93(m,3H),1.76-1.74(m,2H),1.64-1.62(m,2H), 1.25-1.14 (m,1H), 1.06-0.06 (m, 72H).

Example 7: preparation of 2- (2- (isopropoxymethyl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compounds 7-E1 and 7-E2)

Step 1: 1-bromo-2- (isopropoxymethyl) benzene

To a solution of isopropanol (0.72g, 12mmol) in DMF (15mL) at 0 deg.C was added NaH (480mg, 12 mmol). The reaction was stirred at 0 ℃ for 0.5 h, then 1-bromo-2- (bromomethyl) benzene (3.0g, 12mmol) in DMF (5mL) was added dropwise. The reaction was stirred at room temperature for 16H, then quenched with H2O (10mL) and extracted with EtOAc (2X 20 mL). The combined organic layers were concentrated in vacuo and the residue was purified through a silica gel column (petroleum ether: EtOAc ═ 10:1) to give the desired product 1-bromo-2- (isopropoxymethyl) benzene (1.6 g). Yield 58% (ESI 229(M + H) +).

Step 2: 2- (Isopropoxymethyl) phenylboronic acid

To a solution of 1-bromo-2- (isopropoxymethyl) benzene (300mg, 1.32mmol) in THF (5mL) at-78 ℃ was added nBuLi (2.5M, 0.6mL, 1.45mmol) dropwise. The reaction was stirred at-78 ℃ for 1 hour, then trimethyl borate (500mg, 2.64mmol) in THF (2mL) was added dropwise. The reaction was stirred at room temperature for 1 h, then quenched with aqueous HCl (1N, 10mL) and extracted with EtOAc (3X 10 mL). The combined organic layers were concentrated in vacuo and the residue was purified through a silica gel column (petroleum ether: EtOAc ═ 2:1) to give the desired product 2- (isopropoxymethyl) phenylboronic acid (120mg) as a white solid. Yield: 47% (ESI 193(M-H) -).

And step 3: 2- (2- (Isopropoxymethyl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compounds 7-E1 and 7-E2)

A mixture of tert-butyl (3R) -3- (4- (5-methyl-1, 2,3, 4-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidine-1-carboxylate (131mg, 0.48mmol), 2- (isopropoxymethyl) phenylboronic acid (120mg, 0.62mmol) and 50% 2-oxoacetic acid (92mg, 0.62mmol) in MeCN (5mL) was stirred at 70 ℃ for 16 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC B (30-65% MeCN) to give the diastereomeric products compound 7-E1(40mg) and compound 7-E2(34mg) as HCOOH salts.

Compound 7-E1 LC/MS ESI 482(M + H) +. 1H NMR (400MHz, MeOD) δ 8.33(s,2H), 7.68-7.66 (m,1H), 7.52-7.50 (m,1H), 7.46-7.42 (m,3H),6.56(d, J ═ 7.2Hz,1H),5.09(s,1H),4.90-4.88(m,1H), 4.52-4.50 (m,1H),4.23-4.21(m,1H), 3.82-3.80 (m,1H),3.66-3.44(m,7H),3.21-3.19(m,1H),2.81-1.60(m,12H),1.25-1.23(m,6H).

Compound 7-E2 LC/MS ESI 482(M + H) +. 1H NMR (400MHz, MeOD) δ 8.33(s,2H), 7.65-7.63 (m,1H), 7.52-7.50 (m,1H), 7.44-7.42 (m,3H),6.56(d, J ═ 7.2Hz,1H),4.97(s,1H),4.86-4.50(m,2H),4.26-4.24(m,1H), 3.85-3.82 (m,1H),3.61-3.40(m,5H),3.26-3.22(m,3H),2.81-1.60(m,12H),1.28-1.23(m,6H).

Example 8: preparation of 2- (2- (tert-butoxymethyl) -5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 8)

Step 1: 1-bromo-2- (tert-butoxymethyl) -4-fluorobenzene

NaH (60%, 600mg, 15mmol) was added to a solution of 2-methylpropan-2-ol (7.4g, 100mmol) in THF (30mL) at 0 ℃. The mixture was stirred at 0 ℃ for 0.5 h and 2-bromo-1- (bromomethyl) -4-fluorobenzene (2.68g, 10mmol) was added. The mixture was stirred at 80 ℃ overnight, then cooled to room temperature, quenched with water (50mL), and extracted with EtOAc (50 mL). Subjecting the organic layer to Na ₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 15:1) to give the desired product as a yellow oil (300 mg). Yield 11% (ESI 261(M + H) +).

Step 2: 2- (tert-butoxymethyl) -4-fluorophenylboronic acid

n-BuLi (0.4mL, 2.5M in hexanes, 1mmol) was added dropwise to a solution of 1-bromo-2- (tert-butoxymethyl) -4-fluorobenzene (150mg, 0.57mmol) and triisopropyl borate (188mg, 1mmol) in THF (5mL) at-78 ℃. The mixture was stirred at-78 ℃ for 1 hour, then at 25 ℃ for another 1 hour. The mixture was quenched with aqueous HCl (2N) to pH 5 and then extracted with EtOAc (10 mL). Subjecting the organic layer to Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by passing through a silica gel column (petroleum ether: EtOAc 2:1)To give the desired product as a colorless oil (70 mg). Yield 54% (ESI 225(M-H) -).

And step 3: 2- (2- (tert-butoxymethyl) -5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 8)

2- (tert-butoxymethyl) -4-fluorophenylboronic acid (75mg, 0.33mmol), 2-oxoacetic acid (88mg, 50% water, 0.6mmol) and (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (91mg, 0.33mmol) in CH ₃The mixture in CN (5mL) was stirred at 60 ℃ overnight. The solvent was removed in vacuo and the residue was purified by preparative HPLC a (33-65% MeCN) to give compound 8 as a white solid (22mg, 13% yield).

Compound 8 LC/MS ESI 514(M + H)⁺ ¹H NMR(400MHz,MeOD)δ7.50-7.42(m,2H),7.17-7.08(m,2H),6.37(d,J＝7.2Hz,1H),4.81-4.74(m,2H),4.55-4.43(m,1H),4.17(s,1H),3.55-3.32(m,6H),3.20-2.95(m,2H),2.72–2.52(m,4H),2.25-1.55(m,8H),1.34-1.28(m,9H).

Example 9: preparation of 2- (2-Cyclopropylpyridin-3-yl) -2- (3-fluoro-3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetic acid (Compounds 9-E1 and 9-E2)

Step 1: 2-chloro-2- (2-cyclopropylpyridin-3-yl) acetic acid ethyl ester

A solution of ethyl 2- (2-cyclopropylpyridin-3-yl) -2-hydroxyacetate (500mg, 2.26mmol) in SOCl2(5mL) was stirred at room temperature for 17 h. The solvent was removed in vacuo and the residue was purified by silica gel column (petroleum ether: EtOAc4:1) to give the desired product ethyl 2-chloro-2- (2-cyclopropylpyridin-3-yl) acetate as a yellow oil (210 mg). Yield 39% (ESI 240(M + H) +).

Step 2: 2- (2-Cyclopropylpyridin-3-yl) -2- (3-fluoro-3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetic acid ethyl ester

Mixing 7- (5- (3-fluoropyrrolidin-3-yl) pentyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (230mg, 0.632mmol), ethyl 2-chloro-2- (2-cyclopropylpyridin-3-yl) acetate (378mg, 1.580mmol) and K ₂CO₃A mixture of (262mg, 1.896mmol) in acetonitrile (8mL) was stirred at 60 ℃ for 16 h. The solvent was removed in vacuo, and the residue was purified by silica gel column (DCM: MeOH 20:1) to give the desired product ethyl 2- (2-cyclopropylpyridin-3-yl) -2- (3-fluoro-3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetate as a yellow oil (120 mg). Yield 38% (ESI 495(M + H) +).

And step 3: 2- (2-Cyclopropylpyridin-3-yl) -2- (3-fluoro-3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetic acid (Compounds 9-E1 and 9-E2)

Ethyl 2- (2-cyclopropylpyridin-3-yl) -2- (3-fluoro-3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetate (120mg, 0.24mmol) was treated with LiOH-H2O (40mg, 0.97mmol) in MeOH (4mL) and H2O (1mL) at 60 ℃ for 2H. The solvent was removed in vacuo and the residue was purified by preparative HPLC a (30-65% MeCN) to give compound 9 as a white solid (60mg, 53% yield). The racemic product was separated by preparative chiral SFC F to give the diastereomeric products compound 9-E1(10mg) and compound 9-E2(10mg) as white solids, each as a mixture of 2 stereoisomers.

Compound 9-E1 (mixture of 2 stereoisomers) LC/MS ESI 467.4(M + H) +. 1H NMR (400MHz, MeOD) δ 8.32(s,1H),8.03(d, J ═ 7.3Hz,1H)7.28(m,2H),6.41(d, J ═ 7.3Hz,1H),4.81(s,1H), 3.40-2.95 (m,6H), 2.80-2.50 (m,5H), 2.25-1.20 (m,12H), 1.10-0.85 (m,4H), chiral SFC F (45% MeOH): ee 76%, Rt 2.72 min

Compound 9-E1 (mixture of 2 stereoisomers) LC/MS ESI 467.4(M + H) +. 1H NMR (400MHz, MeOD) δ 8.39(s,1H),8.01(d, J ═ 7.3Hz,1H)7.33(m,2H),6.47(d, J ═ 7.3Hz,1H),4.96(s,1H), 3.45-2.95 (m,6H), 2.80-2.50 (m,5H), 2.25-1.20 (m,12H), 1.10-0.85 (m,4H), chiral SFC F (45% MeOH): ee 53%, Rt 3.36 min

Example 10: preparation of 2- (2-cyclopropylpyridin-3-yl) -2- ((R) -3- (4- (4-methoxy-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 10)

Step 1: 2- (2-Cyclopropylpyridin-3-yl) -2- ((R) -3- (4- (4-methoxy-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid ethyl ester

A mixture of (R) -5-methoxy-7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine hydrochloride (215mg, 0.63mmol), ethyl 2-chloro-2- (2-cyclopropylpyridin-3-yl) acetate (150mg, 0.63mmol) and diisopropylethylamine (245mg, 1.89mmol) in acetonitrile (8mL) was stirred at reflux for 24 h. The solvent was removed in vacuo and the residue was purified by column on silica gel (DCM: MeOH 20:1) to give the desired product ethyl 2- (2-cyclopropylpyridin-3-yl) -2- ((R) -3- (4- (4-methoxy-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate as a yellow oil (80 mg). Yield 25% (ESI 509(M + H) +).

Step 2: 2- (2-Cyclopropylpyridin-3-yl) -2- ((R) -3- (4- (4-methoxy-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 10)

Ethyl 2- (2-cyclopropylpyridin-3-yl) -2- ((R) -3- (4- (4-methoxy-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate (105mg, 0.21mmol) was treated with LiOH-H2O (87mg, 2.1mmol) in MeOH (4mL) and H2O (1mL) for 17H at room temperature. The solvent was removed in vacuo and the residue was purified by preparative HPLC a (30-65% MeCN) to yield compound 10 as a white solid (25mg, 25% yield).

Compound 10LC/MS ESI 481(M + H) +. 1H NMR (400MHz, MeOD). delta.8.26-8.25 (m,1H), 8.08-8.06 (m,1H), 7.15-7.11 (m,1H), 6.26-6.24 (m,1H), 4.57-4.52 (m,1H), 4.08-4.07 (m,1H),3.85(s,1H), 3.46-3.41 (m,2H), 3.25-2.50 (m,7H),2.10-1.50(m,8H),1.10-0.80(m,4H).

Example 11: preparation of 2- (2-Cyclobutylpyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compounds 11-E1 and 11-E2)

Step 1: 3-bromo-2-cyclobutylpyridines

A mixture of magnesium turnings (612mg, 25.5mmol) and bromocyclobutyl (3.4g, 25.5mmol) in dry THF (50mL) was heated at 60 deg.C for 3 hours until dissolution of magnesium was complete. The solution was cooled to-78 ℃ and treated with ZnCl2(3.48g, 25.5mmol) in THF (50 mL). The resulting white suspension was gradually warmed to room temperature and stirred for 1 hour. Then, a solution of 2, 3-dibromopyridine (4g, 17mmol) and Pd (PPh3)4(983mg, 0.85mmol) in THF (30mL) was added to the reaction. The mixture was stirred at 60 ℃ under N2 for 1h, then diluted with water (100mL) and extracted with EtOAc (3X 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, and the residue was purified over silica gel column (petroleum ether: EtOAc ═ 10:1) to give the desired product 3-bromo-2-cyclopropylpyridine (2.3g) as a yellow oil. Yield 94% (ESI 212(M + H) +).

Step 2: 2- (2-Cyclobutylpyridin-3-yl) -2-hydroxyacetic acid ethyl ester

To a solution of EtMgBr (1M, 6.54mL, 6.54mmol) in THF (20mL) at 0 deg.C under N2 was added N-BuLi (2.5M, 5.2mL, 13.08 mmol). The solution was stirred at 0 ℃ for 30 minutes, then a solution of 3-bromo-2-cyclobutylpyridine (2.3g, 10.9mmol) in THF (5mL) was added at-10 ℃. The mixture was stirred at the temperature for 30 minutes. Ethyl 2-oxoacetate (50% in toluene, 8.9g, 43.6mmol) was then added and the reaction stirred at 0 ℃ for 2 h, then poured into 20mL of saturated K2CO3 solution and extracted with EtOAc (3X 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc ═ 2:1) to give the desired product ethyl 2- (2-cyclopropylpyridin-3-yl) -2-hydroxyacetate (1.1g) as a yellow oil. Yield 43% (ESI 236(M + H) +).

And step 3: 2-chloro-2- (2-cyclobutylpyridin-3-yl) acetic acid ethyl ester

A solution of ethyl 2- (2-cyclobutylpyridin-3-yl) -2-glycolate (480mg, 2mmol) in SOCl2(5mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo, adjusted to pH 8 with aqueous NaHCO3, and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc ═ 10:1) to give the desired product ethyl 2-chloro-2- (2-cyclobutylpyridin-3-yl) acetate as a yellow oil (310 mg). Yield 47% (ESI 254(M + H) +).

And 4, step 4: 2- (2-Cyclobutylpyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid ethyl ester

A mixture of ethyl 2-chloro-2- (2-cyclobutylpyridin-3-yl) acetate (310mg, 1.2mmol), (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (370mg, 1.35mmol) and diisopropylethylamine (464mg, 3.6mmol) in acetonitrile (10mL) was stirred at 50 ℃ overnight. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH ═ 0% to 10%) to give the desired product ethyl 2- (2-cyclobutylpyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate as a colourless oil (165mg, 0.36 mmol). Yield 28% (ESI 493(M + H) +).

And 5: 2- (2-Cyclobutylpyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compounds 11-E1 and 11-E2)

Ethyl 2- (2-cyclobutylpyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate (165mg, 0.36mmol) was diluted with LiOH-H₂O (70mg, 1.8mmol) in MeOH (4mL) and H₂O (1mL) was treated at room temperature for 2 hours. The solvent was removed in vacuo and the residue was purified by preparative HPLC a (30-60% MeCN) to give compound 11 as a white solid (110mg, 70% yield). The racemic product was isolated by preparative chiral SFC a to give the diastereomeric products compound 11-E1(35mg) and compound 11-E2(35mg) as white solids.

Compound 11-E1 LC/MS ESI 465(M + H)⁺。¹H NMR (500MHz, MeOD) δ 8.54(d, J ═ 4.5Hz,1H),8.02(d, J ═ 7.5Hz,1H),7.29 to 7.23(m,2H),6.43(d, J ═ 7.0Hz,1H),4.71(s,1H),4.26 to 4.15(m,2H),3.54 to 3.38(m,4H),3.22 to 3.07(m,4H),2.75 to 2.55(m,5H),2.44 to 2.33(m,3H),2.13 to 2.05(m,3H),1.92 to 1.87(m,3H),1.79 to 1.74(m,2H),1.67 to 1.63(m,2H), chiral SFC E (45% chiral MeOH): ee 100%, Rt 2.99 min.

Compound 11-E2 LC/MS ESI 465(M + H)⁺。¹H NMR(500MHz,MeOD)δ8.55(d,J＝4.5Hz,1H),7.99(d,J＝7.5Hz,1H),7.30-7.22(m,2H),6.44(d,J＝6.0Hz,1H),4.80(s,1H) 4.20-4.16(m,2H),3.51-3.39(m,5H),3.24-3.22(m,1H),3.01-2.91(m,2H),2.75-2.59(m,5H),2.42-2.30(m,3H),2.08-2.02(m,3H),1.92-1.64(m,7H), chiral SFC E (45% MeOH): ee 100%, Rt 5.21 min.

Example 12: preparation of 2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (tetrahydro-2H-pyran-4-yl) phenyl) acetic acid (Compound 12)

Step 1: 2- (2-iodophenyl) acetic acid methyl ester

To a solution of 2- (2-iodophenyl) acetic acid (3.67g, 14mmol) in MeOH (35mL) was added 2mL of concentrated H2SO 4. The reaction was stirred at 85 ℃ for 2h, then concentrated in vacuo, adjusted to pH 7-8 with saturated NaHCO3 solution, and extracted with EtOAc (2 × 30 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to give the desired product methyl 2- (2-iodophenyl) acetate (3.7g) as an orange oil. Yield 96% (ESI 277(M + H) +).

Step 2: 2- (2- (3, 6-dihydro-2H-pyran-4-yl) phenyl) acetic acid methyl ester

Methyl 2- (2-iodophenyl) acetate (828mg, 3.0mmol), 2- (3, 6-dihydro-2H-pyran-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (945mg, 4.5mmol), PdCl₂(PPh₃)₂A mixture of (89mg, 0.12Mmol) and Na2CO3(636mg, 6.Mmol) in 1, 4-dioxane (30mL) and water (6mL) was stirred under N2 at 90 ℃ overnight. The mixture was diluted with H2O (10mL) and extracted with EtOAc (20 mL). The organic phase was concentrated in vacuo and the residue was purified by column on silica gel (petroleum ether: EtOAc 10:1) to give the desired product tert-butyl 2- (3- (2-methoxypropan-2-yl) isochroman-5-yl) acetate as a pale orange oil (488 mg). Yield 70% (ESI 255.1(M + Na) +).

And step 3: 2- (2- (tetrahydro-2H-pyran-4-yl) phenyl) acetic acid methyl ester

A mixture of tert-butyl 2- (3- (2-methoxyprop-2-yl) isochroman-5-yl) acetate (488mg, 2.1mmol) and Pd (OH)2/C (20%, 120mg) in MeOH (20mL) was stirred under a balloon of hydrogen at 35 ℃ for 6 h. The reaction was filtered and concentrated in vacuo to give the desired product methyl 2- (2- (tetrahydro-2H-pyran-4-yl) phenyl) acetate (460mg) as a colourless oil. Yield 95% (ESI 235.2(M + H) +).

And 4, step 4: 2-bromo-2- (3- (2-methoxyprop-2-yl) isochroman-5-yl) acetic acid tert-butyl ester

To a solution of 2- (2- (tetrahydro-2H-pyran-4-yl) phenyl) acetic acid (234mg, 1.0mmol) in THF (10mL) at-78 deg.C was added dropwise a 2.0M solution of lithium diisopropylamide in THF/hexane (1.0mL, 2.0 mmol). The reaction was stirred at-78 ℃ for 20 minutes. Then, a solution of chlorotrimethylsilane (218mg, 2.0mmol) in THF (0.5mL) was added and the reaction was stirred at-78 deg.C for an additional 10 minutes. Then, a solution of NBS (356mg, 2.0mmol) in THF (4mL) was added and the reaction was stirred at-78 deg.C for 10 min, then poured into water (10mL) and extracted with EtOAc (20 mL). The organic phase was washed with saturated NaHCO3 solution and water and concentrated in vacuo to yield the crude product as a yellow oil (320 mg). Yield 48% (ESI 315.1(M + H) +).

And 5: methyl 2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (tetrahydro-2H-pyran-4-yl) phenyl) acetate

A mixture of tert-butyl 2-bromo-2- (3- (2-methoxyprop-2-yl) isochroman-5-yl) acetate (320mg, 47% purity, 0.48mmol), (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (132mg, 0.48mmol), and diisopropylethylamine (186mg, 1.44mmol) in acetonitrile (12mL) was stirred at room temperature for 1 hour. The mixture was diluted with water (8mL) and extracted with EtOAc (25 mL). The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (NH4HCO3, H2O/MeCN) to give methyl 2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (tetrahydro-2H-pyran-4-yl) phenyl) acetate as a white solid (135 mg). Yield 55% (ESI 508.1(M + H) +).

Step 6: preparation of 2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (tetrahydro-2H-pyran-4-yl) phenyl) acetic acid (Compound 12)

A solution of methyl 2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (tetrahydro-2H-pyran-4-yl) phenyl) acetate (115mg) in THF (5mL) was treated with LiOH (1M H2O, 2.7mL) at room temperature overnight. The solvent was removed in vacuo and the residue was purified by preparative HPLC a (30-64% MeCN/H2O) to give compound 12 as a white solid (82 mg).

Compound 12 LC/MS ESI 494.2(M + H) +. 1H NMR (500MHz, MeOD) δ 7.64(m,1H),7.41(m,2H),7.28(m,1H),7.16(m,1H),6.39(m,1H),4.94(m,1H),4.22(m,1H),4.01(m,2H),3.55-3.64(m,4H),3.40(m,3H),3.33-3.37(m,3H),2.72(t, J ═ 6.5Hz,2H),2.57(t, J ═ 6.5Hz,2H),2.01-2.24(m,2H),1.88-1.98(m,4H), 1.61-1.77 (m,6H).

Example 13: preparation of 2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (tetrahydro-2H-pyran-4-yl) phenyl) acetic acid (compounds 13-E1 and 13-E2)

Step 1: 2- (2-Chloropyridin-3-yl) acetic acid methyl ester

To a solution of 2- (2-chloropyridin-3-yl) acetic acid (1.71g, 10mmol) in MeOH (35mL) was added concentrated H2SO4(2 mL). The reaction was stirred at 85 ℃ for 2h, then concentrated in vacuo, adjusted to pH 7-8 with saturated NaHCO3 solution, and extracted with EtOAc (2 × 30 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to give the desired product methyl 2- (2-chloropyridin-3-yl) acetate as an orange oil (1.51g, 81% yield). (ESI 186(M + H) +).

Step 2: 2- (2- (3, 4-dihydro-2H-pyran-6-yl) pyridin-3-yl) acetic acid methyl ester

A mixture of methyl 2- (2-chloropyridin-3-yl) acetate (372mg, 2.0mmol), 2- (3, 4-dihydro-2H-pyran-6-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (420mg, 2.0mmol), X-Phos Pd G4(68mg, 0.08mmol) and K2CO3(552mg, 4mmol) in 1, 4-dioxane (10mL) and water (2.5mL) was heated by microwaves at 115 ℃ for 2 hours. The mixture was diluted with H2O (10mL) and extracted with EtOAc (20 mL). The organic phase was concentrated in vacuo and the residue was purified by column on silica gel (petroleum ether: EtOAc 10:1) to give the desired product methyl 2- (2- (3, 4-dihydro-2H-pyran-6-yl) pyridin-3-yl) acetate as a pale orange oil (308 mg). Yield 66% (ESI 234.1(M + H) +).

And step 3: 2- (2- (tetrahydro-2H-pyran-4-yl) phenyl) acetic acid methyl ester

Methyl 2- (2- (3, 4-dihydro-2H-pyran-6-yl) pyridin-3-yl) acetate (302mg, 1.3mmol) and Pd (OH)₂A mixture of/C (20%, 100mg) in MeOH (16mL) was stirred under a H2 balloon at 35 ℃ for 4H. The reaction was filtered and concentrated in vacuo to give orangeThe desired product, methyl 2- (2- (tetrahydro-2H-pyran-2-yl) pyridin-3-yl) acetate, was obtained as a pale oil (301 mg). Yield 94% (ESI 236.2(M + H) +).

And 4, step 4: 2-bromo-2- (2- (tetrahydro-2H-pyran-2-yl) pyridin-3-yl) acetic acid methyl ester

To a solution of methyl 2- (2- (tetrahydro-2H-pyran-2-yl) pyridin-3-yl) acetate 2- (2- (tetrahydro-2H-pyran-4-yl) phenyl) acetate (301mg, 1.28mmol) in THF (8mL) at-78 ℃ was added dropwise THF/hexane (1.28mL, 2.56mmol) containing a 2.0M solution of lithium diisopropylamide. The reaction was stirred at-78 ℃ for 20 minutes. Then, a solution of chlorotrimethylsilane (278mg, 2.56mmol) in THF (0.5mL) was added and the reaction was stirred at-78 deg.C for an additional 10 minutes. Then, a solution of NBS (456mg, 2.56mmol) in THF (4mL) was added and the reaction was stirred at-78 deg.C for 10 min, then poured into water (10mL) and extracted with EtOAc (20 mL). The organic phase was washed with saturated NaHCO3 solution and water and concentrated in vacuo to yield the crude product as a yellow oil (390mg, 40% purity). Yield 39% (ESI 315.1(M + H) +).

And 5: methyl 2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (tetrahydro-2H-pyran-2-yl) pyridin-3-yl) acetate

A mixture of methyl 2-bromo-2- (2- (tetrahydro-2H-pyran-2-yl) pyridin-3-yl) acetate (390mg, 40% pure), (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (137mg, 0.50mmol) and diisopropylethylamine (194mg, 1.50mmol) in acetonitrile (10mL) was stirred at room temperature for 2 hours. The mixture was diluted with water (8mL) and extracted with EtOAc (25 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC a (40-75% MeCN) to give the desired product methyl 2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (tetrahydro-2H-pyran-2-yl) pyridin-3-yl) acetate as a white solid (105 mg). Yield 41% (ESI 509.2(M + H) +).

Step 6: preparation of 2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (tetrahydro-2H-pyran-4-yl) phenyl) acetic acid (compounds 13-E1 and 13-E2)

A solution of ethyl 2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (tetrahydro-2H-pyran-4-yl) phenyl) acetate (71mg, 0.14mmol) in THF (5mL) was treated with LiOH (1M in H)₂O, 2.1mL) was treated at room temperature overnight. The mixture was adjusted to pH 5-6 with aqueous HCl (1N) and concentrated in vacuo, and the residue was purified by preparative HPLC a (30-64% MeCN) to yield the diastereomeric products compound 13-E1(23mg) and compound 13-E2(12mg) as white solids, each as a mixture of 2 stereoisomers.

Compound 13-E1 (mixture of 2 stereoisomers) LC/MS ESI 495.3(M + H) +. 1H NMR (500MHz, MeOD). delta.8.46 (m,1H),8.21(m,1H),7.33(m, H),7.16(m,1H),6.38(m,1H),5.12(m,1H),4.41(m,1H),4.05(m,2H),3.75(m,1H),3.75-3.37(m,4H),3.30-2.80(m,2H),2.73-2.69(m,4H),2.64-2.54(m,2H),1.96(m,1H),1.91-1.87(m,6H),1.78-1.58(m,7H).

Compound 13-E2 (mixture of 2 stereoisomers) LC/MS ESI 495.3(M + H) +. 1H NMR (500MHz, MeOD). delta.8.46 (m,1H),8.14(m,1H),7.34(m,1H),7.16(m,1H),6.38(m,1H),5.04(m,1H),4.11(m,2H),3.68(m,1H),3.69-3.37(m,5H),3.11-2.98(m,2H),2.87-2.70(m,4H),2.56-2.54(m,2H),2.06-1.80(m,7H),1.78-1.59(m,7H).

Example 14: preparation of 2- (2-Cyclopropylpyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compounds 14-E1 and 14-E2)

Step 1: (2-Cyclopropylpyridin-3-yl) (hydroxy) methanesulfonic acid sodium salt

2-bromo-3-pyridinecarboxaldehyde (1g, 5.38mmol), cyclopropylboronic acid (1.385g, 16.13mmol) and sodium carbonate (2.279g, 21.50mmol) were dissolved in 1, 2-dimethoxyethane (20mL) and water (5 mL). The mixture was flushed with argon and bis (triphenylphosphine) palladium (II) dichloride (0.377g, 0.538mmol) was added. The reaction was sealed and heated at 100 ℃ for 16 hours, then diluted with water and extracted with diethyl ether. The organic layer was washed twice with water and a solution of sodium bisulfite (1.119g, 10.75mmol) in water and some methanol were added. The diethyl ether was evaporated in vacuo and the resulting water/methanol mixture was used as such in the next step.

Step 2: 2- (2-Cyclopropylpyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetonitrile

A water/methanol mixture containing sodium (2-cyclopropylpyridin-3-yl) (hydroxy) methanesulfonate (1.352g, 5.38mmol) was added to (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (0.963g, 3.50mmol) followed by potassium cyanide (1.752g, 26.9 mmol). After 16 hours, some methanol was added. After 64 hours, the reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the desired product 2- (2-cyclopropylpyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetonitrile (1.511 g). Yield 65% (ESI 430(M-H) ^-)。

And step 3: 2- (2-Cyclopropylpyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetamide

To a solution of 2- (2-cyclopropylpyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetonitrile (1.511g, 3.5mmol) in dichloromethane (10mL) was added sulfuric acid (25mL, 469 mmol). The reaction was stirred at room temperature for 24 hours, then quenched on ice, neutralized with aqueous ammonia, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated, and the residue was purified by reverse phase chromatography (water containing 10mM ammonium bicarbonate solution, 20-60% acetonitrile) to give the desired product 2- (2-cyclopropylpyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetamide (399 mg). Yield 25% (ESI 450(M + H) +).

And 4, step 4: 2- (2-Cyclopropylpyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compounds 14-E1 and 14-E2)

A solution of 2- (2-cyclopropylpyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetamide (399mg, 0.887mmol) in hydrochloric acid (10mL, 40mmol, water with 4N solution) was stirred at 70 ℃ for 88 h. The mixture was concentrated, and the residue was dissolved in water and then freeze-dried. The residue was dissolved in water (10mL) and purified using reverse phase chromatography to give 2- (2-cyclopropylpyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid compound 14(311mg) as a mixture of diastereomers. Yield 78% (ESI 451(M + H) ⁺). The mixture was separated by chiral SFC to give the diastereomeric products compound 14-E1(107mg) and compound 14-E2(100 mg). The method comprises the following steps: water Acquity UPC2 (binary solvent manager, isocratic solvent manager, sample manager, column manager 30S, convergence manager, PDA detector, Acquity QDa detector); column: chiralpak IC (100X 4.6mm, 5 μm) for SFC. Temperature of: 35 ℃ is carried out. Back pressure: 170 bar. Flowing: 2.5 ml/min. Eluent A: CO 2. Eluent B: methanol +20mM ammonia. Gradient: t0 ═ 5% B, t2.5 ═ 50% B, t30 ═ 50% B, after time: 0.5 minute. And (3) detecting the PDA: 210-320 nm. And (3) detecting MS: ESI, mass range: 700-1250 (positive) 1Hz, cone: 15V.

Compound 14-E1: 107mg, LC/MS ESI 451(M + H) +.¹H NMR (400MHz, methanol-d 4) δ 8.37(dd, J ═ 4.7,1.7Hz,1H),7.97(dd, J ═ 8.0,1.8Hz,1H), 7.24-7.08 (m,2H),6.40(d, J ═ 7.3Hz,1H),5.04(s,1H), 4.22-4.13 (m,1H), 3.55-3.33 (m,5H), 3.23-3.10 (m,2H), 2.79-2.66 (m,2H), 2.66-2.46 (m,3H), 2.22-2.05 (m,2H), 1.94-1.82 (m,2H), 1.80-1.45 (m,5H), 1.27-1.15 (m,1H), 1.88-0.07-3H).

Compound 14-E2: 100mg, LC/MS ESI 451(M + H) +. ¹H NMR (400MHz, methanol-d 4) δ 8.38(dd, J ═ 4.8,1.7Hz,1H),7.94(dd, J ═ 7.8,1.7Hz,1H), 7.24-7.13 (m,2H),6.40(d, J ═ 7.3Hz,1H),5.13(s,1H), 4.25-4.14 (m,1H), 3.58-3.32 (m,6H), 3.27-3.14 (m,1H), 3.07-2.95 (m,1H), 2.78-2.66 (m,2H), 2.64-2.49 (m,2H), 2.49-2.38 (m,1H), 2.18-2.02 (m,2H), 1.95-1.82 (m,2H), 1.81-1.45.45 (m,1H), 1.06-1H), 1.06 (m, 1H).

Example 15: preparation of 2- (2-cyclopropylphenyl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyloxy) pyrrolidin-1-yl) acetic acid (compounds 15-E1 and 15-E2)

Step 1: 2- (2-Cyclopropylphenyl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyloxy) pyrrolidin-1-yl) acetic acid (Compounds 15-E1 and 15-E2)

To a solution of (R) -7- (5- (pyrrolidin-3-yloxy) pentyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride (200mg, 0.55mmol) in DMF (2mL) was added 2-cyclopropylphenylboronic acid (116mg, 0.72mmol) and 2-oxoacetic acid (56mg, 0.6 mmol). The reaction was stirred at 80 ℃ for 1 hour. The reaction mixture was purified by preparative HPLC (40-65% MeCN) to yield 90mg of racemic compound 15. The racemic product was isolated by preparative chiral SFC a to give the diastereomeric products compound 15-E1(23mg) and compound 15-E2(22mg) as white solids.

Compound 15-E1 LC/MS ESI 464.2(M + H)⁺。¹H NMR (500MHz, MeOD) δ 7.61(d, J ═ 7.1Hz,1H),7.31(m,2H),7.16(dd, J ═ 21.5,7.4Hz,2H),6.37(d, J ═ 7.3Hz,1H),5.35(s,1H),4.23(s,1H),3.65(m,1H),3.49(t, J ═ 6.4Hz,2H), 3.42-3.36 (m,2H), 3.30-2.99 (m,3H),2.70(t, J ═ 6.3Hz,2H),2.53(t, J ═ 7.5Hz,2H),2.21(m,3H),1.88(m,2H), 1.12-0.94 (m,3H), chiral MeOH (m, 0.70, 1.51 g), chiral MeOH (sfa): ee 98%, Rt 2.46 min.

Compound 15-E2 LC/MS ESI 464.2(M + H)⁺。¹H NMR (500MHz, MeOD) δ 7.54(d, J ═ 7.5Hz,1H),7.17(m,2H), 7.07-6.97 (m,2H),6.26(d, J ═ 7.3Hz,1H),5.08(s,1H),4.06(s,1H), 3.43-3.24 (m,5H), 3.14-2.98 (m,2H),2.59(t, J ═ 6.2Hz,2H), 2.48-2.36 (m,2H),2.15(m,3H), 1.81-1.70 (m,2H), 1.63-1.45 (m,4H), 1.39-1.26 (m,2H), 0.96-0.77 (m,3H), 0.55-0.42 (m,1H), chiral MeOH (sfa) 40%: ee 98%, Rt 3.5 min.

Example 16: preparation of 2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (tetrahydrofuran-2-yl) phenyl) acetic acid (compounds 16-E1 and 16-E2)

Step 1: 2- (2- (furan-2-yl) phenyl) acetic acid methyl ester

To a solution of methyl 2- (2-iodophenyl) acetate (552mg, 2mmol) in 5mL dry DMF was added furan-2-ylboronic acid (224mg, 2mmol), tris (dibenzylideneacetone) dipalladium (0) (91.5mg, 0.1mmol), X-Phos (47.6mg, 0.1mmol) and potassium phosphate (424mg, 2 mmol). The mixture was stirred at 60 ℃ for 1 hour under N2. The reaction was cooled and diluted with ethyl acetate (20mL) and water (20 mL). The organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate (20 mL. times.2). The combined organic layers were washed with brine and over anhydrous Na ₂SO₄And (5) drying. After filtration and concentration, 5-20% EtOAc/petroleum was usedThe residue was chromatographed (Combiflash) with ether as eluent to give methyl 2- (2- (furan-2-yl) phenyl) acetate (340mg 78.3%); (ESI 217(M + H)⁺)。

Step 2: 2- (2- (tetrahydrofuran-2-yl) phenyl) acetic acid methyl ester

To a solution of methyl 2- (2- (furan-2-yl) phenyl) acetate (340mg, 1.57mmol) in 10ml of anhydrous MeOH was added Pd/C (30 mg). The mixture was stirred at 40 ℃ under an atmosphere of H2 (balloon) for 3 hours. After the reaction was completed, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was chromatographed (Combiflash) using 5-20% EtOAc/petroleum ether as eluent to give methyl 2- (2- (tetrahydrofuran-2-yl) phenyl) acetate as an oil (290mg, 84%). (ESI 221(M + H)⁺)

And step 3: 2-bromo-2- (2- (tetrahydrofuran-2-yl) phenyl) acetic acid methyl ester

A solution of methyl 2- (2- (tetrahydrofuran-2-yl) phenyl) acetate (220mg, 1mmol) in 10mL THF was cooled to-78 deg.C under N2 and treated with LDA (1.25mL, 2.5mmol, 2M in THF). The reaction was stirred for 0.5 h, treated with TMSCl (324mg, 3mmol) and after 0.25 h, treated with 10mL dry THF containing a solution of NBS (534mg, 3 mmol). The mixture was stirred at-78 ℃ for 0.5 h, and water (10mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL. times.2). The combined organic layers were washed with brine and over anhydrous Na ₂SO₄And (5) drying. After filtration and concentration, the residue was chromatographed (Combiflash) using 0-20% EtOAc/petroleum ether as eluent to give methyl 2-bromo-2- (2- (tetrahydrofuran-2-yl) phenyl) acetate (210mg, 70.5%); (ESI 299(M + H)⁺)

And 4, step 4: methyl 2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (tetrahydrofuran-2-yl) phenyl) acetate

To a solution of methyl 2-bromo-2- (2- (tetrahydrofuran-2-yl) phenyl) acetate (100mg, 0.33mmol) in 5mL acetonitrile was added (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (92mg, 0.33mmol) and diisopropylethylamine (129mg, 1 mmol). The reaction was stirred for 2 hours, diluted with water (10mL), and extracted with ethyl acetate (20 mL. times.3). The combined organic layers were washed with brine and over anhydrous Na₂SO₄And (5) drying. After filtration and concentration, the residue was chromatographed (Combiflash) using 20-80% EtOAc/petroleum ether as eluent to give methyl 2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (tetrahydrofuran-2-yl) phenyl) acetate (90mg, 54.4%). (ESI 494(M + H)⁺)

And 5: 2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (tetrahydrofuran-2-yl) phenyl) acetic acid (Compounds 16-E1 and 16-E2)

To a solution of methyl 2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (tetrahydrofuran-2-yl) phenyl) acetate (90mg, 0.18mmol) in 5mL methanol was added LiOH (9mg, 0.4mmol) and water (2 mL). The reaction was stirred for 5 hours, filtered and concentrated under reduced pressure. The residue was purified using reverse phase semi-preparative HPLC to give the diastereomeric products compound 16-E1(40mg, 45.7% yield) and compound 16-E2(19mg, 22.7% yield), each as a mixture of two stereoisomers.

Compound 16-E1 (mixture of 2 stereoisomers): LC/MS ESI 480.2(M + H)⁺。¹H NMR(500MHz,MeOD)δ7.69(dd,J＝11.4,7.8Hz,1H),7.55(d,J＝7.8Hz,1H),7.41(t,J＝7.5Hz,1H),7.38–7.29(m,1H),7.15(d,J＝7.3Hz,1H),6.39(dd,J＝7.3,2.7Hz,1H),5.30(dt,J＝33.4,7.0Hz,1H),4.97(s,1H),4.17(d,J＝21.0Hz,1H),4.08(dd,J＝14.1,6.9Hz,1H),3.90(ddt,J＝14.0,9.6,6.9Hz,1H),3.57(s,1H),3.51–3.35(m,4H),3.29–2.98(m,3H),2.71(t,J＝6.3Hz,2H),2.56(t,J＝7.6Hz,2H),2.52–2.42(m,1H),2.18–1.94(m,5H),1.88(dd,J＝11.5,6.1Hz,2H),1.77–1.69(m,2H),1.62(dd,J＝13.6,6.7Hz,2H).

Compound 16-E2 (mixture of 2 stereoisomers) LC/MS ESI 480.2(M + H)⁺。¹H NMR(500MHz,MeOD)δ7.65(d,J＝5.5Hz,1H),7.46(d,J＝7.6Hz,1H),7.41–7.30(m,2H),7.16(d,J＝7.3Hz,1H),6.39(dd,J＝7.3,1.6Hz,1H),5.23–5.10(m,1H),4.96(s,1H),4.19–4.06(m,2H),3.93–3.84(m,1H),3.57(s,1H),3.50–3.36(m,5H),3.16–2.96(m,2H),2.75–2.65(m,2H),2.56(t,J＝7.4Hz,2H),2.45–2.35(m,1H),2.16–1.99(m,5H),1.88(dd,J＝11.4,5.8Hz,2H),1.76–1.68(m,2H),1.65–1.59(m,2H).

Example 17: preparation of 2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (tetrahydro-2H-pyran-2-yl) phenyl) acetic acid (Compound 17)

Step 1: 2- (2- (3, 4-dihydro-2H-pyran-6-yl) phenyl) acetic acid methyl ester

To a solution of methyl 2- (2-iodophenyl) acetate (1.3g, 4.8mmol) in 20mL dry DME and EtOH (5mL) was added 3, 4-dihydro-2H-pyran-6-boronic acid pinacol ester (1.0g, 4.8mmol), tetrakis (triphenylphosphine) palladium (0) (277mg, 0.24mmol), and sodium carbonate (1.0g, 9.6mmol) in N ₂The mixture was then heated at 100 ℃ for 12 hours. The mixture was cooled to room temperature and diluted with ethyl acetate (50mL) and water (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (50 mL. times.3). The organic phases were combined, washed with brine and over anhydrous Na₂SO₄And (5) drying. After filtration and concentration, the residue was chromatographed (Combiflash) using 0-20% EtOAc/petroleum ether as eluent to yieldMethyl 2- (2- (3, 4-dihydro-2H-pyran-6-yl) phenyl) acetate (0.4g, 36%) was obtained as an oil. (ESI 233.1(m +1)⁺)。

Step 2: 2- (2- (tetrahydro-2H-pyran-2-yl) phenyl) acetic acid methyl ester

Methyl 2- (2- (3, 4-dihydro-2H-pyran-6-yl) phenyl) acetate (300mg, 1.3mmol) and Pd (OH)₂A mixture of/C (100mg) in MeOH (25mL) was hydrogenated (balloon) at 35 ℃ for 3 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was chromatographed (Combiflash) using 0-20% EtOAc/petroleum ether as eluent to give methyl 2- (2- (tetrahydro-2H-pyran-2-yl) phenyl) acetate as an oil (180mg, 60%). (ESI 235.1(m +1)⁺)。

And step 3: 2-bromo-2- (2- (tetrahydro-2H-pyran-2-yl) phenyl) acetic acid methyl ester

At-78 ℃ under N₂Next, to a stirred solution of methyl 2- (2- (tetrahydro-2H-pyran-2-yl) phenyl) acetate (150mg, 0.64mmol) in THF (10mL) was added LDA (1.25mL, 2.5mmol, 2M in THF), and the reaction stirred for 0.5H, TMSCl (324mg, 3.0mmol) was added, the reaction stirred for 0.25H, then NBS (445mg, 2.5mmol) as a solution in THF (10mL) was added. The reaction was stirred at-78 ℃ for 0.5 h and quenched by addition of water (10 mL). The mixture was extracted with ethyl acetate (30mL × 3) and the combined organic phases were washed with brine and over anhydrous Na ₂SO₄And (5) drying. After filtration and concentration, chromatographic separation (Combiflash) was performed using 0-20% EtOAc/petroleum ether as eluent to give methyl 2-bromo-2- (2- (tetrahydro-2H-pyran-2-yl) phenyl) acetate (65mg, 33%). (ESI 313.2(m +1)⁺)。

And 4, step 4: methyl 2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (tetrahydro-2H-pyran-2-yl) phenyl) acetate

A mixture of methyl 2-bromo-2- (2- (tetrahydro-2H-pyran-2-yl) phenyl) acetate (65mg,0.21mmol), (57mg, 0.21mmol) and diisopropylethylamine (65mg, 0.5mmol) in acetonitrile (8mL) was stirred at 25 ℃ for 16H. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel (DCM: MeOH 20:1) to give ethyl 2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (tetrahydro-2H-pyran-2-yl) phenyl) acetate as an oil (30mg, 28%). (ESI 508.1(m +1)⁺)

And 5: 2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (tetrahydro-2H-pyran-2-yl) phenyl) acetic acid (Compound 17)

Methyl 2- (2-cyclopropylphenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate (30mg, 0.28mmol) was washed with LiOH (52mg, 1.24mmol) in MeOH (4mL) and H ₂O (1mL) was treated at 25 ℃ for 3 hours. The solvent was removed under reduced pressure and the residue was separated using semi-preparative reverse phase HPLC (preparative HPLC a, 30-65% MeCN) to give compound 17(10mg, 34%) as a solid.

Compound 17: LC/MS ESI 494.2(M + H) +. 1H NMR (400MHz, MeOD) delta¹H NMR(500MHz,MeOD)δ7.68(t,J＝8.3Hz,1H),7.57(d,J＝7.8Hz,1H),7.40(dt,J＝13.8,7.5Hz,2H),7.15(d,J＝7.3Hz,1H),6.38(dd,J＝7.3,3.3Hz,1H),4.89–4.76(m,2H),4.18(d,J＝17.9Hz,1H),4.09–3.94(m,1H),3.72(dd,J＝22.4,10.7Hz,1H),3.54–3.43(m,2H),3.38(dd,J＝10.1,4.5Hz,3H),2.77–2.65(m,2H),2.55(t,J＝6.7Hz,2H),2.17–1.97(m,4H),1.93–1.85(m,2H),1.81–1.58(m,8H),1.51–1.45(m,1H),1.33(d,J＝22.7Hz,3H).

Example 18: preparation of 2- (5-fluoro-2- (tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compounds 18-E1 and 18-E2)

Step 1: 2- (2-bromo-5-fluorophenyl) acetic acid methyl ester

To a solution of 2- (2-bromo-5-fluorophenyl) acetic acid (10g, 43mmol) in 60mL MeOH was added 0.5mL H₂SO₄. The mixture was refluxed for 4 hours, allowed to cool to room temperature and concentrated under reduced pressure. The resulting pale yellow oil (10g, 94.3%) was used without further purification. (ESI 246.1(M + H)⁺)

Step 2: 2- (2- (3, 4-dihydro-2H-pyran-6-yl) -5-fluorophenyl) acetic acid methyl ester

To a solution of methyl 2- (2-bromo-5-fluorophenyl) acetate (6.3g, 25.6mmol) in DMF (60mL) was added 3, 4-dihydro-2H-pyran-6-boronic acid pinacol ester (5g, 23.8mmol), tris (dibenzylideneacetone) dipalladium (0) (468mg, 0.52mmol), X-Phos (238mg, 0.52mmol) and potassium phosphate (2.1g, 25.6 mmol). The mixture was stirred at 60 ℃ for 12 hours under N2. The mixture was allowed to cool to room temperature and partitioned between ethyl acetate (120mL) and water (120 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (60 mL. times.3). The combined organic phases were washed with brine and over anhydrous Na ₂SO₄And (5) drying. After filtration and concentration, the residue was chromatographed (Combiflash) using 0-20% EtOAc/petroleum ether as eluent to give methyl 2- (2- (3, 4-dihydro-2H-pyran-6-yl) -5-fluorophenyl) acetate (5.2g, 87.4%). (ESI 251.1(M + H)⁺)

And step 3: 2- (5-fluoro-2- (tetrahydro-2H-pyran-2-yl) phenyl) acetic acid methyl ester

To a solution of methyl 2- (2- (3, 4-dihydro-2H-pyran-6-yl) -5-fluorophenyl) acetate (500mg, 2mmol) in 25ml dry MeOH was added diisopropylethylamine (0.5ml) and Pd/C (100 mg). The mixture was heated at 40 ℃ under H₂Stirred (balloon) for 3 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was chromatographed (Combiflash) using 0-20% EtOAc/petroleum ether as eluent to give methyl 2- (2- (3, 4-dihydro-2H-pyran-6-yl) -5-fluorophenyl) acetate as an oil (260mg, 52%). (ESI 253.1(M + H)⁺)

And 4, step 4: 2-bromo-2- (5-fluoro-2- (tetrahydro-2H-pyran-2-yl) phenyl) acetic acid methyl ester

At-78 ℃ under N₂LDA (1.25mL, 2.5mmol, 2M in THF) was added to a solution of methyl 2- (5-fluoro-2- (tetrahydro-2H-pyran-2-yl) phenyl) acetate (260mg, 1.03mmol) in 10mL of THF. The reaction was stirred for 0.5 h and TMSCl (324mg, 3mmol) was added. After a further 0.25 h, a solution of NBS (534mg, 3mmol) in 10mL THF was added and the reaction was stirred at-78 deg.C for 0.5 h. The mixture was allowed to warm to room temperature and diluted with water (10 mL). The mixture was extracted with ethyl acetate (30mL × 3) and the combined organic phases were washed with brine and over anhydrous Na ₂SO₄And (5) drying. After filtration and concentration, the residue was chromatographed (Combiflash) using 0-20% EtOAc/petroleum ether as eluent to give methyl 2-bromo-2- (5-fluoro-2- (tetrahydro-2H-pyran-2-yl) phenyl) acetate (280mg, 84.8%). (ESI 333.1(M + H)⁺)。

And 5: 2- (5-fluoro-2- (tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid methyl ester

To a solution of methyl 2-bromo-2- (5-fluoro-2- (tetrahydro-2H-pyran-2-yl) phenyl) acetate (70mg, 0.21mmol) in DMF (5mL) was added (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (57mg, 0.21mmol) and diisopropylethylamine (81mg, 0.63mmol), and the reaction was stirred for 2 hours. The mixture was diluted with water (10mL) and extracted with EtOAc (20 mL. times.2). The combined organic phases were washed with brine and over anhydrous Na₂SO₄And (5) drying. After filtration and concentration, the residue was chromatographed (Combiflash) using 20-80% EtOAc/petroleum ether as eluent to give methyl 2- (5-fluoro-2- (tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate (70mg, 62.8%). (ESI 526.2(M + H)⁺)

Step 6: 2- (5-fluoro-2- (tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compounds 18-E1 and 18-E2)

To a solution of methyl 2- (5-fluoro-2- (tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate (70mg, 0.13mmol) in 5mL MeOH was added LiOH (10mg, 0.4mmol) and water (2 mL). The reaction was stirred for 2 hours, filtered and concentrated under reduced pressure. The residue was separated by semi-preparative reverse phase HPLC chromatography to give the diastereomeric products compound 18-E1(25mg, 36.7%) and compound 18-E2(13mg, 18.3% yield), each as a mixture of 2 stereoisomers.

Compound 18-E1 (mixture of 2 stereoisomers): LC/MS ESI 512.2(M + H)⁺。¹H NMR(500MHz,MeOD)δ7.58(dd,J＝8.8,5.9Hz,1H),7.52–7.42(m,1H),7.21–7.11(m,2H),6.40(d,J＝7.3Hz,1H),4.80(dd,J＝21.1,11.7Hz,2H),4.22–4.12(m,1H),4.04(dd,J＝10.4,5.6Hz,1H),3.76–3.66(m,1H),3.61(d,J＝8.1Hz,1H),3.49(dtd,J＝12.6,6.3,3.3Hz,2H),3.42–3.34(m,3H),3.22–2.99(m,2H),2.72(t,J＝6.2Hz,2H),2.60–2.51(m,2H),2.16–1.96(m,4H),1.92–1.82(m,2H),1.70(dddd,J＝28.3,22.6,9.4,4.8Hz,9H).

Compound 18-E2 (mixture of 2 stereoisomers): LC/MS ESI 512.2(M + H)⁺。¹H NMR(500MHz,MeOD)δ7.44(dt,J＝8.5,6.0Hz,2H),7.18(t,J＝7.7Hz,1H),7.10(qd,J＝8.4,2.6Hz,1H),6.39(dd,J＝7.3,4.0Hz,1H),5.21(s,1H),4.74(dd,J＝29.6,11.1Hz,1H),4.10(dd,J＝26.7,15.4Hz,2H),3.66(dd,J＝20.8,9.7Hz,1H),3.54–3.37(m,6H),3.15–2.96(m,2H),2.72(t,J＝6.2Hz,2H),2.58(dt,J＝14.9,6.9Hz,2H),2.10(dd,J＝34.9,11.9Hz,2H),1.99–1.80(m,5H),1.77–1.66(m,4H),1.63–1.55(m,3H).

Example 19: preparation of 2- (5-fluoro-2- (tetrahydrofuran-3-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compounds 19-E1, 19-E2, 19-E3 and 19-E4)

Step 1: 2- (2-bromo-5-fluorophenyl) acetic acid methyl ester

To a solution of 2- (2-bromo-5-fluorophenyl) acetic acid (10g, 43mmol) in MeOH (60mL) was added 0.5mL H₂SO₄. The mixture was refluxed for 4 hours, allowed to cool to room temperature, and the solvent was removed under reduced pressure. The resulting oil (10g, 94.3%) was used without further purification. (ESI 246.1(M + H) ⁺)

Step 2: 2- (2- (2, 5-dihydrofuran-3-yl) -5-fluorophenyl) acetic acid methyl ester

To a solution of methyl 2- (2-bromo-5-fluorophenyl) acetate (492mg, 2mmol) in DMF (5mL) was added 2- (2, 5-dihydrofuran-3-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (392mg, 2mmol), tris (dibenzylideneacetone) dipalladium (0) (91mg, 0.1mmol), X-Phos (4)7.6mg, 0.1mmol) and potassium phosphate (424mg, 2 mmol). The resulting mixture was heated at 60 ℃ under N₂Stir for 2 hours, cool to room temperature and partition between ethyl acetate (20mL) and water (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (20 mL. times.3). The combined organic phases were washed with brine and over anhydrous Na₂SO₄And (5) drying. After filtration and concentration, the residue was chromatographed (Combiflash) using 20-80% EtOAc/petroleum ether as eluent to give methyl 2- (2- (2, 5-dihydrofuran-3-yl) -5-fluorophenyl) acetate (350mg, 73%). (ESI 237.2(M + H)⁺)

And step 3: 2- (5-fluoro-2- (tetrahydrofuran-3-yl) phenyl) acetic acid methyl ester

To a solution of methyl 2- (2- (2, 5-dihydrofuran-3-yl) -5-fluorophenyl) acetate (350mg, 1.48mmol) in methanol (10mL) was added Pd/C (50 mg). The mixture was heated at 40 ℃ under H₂Stirred (balloon) for 3 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was chromatographed (Combiflash) using 5-20% EtOAc/petroleum ether as eluent to give methyl 2- (5-fluoro-2- (tetrahydrofuran-3-yl) phenyl) acetate as an oil (260mg, 73%). LCMS: 239(M + H) ⁺

And 4, step 4: 2-bromo-2- (5-fluoro-2- (tetrahydrofuran-3-yl) phenyl) acetic acid methyl ester

A solution of methyl 2- (5-fluoro-2- (tetrahydrofuran-3-yl) phenyl) acetate (260mg, 1.09mmol) in THF (10mL) was dissolved in N₂It was cooled to-78 ℃ and treated with LDA (1.25mL, 2.5mmol, 2M in THF), and the mixture was stirred for 0.5 h. TMSCl (324mg, 3mmol) was added, the reaction stirred for 0.25 h, and NBS (534mg, 3mmol) in THF (10mL) was added. The reaction was stirred for 0.5 h, diluted with water and extracted with ethyl acetate (30 mL. times.3). The combined organic phases were washed with brine and over anhydrous Na₂SO₄And (5) drying. After filtration and concentration, the residue was chromatographed (Combiflash) using 5-20% EtOAc/petroleum ether as eluent to give methyl 2-bromo-2- (5-fluoro-2- (tetrahydrofuran-3-yl) phenyl) acetate as an oil (250mg, 71.8%). (ESI 317.2(M + H)⁺)

And 5: 2- (5-fluoro-2- (tetrahydrofuran-3-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid methyl ester

To a solution of methyl 2-bromo-2- (5-fluoro-2- (tetrahydrofuran-3-yl) phenyl) acetate (100mg, 0.31mmol) in 5mL dry DMF was added (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (87mg, 0.31mmol) and diisopropylethylamine (120mg, 0.93 mmol). The reaction was stirred for 2 hours, diluted with water (10mL), and extracted with ethyl acetate (20 mL. times.3). The combined organic phases were washed with brine and over anhydrous Na ₂SO₄And (5) drying. After filtration and concentration, the residue was chromatographed (Combiflash) using 20-80% EtOAc/petroleum ether as eluent to give methyl 2- (5-fluoro-2- (tetrahydrofuran-3-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate (110mg, 68%) as a solid. (ESI 512(M + H)⁺)。

Step 6: 2- (5-fluoro-2- (tetrahydrofuran-3-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compounds 19-E1, 19-E2, 19-E3 and 19-E4)

To a solution of methyl 2- (5-fluoro-2- (tetrahydrofuran-3-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate (110mg, 0.21mmol) in methanol (5mL) was added LiOH (20mg, 0.8mmol) and water (4 mL). The reaction was stirred for 2 hours, filtered and concentrated under reduced pressure. The resulting residue was separated using semi-preparative reverse phase HPLC chromatography to give diastereomeric compounds compound 19-E1(10mg, 9.3% yield), compound 19-E2(10mg, 9.3% yield), compound 19-E3(10mg, 9.3% yield) and compound 19-E4(10mg, 9.3% yield).

Compound 19-E1: LC/MS ESI 498.2(M + H)⁺。¹H NMR(500MHz,MeOD)δ7.48(dd,J＝8.8,5.7Hz,1H),7.42(dd,J＝10.1,2.7Hz,1H),7.23(d,J＝7.3Hz,1H),7.14(td,J＝8.4,2.8Hz,1H),6.41(dd,J＝20.8,7.3Hz,1H),4.95(s,1H),4.58–4.46(m,1H),4.18(d,J＝18.9Hz,1H),4.05–3.98(m,2H),3.86(dd,J＝15.5,7.5Hz,2H),3.79(dd,J＝8.3,6.3Hz,1H),3.50(t,J＝6.2Hz,2H),3.42(dd,J＝14.2,8.7Hz,3H),3.28(s,1H),3.12–2.98(m,2H),2.73(t,J＝6.2Hz,2H),2.60(ddd,J＝15.0,9.5,5.5Hz,2H),2.51–2.38(m,1H),2.08(ddd,J＝14.9,8.4,4.6Hz,3H),1.90(dd,J＝11.8,5.7Hz,2H),1.80–1.60(m,4H).

Compound 19-E2: LC/MS ESI 498.2(M + H) ⁺。¹H NMR(500MHz,MeOD)δ7.51–7.46(m,1H),7.42(dd,J＝10.1,2.7Hz,1H),7.23(d,J＝7.3Hz,1H),7.13(td,J＝8.4,2.8Hz,1H),6.43(d,J＝7.3Hz,1H),4.94(s,1H),4.17(dd,J＝19.1,11.5Hz,2H),4.11–4.03(m,1H),3.95–3.80(m,3H),3.76–3.68(m,1H),3.52–3.46(m,3H),3.43–3.37(m,2H),3.26(d,J＝12.5Hz,1H),3.13–2.99(m,2H),2.73(t,J＝6.2Hz,2H),2.60(t,J＝7.2Hz,2H),2.42–2.29(m,1H),2.07(dtd,J＝42.5,12.5,7.8Hz,4H),1.94–1.86(m,2H),1.78–1.69(m,2H),1.68–1.58(m,3H).

Compound 19-E3: LC/MS ESI 498.2(M + H)⁺。¹H NMR(500MHz,MeOD)δ7.52–7.39(m,2H),7.23(d,J＝7.3Hz,1H),7.13(td,J＝8.4,2.8Hz,1H),6.42(t,J＝10.9Hz,1H),4.87–4.81(m,1H),4.17(s,1H),4.04(ddt,J＝33.6,28.5,7.3Hz,3H),3.88(dd,J＝15.7,7.6Hz,1H),3.79(dd,J＝8.2,6.2Hz,1H),3.56–3.51(m,1H),3.46–3.34(m,4H),3.16(ddd,J＝16.9,15.7,6.6Hz,3H),2.73(t,J＝6.2Hz,2H),2.62(dd,J＝16.3,7.8Hz,2H),2.48(d,J＝7.6Hz,1H),2.18–2.12(m,2H),2.09–2.01(m,1H),1.92–1.86(m,2H),1.75(dd,J＝12.1,7.4Hz,2H),1.68–1.60(m,2H).

Compound 19-E4: LC/MS ESI 498.2(M + H)⁺。¹H NMR(500MHz,MeOD)δ7.46(ddd,J＝13.0,9.5,4.3Hz,2H),7.24(d,J＝7.3Hz,1H),7.13(td,J＝8.4,2.8Hz,1H),6.43(d,J＝7.3Hz,1H),4.86(s,1H),4.23–4.14(m,2H),4.09(td,J＝8.3,4.6Hz,1H),3.98(dd,J＝14.8,7.4Hz,1H),3.86(dd,J＝15.9,7.7Hz,1H),3.71(dd,J＝8.6,6.5Hz,1H),3.54(dt,J＝9.1,6.1Hz,1H),3.46–3.35(m,4H),3.25–3.08(m,3H),2.73(t,J＝6.2Hz,2H),2.69–2.54(m,2H),2.39(d,J＝7.8Hz,1H),2.16(d,J＝3.6Hz,2H),2.02(dq,J＝12.4,7.8Hz,1H),1.95–1.83(m,2H),1.75(dd,J＝12.3,7.4Hz,2H),1.62(dd,J＝13.6,7.0Hz,2H).

Example 20: preparation of 2- (2-Cyclopropoxy-5-fluorophenyl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetic acid (Compounds 20-E1 and 20-E2)

Step 1: 2-bromo-1-cyclopropoxy-4-fluorobenzene

2-bromo-4-fluorophenol (250mg, 1.31mmol), bromocyclopropane (792mg, 6.54mmol), NaI (2mg, 0.013mmol) and K₂CO₃A mixture of (543mg, 3.93mmol) in DMF (4mL) was stirred and heated to 150 ℃ under microwave radiation (Biotage) for 2 hours. The reaction mixture was diluted with water (10mL) and ethyl acetate (10mL), the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (10 mL. times.3). The combined organic layers were washed with brine and over anhydrous Na₂SO₄And (5) drying. After filtration and concentration, the residue was chromatographed (Combiflash) using EtOAc/petroleum ether (1:10) as eluent to give 2-bromo-1-cyclopropoxy-4-fluorobenzene (50mg, 16.5%).¹H NMR(500MHz,CDCl₃)δ7.28–7.22(m,1H),7.18(dd,J＝9.1,4.9Hz,1H),7.03–6.94(m,1H),3.76(tt,J＝5.9,3.1Hz,1H),0.87–0.69(m,4H).

Step 2: 2-Cyclopropoxy-5-fluorophenylboronic acid

To a solution of 2-bromo-1-cyclopropoxy-4-fluorobenzene (250mg, 1.08mmol) in THF (15mL) at-78 deg.C under Ar was added nBuLi (0.87mL, 2.16mmol, 2.5M in THF). The mixture was stirred for 0.5 h, then triisopropyl borate (224mg, 1.19mmol) was added slowly via syringe. The mixture was stirred continuously at-78 ℃ for 2 hours, then by addition of saturated aqueous NH ₄The Cl solution (5mL) was quenched. The mixture was allowed to cool to room temperature and partitioned between water (10mL) and ethyl acetate (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (15 mL. times.3), washed with brine and over anhydrous Na₂SO₄And (5) drying. The organic phase was concentrated to dryness to give 2-bromo-1-cyclopropoxy-4-fluorobenzene (70mg, yield 33.0%).

Step 32- (2-Cyclopropoxy-5-fluorophenyl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetic acid (Compounds 20-E1 and 20-E2)

A mixture of (R) -7- (5- (pyrrolidin-3-yl) pentyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (60mg, 0.22mmol), 2-cyclopropoxy-5-fluorophenylboronic acid (47mg, 0.24mmol) and 2-oxoacetic acid (18mg, 0.24mmol) in MeCN (4mL) was stirred for 2 hours. The residue was chromatographed using semi-preparative reverse phase HPLC (30-65% MeCN) to give compound 20(45mg, 42.6%). The racemic product was separated by chiral SFC to give the diastereomeric products compound 20-E1(9.3mg) and compound 20-E2(11.1 mg).

Compound 20-E1 LC/MS ESI 482.2(M + H)⁺。¹H NMR(500MHz,MeOD)δ7.42(dd,J＝9.1,4.5Hz,1H),7.31(dd,J＝8.9,2.8Hz,1H),7.16(ddd,J＝20.7,12.9,5.2Hz,2H),6.35(d,J＝7.3Hz,1H),4.86(s,1H),4.11–3.80(m,1H),3.48–3.35(m,3H),3.17(dd,J＝23.9,15.4Hz,2H),2.87(s,1H),2.71(t,J＝6.3Hz,2H),2.50(t,J＝7.6Hz,2H),2.38–2.25(m,1H),2.24–2.08(m,1H),1.89(dt,J＝12.2,6.1Hz,2H),1.62(dd,J＝13.5,7.4Hz,3H),1.41(s,2H),1.32(dd,J＝22.3,9.5Hz,5H),0.98–0.71(m,4H).

Compound 20-E2 LC/MS ESI 482.2(M + H)⁺。¹H NMR(500MHz,MeOD)δ7.43(dd,J＝9.1,4.5Hz,1H),7.33(dd,J＝8.9,2.9Hz,1H),7.22–7.15(m,1H),7.14(d,J＝7.3Hz,1H),6.36(t,J＝5.8Hz,1H),4.88–4.82(m,1H),4.00–3.87(m,1H),3.60(s,1H),3.44–3.34(m,3H),3.16–3.04(m,1H),2.72(dd,J＝15.9,9.5Hz,3H),2.56–2.46(m,2H),2.42–2.31(m,1H),2.22–2.07(m,1H),1.94–1.83(m,2H),1.67–1.60(m,3H),1.43(s,2H),1.35(d,J＝4.6Hz,5H),0.95–0.70(m,4H).

Example 21: preparation of 2- (2-Cyclobutylpyridin-3-yl) -2- ((3R) -3- (4- (1,2,3, 4-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compounds 21-B-E1, 21-B-E2 and 21-A)

Step 1: stereoisomer B of ethyl 2- (2-cyclobutylpyridin-3-yl) -2- ((R) -3- (4- ((R) -1,2,3, 4-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate

A mixture of 2- (4- (((R) -pyrrolidin-3-yl) oxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine stereoisomer B (120mg, 0.44mmol), ethyl 2-chloro-2- (2-cyclobutylpyridin-3-yl) acetate (110mg, 0.44mmol) and diisopropylethylamine (513mg, 3.72mmol) in acetonitrile (8mL) was stirred at 50 ℃ for 16 h. The solvent was removed in vacuo and the residue was purified by column on silica gel (DCM: MeOH 20:1) to give the desired product ethyl 2- (2-cyclobutylpyridin-3-yl) -2- ((R) -3- (4- ((R) -1,2,3, 4-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate stereoisomer B (95mg) as a yellow oil. Yield 44% (ESI 493(M + H) +).

Step 2: stereoisomer B of 2- (2-Cyclobutylpyridin-3-yl) -2- ((3R) -3- (4- (1,2,3, 4-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compounds 21-B-E1 and 21-B-E2)

Ethyl 2- (2-cyclobutylpyridin-3-yl) -2- ((R) -3- (4- ((R) -1,2,3, 4-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate stereoisomer B (95mg, 0.19mmol) was treated with LiOH-H2O (52mg, 1.24mmol) in MeOH (4mL) and H2O (1mL) at 40 ℃ for 4 hours. The solvent was removed in vacuo, and the residue was purified by preparative HPLC a (30-65% MeCN) to give compound 21-B as a white solid (68mg, 77% yield). The racemic product was separated by preparative chiral SFC F to give the diastereomeric products compound 21-B-E1(4mg) and compound 21-B-E2(6mg) as white solids.

Compound 21-B-E1 LC/MS ESI 465(M + H) +. 1H NMR (500MHz, MeOD) δ 8.68(m,1H),8.08(d, J ═ 9.5Hz,1H),7.71(m,1H),7.31(m,2H),6.52(m,1H),4.82(s,1H),4.23(m,2H),3.55-3.35(m,4H),3.20(m,3H),2.76(m,2H),2.63-1.86(m,9H),1.75-1.50(m,7H), chiral SFC F: ee 100%, Rt 7.78 min.

Compound 21-B-E2 LC/MS ESI 465(M + H) +. 1H NMR (500MHz, MeOD) δ 8.58(m,1H),8.08(d, J ═ 9.5Hz,1H),7.75(m,1H),7.31(m,2H),6.52(m,1H),4.82(s,1H),4.23(m,2H),3.55-3.35(m,4H),3.20(m,3H),2.76(m,2H),2.63-1.86(m,9H),1.75-1.50(m,7H), chiral SFC F: ee 100%, Rt 12.02 min.

And step 3: stereoisomer A of 2- (2-Cyclobutylpyridin-3-yl) -2- ((R) -3- (4- ((S) -1,2,3, 4-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 21-A)

The 2- (2-cyclobutylpyridin-3-yl) -2- ((R) -3- (4- ((S) -1,2,3, 4-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid stereoisomer a (compound 21-a) was synthesized from 2- (4- (((R) -pyrrolidin-3-yl) oxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine stereoisomer a by the same procedure as for stereoisomer B.

The compound 21-ALC/MS ESI 465.3(M + H) + 1H NMR (500MHz, MeOD) delta 8.56-8.54(M,1H),8.08-8.01(M,1H),7.72-7.70(M,1H),7.32-7.29(M,2H),6.56-6.52(M,1H),4.82-4.73(M,1H),4.30-4.18(M,2H),3.78-3.35(M,4H),3.28-2.95(M,3H),2.81-2.28(M,6H),2.24-1.88(M,5H),1.74-1.48(M,7H).

Example 22: preparation of 2- (5-fluoro-2- (tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 92-A-E1, 92-A-E2, 92-B-E1 and 92-B-E2)

Step 1: 2- (5-fluoro-2- (tetrahydro-2H-pyran-2-yl) phenyl) acetic acid methyl ester

To a solution of methyl 2- (5-fluoro-2- (tetrahydro-2H-pyran-2-yl) phenyl) acetate (2.4g, 9.6mmol) in 100mL anhydrous MeOH was added Pd (OH)₂(100mg) and TEA (2 mL). The mixture was heated at 40 ℃ under H₂Stirring was carried out under an atmosphere (balloon) for 8 hours.

The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica (Combiflash) using 5-20% EtOAc/petroleum ether as eluent to give racemic methyl 2- (5-fluoro-2- (tetrahydro-2H-pyran-2-yl) phenyl) acetate (2.2g, 92%). Chiral separation using SFC (AY-H (250 × 4.6mm 5um) mobile phase, hexane (0.1% DEA): EtOH (0.1% DEA) ═ 95:5) yielded stereoisomer a (identified as methyl (R) -2- (5-fluoro-2- (tetrahydro-2H-pyran-2-yl) phenyl) acetate, 960mg, 43.5%) and stereoisomer B (identified as methyl (S) -2- (5-fluoro-2- (tetrahydro-2H-pyran-2-yl) phenyl) acetate, 904mg, 40.7%); (ESI 253.2(M + H) ⁺)。

Step 2: 2-bromo-2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) acetic acid methyl ester (stereoisomer B)

In N₂LDA (25mL, 50mmol, 2M in THF) was added to (S) -2- (5-fluoro-2- (tetrahydro-2H-pyran-2-yl) phenyl) acetic acid at-78 deg.CA solution of methyl ester (stereoisomer B, 4.2g, 16.7mmol) in THF (100 mL). The reaction was stirred for 0.5 h and TMSCl (5.4g, 50mmol) was added. After a further 15 minutes, a solution of NBS (8.9g, 50mmol) in THF (50mL) was added and the reaction was stirred at-78 deg.C for 0.5 h. The reaction was diluted with water (10mL) and extracted with ethyl acetate (50 mL. times.2). The combined organic phases were washed with brine and over anhydrous Na₂SO₄And (5) drying. After filtration and concentration, the residue was chromatographed on silica (Combiflash) using 0-20% EtOAc/petroleum ether as eluent to give methyl 2-bromo-2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) acetate (stereoisomer B, 4.1g, 74.5%); (ESI 331.3(M + H)⁺)。

And step 3: methyl 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate (stereoisomer B)

To a solution of methyl 2-bromo-2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) acetate (stereoisomer B, 4.1g, 12.4mmol) in acetonitrile (30mL) was added (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (3.4g, 12.4mmol) and DIPEA (4.8g, 37.2 mmol). The reaction was stirred for 1c, diluted with water (50mL), and extracted with ethyl acetate (50 mL. times.3). The combined organic phases were washed with brine and over anhydrous Na ₂SO₄And (5) drying. After filtration and concentration, the residue was chromatographed on silica (Combiflash) using 20-80% EtOAc/petroleum ether as eluent to yield methyl 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate as a mixture of diastereomers (stereoisomer B, 4.9g, 75%); (ESI 526.2(M + H)⁺)；¹H NMR(500MHz,MeOD)δ7.51(ddd,J＝20.9,8.7,5.9Hz,1H),7.34(dt,J＝10.3,3.4Hz,1H),7.11(d,J＝7.3Hz,1H),7.09–7.03(m,1H),6.36(d,J＝7.3Hz,1H),4.86(m,2H),4.47(m,1H),4.08–3.97(m,2H),3.69–3.61(m,4H),3.39(m,3H),2.87(m,1H),2.75–2.63(m,3H),2.56–2.35(m,4H),2.00(m,1H),1.97–1.75(m,5H),1.72–1.63(m,4H),1.57(m,4H).

And 4, step 4: 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compounds 92-B-E1 and 92-B-E2)

To a solution of methyl 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate (stereoisomer B, 4.9g, 9.3mmol) in methanol (50mL) was added LiOH (480mg, 20mmol) and water (20 mL). The reaction was stirred at 25 ℃ for 16H, filtered and concentrated under reduced pressure, then purified by semi-preparative reverse phase HPLC to give the individual diastereomers (S) -2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid compound 92-B-E1(1.88g) (39.4% yield) and (R) -2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid compound 92-B-E2(1.33g) (27.9% yield).

Compound 92-B-E1: LC/MS ESI 512.3(M + H)⁺。1H NMR(400MHz,MeOD)δ7.58(dd,J＝8.8,5.9Hz,1H),7.46(dd,J＝10.0,2.7Hz,1H),7.22–7.11(m,2H),6.40(d,J＝7.3Hz,1H),4.90(s,1H),4.77(d,J＝10.3Hz,1H),4.20(m,1H),4.04(dd,J＝7.5,5.6Hz,1H),3.68(t,J＝11.6Hz,1H),3.62(d,J＝9.2Hz,1H),3.49(t,J＝5.6Hz,2H),3.42–3.35(m,3H),3.23(d,J＝12.6Hz,1H),3.04(m,1H),2.72(t,J＝6.2Hz,2H),2.57(t,J＝7.6Hz,2H),2.2-1.95(m,4H),1.9-1.8(m,2H),1.8-1.55(m,8H).

Compound 92-B-E2: LC/MS ESI 512.3(M + H)⁺。¹H NMR(500MHz,MeOD)δ7.47–7.39(m,2H),7.19(d,J＝7.3Hz,1H),7.11(td,J＝8.4,2.6Hz,1H),6.40(d,J＝7.3Hz,1H),4.75(d,J＝11.1Hz,2H),4.15(d,J＝9.4Hz,1H),4.08(s,1H),3.67(t,J＝10.7Hz,1H),3.53–3.42(m,3H),3.38(d,J＝5.3Hz,2H),3.10(m,2H),2.72(t,J＝6.2Hz,2H),2.58(m,2H),2.15(s,1H),2.09(s,1H),1.95(d,J＝7.8Hz,2H),1.92–1.82(m,3H),1.73(m,4H),1.61(m,4H).

And 5: 2- (5-fluoro-2- ((R) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compounds 92-A-E1 and 92-A-E2)

Synthesis of (R) -2- (5-fluoro-2- ((R) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid compound 92-A-E1 and (S) -2- (5-fluoro-2- ((R) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) from methyl (R) -2- (5-fluoro-2- (tetrahydro-2H-pyran-2-yl) acetate (stereoisomer A) by the same procedure as for stereoisomer B -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid compound 92-a-E2.

Compound 92-a-E1: LC/MS ESI 512.1(M + H)⁺,¹H NMR(500MHz,MeOD)δ7.58–7.50(m,2H),7.16(d,J＝7.4Hz,1H),7.11–7.04(m,1H),6.38(d,J＝7.3Hz,1H),4.87(d,J＝10.9Hz,1H),4.62(s,1H),4.11(d,J＝2.5Hz,1H),4.04(m,1H),3.72(m,1H),3.47–3.35(m,5H),3.16–3.03(m,2H),2.70(d,J＝6.1Hz,2H),2.58–2.50(m,2H),2.16–1.95(m,4H),1.90–1.85(m,2H),1.73–1.65(m,4H),1.64–1.56(m,4H).

Compound 92-a-E2: LC/MS ESI 512.1(M + H)⁺,¹H NMR(500MHz,MeOD)δ7.50–7.39(m,2H),7.16(d,J＝7.3Hz,1H),7.09(td,J＝8.4,2.7Hz,1H),6.38(d,J＝7.3Hz,1H),5.08(s,1H),4.76(d,J＝11.0Hz,1H),4.14(d,J＝3.5Hz,1H),4.07(d,J＝12.2Hz,1H),3.44(m,3H),3.38(d,J＝5.5Hz,3H),2.99–2.92(m,1H),2.71(t,J＝6.2Hz,2H),2.55(t,J＝7.5Hz,2H),2.10–2.03(m,2H),1.95–1.81(m,5H),1.73–1.67(m,4H),1.60(m,4H).

Example 23: preparation of 2- (5-fluoro-2- (tetrahydrofuran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compounds 93-A-E1, 93-A-E2, 93-B-E1 and 93-B-E2)

Step 1: 2- (2-bromo-5-fluorophenyl) acetic acid methyl ester

To a solution of 2- (2-bromo-5-fluorophenyl) acetic acid (10g, 43mmol) in 60mL MeOH was added 0.5mL H ₂SO₄And the mixture was heated at reflux for 4 hours. The solvent was removed under reduced pressure to give methyl 2- (2-bromo-5-fluorophenyl) acetate (10g, yield: 94.3%) as an oil, which was used without further purification. (ESI 246.1(M + H)⁺)

Step 2: 2- (5-fluoro-2- (furan-2-yl) phenyl) acetic acid methyl ester

To a solution of methyl 2- (2-bromo-5-fluorophenyl) acetate (5g, 20.2mmol) in 100mL of DMF was added furan-2-ylboronic acid (2.72g, 24mmol), tris (dibenzylideneacetone) dipalladium (0) (915mg, 1mmol), X-Phos (476mg, 1mmol) and potassium phosphate (8.5g, 40 mmol). The mixture was heated at 60 ℃ under N₂Stirred for 8 hours. The reaction was diluted with 200mL of ethyl acetate and 200mL of water, and the organic layer was separated. The aqueous layer was extracted three times with ethyl acetate (200mL × 3), and the combined organic layers were washed with brine and over anhydrous Na₂SO₄And (5) drying. After filtration and concentration, the residue was chromatographed on silica (Combiflash) using 0-20% ethyl acetate/petroleum ether as eluent to give methyl 2- (5-fluoro-2- (furan-2-yl) phenyl) acetate (3.9g, 82.7% yield); ESI 237.2(M + H)⁺

And step 3: 2- (5-fluoro-2- (tetrahydrofuran-2-yl) phenyl) acetic acid methyl ester

To 2- (5-fluoro)To a solution of methyl (2.34g, 10mmol) 2- (furan-2-yl) phenyl) acetate in 30mL EtOAC was added Pd/C (1g) and DIEA (2.58g, 20 mmol). The mixture was heated at 35 ℃ under H ₂Stir under atmosphere (balloon) for 5 hours. After the reaction was completed, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica (Combiflash) using 5-20% ethyl acetate/petroleum ether as eluent to give methyl 2- (5-fluoro-2- (tetrahydrofuran-2-yl) phenyl) acetate as an oil (1.56g, 66.7%).

Racemic compound was separated by SFC (SFC (AY-H (250X 4.6mm 5um) mobile phase: hexane (0.1% DEA): EtOH (0.1% DEA) ═ 95:5) to give stereoisomer A (950mg) and stereoisomer B (920mg) as oil, ESI 239.1(M + H)⁺

And 4, step 4: stereoisomer A of methyl 2-bromo-2- (5-fluoro-2- (tetrahydrofuran-2-yl) phenyl) acetate

In N₂Next, to a solution of methyl 2- (5-fluoro-2- (tetrahydrofuran-2-yl) phenyl) acetate stereoisomer A (250mg, 1.05mmol) in 10mL dry THF at-78 deg.C was added LDA (1.25mL, 2.5mmol, 2M in THF). The reaction was stirred for 0.5 h and TMSCl (324mg, 3mmol) was added. After stirring for 15 min, 10mL THF containing NBS (534mg, 3mmol) was added and the mixture was stirred at-78 deg.C for 0.5 h. The mixture was diluted with water and extracted with ethyl acetate (30mL × 3). The combined organic layers were washed with brine and over anhydrous Na ₂SO₄And (5) drying. After filtration and concentration, the residue was chromatographed on silica (Combiflash) using 5-20% ethyl acetate/petroleum ether as eluent to give methyl 2-bromo-2- (5-fluoro-2- (tetrahydrofuran-2-yl) phenyl) acetate stereoisomer a as an oil (240mg, 71%); ESI 317.2(M + H)⁺

And 5: methyl 2- (5-fluoro-2- (tetrahydrofuran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate stereoisomer a

To a solution of methyl 2-bromo-2- (5-fluoro-2- (tetrahydrofuran-2-yl) phenyl) acetate stereoisomer a (240mg, 0.76mmol) in 10mL ACN was added (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (213mg, 0.76mmol) and DIPEA (295mg, 2.28 mmol). The reaction was stirred for 4 hours, diluted with water (30mL) and extracted with ethyl acetate (50 mL. times.3). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was chromatographed on silica (Combiflash) using 20-80% ethyl acetate/petroleum ether as eluent to give methyl 2- (5-fluoro-2- ((S) -tetrahydrofuran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate stereoisomer a as a solid (300mg, 77%); ESI 512(M + H) ⁺

Step 6: 2- (5-fluoro-2- ((S) -tetrahydrofuran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid stereoisomer B (Compounds 93-A-E1 and 93-A-E2)

To a solution of methyl 2- (5-fluoro-2- (tetrahydrofuran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate stereoisomer a (330mg, 0.59mmol) in 10mL methanol was added LiOH (40mg, 1.6mmol) and water (10 mL). The reaction was stirred at 25 ℃ for 16 hours. 1N HCl was added to the mixture to adjust the pH to 5-6. The mixture was concentrated under reduced pressure, and the residue was purified by semi-preparative HPLC to give compound 93-a-E1(56mg, 18%) and compound 93-a-E2(45mg, 15%) as solids.

Compound 93-A-E1 ESI 498.2(M + H)⁺,¹H NMR(500MHz,MeOD)δ7.58(dd,J＝8.8,5.9Hz,1H),7.45(dd,J＝10.0,2.7Hz,1H),7.18(d,J＝7.4Hz,1H),7.15(dd,J＝8.4,5.8Hz,1H),6.41(d,J＝7.3Hz,1H),5.22(t,J＝7.0Hz,1H),4.96(s,1H),4.19(s,1H),4.07(dd,J＝14.4,7.3Hz,1H),3.88(dt,J＝14.1,7.0Hz,1H),3.60–3.43(m,3H),3.43–3.37(m,2H),3.26(dd,J＝33.4,10.4Hz,2H),3.04(t,J＝7.6Hz,1H),2.72(t,J＝6.2Hz,2H),2.58(t,J＝7.6Hz,2H),2.44(dt,J＝12.0,5.9Hz,1H),2.16–1.93(m,5H),1.92–1.86(m,2H),1.75(m,2H),1.68–1.56(m,2H)

Compound 93-A-E2 ESI 498.2(M + H)⁺,¹H NMR(500MHz,MeOD)δ7.49(dd,J＝8.7,5.9Hz,1H),7.46(d,J＝10.3Hz,1H),7.21(d,J＝7.2Hz,1H),7.11(t,J＝6.9Hz,1H),6.42(d,J＝7.3Hz,1H),5.18(s,1H),4.87–4.81(m,1H),4.16(s,1H),4.16–4.09(m,1H),3.88(t,J＝7.1Hz,1H),3.50(t,J＝6.1Hz,3H),3.42–3.36(m,2H),3.10(d,J＝7.6Hz,2H),2.73(t,J＝6.2Hz,2H),2.67–2.54(m,2H),2.41(d,J＝10.7Hz,1H),2.16–1.96(m,5H),1.93–1.85(m,2H),1.75(m,2H),1.64(m,2H).

And 7: stereoisomer B of methyl 2-bromo-2- (5-fluoro-2- (tetrahydrofuran-2-yl) phenyl) acetate

In N₂Next, LDA (1.25mL, 2.5mmol, 2M in THF) was added to a solution of methyl 2- (5-fluoro-2- (tetrahydrofuran-2-yl) phenyl) acetate stereoisomer B (250mg, 1.05mmol) in 10mL dry THF at-78 ℃. The reaction was stirred for 0.5 h and TMSCl (324mg, 3mmol) was added. After stirring for 15 min, 10mL THF containing NBS (534mg, 3mmol) was added and the mixture was stirred at-78 deg.C for 0.5 h. The mixture was diluted with water and extracted with ethyl acetate (30mL × 3). The combined organic layers were washed with brine and over anhydrous Na ₂SO₄And (5) drying. After filtration and concentration, the residue was chromatographed on silica (Combiflash) using 5-20% ethyl acetate/petroleum ether as eluent to give methyl 2-bromo-2- (5-fluoro-2- (tetrahydrofuran-2-yl) phenyl) acetate stereoisomer B (235mg, 70.8%) as an oil; ESI 317.2(M + H)⁺

And 8: methyl 2- (5-fluoro-2- (tetrahydrofuran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate stereoisomer B

To a solution of methyl 2-bromo-2- (5-fluoro-2- (tetrahydrofuran-2-yl) phenyl) acetate stereoisomer B (100mg, 0.31mmol) in 5mL ACN was added (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (87mg, 0.31mmol) and DIPEA (120mg, 0.93 mmol). The reaction was stirred for 4 hours, diluted with water (10mL) and extracted with ethyl acetate (20 mL. times.3). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was chromatographed on silica (Combiflash) using 20-80% ethyl acetate/petroleum ether as eluent to give methyl 2- (5-fluoro-2- ((S) -tetrahydrofuran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate stereoisomer B as a solid (120mg, 78%); ESI 512.2(M + H) ⁺

And step 9: stereoisomer B of 2- (5-fluoro-2- (tetrahydrofuran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compounds 93-B-E1 and 93-B-E2)

To a solution of methyl 2- (5-fluoro-2- (tetrahydrofuran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate stereoisomer B (300mg, 0.59mmol) in 10mL methanol was added LiOH (40mg, 1.6mmol) and water (10 mL). The reaction was stirred at 25 ℃ for 16 hours. 1N HCl was added to the mixture to adjust the pH to 5-6. The mixture was concentrated under reduced pressure, and the residue was purified by semi-preparative HPLC to give compound 93-B-E1(27mg, 9%) and compound 93-B-E2(30mg, 10%) as solids.

Compound 93-B-E1ESI 498.2(M+H)⁺,¹H NMR(500MHz,MeOD)δ7.58(dd,J＝8.8,6.0Hz,1H),7.48(d,J＝10.1Hz,1H),7.17(dd,J＝20.5,7.7Hz,2H),6.41(d,J＝7.3Hz,1H),5.29(t,J＝7.1Hz,1H),4.9(s,1H),4.17(s,1H),4.08(dd,J＝14.6,7.2Hz,1H),3.89(dd,J＝13.8,7.8Hz,1H),3.60–3.38(m,5H),3.16(d,J＝7.5Hz,1H),2.72(t,J＝6.2Hz,2H),2.59(dd,J＝14.4,7.2Hz,2H),2.48(dd,J＝11.9,5.2Hz,1H),2.18(s,2H),2.12–1.99(m,2H),2.01–1.85(m,4H),1.74(m,2H),1.64(m,2H).

Compound 93-B-E2 ESI 498.2(M + H)⁺,¹H NMR(500MHz,MeOD)δ7.49(dd,J＝8.7,5.8Hz,1H),7.44(d,J＝10.1Hz,1H),7.19(d,J＝7.3Hz,1H),7.12(t,J＝7.0Hz,1H),6.41(d,J＝7.3Hz,1H),5.12(s,1H),4.97(s,1H),4.18(s,1H),4.14–4.08(m,1H),3.86(t,J＝6.9Hz,1H),3.48(t,J＝6.2Hz,3H),3.42–3.38(m,3H),3.19(s,1H),3.04(s,1H),2.73(t,J＝6.3Hz,2H),2.58(t,J＝6.2Hz,2H),2.37(s,1H),2.17–1.99(m,5H),1.94–1.84(m,2H),1.74(m,2H),1.64(m,2H).

Example 24: preparation of 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- ((3- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propoxy) methyl) pyrrolidin-1-yl) acetic acid (compounds 94-E1 and 94-E2)

Step 1: 3- (allyloxymethyl) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester

A mixture of (R) -tert-butyl 3- (hydroxymethyl) pyrrolidine-1-carboxylate (5g, 24.8mmol) and NaH (1.09g, 27.3mmol) in DMF (20mL) was stirred at 0 ℃ for 1 h. A solution of 3-bromoprop-1-ene (4.5g, 37.2mmol) in DMF (10mL) was added dropwise to the above mixture at 0 deg.C, and the reaction mixture was stirred at 50 deg.C overnight. The solvent was removed in vacuo and the residue was purified by silica gel column (petroleum ether: EtOAc 1:1) to give the desired product as a colorless oil (5.1 g). Yield 85% (ESI 186(M + H-56) ⁺)。

Step 2: 3- ((3- (1, 8-naphthyridin-2-yl) propoxy) methyl) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester

To a solution of (R) -tert-butyl 3- (allyloxymethyl) pyrrolidine-1-carboxylate (600mg, 2.49mmol) in THF (dry, 5mL) under Ar was added 9-BBN (THF as a 0.5M solution, 9.95mL, 4.97 mmol). The reaction was stirred at 50 ℃ for 2 hours and then cooled to room temperature. This solution was added to a mixture of 2-bromo-1, 8-naphthyridine (520mg, 2.49mmol), cesium carbonate (2.44g, 7.47mmol) and Pd (PPh3)4(144mg, 0.125mmol) in 1, 4-dioxane (10 mL). The reaction was stirred at 90 ℃ for 1.5 hours. The solvent was removed in vacuo and the residue was purified by column of silica gel (DCM: MeOH 30:1) to give the desired product 3- ((3- (1, 8-naphthyridin-2-yl) propoxy) methyl) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester as a yellow oil (200 mg). Yield 22% (ESI 372(M + H) +).

And step 3: (R) -tert-butyl 3- ((3- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propoxy) methyl) pyrrolidine-1-carboxylate

A mixture of 3- ((3- (1, 8-naphthyridin-2-yl) propoxy) methyl) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester (200mg, 0.54mmol) and Pd/C (40mg, 20 Wt%) in ethyl acetate (10mL) in H₂The mixture was stirred under a balloon at 40 ℃ for 16 hours. The solids were removed by filtration and the filtrate was concentrated in vacuo to give the desired product 3- ((3- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propoxy) methyl) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester as a yellow oil (200 mg). Yield 99% (ESI 376(M + H) +).

And 4, step 4: (R) -7- (3- (pyrrolidin-3-ylmethoxy) propyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine

(R) -tert-butyl 3- ((3- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propoxy) methyl) pyrrolidine-1-carboxylate (200mg, 0.53mmol) was treated with 1, 4-dioxane containing HCl (4M, 10mL) at room temperature for 2 hours. The solvent was removed in vacuo to yield the desired product (R) -7- (3- (pyrrolidin-3-ylmethoxy) propyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (150mg) as the HCl salt. Yield 81% (ESI 276(M + H) +).

And 5: methyl 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- ((3- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propoxy) methyl) pyrrolidin-1-yl) acetate

A mixture of (R) -7- (3- (pyrrolidin-3-ylmethoxy) propyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (150mg, 0.43mmol), methyl 2-bromo-2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) acetate (142mg, 0.43mmol), and DIPEA (166mg, 1.29mmol) in acetonitrile (10mL) was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH 10:1) to give the desired product methyl 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- ((3- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propoxy) methyl) pyrrolidin-1-yl) acetate as a yellow oil (140 mg). The yield was 62%. (ESI 526(M + H) +).

Step 6: 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- ((3- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propoxy) methyl) pyrrolidin-1-yl) acetic acid (compounds 94-E1 and 94-E2)

Methyl 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- ((3- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propoxy) methyl) pyrrolidin-1-yl) acetate (140mg, 0.27mmol) was treated with a solution containing LiOH-H₂O (126mg, 3.0mmol) in MeOH (4mL) and H₂O (1mL) was treated at room temperature for 2 hours. The solvent was removed in vacuo and the residue was passed through preparative HPLC A (30)-60% MeCN) to yield the diastereomeric products compound 94-E1(17mg) and compound 94-E2(49mg) as white solids.

Compound 94-E1 LC/MS ESI 512(M + H)⁺ ¹H NMR(500MHz,MeOD)δ7.65-7.54(m,2H),7.36-7.21(m,2H),6.62(d,J＝7.5Hz,1H),5.06(s,1H),4.77-4.75(m,1H),4.11-4.08(m,1H),3.81-3.33(m,8H),3.25-3.14(m,2H),2.95-2.66(m,5H),2.37-1.58(m,13H).

Compound 94-E2 LC/MS ESI 512(M + H)⁺ ¹H NMR(500MHz,MeOD)δ7.48-7.39(m,2H),7.15-7.08(m,2H),6.35(d,J＝7.0Hz,1H),5.25(s,1H),4.73-4.71(m,1H),4.14-4.12(m,1H),3.81-3.33(m,8H),3.25-3.14(m,2H),2.73-2.56(m,5H),2.18-1.52(m,13H).

Example 25: preparation of 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((S) -3- (2- (2- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) ethyl) pyrrolidin-1-yl) acetic acid (compounds 95-E1 and 95-E2)

Step 1: (S) -3- (2- (3-methoxy-3-oxoprop-1-enyloxy) ethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl (S) -3- (2-hydroxyethyl) pyrrolidine-1-carboxylate (3.3g, 15.5mmol) and 4-methylmorpholine (1.85g, 18.5mmol) in DCM (40mL) was added methyl propiolate (1.55g, 18.5mmol) at room temperature. The mixture was stirred at room temperature for 15 hours, then concentrated in vacuo. The residue was purified by column on silica gel (petroleum ether: EtOAc 4:1) to give tert-butyl (S) -3- (2- (3-methoxy-3-oxoprop-1-enyloxy) ethyl) pyrrolidine-1-carboxylate (4.0g) as a colorless oil. Yield 87% (ESI 200(M + H-Boc) +).

Step 2: (S) -3- (2- (3-methoxy-3-oxopropoxy) ethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

A mixture of tert-butyl (S) -3- (2- (3-methoxy-3-oxoprop-1-enyloxy) ethyl) pyrrolidine-1-carboxylate (4.0g, 16.0mmol) and Pd/C (10%, 200mg) in EtOAc (25mL) was stirred at room temperature under H2 overnight. The solid was removed by filtration and the filtrate was concentrated in vacuo to give the desired product (S) -tert-butyl 3- (2- (3-methoxy-3-oxopropoxy) ethyl) pyrrolidine-1-carboxylate (4.0g) as a yellow oil. Yield 96% (ESI 202(M + H-Boc) +).

And step 3: (S) -3- (2- (4- (dimethoxyphosphoryl) -3-oxobutoxy) ethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of (S) -3- (2- (3-methoxy-3-oxopropoxy) ethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (1.5g, 5.0mmol) and dimethyl methylphosphonate (0.682g, 5.5mmol) in dry THF (10mL) at 0 deg.C under Ar was added LDA (2M in THF, 5.25mL, 10.5mmol) dropwise. After stirring at 0 ℃ for 10 min, the reaction was quenched with MeOH (5 mL). The mixture was concentrated in vacuo and the residue was purified by column on silica gel (petroleum ether: EtOAc 2:1) to give the desired product tert-butyl (S) -3- (2- (4- (dimethoxyphosphoryl) -3-oxobutoxy) ethyl) pyrrolidine-1-carboxylate (1.1g) as a yellow oil. Yield 57% (ESI 394(M + H) +).

And 4, step 4: (S) -3- (2- (2- (1, 8-naphthyridin-2-yl) ethoxy) ethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

A mixture of 2-aminonicotinaldehyde (128mg, 1.1mmol), (S) -3- (2- (4- (dimethoxyphosphoryl) -3-oxobutoxy) ethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (400mg, 1.1mmol) and NaOH (81mg, 2.2mmol) in MeOH (6mL) and H2O (2mL) was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by preparative HPLC a (40-70% MeCN) to give the desired product (S) -tert-butyl 3- (2- (2- (1, 8-naphthyridin-2-yl) ethoxy) ethyl) pyrrolidine-1-carboxylate (60mg) as a colourless oil. Yield 16% (ESI 372(M + H) +).

And 5: (S) -7- (2- (2- (pyrrolidin-3-yl) ethoxy) ethyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride

A mixture of tert-butyl (S) -3- (2- (2- (1, 8-naphthyridin-2-yl) ethoxy) ethyl) pyrrolidine-1-carboxylate (400mg, 1.08mmol) and Pd/C (80mg, 10%) in EtOAc (20mL) was stirred at room temperature under H2 overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was treated with a solution of HCl in dioxane (4.0M, 4mL) at room temperature for 2 hours, then the solvent was removed in vacuo to yield the desired product (S) -7- (2- (2- (pyrrolidin-3-yl) ethoxy) ethyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride (325mg) as a white solid. Yield 96% (ESI 276.2(M + H) +).

Step 6: 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((S) -3- (2- (2- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) ethyl) pyrrolidin-1-yl) acetic acid methyl ester

A mixture of (S) -7- (2- (2- (pyrrolidin-3-yl) ethoxy) ethyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine dihydrochloride (226mg, 0.65mmol), methyl 2-bromo-2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) acetate (240mg, 0.65mmol), and DIEA (252mg, 1.95mmol) in acetonitrile (10mL) was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH 20:1) to give the desired product methyl 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((S) -3- (2- (2- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) ethyl) pyrrolidin-1-yl) acetate as a yellow oil (310 mg). Yield 84% (ESI 526(M + H) +).

And 7: 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((S) -3- (2- (2- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) ethyl) pyrrolidin-1-yl) acetic acid (compounds 95-E1 and 95-E2)

Methyl 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((S) -3- (2- (2- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) ethoxy) ethyl) pyrrolidin-1-yl) acetate (310mg, 0.55mmol) was washed with LiOH-H2O (250mg, 5.95mmol) in MeOH (5mL) and H ₂O (1mL) was treated at 40 ℃ overnight. The solvent was removed in vacuo and the residue was purified by preparative HPLC a (30-60% MeCN) to give the diastereomeric products compound 95-E1(67mg) and compound 95-E2(37mg) as white solids.

Compound 95-E1 LC/MS ESI 512.3(M + H) +. 1H NMR (400MHz, MeOD) δ 7.62-7.55(m,1H),7.54-7.50(m,1H),7.20-7.10(m,2H),6.35(d, J ═ 7.3Hz,1H),4.88-4.78(m,2H),4.08-4.04(m,1H), 3.82-3.75 (m,1H),3.70-3.61(m,3H),3.49-3.40(m,3H),3.38-3.31(m,2H),3.06-2.99(m,1H),2.68-2.77(m,5H),2.50-2.39(m,1H),2.20-1.90(m,3H),1.95-1.60(m,9H).

Compound 95-E2 LC/MS ESI 512.3(M + H) +. 1H NMR (400MHz, MeOD) δ 7.43-7.36(m,2H),7.18-7.09(m,2H),6.38-6.33(d, J ═ 7.3Hz,1H),5.42(s,1H),4.80-4.50(m,1H),4.18-4.04(m,1H),3.65-3.62(m,3H),3.50-3.41(m,2H),3.38-3.31(m,3H),3.20-3.00(m,3H),2.75-2.65(m,4H),2.40-2.30(m,1H),2.20-2.05(m,2H),1.98-1.93(m,1H),1.90-1.58(m,9H).

Example 26: preparation of 2- (2- (5, 5-dimethyltetrahydrofuran-2-yl) -5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compounds 96-E1 and 96-E2)

Step 1: 1- (2-bromo-4-fluorophenyl) -4-methylpent-4-en-1-ol

Equipped with a magnetic stirring rod, a cooler, a nitrogen inlet and a partitionOven dried 3-neck round bottom flask of film was charged with magnesium (0.489g, 20.1 mmol). The magnesium was dried under a nitrogen stream while stirring using a heat gun, and then stirred under a nitrogen stream overnight. Next, dry tetrahydrofuran (12mL) was added and the mixture was refluxed using a hot air gun. A small amount of 1, 2-dibromoethane (0.116mL, 1.34mmol) was added and the mixture was again refluxed. A solution of 4-bromo-2-methylbut-1-ene (1.6mL, 13.4mmol) in dry tetrahydrofuran (10mL) was added dropwise at a rate that maintained the exothermic reaction. After the addition was complete, the dark brown reaction mixture was stirred for an additional 20 minutes and then slowly cooled to room temperature. The Grignard reagent (Grignard reagent) was drawn into a syringe and added dropwise to a solution of 2-bromo-4-fluorobenzaldehyde (2.72g, 13.4mmol) in dry tetrahydrofuran (15mL) at 0 ℃ under an argon atmosphere. After complete addition, the mixture was allowed to reach room temperature, stirred for 30 minutes, quenched with saturated ammonium chloride, and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography (silica, 1% to 15% diisopropyl ether in heptane) gave the desired product 1- (2-bromo-4-fluorophenyl) -4-methylpent-4-en-1-ol (1.43 g). The yield was 39%. ¹H NMR (400MHz, chloroform-d) δ 7.58-7.51 (m,1H), 7.30-7.23 (m,1H), 7.11-7.02 (m,1H), 5.09-5.01 (m,1H),4.76(s,2H), 2.29-2.10 (m,2H),2.03(d, J ═ 3.6Hz,1H), 1.96-1.83 (m,1H), 1.83-1.68 (m,4H).

Step 2: 5- (2-bromo-4-fluorophenyl) -2, 2-dimethyltetrahydrofuran

To a solution of 1- (2-bromo-4-fluorophenyl) -4-methylpent-4-en-1-ol (1.43g, 5.24mmol) in toluene (30mL) was added p-toluenesulfonic acid monohydrate (0.996g, 5.24 mmol). The mixture was stirred at 80 ℃ for one hour, cooled to room temperature, quenched with saturated aqueous sodium bicarbonate, and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. By column chromatography (silica, containing 0% to 8% diisopropyl ether)Ethereal heptane) to give the desired product 5- (2-bromo-4-fluorophenyl) -2, 2-dimethyltetrahydrofuran (1.28 g). The yield was 89%.¹H NMR (400MHz, chloroform-d) δ 7.60-7.52 (m,1H), 7.29-7.21 (m,1H), 7.07-6.98 (m,1H),5.19(t, J ═ 7.2Hz,1H), 2.64-2.53 (m,1H), 1.93-1.77 (m,2H), 1.74-1.61 (m,1H),1.42(s,3H),1.36(s,3H).

And step 3: 2- (2- (5, 5-Dimethyltetrahydrofuran-2-yl) -5-fluorophenyl) acetic acid tert-butyl ester

An oven-dried flask was charged with zinc powder (1.202g, 18.4mmol) and heated under a flow of argon with a hot air gun. After cooling to room temperature, dry tetrahydrofuran (26mL) was added followed by 1, 2-dibromoethane (0.04mL, 0.46 mmol). The mixture was heated to reflux and cooled to room temperature 3 times. Then, trimethylchlorosilane (0.059mL, 0.46mmol) was added, which resulted in spontaneous reflux of the mixture and the zinc changed morphology. After stirring for 20 minutes, tert-butyl bromoacetate (1.34mL, 9.19mmol) was added dropwise, resulting in an exotherm. The mixture was held at elevated temperature (45 ℃) for 30 minutes and then allowed to cool to room temperature. A separate flask was charged with 5- (2-bromo-4-fluorophenyl) -2, 2-dimethyltetrahydrofuran (1.26g, 4.59mmol), tri-tert-butylphosphine tetrafluoroborate (0.147g, 0.505mmol), and bis (dibenzylideneacetone) palladium (0.264g, 0.459 mmol). The reaction vessel was flushed with argon, dry tetrahydrofuran (26mL) was added, and argon was bubbled through for five minutes. The zincate solution was added via syringe and the reaction mixture was heated to reflux for 1 hour. The mixture was cooled to room temperature overnight, quenched with saturated aqueous ammonium chloride, and extracted three times with heptane/ethyl acetate (1/1, v/v). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography (silica, 1% to 6% acetone in heptane) gave the desired product tert-butyl 2- (2- (5, 5-dimethyltetrahydrofuran-2-yl) -5-fluorophenyl) acetate (1.31 g). The yield was 92%. ¹H NMR (400MHz, chloroform-d) δ 7.51(dd, J ═ 8.6,6.0Hz,1H), 7.00-6.88 (m,2H),5.10(dd, J ═ 8.5,6.2Hz,1H),3.57(q,J＝15.5Hz,2H),2.38–2.28(m,1H),1.92–1.71(m,3H),1.43(s,9H),1.40(s,3H),1.34(s,3H).

and 4, step 4: 2-bromo-2- (2- (5, 5-dimethyltetrahydrofuran-2-yl) -5-fluorophenyl) acetic acid tert-butyl ester

To a solution of tert-butyl 2- (2- (5, 5-dimethyltetrahydrofuran-2-yl) -5-fluorophenyl) acetate (200mg, 0.65mmol) in THF (4mL) at-78 deg.C was added dropwise THF/hexane (1.3mL, 1.3mmol) containing a 1.0M solution of lithium diisopropylamide. The reaction was stirred at-78 ℃ for 30 minutes, then chlorotrimethylsilane (141mg, 1.3mmol) was added and the reaction was stirred at-78 ℃ for an additional 30 minutes. Then, a solution of NBS (231mg, 1.3mmol) in THF (2mL) was added and the reaction was stirred at-78 deg.C for 1 hour. The reaction was quenched with MeOH (2mL), the solvent was removed in vacuo, and the residue was purified through a silica gel column (petroleum ether: EtOAc 10:1) to give the desired product tert-butyl 2-bromo-2- (2- (5, 5-dimethyltetrahydrofuran-2-yl) -5-fluorophenyl) acetate as a colorless oil (180 mg). Yield: 72% (ESI 387(M + H) +).

And 5: 2- (2- (5, 5-Dimethyltetrahydrofuran-2-yl) -5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid tert-butyl ester

A mixture of tert-butyl 2-bromo-2- (2- (5, 5-dimethyltetrahydrofuran-2-yl) -5-fluorophenyl) acetate (650mg, 1.68mmol), (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (584mg, 1.68mmol) and DIPEA (650mg, 5.04mmol) in acetonitrile (20mL) was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue was purified by column of silica gel (DCM: MeOH 10:1) to give the desired product tert-butyl 2- (2- (5, 5-dimethyltetrahydrofuran-2-yl) -5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate as a yellow oil (550 mg). The yield was 56%. (ESI 582(M + H) +).

Step 6: 2- (2- (5, 5-Dimethyltetrahydrofuran-2-yl) -5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compounds 96-E1 and 96-E2)

Tert-butyl 2- (2- (5, 5-dimethyltetrahydrofuran-2-yl) -5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate (550mg, 0.95mmol) was treated with HCl in 1, 4-dioxane (4M, 10mL) at 25 ℃ for 2 hours. The solvent was removed in vacuo and the residue was purified by preparative HPLC a (33-65% MeCN) to yield 96 as a white solid (220mg, 44% yield). The racemic product was separated by preparative chiral SFC E to give the diastereomeric products 96-E1(44mg) and 96-E2(49mg) as white solids, each as a mixture of 2 stereoisomers.

Compound 96-E1 (mixture of 2 stereoisomers) LC/MS ESI 526(M + H) +. 1H NMR (500MHz, MeOD) δ 7.65-7.61(m,1H),7.48(dd, J ═ 10Hz,2.5Hz,1H),7.18-7.15(m,2H),6.39(d, J ═ 7.5Hz,1H),5.42(m,1H),4.85(s,1H),4.20(s,1H), 3.49-3.36 (m,5H), 3.22-3.18 (m,2H),2.73-2.52(m,5H), 2.21-1.87 (m,7H), 1.75-1.61 (m,4H), 1.45-1.36 (m,7H), chiral SFC E (45% MeOH): ee 100%, Rt 3.49 min

Compound 96-E2 (mixture of 2 stereoisomers) LC/MS ESI 526(M + H) +. 1H NMR (500MHz, MeOD) δ 7.65-7.61(m,1H),7.45(dd, J ═ 10Hz,2.5Hz,1H),7.18-7.16(m,2H),6.39(d, J ═ 7.5Hz,1H),5.35(m,1H),4.97(s,1H),4.20(s,1H), 3.54-3.36 (m,5H), 3.22-3.05 (m,2H),2.73-2.50(m,5H), 2.22-1.88 (m,7H), 1.76-1.62 (m,4H), 1.41-1.36 (m,7H), chiral SFC E (45% MeOH): ee 98%, Rt 4.52 min.

Example 27: preparation of 2- (2- (4, 4-dimethyltetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compounds 97-A-E1, 97-A-E2, 97-B-E1 and 97-B-E2)

Step 1: 4, 4-Dimethyltetrahydro-2H-pyran-2-one

To a suspension of lithium aluminium hydride (220mg, 5.79mmol) in THF (dry, 15mL) at-55 deg.C was added dropwise a solution of 4, 4-dimethyldihydro-2H-pyran-2, 6(3H) -dione (1.42g, 10.0mmol) in THF (10 mL). The reaction was gradually heated to 0 ℃ and stirred for 20 minutes, then cooled to-15 ℃ and aqueous HC1(6N, 4mL) was added dropwise to quench the reaction. The mixture was extracted with ether (3 × 15mL) and the combined organic layers were dried over Na2SO 4. The solvent was removed in vacuo to yield the desired product 4, 4-dimethyltetrahydro-2H-pyran-2-one as an oil (0.91g, 71% yield). ¹H NMR(400MHz,CDC13)δ4.40(t,J＝6.0Hz,2H),2.35(s,2H),1.75(t,J＝6.0Hz,2H),1.10(s,6H).

Step 2: 2- (2-bromophenyl) -4, 4-dimethyltetrahydro-2H-pyran-2-ol

To a solution of 1-bromo-2-iodobenzene (727mg, 2.58mmol) in THF (15mL) at-25 deg.C was added dropwise a solution of isopropyl magnesium chloride (2M in THF, 1.3mL, 2.6 mmol). The reaction mixture was stirred at-25 ℃ for 1 hour, then a solution of 4, 4-dimethyltetrahydro-2H-pyran-2-one (300mg, 2.34mmol) in THF (3mL) was added dropwise at-25 ℃. The reaction mixture was warmed to room temperature over 1 hour, quenched with MeOH (5mL), and concentrated in vacuo. The residue was purified by column on silica gel (petroleum ether: EtOAc 4:1) to give the desired product 2- (2-bromophenyl) -4, 4-dimethyltetrahydro-2H-pyran-2-ol as a yellow oil (130 mg). Yield 18% (ESI 285/287[ M + H ] +).

And step 3: 2- (2-bromophenyl) -4, 4-dimethyltetrahydro-2H-pyran

To a solution of 2- (2-bromophenyl) -4, 4-dimethyltetrahydro-2H-pyran-2-ol (130mg, 0.46mmol) and TFA (0.23mL) in DCM (6mL) at 0 deg.C was added Et3SiH (267mg, 2.3mmol) dropwise. The reaction mixture was stirred at room temperature for 1 hour, then quenched with saturated NaHCO3 solution (20mL) and extracted with DCM (3X 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column on silica gel (petroleum ether: EtOAc10:1) to give the desired product 2- (2-bromophenyl) -4, 4-dimethyltetrahydro-2H-pyran as a yellow oil (90 mg). Yield 78% (ESI 269/271[ M + H ] +).

And 4, step 4: 2- (2- (4, 4-Dimethyltetrahydro-2H-pyran-2-yl) phenyl) acetic acid tert-butyl ester

A mixture of 2- (2-bromophenyl) -4, 4-dimethyltetrahydro-2H-pyran (180mg, 0.68mmol), (2-tert-butoxy-2-oxoethyl) zinc (II) bromide solution (containing 0.5M THF, 6.8mL, 3.4mmol), Pd2(dba)3(35mg, 0.034mmol), and Qphos (25mg, 0.034mmol) in THF (2mL) was stirred at 80 ℃ for 2 hours. The reaction mixture was then poured into saturated NaHCO3 solution (50mL) and extracted with EtOAc (3X 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column on silica gel (petroleum ether: EtOAc 10:1) to give the desired product tert-butyl 2- (2- (4, 4-dimethyltetrahydro-2H-pyran-2-yl) phenyl) acetate as a red oil (150 mg). Yield 73% (ESI 327[ M + Na ] +).

And 5: 2-bromo-2- (2- (4, 4-dimethyltetrahydro-2H-pyran-2-yl) phenyl) acetic acid tert-butyl ester

To a solution of tert-butyl 2- (3-isopropyl-3, 4-dihydro-1H-pyrano [3,4-c ] pyridin-5-yl) acetate (600mg, 2.0mmol) in THF (10mL) at-78 deg.C was added dropwise a solution of lithium diisopropylamide (2.0M, 2.5mL, 5.0 mmol). The reaction was stirred at-78 ℃ for 30 minutes, then a solution of chlorotrimethylsilane (540mg, 5.0mmol) in THF (1mL) was added and the reaction was stirred at-78 ℃ for an additional 30 minutes. Then, a solution of NBS (890mg, 5.0mmol) in THF (10mL) was added and the reaction was stirred at-78 deg.C for 1 hour. The reaction was quenched with MeOH (2mL), the solvent was removed in vacuo, and the residue was purified through silica gel column (petroleum ether: EtOAc 10:1) to give the desired product tert-butyl 2-bromo-2- (2- (4, 4-dimethyltetrahydro-2H-pyran-2-yl) phenyl) acetate (650mg) as a colorless oil. Yield 86% (ESI 327[ M-Bu + H ] +).

Step 6: 2- (2- (4, 4-Dimethyltetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid tert-butyl ester

A mixture of tert-butyl 2-bromo-2- (2- (4, 4-dimethyltetrahydro-2H-pyran-2-yl) phenyl) acetate (375mg, 1.0mmol), (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (306mg, 1.0mmol), DIPEA (774mg, 6.0mmol) and NaI (50mg) in acetonitrile (10mL) was stirred at 40 ℃ for 12H. The mixture was diluted with water (8mL) and EtOAc (25 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column on silica gel (DCM: MeOH 20:1) to give the desired product tert-butyl 2- (2- (4, 4-dimethyltetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate as a colorless oil (410 mg). Yield 72% (ESI 578[ M + H ] +).

And 7: 2- (2- (4, 4-Dimethyltetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compounds 97-A-E1, 97-A-E2, 97-B-E1 and 97-B-E2)

Tert-butyl 2- (2- (4, 4-dimethyltetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate (570mg, 1.0mmol) was treated with 1, 4-dioxane containing HCl (4M, 10mL) at 25 ℃ for 6 hours. The solvent was removed in vacuo, and the residue was purified by preparative HPLC A (40-70% MeCN) to give 97-A (102mg) and 97-B (130 mg). 97-A was isolated by preparative chiral SFC H to give the products 97-A-E1(36mg) and 97-A-E2(31mg) as white solids. 97-B was separated by preparative chiral SFC H to give the products 97-B-E1(30mg) and 97-B-E2(44mg) as white solids.

Compound 97-A-E1 LC/MS ESI 522(M + H) +. 1H NMR (400MHz, MeOD) δ 7.68-7.66 (m,1H),7.54-7.52(m,1H),7.41-7.34(m,2H), 7.15-7.13 (m,1H),6.36(d, J ═ 7.6Hz,1H),5.02-4.95(m,2H),4.21-4.19(m,1H), 3.88-3.86 (m,2H), 3.62-3.60 (m,1H), 3.50-3.41 (m,5H),3.20-3.18(m,1H), 3.05-3.02 (m,1H),2.70-2.68(m,2H),2.55-2.52(m,2H),2.10-2.07(m,2H),1.90-1.50(m,9H), 1.31H (m,1H), 1H), chiral MeOH (m,1H), 1H: ee 100%, Rt 2.81 min.

Compound 97-A-E2 LC/MS ESI 522(M + H) +. 1H NMR (400MHz, MeOD) δ 7.69-7.67 (m,1H),7.54-7.52(m,1H),7.41-7.31(m,2H), 7.15-7.13 (m,1H),6.36(d, J ═ 7.6Hz,1H),5.02-5.00(m,1H),4.84(s,1H),4.16-4.14(m,1H), 3.90-3.88 (m,2H), 3.62-3.60 (m,1H), 3.50-3.41 (m,5H),3.20-3.18(m,2H),2.70-2.68(m,2H),2.54-2.52(m,2H),2.10-2.07(m,2H),1.90-1.50(m,9H), 1.31H (m,1H), 1.31H), 1H (m,1H), 1H, 31H), 1H (m,1H), 1H), chiral MeOH (m, 40% c): ee 100%, Rt 3.78 min.

Compound 97-B-E1 LC/MS ESI 522(M + H) +. 1H NMR (400MHz, MeOD) δ 7.68-7.66 (m,1H),7.54-7.52(m,1H),7.41-7.34(m,2H), 7.15-7.13 (m,1H),6.36(d, J ═ 7.6Hz,1H),5.02-4.90(m,2H),4.16-4.14(m,1H), 3.90-3.88 (m,2H), 3.62-3.60 (m,1H), 3.50-3.41 (m,5H),3.20-3.18(m,1H), 3.05-3.02 (m,1H),2.70-2.68(m,2H),2.54-2.52(m,2H),2.10-2.07(m,2H),1.90-1.50(m,9H), 1.31H (m,1H), 1H), chiral MeOH (m,1H), 1H: ee 100%, Rt 2.76 min.

Compound 97-B-E2 LC/MS ESI 522(M + H) +. 1H NMR (400MHz, MeOD) δ 7.68-7.66 (m,1H),7.54-7.52(m,1H),7.44-7.34(m,3H),6.49(d, J ═ 7.2Hz,1H),5.02-4.90(m,2H),4.16-4.14(m,1H), 3.92-3.90 (m,2H), 3.70-3.20 (m,8H),2.70-2.68(m,2H),2.54-2.52(m,2H),2.10-2.07(m,2H),1.90-1.50(m,9H),1.31-1.29(m,1H),1.20(s,3H),1.05(s,3H), chiral SFC H (40% chiral MeOH): ee 100%, Rt 3.85 min.

Example 28: preparation of 2- (5-fluoro-2- (5-oxaspiro [2.5] octan-6-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compounds 98-A-E1, 98-A-E2 and 98-B)

Step 1: 2-bromo-4-fluorobenzoic acid cyanomethyl ester

To a solution of 2-bromo-4-fluorobenzoic acid (5.0g, 0.23mol) in dry DCM (20mL) was added triethylamine (9.2g, 0.69mol) and chloroacetonitrile (3.5g, 0.46mol) at 0 deg.C. The reaction was then heated to reflux and stirred overnight. After cooling to room temperature, the reaction mixture was washed successively with aqueous HCl (2M, 20mL) and saturated NaHCO3 solution (20 mL). The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo to give the desired product cyanomethyl 2-bromo-4-fluorobenzoate (4.0g) as a pale yellow oil. Yield 68% (ESI 258/260[ M + H ] +).

Step 2: 1- (2-bromo-4-fluorophenyl) -5-hydroxypentane-1, 4-dione

To a solution of cyanomethyl 2-bromo-4-fluorobenzoate (3.4g, 13.2mmol) and Ti (OiPr)4(4.15g, 14.6mmol) in Et2O (70mL) was added EtMgBr (28mL, 28mmol, 1M in THF) dropwise under argon at 0 ℃. After addition of the grignard reagent, the mixture was warmed to room temperature and stirred for 1 hour. The cloudy yellow mixture was quenched with water (10mL), then 1M HCl (30mL) was added and extracted with EtOAc (3X 50 mL). The combined organic phases were washed with saturated aqueous NaHCO3 and dried (MgSO 4). After evaporation of the solvent, the residue was purified by column on silica gel (petroleum ether: EtOAc 3:1) to give the desired product 1- (2-bromo-4-fluorophenyl) -5-hydroxypentane-1, 4-dione as a colorless oil (901 mg). Yield 25% (ESI 289/271[ M + H ] +).

And step 3: 6- (2-bromo-4-fluorophenyl) tetrahydro-2H-pyran-3-ol

To a solution of 1- (2-bromo-4-fluorophenyl) -5-hydroxypentane-1, 4-dione (900mg, 3.13mmol) in DCM (40mL) at 0 deg.C was added boron trifluoride (diethyl ether complex, 1110mg, 7.8mmol) dropwise. After addition, triethylsilane (910mg, 7.8mmol) was added and the reaction was stirred at 0 ℃ for 1 hour. The reaction mixture was quenched with saturated NaHCO3(20mL) and extracted with DCM (2X 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column on silica gel (petroleum ether: EtOAc 3:1) to give the desired product 6- (2-bromo-4-fluorophenyl) tetrahydro-2H-pyran-3-ol (650mg) as a colorless oil. Yield 80% (ESI 275/277[ M + H ] +).

And 4, step 4: 6- (2-bromo-4-fluorophenyl) dihydro-2H-pyran-3 (4H) -one

To a solution of 6- (2-bromo-4-fluorophenyl) tetrahydro-2H-pyran-3-ol (100mg, 0.37mmol) in DCM (5mL) was added tass-Martin periodinane (Dess-Martin periodinane) (150mg, 0.50mmol) in portions. After addition, the reaction mixture was stirred at room temperature for 2 hours and then quenched with saturated NaHCO3 solution (5 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column on silica gel (petroleum ether: EtOAc 10:1) to give the desired product 6- (2-bromo-4-fluorophenyl) dihydro-2H-pyran-3 (4H) -one (20mg) as a colorless oil. Yield 20% (ESI 273/275[ M + H ] +).

And 5: 2- (2-bromo-4-fluorophenyl) -5-methylenetetrahydro-2H-pyran

To a solution of methyltriphenylphosphonium bromide (134mg, 0.52mmol) in THF (3mL) at 0 deg.C was added n-BuLi (2.5M in hexanes, 0.21mL, 0.52mmol) and the reaction was stirred at 0 deg.C over 30 minutes, then a solution of 6- (2-bromo-4-fluorophenyl) dihydro-2H-pyran-3 (4H) -one (70mg, 0.26mmol) in THF (2 mL). The reaction was stirred at room temperature for 12 h, quenched with saturated aqueous NH4Cl, and extracted with DCM (2 × 10 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column on silica gel (petroleum ether: EtOAc 10:1) to give the desired product 2- (2-bromo-4-fluorophenyl) -5-methylenetetrahydro-2H-pyran as a colorless oil (51mg, 70% yield). 1H NMR (400MHz, CDCl 3). delta.7.52-7.50 (m,1H),7.27-7.25(m,1H),7.05-7.01(m,1H),4.89-4.88(m,2H),4.75-4.73(m,1H),4.37-4.34(m,1H), 4.20-4.17 (m,1H), 2.50-2.46 (m,2H),2.15-2.10(m,1H),1.52-1.50(m,1H).

Step 6: 6- (2-bromo-4-fluorophenyl) -5-oxaspiro [2.5] octane

To a solution of ZnEt2 (1M in THF, 6mL, 6.0mmol) in DCM (20mL) at 0 deg.C was added TFA (690mg, 6.0 mmol). The reaction was stirred at 0 ℃ for 0.5 h, then CH2I2(1.7g, 6.0mmol) was added dropwise. The reaction was stirred at 0 ℃ for 0.5H, then 2- (2-bromo-4-fluorophenyl) -5-methylenetetrahydro-2H-pyran (280mg,1.0mmol) in DCM (1mL) was added. The reaction mixture was stirred at room temperature for 2h, quenched with saturated NaHCO3 solution (20mL), and the DCM layer was dried over Na2SO 4. The solvent was removed in vacuo and the residue was purified by column on silica gel (petroleum ether: EtOAc 50:1) to give the desired product 6- (2-bromo-4-fluorophenyl) -5-oxaspiro [2.5] octane as a yellow oil (250 mg). Yield 80% (ESI 267/269[ M + H-H2O ] +).

And 7: 2- (5-fluoro-2- (5-oxaspiro [2.5] octan-6-yl) phenyl) acetic acid tert-butyl ester

A mixture of 6- (2-bromo-4-fluorophenyl) -5-oxaspiro [2.5] octane (250mg, 0.88mmol), THF (10mL, 5mmol) containing a 0.5M solution of zinc (II) bromide (2-tert-butoxy-2-oxyethyl), Pd2(dba)3(40mg, 0.05mmol) and Qphos (31mg, 0.05mmol) in THF (2mL) was stirred at 80 ℃ for 2 hours. The mixture was then poured into saturated NaHCO3 solution (50mL) and EtOAc (60 mL). The mixture was filtered, the organic layer was washed with brine, dried over Na2SO4, concentrated in vacuo, and the residue was purified through a silica gel column (petroleum ether: EtOAc 10:1) to give the desired product tert-butyl 2- (5-fluoro-2- (5-oxaspiro [2.5] octan-6-yl) phenyl) acetate (160mg) as a red oil. Yield 53% (ESI 343[ M + Na ] +).

And 8: 2-bromo-2- (5-fluoro-2- (5-oxaspiro [2.5] octan-6-yl) phenyl) acetic acid tert-butyl ester

To a solution of tert-butyl 2- (5-fluoro-2- (5-oxaspiro [2.5] octane-6-yl) phenyl) acetate (160mg, 0.5mmol) in THF (5mL) at-78 deg.C was added dropwise THF/hexane (0.62mL, 1.25mmol) containing a 2.0M solution of lithium diisopropylamide. The reaction was stirred at-78 ℃ for 30 minutes, then a solution of chlorotrimethylsilane (135mg, 1.25mmol) in THF (1mL) was added and the reaction was stirred at-78 ℃ for an additional 30 minutes. Then, a solution of NBS (221mg, 1.25mmol) in THF (10mL) was added and the reaction was stirred at-78 deg.C for 1 hour. The reaction was quenched with MeOH (2mL), the solvent removed in vacuo, and the residue purified by silica gel column (petroleum ether: EtOAc 10:1) to give the desired product tert-butyl 2-bromo-2- (5-fluoro-2- (5-oxaspiro [2.5] octan-6-yl) phenyl) acetate as a colorless oil (130 mg). Yield 60% (ESI 419/421[ M + Na ] +).

And step 9: tert-butyl 2- (5-fluoro-2- (5-oxaspiro [2.5] octan-6-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate

A mixture of tert-butyl 2-bromo-2- (5-fluoro-2- (5-oxaspiro [2.5] octan-6-yl) phenyl) acetate (130mg, 0.33mmol), (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (101mg, 0.33mmol), DIPEA (126mg, 0.99mmol) and NaI (50mg) in acetonitrile (10mL) was stirred at 40 ℃ for 12 hours. The mixture was diluted with water (8mL) and EtOAc (25 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column on silica gel (DCM: MeOH 20:1) to give the desired product tert-butyl 2- (5-fluoro-2- (5-oxaspiro [2.5] octan-6-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate as a colorless oil (101 mg). Yield was 52% (ESI 595[ M + H ] +).

Step 10: 2- (5-fluoro-2- (5-oxaspiro [2.5] octan-6-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compounds 98-A-E1, 98-A-E2 and 98-B)

A solution of tert-butyl 2- (5-fluoro-2- (5-oxaspiro [2.5] octan-6-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate (210mg, 0.35mmol) in TFA (2mL) and DCM (2mL) was stirred at room temperature for 15 h. Then, it was concentrated and purified by preparative HPLC A (40-70% MeCN) to give 98-A (106mg) and 98-B (16 mg). 98-A was isolated by preparative chiral SFC C to give the products 98-A-E1(35mg) and 98-A-E2(31mg) as white solids.

Compound 98-A-E1 LC/MS ESI 538(M + H) +. 1H NMR (500MHz, MeOD) δ 7.64-7.61 (m,1H),7.49-7.46(m,1H),7.18-7.16(m,2H),6.39(d, J ═ 7.5Hz,1H),4.93(s,1H),4.82-4.85(m,1H),4.19(br s,1H),4.12-4.10(m,1H),3.61(m,1H),3.49(t, J ═ 6.5Hz,2H), 3.341-3.38 (m,3H),3.23(d, J ═ 12.5H,1H), 3.11-3.09 (m,2H),2.72(t, J ═ 6.0Hz,2H),2.56(t, J ═ 7.5, 2H), 2.11-3.09 (m,2H),2.72(t, J ═ 6.0, 2H),2.56(t, J ═ 7.5, 2H), 2H- (1.88-1H), 2H, 1H), 1H, 5H,1H, 0 (m-6H), 1H, 5H: ee 100%, Rt 1.29 min.

Compound 98-A-E2 LC/MS ESI 538(M + H) +. 1H NMR (400MHz, MeOD) δ 7.63-7.61 (m,1H),7.50-7.48(m,1H),7.22-7.16(m,2H),6.39(d, J ═ 7.6Hz,1H),4.82-4.80(m,1H),4.20-4.12(m,2H), 3.60-3.32 (m,6H), 3.30-3.05 (m,4H), 2.75-2.55 (m,4H), 2.25-1.58 (m,12H),0.58-0.30(m,4H), chiral SFC (20% EtOH): ee 100%, Rt 2.17 min.

Compound 98-B (mixture of 2 stereoisomers) LC/MS ESI 538(M + H) +. 1H NMR (400MHz, MeOD). delta.7.41-7.32 (m,2H),7.08-6.98(m,2H),6.28-6.22(m,1H),4.80-4.75(m,1H),4.05-3.85(m,2H), 3.60-3.32 (m,6H), 3.10-2.85 (m,4H), 2.62-2.58 (m,2H),2.47-2.41(m,2H), 2.21-1.40 (m,12H),0.55-0.20(m,4H).

Example 29: preparation of 2- (2- (5, 5-difluorotetrahydro-2H-pyran-2-yl) -5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compounds 99-E1 and 99-E2)

Step 1: 1- (2-bromo-4-fluorophenyl) cyclopropanol

TMSOTf (6.17g, 27.8mmol) was added dropwise over a period of 10 minutes to a solution of 1- (2-bromo-4-fluorophenyl) ethanone (5.0g, 23.1mmol) and Et3N (3.51g, 34.7mmol) in DCM (50mL) under nitrogen at 0 deg.C by syringe. The reaction mixture was stirred at room temperature overnight, then quenched with saturated aqueous NaHCO3(20mL), and the aqueous solution was extracted with DCM (2X 30 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude ether. The crude ether was dissolved in anhydrous DCM (50mL), diiodomethane (25.0g, 92.4mmol) was added, cooled to 0 deg.C, and diethyl zinc (1M in THF, 93mL, 93mmol) was added dropwise. The reaction was stirred at room temperature for 16 h, then quenched with saturated NH4Cl solution (30mL) and extracted with DCM (2X 50 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude material. The crude material was dissolved in MeOH (20mL), then K2CO3(3.2g, 23.1mmol) was added, followed by stirring at room temperature for 30 min. The solvent was removed in vacuo, H2O (20mL) was added, and the mixture was extracted with EtOAc (2X 40 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column on silica gel (petroleum ether: EtOAc5:1) to give the desired product 1- (2-bromo-4-fluorophenyl) cyclopropanol as a colorless oil (3.1 g). Yield 86% (ESI 213/215[ M + H ] +).

Step 2: 5- (2-bromo-4-fluorophenyl) -2, 2-difluoro-5-oxopentanoic acid ethyl ester

A mixture of 1- (2-bromo-4-fluorophenyl) cyclopropanol (100mg, 0.44mmol), ethyl 2-bromo-2, 2-difluoroacetate (351mg, 1.74mmol), CuI (8.2mg, 0.044mmol), phenanthroline (17.2mg, 0.088mmol) and K2CO3(120mg, 0.88mmol) in MeCN (5mL) was stirred at 90 ℃ for 17 h. The reaction was quenched with water (10mL) and extracted with EtOAc (3X 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo, and the residue was purified over silica gel column (petroleum ether: EtOAc 5:1) to give the desired product ethyl 5- (2-bromo-4-fluorophenyl) -2, 2-difluoro-5-oxopentanoate (81mg) as a colorless oil. Yield 53% (ESI 353/355[ M + H ] +).

And step 3: 2- (2-bromo-4-fluorophenyl) -5, 5-difluorotetrahydro-2H-pyran

To a solution of ethyl 5- (2-bromo-4-fluorophenyl) -2, 2-difluoro-5-oxopentanoate (100mg, 0.28mmol) in MeOH (5mL) at 0 deg.C was added NaBH4(44mg, 1.12 mmol). The reaction solution was stirred at room temperature for 15 hours. The solvent was removed in vacuo, H2O (10mL) was added, and extracted with DCM (3X 10 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in DCM (3mL) and trifluoromethanesulfonic acid (100mg, 0.32mmol) was added. The reaction was stirred at room temperature for 15 h, then quenched by saturated aqueous NaHCO3(5mL) and extracted with DCM (2X 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo, and the residue was purified through a silica gel column (petroleum ether: EtOAc 10:1) to give the desired product 2- (2-bromo-4-fluorophenyl) -5, 5-difluorotetrahydro-2H-pyran as a colorless oil (40 mg). Yield 47% (ESI 297/299[ M + H ] +).

And 4, step 4: 2- (2- (5, 5-Difluorotetrahydro-2H-pyran-2-yl) -5-fluorophenyl) acetic acid tert-butyl ester

A mixture of 2- (2-bromo-4-fluorophenyl) -5, 5-difluorotetrahydro-2H-pyran (800mg, 2.93mmol), a solution of (2-tert-butoxy-2-oxoethyl) zinc (II) bromide (containing 0.5M THF, 30mL, 15mmol), Pd2(dba)3(152mg, 0.15mmol), and Q-phos (105mg, 0.15mmol) in THF (2mL) was stirred at 80 ℃ for 2 hours. The reaction mixture was poured into saturated NaHCO3 solution (20mL) and EtOAc (30 mL). The mixture was filtered, the organic layer was washed with brine, dried over Na2SO4, concentrated in vacuo, and the residue was purified through a silica gel column (petroleum ether: EtOAc 10:1) to give the desired product tert-butyl 2- (2- (5, 5-difluorotetrahydro-2H-pyran-2-yl) -5-fluorophenyl) acetate (703mg) as a red oil. Yield 78% (ESI 275[ M + H-tBu ] +).

And 5: 2-bromo-2- (2- (5, 5-difluorotetrahydro-2H-pyran-2-yl) -5-fluorophenyl) acetic acid tert-butyl ester

To a solution of tert-butyl 2- (2- (5, 5-difluorotetrahydro-2H-pyran-2-yl) -5-fluorophenyl) acetate (703mg, 2.12mmol) in THF (5mL) at-78 deg.C was added dropwise a solution of lithium diisopropylamide (2M, 2.65mL, 5.3 mmol). The reaction was stirred at-78 ℃ for 30 minutes, then a solution of chlorotrimethylsilane (573mg, 5.3mmol) in THF (1mL) was added and the reaction was stirred at-78 ℃ for an additional 30 minutes. Then, a solution of NBS (944mg, 5.3mmol) in THF (10mL) was added and the reaction was stirred at-78 deg.C for 1 hour. The reaction was quenched with MeOH (2mL), the solvent was removed in vacuo, and the residue was purified through a silica gel column (petroleum ether: EtOAc 10:1) to give the desired product, tert-butyl 2-bromo-2- (2- (5, 5-difluorotetrahydro-2H-pyran-2-yl) -5-fluorophenyl) acetate (816mg) as a red oil. Yield 66% (ESI 352/354[ M + H-tBu ] +).

Step 6: tert-butyl 2- (2- (5, 5-difluorotetrahydro-2H-pyran-2-yl) -5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate

A mixture of tert-butyl 2-bromo-2- (2- (5, 5-difluorotetrahydro-2H-pyran-2-yl) -5-fluorophenyl) acetate (816mg, 2.0mmol), (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (660mg, 2.0mmol), DIPEA (821mg, 6.0mmol) and NaI (50mg) in acetonitrile (20mL) was stirred at 40 ℃ for 6H. The mixture was diluted with water (8mL) and EtOAc (25 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column on silica gel (DCM: MeOH 20:1) to give the desired product tert-butyl 2- (2- (5, 5-difluorotetrahydro-2H-pyran-2-yl) -5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate as a colorless oil (710 mg). Yield 58% (ESI 604[ M + H ] +).

And 7: 2- (2- (5, 5-Difluorotetrahydro-2H-pyran-2-yl) -5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compounds 99-E1 and 99-E2)

To a solution of tert-butyl 2- (2- (5, 5-difluorotetrahydro-2H-pyran-2-yl) -5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate (710mg, 1.2mmol) in DCM (10mL) was added TFA (10 mL). The reaction was stirred at room temperature for 15 hours. Then, it was concentrated and purified by preparative HPLC a (40-70% MeCN) to give 99 as a white solid (400mg, 63% yield). The racemic product was separated by preparative chiral SFC A to give the diastereomeric products 99-E1(74mg) and 99-E2(88mg) as white solids.

Compound 99-E1 LC/MS ESI 548(M + H) +. 1H NMR (400MHz, MeOD) δ 7.61-7.59 (m,1H),7.51-7.48(m,1H),7.22-7.13(m,2H),6.41(d, J ═ 7.2Hz,1H),4.99-4.90(m,1H),4.80(s,1H),4.19-4.17(m,1H), 4.01-3.80 (m,2H), 3.50-3.35 (m,6H), 3.20-3.18 (m,1H), 3.02-2.98 (m,1H), 2.81-2.79 (m,2H),2.62-2.59(m,2H), 2.30-2.01 (m,6H),1.82-1.80(m,2H), 1.75-1.60 (m,4H), chiral MeOH (SFC) (40%) was: ee 100%, Rt 1.92 min.

Compound 99-E2 LC/MS ESI 548(M + H) +. 1H NMR (400MHz, MeOD) δ 7.62-7.60 (m,1H),7.53-7.51(m,1H),7.28(d, J ═ 7.6Hz,1H),7.17-7.14(m,1H),6.44(d, J ═ 7.2Hz,1H),4.99-4.90(m,1H),4.79(s,1H),4.19-4.17(m,1H), 4.01-3.80 (m,2H), 3.60-3.35 (m,6H), 3.20-3.18 (m,2H), 2.81-2.79 (m,2H),2.62-2.59(m,2H), 2.30-2.01 (m,6H),1.82-1.80(m,2H), 1.75-1.60 (m,4H), chiral MeOH (SFC 40): ee 98%, Rt 2.47 min.

Example 30: preparation of 2- (2- (5, 5-dimethyltetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compounds 100-E1 and 100-E2)

Step 1: 3- (2-bromophenyl) acrylic acid ethyl ester

To a solution of 2-bromobenzaldehyde (5.00g, 27.0mmol) in THF (30mL) was added ethyl 2- (triphenyl-l 5-phosphoranylidene) acetate (ethyl 2- (triphenyl-l 5-phosphanylidene) acetate) (9.89g, 28.4mmol), and the mixture was stirred at 60 ℃ overnight. The solvent was removed in vacuo and the residue was purified by silica gel column (petroleum ether: EtOAc 10:1) to give the desired product as a yellow oil (6.51 g). The yield was 93%. ¹H NMR(400MHz,CDCl3)δ8.06(d,1H),7.61(m,2H),7.24-7.19(m,2H),6.40(d,1H),4.31-4.08(m,2H),1.36-1.15(m,3H).

Step 2: 3- (2-bromophenyl) prop-2-en-1-ol

DIBAL-H (1M, 61.3mL, 61.3mmol) was added dropwise to a solution of 3- (2-bromophenyl) acrylic acid (6.5g, 30.7mmol) in THF (50mL) at 0 ℃. The mixture was stirred at 0 ℃ for 30 minutes and then heated to room temperature for one hour. The reaction solvent was poured into aqueous HCl (1N, 200mL) and stirred at room temperature overnight. The mixture was extracted with ethyl acetate (50 mL. times.3). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 10:3) to give the desired product as a pale yellow oil (5.10 g). The yield was 89%.¹H NMR(400MHz,CDCl3)δ7.59-7.30(m,3H),7.18-7.08(m,2H),6.34-6.30(m,1H),4.37-4.27(m,2H).

And step 3: 1-bromo-2- (3-bromoprop-1-enyl) benzene

To a solution of 3- (2-bromophenyl) prop-2-en-1-ol (4.80g, 22.64mmol) in diethyl ether (dry, 50mL) at 0 deg.C was added phosphorus tribromide (1.27mL, 9.06 mmol). The reaction was stirred at 0 ℃ for 1 hour, then quenched with saturated NaHCO3 and extracted with diethyl ether (50 mL. times.2). The combined organic layers were washed with brineDried over sodium sulfate, filtered and concentrated in vacuo to give the desired product 1-bromo-2- (3-bromoprop-1-enyl) benzene as a yellow oil (5.20 g). The yield was 79%. ¹H NMR(400MHz,CDCl3)δ7.56-7.46(m,2H),7.34-7.26(m,2H),6.36-6.34(m,1H),4.18-4.03(m,2H).

And 4, step 4: 5- (2-bromophenyl) -2, 2-dimethylpent-4-enoic acid methyl ester

To a solution of methyl isobutyrate (2.13g, 20.88mmol) in THF (dry, 40mL) at-78 deg.C was added LDA (1M, 20.88mL, 20.88mmol) dropwise. The mixture was stirred at-78 ℃ for 30 minutes, then a solution of 1-bromo-2- (3-bromoprop-1-en-1-yl) benzene (5.20g, 18.98mmol) in THF (10mL) was added dropwise. The reaction was stirred at-78 ℃ for 30 minutes and then heated to room temperature for another 1 hour. The reaction was quenched with saturated NH4Cl and extracted with EtOAc (50mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 5:1) to give the desired product as a yellow oil (4.36g, 78% yield). 1H NMR (400MHz, CDCl 3). delta.7.58-7.46 (m,2H),7.23-7.09(m,2H),6.74-6.51(m,1H),6.10-6.02(m,1H),3.69-3.64(m,3H),2.48-2.40(m,2H),1.24-1.15(m,6H).

And 5: 5- (2-bromophenyl) -2, 2-dimethylpent-4-en-1-ol

To a solution of methyl 5- (2-bromophenyl) -2, 2-dimethylpent-4-enoate (4.36g, 14.53mmol) in THF (dry, 20mL) at-78 deg.C was added dropwise a solution of lithium aluminum hydride in tetrahydrofuran (2.4M, 6.66mL, 11.80 mmol). The mixture was stirred at-78 ℃ for 3 hours and then quenched with 1M HCl (ca. 100mL, starting dropwise). The reaction was extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo . The residue was purified by silica gel column (petroleum ether: EtOAc 10:3) to give the desired product as a yellow oil (3.74g, 93% yield). ESI: 267(M + H)⁺

Step 6: 3- (2-bromophenyl) acrylic acid ethyl ester

To a solution of 5- (2-bromophenyl) -2, 2-dimethylpent-4-en-1-ol (3.74g, 13.95mmol) in dichloroethane (20mL) was added tetrabutylammonium hexafluorophosphate (0.27g, 0.70mmol) and calcium (II) bis (trifluoromethanesulfonyl) imide (0.22g, 0.70 mmol). The mixture was stirred at 90 ℃ for 20 h, concentrated in vacuo, and the residue was purified by silica gel column (petroleum ether: EtOAc 10:1) to give the desired product ethyl bromo 3- (2-bromophenyl) acrylate as a yellow oil (1.50g, 40% yield). 1H NMR (400MHz, CDCl3) δ 7.54(d, J ═ 6.8Hz,2H),7.33(t, J ═ 8.0Hz,1H),7.10(t, J ═ 7.2Hz,1H),4.56(d, J ═ 9.6Hz,1H),3.3(d, J ═ 11.2Hz,1H),3.38(d, J ═ 11.2Hz,1H),1.88-1.84(m,1H),1.59-1.53(m,4H),1.13(s,3H),0.88(s,3H).

And 7: 2- (2- (5, 5-Dimethyltetrahydro-2H-pyran-2-yl) phenyl) acetic acid butyl ester

To a mixture of ethyl 3- (2-bromophenyl) acrylate (1.50g, 5.60mmol), tris (dibenzylideneacetone) dipalladium (0.29g, 0.28mmol) and 1,2,3,4, 5-pentaphenyl-1' - (di-tert-butylphosphino) ferrocene (0.20g, 0.28mmol) in THF (10mL) was added (2-tert-butoxy-2-oxyethyl) zinc (II) bromide (1M in THF, 28mL, 28 mmol). The reaction was stirred at 60 ℃ for 2 hours. The reaction mixture was poured into saturated NaHCO ₃To (100mL), extract with EtOAc (50 mL. times.3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 10:1) to give the desired product as a red oil (1.21g, 71% yield).ESI：249(M-C₄H₉+H)⁺

And 8: 2-bromo-2- (2- (5, 5-dimethyltetrahydro-2H-pyran-2-yl) phenyl) acetic acid tert-butyl ester

To a solution of tert-butyl 2- (2- (5, 5-dimethyltetrahydro-2H-pyran-2-yl) phenyl) acetate (1.21g, 3.17mmol) in THF (10mL) at-78 deg.C was added dropwise a solution of 2.0M lithium diisopropylamide in THF/hexane (4.0mL, 8.0 mmol). The reaction was stirred at-78 ℃ for 30 minutes, then chlorotrimethylsilane (864mg, 8.0mmol) was added and the reaction was stirred at-78 ℃ for an additional 30 minutes. Then, a solution of NBS (1.43g, 8.0mmol) in THF (10mL) was added and the reaction was stirred at-78 deg.C for 1 hour. The reaction was quenched with MeOH (2mL), the solvent was removed in vacuo, and the residue was purified by silica gel column (petroleum ether: EtOAc 10:1) to give the desired product tert-butyl 2-bromo-2- (2- (5, 5-dimethyltetrahydro-2H-pyran-2-yl) phenyl) acetate as a yellow oil (1.31g, 85% yield). ESI: 327 (M-C) ₄H₉+H)⁺

And step 9: 2- (2- (5, 5-Dimethyltetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid tert-butyl ester

A mixture of (S) -7- (4, 4-difluoro-5- (pyrrolidin-3-yl) pentyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (200mg, 0.65mmol), 2-bromo-2- (2- (5, 5-dimethyltetrahydro-2H-pyran-2-yl) pentyl) acetic acid (220mg, 0.65mmol), DIEA (252mg, 1.95mmol) and NaI (19.5mg, 0.13mmol) in acetonitrile (10mL) was stirred at 50 ℃ C. for 6 hours. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH 20:1) to give the desired product 2- (2- (5, 5-dimethyltetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro) -2-pyran-2-yl) as a yellow oil-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid tert-butyl ester (150mg, 45% yield). ESI: 578(M + H)⁺

Step 10: tert-butyl 2- (2- (5, 5-dimethyltetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate (compounds 100-E1 and 100-E2)

Tert-butyl 2- (2- (5, 5-dimethyltetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate (150mg, 0.26mmol) was treated with a mixture of DCM (3mL) and TFA (3mL) at 25 ℃ overnight. The solvent was removed in vacuo and the residue was purified by preparative HPLC a (30-65% MeCN) to yield the desired product tert-butyl 2- (2- (5, 5-dimethyltetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate (compound 100) as a white solid (96mg, 70%). The racemic product was separated by preparative chiral SFC H to give the diastereomeric products 100-E1(29mg) and 100-E2(26mg) as white solids.

Compound 100-E1 LC/MS ESI 522.7(M + H) +.¹H NMR (400MHz, MeOD) δ 7.68(d, J ═ 8.0Hz,1H),7.59(d, J ═ 8.0Hz,1H),7.45-7.38(m,2H),7.15(d, J ═ 8.0Hz,1H),6.37(d, J ═ 7.2Hz,1H),4.93(s,1H),4.73(d, J ═ 8.0Hz,1H),4.19(s,1H),3.56-3.36(m,7H),3.22-3.05(m,3H),2.70(t, J ═ 6.0Hz,2H),2.57(t, J ═ 6.0Hz,2H),2.14-1.92(m,6H),1.76-1.61(m,6H), chiral MeOH (m, 1.95H), chiral MeOH (sfh, 45H): ee 98%, Rt 1.54 min.

Compound 100-E2 LC/MS ESI 522.7(M + H) +.¹H NMR (400MHz, MeOD) δ 7.68(d, J ═ 8.0Hz,1H),7.59(d, J ═ 8.0Hz,1H),7.45-7.38(m,2H),7.15(d, J ═ 8.0Hz,1H),6.37(d, J ═ 7.2Hz,1H),4.81-4.78(m,2H),4.17(s,1H),3.58-3.32(m,8H),3.22-3.15(m,2H),2.70(t, J ═ 6.0Hz,2H),2.55(t, J ═ 6.0Hz,2H),2.18-1.92(m,6H),1.76-1.61(m,6H),1.12(s,3H), chiral MeOH (SFC, 45%) as follows: ee 100%, Rt 2.35 min.

Example 31: preparation of 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (7-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 101-A-E1, 101-A-E2, 101-B-E1 and 101-B-E2)

Step 1: 4- (2, 6-dichloropyridin-3-yl) but-3-en-2-one

A mixture of 2, 6-dichloronicotinaldehyde (25g, 143.5mmol) and 1- (triphenylphosphoranylidene) -2-propanone (1- (triphenylphosphoranylidene) -2-propanone) (57.2g, 179.6mmol) in toluene (180mL) was stirred at 110 ℃ for 16 h. The mixture was cooled to room temperature, H2O (40mL) was added, and the mixture was extracted with ethyl acetate (3X 50 mL). The combined organic layers were dried over Na2SO4, filtered, and the solvent was removed in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 1:1) to give the desired product as a yellow solid (13.3 g). Yield 43% (ESI 216.0(M + H) +).

Step 2: 4- (2, 6-dichloropyridin-3-yl) butan-2-amine

A mixture of 4- (2, 6-dichloropyridin-3-yl) but-3-en-2-one (12g, 55.8mmol), NH4OAc (21.5g, 279.1mmol) and NaBH3CN (10.6g, 167.4mmol) in MeOH (100mL) was stirred at 30 ℃ for 16 h. The mixture was concentrated in vacuo and the residue was purified by column of silica gel (DCM: MeOH 40:1) to give the desired product as a yellow oil (7.94 g). Yield 58% (ESI 219.0(M + H) +).

And step 3: (R) -7-chloro-2-methyl-1, 2,3, 4-tetrahydro-1, 8-naphthyridine and (S) -7-chloro-2-methyl-1, 2,3, 4-tetrahydro-1, 8-naphthyridine

A mixture of 4- (2, 6-dichloropyridin-3-yl) butan-2-amine (7g, 32.1mmol) and Cs2CO3(52g, 160.6mmol) in DMF (120mL) was stirred at 140 ℃ for 16 h. The mixture was cooled to room temperature, EtOAc (100mL) was added and washed with H2O (3X 100 mL). The organic layer was removed in vacuo and the residue was purified through a silica gel column (petroleum ether: EtOAc 1:1) to yield the desired product as a yellow oil (1.9 g). Yield 32% (ESI 183.0(M + H) +). The racemic product was separated by preparative chiral SFC B to give stereoisomer a (870mg) and stereoisomer B (890mg) as a yellow oil.

And 4, step 4: 7-chloro-2-methyl-3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxylic acid (R) -tert-butyl ester stereoisomer A

A mixture of 7-chloro-2-methyl-1, 2,3, 4-tetrahydro-1, 8-naphthyridine stereoisomer A (870mg, 4.75mmol), (Boc)2O (3.13g, 14.35mmol), and DMAP (1.75g, 14.35mmol) in THF (40mL) was stirred at 60 deg.C for 2 hours. The solvent was removed in vacuo and the residue was purified by silica gel column (petroleum ether: EtOAc 10:1) to give the desired product as a yellow solid (1.2 g). Yield 89% (ESI 283.0(M + H) +).

And 5: stereoisomer A of tert-butyl 7- (4- ((R) -1- (tert-butoxycarbonyl) pyrrolidin-3-yloxy) butyl) -2-methyl-3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxylate

To a solution of (R) -tert-butyl 3- (but-3-enyloxy) pyrrolidine-1-carboxylate (512mg, 2.13mmol) in THF (dry, 5mL) under Ar was added 9-BBN (THF as a 0.5M solution, 8.5mL, 4.25 mmol). The reaction was stirred at 50 ℃ for 2H, then cooled to room temperature and 7-chloro-2-methyl-3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxylic acid tert-butyl ester stereoisomer A (600mg, 2.13mmol), tricyclohexylphosphine (60mg, 0.21mmol), Pd (OAc)2(47mg, 0.21mmol) and NaOH (127mg, 3.19mmol) were added. The mixture was stirred at 70 ℃ C for 2 hours. The solvent was removed in vacuo and the residue was purified by silica gel column (petroleum ether: EtOAc 8:1) to give the desired product as a yellow solid (988 mg). Yield 95% (ESI 490.0(M + H) +).

Step 6: 2-methyl-7- (4- ((R) -pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine stereoisomer A

Tert-butyl 7- (4- ((R) -1- (tert-butoxycarbonyl) pyrrolidin-3-yloxy) butyl) -2-methyl-3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxylate stereoisomer a (1.2g, 2.45mmol) was treated with HCl in 1, 4-dioxane (4M, 8mL) at 25 ℃ for 16H. The solvent was removed in vacuo to yield the desired product as a white solid (781.7 mg). Yield 88% (ESI 290.0(M + H) +).

And 7: stereoisomer a of 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (7-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid tert-butyl ester

A mixture of 2-methyl-7- (4- ((R) -pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine stereoisomer A (200mg, 0.55mmol), tert-butyl 2-bromo-2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) acetate (206mg, 0.55mmol), and DIPEA (178mg, 1.38mmol) in acetonitrile (8mL) was stirred at 50 ℃ for 4 hours. The solvent was removed in vacuo and the residue was purified by column of silica gel (DCM: MeOH 10:1) to give the desired product tert-butyl 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (7-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate stereoisomer a (120mg) as a yellow oil. Yield 37% (ESI 582.3(M + H) +).

And 8: stereoisomer a of 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (7-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compounds 101-a-E1 and 101-a-E2)

To a solution of tert-butyl 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (7-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate stereoisomer a (120mg, 0.21mmol) in DCM (2.5mL) was added TFA (2.5mL) and the mixture was stirred at room temperature for 16H. The solvent was removed in vacuo and the residue was purified by preparative HPLC a (30-65% MeCN) to give the diastereomeric products compound 101-a-E1(40mg) and compound 101-a-E2(1.5mg) as white solids.

Compound 101-A-E1 LC/MS ESI 526.3(M + H) +. 1H NMR (400MHz, MeOD) δ 7.62-7.58(m,1H),7.46-7.43(m,1H)7.28-7.18(m,2H),6.45(d, J ═ 7.2Hz,1H),5.02(s,1H),4.74(d, J ═ 10.8Hz,1H),4.21(s,1H),4.01(d, J ═ 7.2Hz,1H), 3.71-3.69 (m,1H), 3.59-3.40 (m,5H),3.15-3.10(m,1H),2.77-2.74(m,2H),2.62-2.58(m,2H), 2.05-1.89 (m,5H), 1.88-1.42 (m,10H),1.22(d, 10H), 1.8 (m,10H), 3.8 (J ═ 3H).

Compound 101-A-E2 LC/MS ESI 526.3(M + H) +. 1H NMR (400MHz, MeOD) δ 7.46-7.41(m,2H),7.31-7.29(m,1H)7.16-7.13(m,1H),6.47(d, J ═ 7.2Hz,1H),5.32(s,1H),4.70(d, J ═ 6.8Hz,1H),4.19(s,1H),4.10(d, J ═ 10.0Hz,1H), 3.71-3.40 (m,4H), 3.19-3.16 (m,3H),2.78-2.76(m,2H),2.65-2.61(m,2H), 2.25-2.02 (m,2H), 2.00-1.96 (m,3H), 1.88-1.42 (m,10H),1.22(d, 10H), 10.8 (J ═ 3H), 3H).

And step 9: stereoisomer B of 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (7-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compounds 101-B-E1 and 101-B-E2)

The 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (7-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid stereoisomer B (compounds 101-B-E1 and 101-B-E2) was synthesized from 7-chloro-2-methyl-3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxylic acid tert-butyl ester stereoisomer B by the same method as that of stereoisomer a.

Compound 101-B-E1 LC/MS ESI 526.3(M + H) +. 1H NMR (400MHz, MeOD) δ 7.62-7.58(m,1H),7.46-7.43(m,1H)7.26-7.18(m,2H),6.44(d, J ═ 7.2Hz,1H),4.99(s,1H),4.74(d, J ═ 10.4Hz,1H),4.21(s,1H),4.03(d, J ═ 10.8Hz,1H), 3.71-3.69 (m,1H), 3.59-3.40 (m,5H),3.10(s,1H),2.76-2.73(m,2H),2.61-2.57(m,2H), 2.20-1.89 (m,5H), 1.81-1.42 (m,10H),1.22(d, 10J ═ 8, 3H).

Compound 101-B-E2 LC/MS ESI 526.3(M + H) +. 1H NMR (400MHz, MeOD) δ 7.47-7.37(m,3H),7.17-7.12(m,1H),6.49(d, J ═ 7.2Hz,1H),5.32(s,1H),4.69(d, J ═ 9.2Hz,1H),4.19(s,1H),4.10(d, J ═ 10.0Hz,1H), 3.71-3.40 (m,5H), 3.19-3.16 (m,2H),2.79-2.76(m,2H),2.68-2.63(m,2H), 2.35-2.22 (m,1H), 2.10-1.96 (m,4H), 1.86-1.44 (m,10H),1.22(d, J ═ 10.8, 1H).

Example 32: preparation of 2- (5-fluoro-2- (2, 9-dioxaspiro [5.5] undecan-3-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compounds 102-A-E1, 102-A-E2 and 102-B)

Step 1: 4- (but-3-en-1-yl) tetrahydro-2H-pyran-4-carboxylic acid ethyl ester

To a solution of diisopropylamine (3.19mL, 22.8mmol) in dry tetrahydrofuran (20mL) at-78 deg.C under a nitrogen atmosphere was added n-butyllithium-containing hexane (2.5M, 7.28mL, 18.2 mmol). This mixture was stirred at-78 ℃ for 45 minutes, then tetrahydropyran-4-carboxylic acid ethyl ester (2.87mL, 19.0mmol) was added dropwise, and the mixture was stirred at-78 ℃ for 30 minutes. A mixture of 4-bromo-1-butene (2.5mL, 24.6mmol) and HMPA (1.85mL, 10.6mmol) in dry tetrahydrofuran (5mL) was added dropwise. Mixing the raw materialsThe material was stirred at-78 ℃ for five minutes, removed from the acetone/dry ice bath and stirred at 0 ℃ in the ice/water bath for 20 minutes and then at room temperature for 25 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted three times with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography (silica, pentane with 3% to 15% diethyl ether) gave the desired ethyl 4- (but-3-en-1-yl) tetrahydro-2H-pyran-4-carboxylate (3.19 g). The yield was 79%. ¹H NMR (400MHz, chloroform-d) δ 5.82-5.69 (m,1H), 5.04-4.91 (m,2H),4.19(q, J ═ 7.1Hz,2H), 3.87-3.78 (m,2H), 3.53-3.39 (m,2H), 2.14-2.05 (m,2H), 2.02-1.92 (m,2H), 1.66-1.59 (m,2H), 1.55-1.45 (m,2H),1.28(t, J ═ 7.1Hz,3H).

Step 2: (4- (but-3-en-1-yl) tetrahydro-2H-pyran-4-yl) methanol

To a solution of ethyl 4- (but-3-en-1-yl) tetrahydro-2H-pyran-4-carboxylate (3.17g, 14.9mmol) in dry tetrahydrofuran (30mL) at 0 deg.C under an argon atmosphere was added lithium aluminum hydride-containing tetrahydrofuran (2.4M, 6.22mL, 14.9 mmol). The mixture was stirred at room temperature for 1 hour and quenched by the slow addition of ethyl acetate (20 mL). The mixture was washed with 1M hydrochloric acid, the layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 1M hydrochloric acid and brine, dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography (silica, 15% to 50% ethyl acetate in heptane) gave the desired product (4- (but-3-en-1-yl) tetrahydro-2H-pyran-4-yl) methanol (2.21 g). The yield was 87%.¹H NMR (400MHz, chloroform-d) delta 5.91-5.78 (m,1H), 5.10-4.92 (m,2H), 3.76-3.60 (m,4H),3.53(s,2H), 2.09-1.98 (m,2H), 1.59-1.48 (m,4H), 1.48-1.40 (m,2H),1.36(br.s,1H).

And step 3: 4-Methylbenzenesulfonic acid (4- (but-3-en-1-yl) tetrahydro-2H-pyran-4-yl) methyl ester

To a solution of (4- (but-3-en-1-yl) tetrahydro-2H-pyran-4-yl) methanol (1.75g, 10.3mmol) in dichloromethane (39mL) at 0 deg.C was added pyridine (2.5mL, 30.9mmol) and p-toluenesulfonyl chloride (3.14g, 16.5 mmol). The reaction mixture was stirred at room temperature for 4 days, concentrated in vacuo, diluted with saturated aqueous sodium bicarbonate and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography (silica, 10% to 30% ethyl acetate in heptane) gave the desired product, 4-methylbenzenesulfonic acid (4- (but-3-en-1-yl) tetrahydro-2H-pyran-4-yl) methyl ester (3.15 g). The yield was 94%.¹H NMR (400MHz, chloroform-d) δ 7.84-7.75 (m,2H),7.36(d, J ═ 8.0Hz,2H), 5.78-5.64 (m,1H), 5.00-4.89 (m,2H),3.88(s,2H), 3.67-3.47 (m,4H),2.46(s,3H), 1.90-1.79 (m,2H), 1.56-1.47 (m,2H),1.44(t, J ═ 5.6Hz,4H).

And 4, step 4: 4-Methylbenzenesulfonic acid (4- (3-oxopropyl) tetrahydro-2H-pyran-4-yl) methyl ester

To a solution of 4-methylbenzenesulfonic acid (4- (but-3-en-1-yl) tetrahydro-2H-pyran-4-yl) methyl ester (3.15g, 9.70mmol) in tetrahydrofuran (74mL) and water (24mL) were added sodium periodate (5.19g, 24.3mmol) and osmium tetroxide solution (containing 4 wt% water, 9.9mg, 0.04 mmol). The mixture was stirred at room temperature for 1.5 hours, diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. This gave the desired product, 4-methylbenzenesulfonic acid (4- (3-oxopropyl) tetrahydro-2H-pyran-4-yl) methyl ester (3.17 g). The yield was 100%. ¹H NMR (400MHz, chloroform-d) δ 9.73(d, J ═ 1.7Hz,1H),7.83 to 7.75(m,2H),7.37(d, J ═ 8.1Hz,2H),3.87(s,2H),3.70 to 3.57(m,2H),3.57 to 3.46(m,2H),2.47(s,3H),2.36 to 2.25(m,2H),1.84 to 1.72(m,2H),1.50 to 1.36(m,4H).

And 5: 4-Methylbenzenesulfonic acid (4- (3- (2-bromo-4-fluorophenyl) -3-hydroxypropyl) tetrahydro-2H-pyran-4-yl) methyl ester

To a solution of 2-bromo-4-fluoroiodobenzene (1.66mL, 12.8mmol) in dry toluene (80mL) at-18 deg.C under an argon atmosphere was added isopropylmagnesium chloride (2M in THF, 6.37mL, 12.7 mmol). After stirring for 20 minutes, a solution of 4-methylbenzenesulfonic acid (4- (3-oxopropyl) tetrahydro-2H-pyran-4-yl) methyl ester (3.2g, 9.8mmol) in dry tetrahydrofuran (50mL) was added. The mixture was allowed to reach room temperature overnight, then quenched by pouring it into saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography (silica, 15% to 55% ethyl acetate in heptane) gave the desired product, 4-methylbenzenesulfonic acid (4- (3- (2-bromo-4-fluorophenyl) -3-hydroxypropyl) tetrahydro-2H-pyran-4-yl) methyl ester (3.1 g). The yield was 63%.¹H NMR (400MHz, chloroform-d) δ 7.78(d, J ═ 8.0Hz,2H),7.54 to 7.46(m,1H),7.34(d, J ═ 8.0Hz,2H),7.31 to 7.23(m,1H),7.11 to 7.01(m,1H),4.98 to 4.89(m,1H),3.86(s,2H),3.65 to 3.47(m,4H),2.45(s,3H),2.10(d, J ═ 4.0Hz,1H),1.80 to 1.36(m,8H).

Step 6: 3- (2-bromo-4-fluorophenyl) -2, 9-dioxaspiro [5.5] undecane

To a solution of 4-methylbenzenesulfonic acid (4- (3- (2-bromo-4-fluorophenyl) -3-hydroxypropyl) tetrahydro-2H-pyran-4-yl) methyl ester (3.1g, 6.2mmol) in dry tetrahydrofuran (250mL) was added sodium hydride (60% dispersant in mineral oil, 0.37g, 9.3mmol) at room temperature under an argon atmosphere. The mixture was stirred at room temperature overnight, quenched with saturated aqueous ammonium chloride, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. By column chromatography (silica, 2% to 12% ethyl acetateHeptane) purification yielded the desired product 3- (2-bromo-4-fluorophenyl) -2, 9-dioxaspiro [5.5]Undecane (844 mg). The yield was 42%.¹H NMR (400MHz, chloroform-d) δ 7.54-7.47 (m,1H), 7.29-7.22 (m,1H), 7.09-7.00 (m,1H), 4.64-4.50 (m,1H), 4.10-4.02 (m,1H), 3.80-3.57 (m,4H),3.36(d, J ═ 11.5Hz,1H), 2.02-1.83 (m,3H), 1.77-1.67 (m,1H), 1.60-1.44 (m,2H), 1.43-1.31 (m,2H).

Isolation of 3- (2-bromo-4-fluorophenyl) -2, 9-dioxaspiro [5.5] spiro by chiral preparative SFC]Racemic mixture of undecane (1.165 g). Equipment: vochtik 100SFC UV/MS guidance system; vortex 2998 photodiode array (PDA) detectors; a Watts corporation Acquity QDa MS detector; vortish 2767 sample manager; column: lux amylose-1 (250X 21mm, 5 μm) from Phlomas, column temperature: 35 ℃; flowing: 100 ml/min; ABPR: 120 bar; eluent A: CO 2 ₂And eluent B: isopropanol with 20mM ammonia; the isocratic method comprises the following steps: 5% B for 4 min; loading: 25 mg; and (3) detection: PDA (210 and 400 nm); fractions based on PDA TIC were collected.

The first eluting fraction (stereoisomer a, 0.43g) was isolated as a white solid in 37% yield. RT: 1.44 min, 100% ee. Equipment: acquisty UPC, Vortish²A system; column: amylose-1 (100X 4.6mm, 5 μm) from Phlomis, column temperature: 35 ℃; flowing: 2.5 ml/min; BPR: 170 bar; eluent A: CO 2₂And eluent B: isopropanol with 20mM ammonia; gradient method: t-0 min 5% B, t-5 min 15% B, t-6 min 15% B. And (3) detection: PDA (210-320 nm). The second eluting fraction was isolated as a white solid (stereoisomer B, 0.43g) in 37% yield. RT: 1.96 min, 96% ee. Equipment: acquisty UPC, Vortish²A system; column: amylose-1 (100X 4.6mm, 5 μm) from Phlomis, column temperature: 35 ℃; flowing: 2.5 ml/min; BPR: 170 bar; eluent A: CO 2₂And eluent B: isopropanol with 20mM ammonia; gradient method: t-0 min 5% B, t-5 min 15% B, t-6 min 15% B. And (3) detection: PDA (210-320 nm).

And 7: (-) -2- (5-fluoro-2- (2, 9-dioxaspiro [5.5] undecan-3-yl) phenyl) acetic acid tert-butyl ester stereoisomer A

An oven-dried flask was charged with zinc powder (0.342g, 5.22mmol) and heated under a flow of argon with a hot air gun. After cooling to room temperature, dry tetrahydrofuran (6mL) was added followed by 1, 2-dibromoethane (0.011mL, 0.13 mmol). The mixture was heated to reflux and cooled to room temperature 3 times. Then, trimethylchlorosilane (0.017mL, 0.13mmol) was added, which resulted in spontaneous reflux of the mixture and the zinc changed morphology. After stirring for 20 minutes, tert-butyl bromoacetate (0.38mL, 2.61mmol) was added dropwise, resulting in an exotherm. The mixture was held at elevated temperature (45 ℃) for 30 minutes and then allowed to cool to room temperature. A separate flask was charged with 3- (2-bromo-4-fluorophenyl) -2, 9-dioxaspiro [5.5]]Undecane stereoisomer A (0.43g, 1.31mmol), tri-tert-butylphosphine tetrafluoroborate (0.038g, 0.13mmol) and bis (dibenzylideneacetone) palladium (0.075g, 0.13 mmol). The reaction vessel was flushed with argon, dry tetrahydrofuran (6mL) was added, and argon was bubbled through for five minutes. The zincate solution was added via syringe and the reaction mixture was heated to reflux for 2 hours. The mixture was cooled to room temperature overnight, quenched with saturated aqueous ammonium chloride, and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography (silica, 0% to 15% ethyl acetate in heptane) gave the desired product (-) -2- (5-fluoro-2- (2, 9-dioxaspiro [5.5] ]Undecan-3-yl) phenyl) acetic acid tert-butyl ester stereoisomer A (251 mg). The yield was 53%.¹H NMR (400MHz, chloroform-d) δ 7.45-7.38 (m,1H), 7.01-6.91 (m,2H),4.42(dd, J ═ 11.3,2.4Hz,1H),4.03(dd, J ═ 11.4,2.7Hz,1H), 3.78-3.49 (m,6H),3.32(d, J ═ 11.4Hz,1H), 2.04-1.58 (m,5H), 1.53-1.23 (m,12H), specific optical rotation: -41.2 ℃, c ═ 0.3, CHCl₃，20.3℃，589nm。

And 8: stereoisomer A of tert-butyl 2-bromo-2- (5-fluoro-2- ((S) -2, 9-dioxaspiro [5.5] undecan-3-yl) phenyl) acetate

To a solution of tert-butyl 2- (5-fluoro-2- (2, 9-dioxaspiro [5.5] undecan-3-yl) phenyl) acetate stereoisomer A (110mg, 0.32mmol) in THF (3mL) at-78 deg.C was added dropwise THF/hexane (0.32mL, 0.64mmol) containing a 2.0M solution of lithium diisopropylamide. The reaction was stirred at-78 ℃ for 30 minutes, then chlorotrimethylsilane (70mg, 0.64mmol) was added and the reaction was stirred at-78 ℃ for an additional 30 minutes. Then, a solution of NBS (114mg, 0.64mmol) in THF (2mL) was added and the reaction was stirred at-78 deg.C for 1 hour. The reaction was quenched with MeOH (2mL), the solvent was removed in vacuo, and the residue was purified by silica gel column (petroleum ether: EtOAc 10:1) to give the desired product tert-butyl 2-bromo-2- (5-fluoro-2- (2, 9-dioxaspiro [5.5] undecan-3-yl) phenyl) acetate stereoisomer a (120mg) as a yellow oil. Yield 85% (ESI 465.0(M + Na) +).

And step 9: stereoisomer a of tert-butyl 2- (5-fluoro-2- (2, 9-dioxaspiro [5.5] undecan-3-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate

A mixture of tert-butyl 2-bromo-2- (5-fluoro-2- (2, 9-dioxaspiro [5.5] undecan-3-yl) phenyl) acetate stereoisomer A (120mg, 0.27mmol), (R) -7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (94mg, 0.27mmol), and DIPEA (95mg, 0.74mmol) in acetonitrile (8mL) was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue was purified by column of silica gel (DCM: MeOH 10:1) to give the desired product tert-butyl 2- (5-fluoro-2- (2, 9-dioxaspiro [5.5] undecan-3-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate stereoisomer a (112mg) as a yellow oil. Yield 65% (ESI 638.3(M + H) +).

Step 10: stereoisomer A of 2- (5-fluoro-2- (2, 9-dioxaspiro [5.5] undecan-3-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compounds 102-A-E1 and 102-A-E2)

To a solution of 2- (5-fluoro-2- (2, 9-dioxaspiro [5.5] undecan-3-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid stereoisomer a (112mg, 0.18mmol) in DCM (5mL) was added TFA (0.5mL), and the mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was purified by preparative HPLC a (30-65% MeCN) to give the diastereomeric products 102-a-E1(20mg) and 102-a-E2(11mg) as white solids.

Compound 102-A-E1 LC/MS ESI 582.3(M + H) +. 1H NMR (400MHz, MeOD) δ 7.61(dd, J ═ 8.8,5.9Hz,1H),7.46(dd, J ═ 10.0,2.7Hz,1H),7.17(t, J ═ 7.6Hz,2H),6.41(d, J ═ 7.3Hz,1H),4.93(s,1H),4.75(d, J ═ 10.7Hz,1H),4.21(s,1H),3.95(dd, J ═ 11.2,2.3Hz,1H), 3.74-3.37(m,11H), 3.27(s,1H),3.05(s,1H),2.72(t, J ═ 6.2Hz,2H),2.58(t, J ═ 7.6, 2H), 2.27 (s,1H),3.05(s,1H),2.72(t, 1H), 2.58(t, J ═ 7.6, 2H), 14.83, 1H), 1.3.3.3.3 (m,1H), 3.3.3.3.3, 1H), 1H, 3.3.3, 1H.

Compound 102-A-E2 LC/MS ESI 582.3(M + H) +. 1H NMR (400MHz, MeOD) δ 7.45(dd, J ═ 12.3,6.2Hz,2H),7.22(d, J ═ 7.0Hz,1H), 7.17-7.10 (m,1H),6.42(d, J ═ 7.3Hz,1H),5.14(s,1H),4.73(d, J ═ 12.9Hz,1H),4.17(s,1H),3.96(d, J ═ 11.8Hz,1H),3.74-3.37(m,11H),3.09-3.05(m,2H),2.73(t, J ═ 6.3Hz,2H),2.63-2.59(m,2H),2.17-2.07(m,4H), 1.92-1.63 (m,10, 1.35H), 1.31-2H (m, 1H).

Step 11: stereoisomer B of 2- (5-fluoro-2- (2, 9-dioxaspiro [5.5] undecan-3-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compound 102-B)

Preparation of 2- (5-fluoro-2- (2, 9-dioxaspiro [5.5] undecan-3-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid stereoisomer B (compound 102-B) from 3- (2-bromo-4-fluorophenyl) -2, 9-dioxaspiro [5.5] undecane stereoisomer B by the same method as that for stereoisomer A.

Compound 102-B LC/MS ESI 582.3(M + H) +. 1H NMR (400MHz, MeOD) δ 7.63-7.60 (m,1H), 7.50-7.47 (m,1H), 7.25-7.17 (m,2H),6.43(d, J ═ 7.2Hz,1H),4.93(s,1H), 4.87-4.77 (m,1H),4.19(s,1H),3.96(d, J ═ 12.0Hz,1H),3.71-3.39(m,11H), 3.21-3.18 (m,2H),2.73(t, J ═ 12.0Hz,2H),2.60(t, J ═ 12Hz,2H),2.18(s,2H),2.06-2.05(m,1H),1.96-1.91(m,4H), 1.89-1.52 (m, 7.35H), 1.8 (m, 8H).

Example 33: preparation of 2- ((R) -3- (4- (7, 7-dimethyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) acetic acid (compounds 123-E1 and 123-E2)

Step 1: 4- (2, 6-dichloropyridin-3-yl) -2-methylbut-3-yn-2-amine

A solution of 2, 6-dichloro-3-iodopyridine (4.48g, 16.4mmol) in dry acetonitrile (36mL) and triethylamine (36mL, 259mmol) was flushed with argon for 15 minutes. Then, 1-dimethyl-prop-2-ynylamine (1.78mL, 18.0mmol), copper (I) iodide (94mg, 0.49mmol) and bis (triphenylphosphine) palladium (II) dichloride (345mg, 0.49mmol) were added. The mixture was placed in a pre-heated oil bath at 60 ℃ for 1 hour, then cooled to room temperature, diluted with ethyl acetate, washed twice with water and saturated aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (silica, heptane with gradient 50% to 100% (ethyl acetate with 3% triethylamine)) to yield the desired 4- (2, 6-dichloropyridin-3-yl) -2-methylbut-3-yn-2-amine (2.95g) as a yellow-orange oil. Yield: 79 percent. ¹H NMR (400MHz, chloroform-d)δ7.66(d,J＝8.1Hz,1H),7.22(d,J＝8.0Hz,1H),1.70(s,2H),1.51(s,6H).

Step 2: 4- (2, 6-dichloropyridin-3-yl) -2-methylbutan-2-amine

To a solution of 4- (2, 6-dichloropyridin-3-yl) -2-methylbut-3-yn-2-amine (2.95g, 12.9mmol) in degassed ethanol (90mL) was added Wilkinson's catalyst (1.19g, 1.29 mmol). The mixture was flushed with hydrogen and stirred at 35 ℃ under a hydrogen pressure of 5bar for 3 days. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (silica, 10% to 15% ethyl acetate in heptane) to yield the desired 4- (2, 6-dichloropyridin-3-yl) -2-methylbutan-2-amine (1.4g) as a brown oil. The yield was 47%.¹H NMR (400MHz, chloroform-d) δ 7.52(d, J ═ 7.9Hz,1H),7.21(d, J ═ 7.9Hz,1H), 2.80-2.71 (m,2H), 1.67-1.57 (m,2H),1.41(s,2H),1.20(s,6H).

And step 3: 7-chloro-2, 2-dimethyl-1, 2,3, 4-tetrahydro-1, 8-naphthyridine

To a solution of 4- (2, 6-dichloropyridin-3-yl) -2-methylbutan-2-amine (1.24g, 4.2mmol) in dry N, N-dimethylacetamide (40mL) was added N, N-diisopropylethylamine (8.78mL, 50.4 mmol). The mixture was heated to 120 ℃ for 2 days, cooled to room temperature, diluted with water (400mL), and extracted three times with a 1:1 mixture of heptane and ethyl acetate. The combined organic extracts were washed twice with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica, heptane containing 5% to 15% ethyl acetate) to give the desired 7-chloro-2, 2-dimethyl-1, 2,3, 4-tetrahydro-1, 8-naphthyridine (470mg) as a pale yellow oil which crystallized on standing. Yield: 57 percent. ¹H NMR (400MHz, chloroform-d) δ 7.12(d, J ═ 7.5Hz,1H),6.48(d, J ═ 7.5Hz,1H),4.78(s,1H),2.70(t,J＝6.6Hz,2H),1.67(t,J＝6.6Hz,2H),1.24(s,6H).

and 4, step 4: 3- (4- (7, 7-dimethyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester

To a solution of (R) -tert-butyl 3- (but-3-enyloxy) pyrrolidine-1-carboxylate (796mg, 3.3mmol) in THF (dry, 3mL) at room temperature under Ar was added a solution of 9-BBN (0.5M in THF, 13.2mL, 6.6 mmol). The reaction was stirred at 50 ℃ for 2 hours and then cooled to room temperature. This solution was added to a mixture of 7-chloro-2, 2-dimethyl-1, 2,3, 4-tetrahydro-1, 8-naphthyridine (433mg, 2.2mmol), Pd (OAc)2(25mg, 0.11mmol), PCy3(62mg, 0.22mmol) and KOH (148mg, 2.64mmol) in THF (5 mL). The reaction mixture was stirred at 70 ℃ under Ar for 3 hours then concentrated in vacuo and the residue was purified by silica gel column (petroleum ether/EtOAc ═ 30% to 100%) to give the desired product 3- (4- (7, 7-dimethyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidine-1-carboxylic acid (R) -tert-butyl ester (764mg) as a brown oil. Yield 86% (ESI 404.2(M + H) +).

And 5: (R) -2, 2-dimethyl-7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine

To a solution of (R) -tert-butyl 3- (4- (7, 7-dimethyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidine-1-carboxylate (764mg, 1.89mmol) in MeOH (5mL) was added HCl/dioxane (4M, 4.7 mL). The reaction was stirred at room temperature for 2 hours and then quenched with NH3/MeOH (7N) to pH 7-8. The solvent was removed in vacuo and the residue was purified by silica gel column (DCM: MeOH ═ 10:1-4:1) to give the desired product (R) -2, 2-dimethyl-7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (522mg) as a yellow oil. Yield 91% (ESI 304.2(M + H) +).

Step 6: tert-butyl 2- ((R) -3- (4- (7, 7-dimethyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) acetate

A mixture of (R) -2, 2-dimethyl-7- (4- (pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine (405mg, 1.33mmol), tert-butyl 2-bromo-2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) acetate (745mg, 2.0mmol) and DIPEA (517mg, 4.0mmol) in acetonitrile (12mL) was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was purified by column on silica gel (DCM: MeOH ═ 100:1-20:1) to give the desired product tert-butyl 2- ((R) -3- (4- (7, 7-dimethyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) acetate as a colourless oil (380 mg). Yield 48% (ESI 596.3(M + H) +).

And 7: 2- ((R) -3- (4- (7, 7-dimethyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) acetic acid (Compounds 123-E1 and 123-E2)

To a solution of tert-butyl 2- ((R) -3- (4- (7, 7-dimethyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) acetate (380mg, 0.64mmol) in DCM (4.0mL) was added TFA (4.0 mL). The mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was purified by preparative HPLC a (30-65% MeCN) to give compounds 123-E1(168mg) and 123-E2(25mg) as white solids.

Compound 123-E1 LC/MS ESI 540.3(M + H)⁺。1H NMR(400MHz,MeOD)δ7.60-7.56(m,1H),7.48-7.44(m,1H),7.25(d,J＝7.2Hz,1H),7.18-7.14(m,1H),6.42(d,J＝7.2Hz,1H),4.91(s,1H),4.76-4.75(m,1H),4.19(s,1H),4.04-4.02(m,1H),3.71-3.24(m,6H),3.06-3.03(m,1H),2.74-2.74(m,2H),2.60-2.56(m,2H),2.14-1.98(m,4H),1.79-1.62(m,10H),1.26(s,6H).

Compound 123-E2 LC/MS ESI 540.3(M + H)⁺。1H NMR(400MHz,MeOD)δ7.46-7.42(m,2H),7.25(d,J＝7.2Hz,1H),7.13-7.10(m,1H),6.42(d,J＝7.2Hz,1H),5.14(s,1H),4.74-4.72(m,1H),4.16-4.08(m,2H),3.69-3.37(m,4H),3.12-3.08(m,2H),2.78-2.74(m,2H),2.61-2.56(m,2H),2.14–2.03(m,2H),1.95-1.82(m,3H),1.75-1.58(m,9H),1.26-1.24(m,6H).

Example 34: preparation of 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (4-methoxy-7-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid Me-stereoisomer A (Compounds 124-A-E1, 124-A-E2 and 124-B-E1)

Step 1: 2, 6-dichloro-4-methoxynicotinaldehyde

To a solution of 2, 6-dichloro-4-methoxypyridine (3.49g, 19.6mmol) in dry tetrahydrofuran (100mL) was added n-butyllithium (2.5M solution in hexane, 8.63mL, 21.6mmol) at-78 ℃. After 30 min, ethyl formate (14.2mL, 177mmol) was added and the mixture was stirred at-78 ℃ for another 15 min. The reaction was quenched with saturated aqueous ammonium chloride, warmed to room temperature, diluted with water, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica, heptane containing 5% to 40% ethyl acetate) gave the desired product 2, 6-dichloro-4-methoxynicotinaldehyde (1.83 g). The yield was 45%. ¹H NMR (400MHz, chloroform-d) delta 10.40(s,1H),6.94(s,1H),4.02(s,3H).

Step 2: 4- (2, 6-dichloro-4-methoxypyridin-3-yl) but-3-en-2-one

A mixture of 2, 6-dichloro-4-methoxynicotinaldehyde (4.43g, 21.5mmol), acetonyltriphenylphosphonium chloride (8.01g, 22.6mmol), potassium carbonate (5.94g, 43.0mmol) and 18-crown-6 (5.68g, 21.5mmol) in toluene (150mL) was heated to 80 ℃ for 2.5 hours. The mixture was cooled to room temperature, diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica, heptane containing 5% to 40% ethyl acetate) to give the desired product 4- (2, 6-dichloro-4-methoxypyridin-3-yl) but-3-en-2-one (3.68 g). The yield was 69%.¹H NMR (400MHz, chloroform-d) δ 7.66(d, J ═ 16.6Hz,1H),7.07(d, J ═ 16.6Hz,1H),6.88(s,1H),4.00(s,3H),2.40(s,3H).

And step 3: 4- (2, 6-dichloro-4-methoxypyridin-3-yl) butan-2-one

A mixture of 4- (2, 6-dichloro-4-methoxypyridin-3-yl) but-3-en-2-one (4.4g, 17.9mmol) and Wilkinson's catalyst (716mg, 1.79mmol) in ethanol (160mL) was subjected to a 4Bar hydrogen pressure in an autoclave for 6 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography (silica, heptane containing 5% to 40% ethyl acetate) to give the desired product 4- (2, 6-dichloro-4-methoxypyridin-3-yl) butan-2-one (3.76 g). The yield was 85%. ¹H NMR (400MHz, chloroform-d) delta 6.76(s,1H),3.90(s,3H), 3.05-2.87 (m,2H), 2.71-2.53 (m,2H),2.19(s,3H).

And 4, step 4: (4- (2, 6-dichloro-4-methoxypyridin-3-yl) but-2-yl) carbamic acid tert-butyl ester

4- (2, 6-dichloro-4-methoxypyridin-3-yl) butan-2-one (3.74g, 15.1mmol) and ammonium acetate (11.64g, 151mmol) in methanol (10 g)0mL) was stirred for 30 minutes. Sodium cyanoborohydride (947mg, 15.1mmol) was added. After 2h, additional sodium cyanoborohydride (1.89g, 30.1mmol) was added and the mixture was stirred at room temperature for 20 h. The reaction mixture was quenched with sodium hydroxide (20mL, water containing 1N solution), diluted with water, and extracted with ethyl acetate. The aqueous phase was saturated with sodium chloride and extracted three more times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was diluted with hydrochloric acid (water containing 1N solution) and washed three times with ethyl acetate. The aqueous layer was concentrated in vacuo and the residue was dissolved in 1, 4-dioxane (27 mL). A solution of sodium hydroxide (1.04g, 26.1mmol) in water (27mL) and di-tert-butyl dicarbonate (3.03mL, 13.03mmol) were added. After 3 hours, the reaction was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica, heptane with 5% to 40% ethyl acetate) to give the desired product tert-butyl (4- (2, 6-dichloro-4-methoxypyridin-3-yl) but-2-yl) carbamate (1.48 g). The yield was 28%. ¹H NMR (400MHz, chloroform-d) δ 6.75(s,1H),4.38(s,1H),3.89(s,3H),3.71(s,1H), 2.84-2.61 (m,2H), 1.71-1.37 (m,11H),1.17(d, J ═ 6.6Hz,3H).

And 5: 4- (2, 6-dichloro-4-methoxypyridin-3-yl) but-2-amine hydrochloride

To a solution of tert-butyl (4- (2, 6-dichloro-4-methoxypyridin-3-yl) but-2-yl) carbamate (1.48g, 4.23mmol) in methanol (15mL) was added dioxane (4M, 30mL, 120mmol) containing hydrochloric acid. After 105 minutes, the mixture was concentrated in vacuo to give the desired product, 4- (2, 6-dichloro-4-methoxypyridin-3-yl) but-2-amine hydrochloride (1.21 g). The yield was 100%.¹H NMR(400MHz,DMSO-d₆)δ8.07(s,3H),7.28(s,1H),3.95(s,3H),3.22–3.09(m,1H),2.75–2.59(m,2H),1.88–1.72(m,1H),1.65–1.51(m,1H),1.26(d,J＝6.5Hz,3H).

Step 6: 7-chloro-5-methoxy-2-methyl-1, 2,3, 4-tetrahydro-1, 8-naphthyridine

A mixture of 4- (2, 6-dichloro-4-methoxypyridin-3-yl) butan-2-amine hydrochloride (1.59g, 5.57mmol) and potassium carbonate (2.31g, 16.7mmol) in 2-propanol (50mL) was heated to 120 ℃ for 68 hours. The mixture was cooled to room temperature, diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the desired product 7-chloro-5-methoxy-2-methyl-1, 2,3, 4-tetrahydro-1, 8-naphthyridine (1.16 g). The yield was 98%.¹H NMR (400MHz, chloroform-d) δ 6.19(s,1H),4.65(s,1H),3.80(s,3H), 3.55-3.38 (m,1H), 2.77-2.65 (m,1H), 2.51-2.35 (m,1H), 1.99-1.86 (m,1H), 1.55-1.39 (m,1H),1.21(d, J ═ 6.3Hz,3H).

The racemic mixture of 7-chloro-5-methoxy-2-methyl-1, 2,3, 4-tetrahydro-1, 8-naphthyridine (1.16 g) was isolated by chiral preparative SFC. Equipment: vochtik 100SFC UV/MS guidance system; vortex 2998 photodiode array (PDA) detectors; a Watts corporation Acquity QDa MS detector; vortish 2767 sample manager; column: lux amylose-1 (250X 21mm, 5 μm) from Phlomas; column temperature: 35 ℃; flowing: 70 ml/min; ABPR: 120 bar; eluent A: CO 2₂And eluent B: methanol with 20mM ammonia; linear gradient: t is 0 min 10% B, t is 5 min 50% B; t 7.5 min 50% B; and (3) detection: PDA (210 and 400 nm); fractions based on PDA TIC were collected. The first eluting fraction (stereoisomer a, 425mg) was isolated as a white solid in 36% yield. t is t_R: 2.078 min, 100% ee. Equipment: acquisty UPC, Vortish²: woltz ACQ-ccBSM binary pump; woltz ACQ-CCM Convergence manager; wawter ACQ-SM sample manager-fixed loop; vochthich ACQ-CM column manager-30S; woltz ACQ-PDA photodiode array Detector; a Watcht ACQ-ISM charge pump, a Watcht Acquity QDa MS detector; column: lux amylose of Phlom corporation- 1 (100X 4.6mm, 5 μm); column temperature: 35 ℃; flowing: 2.5 ml/min; ABPR: 170 bar; eluent A: CO 2₂And eluent B: methanol with 20mM ammonia; linear gradient: t is 0 min 5% B, t is 5 min 50% B; t is 6 min 50% B; and (3) detection: PDA (210-400 nm). Specific optical rotation: -59.9 ℃, c ═ 0.5, methanol, 21.4 ℃, 589 nm.

The second eluting fraction was isolated as a white solid (stereoisomer B, 415mg) in 35% yield. t is t_R: 3.147 min, 99% ee. Equipment: acquisty UPC, Vortish²: woltz ACQ-ccBSM binary pump; woltz ACQ-CCM Convergence manager; wawter ACQ-SM sample manager-fixed loop; vochthich ACQ-CM column manager-30S; woltz ACQ-PDA photodiode array Detector; a Watcht ACQ-ISM charge pump, a Watcht Acquity QDa MS detector; column: lux amylose-1 (100X 4.6mm, 5 μm) from Phlomas; column temperature: 35 ℃; flowing: 2.5 ml/min; ABPR: 170 bar; eluent A: CO 2₂And eluent B: methanol with 20mM ammonia; linear gradient: t is 0 min 5% B, t is 5 min 50% B; t is 6 min 50% B; and (3) detection: PDA (210-400 nm). Specific optical rotation: 72.4 ℃, c ═ 0.5, methanol, 21.5 ℃, 589 nm.

And 7: 7-chloro-5-methoxy-2-methyl-3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxylic acid tert-butyl ester stereoisomer A

To a mixture of 7-chloro-5-methoxy-2-methyl-1, 2,3, 4-tetrahydro-1, 8-naphthyridine stereoisomer a (190mg, 0.89mmol) in THF (8mL) was added Boc2O (389mg, 1.78mmol) and DMAP (218mg, 1.78 mmol). The reaction mixture was stirred at 60 ℃ for 16 h, then quenched with saturated aqueous NH4Cl (20mL) and extracted with EtOAc (3X 20 mL). The combined organic phases were concentrated in vacuo and the residue was purified through a silica gel column (petroleum ether: EtOAc 10:1) to give the desired product 7-chloro-5-methoxy-2-methyl-3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxylic acid tert-butyl ester stereoisomer a as a yellow oil (260 mg). Yield 93% (ESI 313.0(M + H) +).

And 8: 7- (4- ((R) -1- (tert-Butoxycarbonyl) pyrrolidin-3-yloxy) butyl) -5-methoxy-2-methyl-3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxylic acid tert-butyl ester stereoisomer A

To a solution of (R) -tert-butyl 3- (but-3-enyloxy) pyrrolidine-1-carboxylate (403mg, 1.67mmol) in THF (dry, 4mL) at room temperature under Ar was added THF (3.34mL, 1.67mmol) containing a 0.5M solution of 9-BBN. The reaction was stirred at 50 ℃ for 2 hours and then cooled to room temperature. This solution was added to a mixture of 7-chloro-5-methoxy-2-methyl-3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxylic acid tert-butyl ester stereoisomer a (260mg, 0.84mmol), pd (oac)2(10mg, 0.042mmol), PCy3(23mg, 0.084mmol), and K3PO 4. H2O (533mg, 2.51mmol) in THF (5 mL). The reaction mixture was stirred at 70 ℃ for 3 hours under Ar. The solvent was removed in vacuo and the residue was purified by silica gel column (petroleum ether/EtOAc ═ 10% to 50%) to give the desired product 7- (4- ((R) -1- (tert-butoxycarbonyl) pyrrolidin-3-yloxy) butyl) -5-methoxy-2-methyl-3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxylic acid tert-butyl ester stereoisomer a (350mg) as a yellow oil. Yield 80% (ESI 520.0(M + H) +).

And step 9: 5-methoxy-2-methyl-7- (4- ((R) -pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine stereoisomer A

To a solution of 7- (4- ((R) -1- (tert-butoxycarbonyl) pyrrolidin-3-yloxy) butyl) -5-methoxy-2-methyl-3, 4-dihydro-1, 8-naphthyridine-1 (2H) -carboxylic acid tert-butyl ester stereoisomer a (350mg, 0.67mmol, 1.0 eq) in DCM (6mL) was added dropwise a HCl solution (4.0M in 1, 4-dioxane, 1.8mL, 5.36 mmol). The reaction was stirred at 25 ℃ for 16 h, then concentrated in vacuo to give the desired product 5-methoxy-2-methyl-7- (4- ((R) -pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine stereoisomer a as a yellow oil (240 mg). Yield 93% (ESI 320.0(M + H) +).

Step 10: 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (4-methoxy-7-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid tert-butyl ester Me-stereoisomer a

A mixture of 5-methoxy-2-methyl-7- (4- ((R) -pyrrolidin-3-yloxy) butyl) -1,2,3, 4-tetrahydro-1, 8-naphthyridine stereoisomer A (240mg, 0.61mmol), tert-butyl 2-bromo-2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) acetate (273mg, 0.73mmol) and DIPEA (236mg, 1.83mmol) in acetonitrile (8mL) was stirred at 60 ℃ for 2 hours. The solvent was removed in vacuo and the residue was purified by column of silica gel (DCM: MeOH 10:1) to give the desired product 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (4-methoxy-7-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid tert-butyl ester Me-stereoisomer a (160mg) as a yellow oil. Yield 42% (ESI 612.0(M + H) +).

Step 11: 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (4-methoxy-7-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid Me-stereoisomer A (Compounds 124-A-E1 and 124-A-E2)

To a solution of 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (4-methoxy-7-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid tert-butyl ester Me-stereoisomer a (160mg, 0.26mmol) in DCM (5mL) was added TFA (1 mL). The reaction was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was purified by preparative HPLC a (30-65% MeCN) to give compound 124-a-E1(22mg) and compound 124-a-E2(2mg) as white solids.

Compound 124-A-E1 LC/MS ESI 556.3(M + H) +.¹H NMR(400MHz,MeOD)δ7.59–7.45(m,2H),7.14–7.12(m,1H),6.31(s,1H),4.86(s,1H),4.79(d,J＝9.0Hz,1H),4.18(s,1H),4.03(d,J＝11.4Hz,1H),3.87(s,3H),3.69–3.67(m,1H),3.56–3.40(m,3H),2.99-2.97(m,1H),2.85–2.42(m,4H),2.25–1.89(m,6H),1.88–1.38(m,11H),1.24(d,J＝6.3Hz,3H).

Compound 124-A-E2 LC/MS ESI 556.3(M + H) +.¹H NMR(400MHz,MeOD)δ7.52–7.44(m,2H),7.12–7.10(m,1H),6.40(s,1H),4.86-4.75(m,2H),4.17-4.08(m,2H),3.92(s,3H),3.69–3.45(m,4H),3.02-2.99(m,1H),2.85–2.42(m,4H),2.25–1.89(m,6H),1.88–1.38(m,11H),1.24(d,J＝6.3Hz,3H).

Step 12: preparation of 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (4-methoxy-7-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid Me-stereoisomer B (Compound 124-B-E1)

Synthesis of 2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (4-methoxy-7-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid Me-stereoisomer B (compound 124-B-E1) from 7-chloro-5-methoxy-2-methyl-1, 2,3, 4-tetrahydro-1, 8-naphthyridine stereoisomer B by the same procedure as for stereoisomer a.

Compound 124-B-E1 LC/MS ESI 556.3(M + H) +.¹H NMR(400MHz,MeOD)δ7.57-7.54(m,1H),7.49-7.46(m,1H),7.11-7.10(m,1H),6.30(s,1H),4.81(d,J＝8.0Hz,1H),4.73(s,1H),4.15(s,1H),4.05-4.02(d,J＝12.0Hz,1H),3.87(s,3H),3.73-3.68(m,1H),3.51–3.45(m,3H),3.39-3.36(m,1H),3.30-3.22(m,1H),3.12-3.10(d,J＝8.0Hz,1H),2.91-2.86(m,1H),2.76-2.71(m,1H),2.62-2.59(t,J＝12.0Hz,2H),2.52-2.45(m,1H),2.09-1.93(m,5H),1.82–1.60(m,8H),1.51-1.43(m,1H),1.25-1.23(d,J＝8.0Hz,3H).

Further examples

Compounds 22-91, 103-122 and 125-129 were prepared using the general procedure based on the methods used for the preparation of compounds 1-21, 92-102 and 123-124.

2- (2- (cyclopropylmethoxy) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 22-E1 and 22-E2)

22-E1 LC/MS ESI 480.2(M+H)⁺。¹H NMR (400MHz, MeOD) δ 7.44(d, J ═ 7.2Hz,1H),7.22(t, J ═ 8.0Hz,1H),7.01(d, J ═ 7.2Hz,1H), 6.92-6.83 (m,2H),6.25(d, J ═ 7.2Hz,1H),4.89(s,1H),4.04(s,1H), 3.82-3.77 (m,2H), 3.50-3.35 (m,6H), 2.98-2.80 (m,2H),2.59(t, J ═ 6.4Hz,2H),2.41(t, J ═ 7.2Hz,2H), 1.94-1.17 (m,9H), 0.49-0.27 (m,4H), chiral SFC (45% MeOH): ee 100%, Rt 2.06 min.

22-E2 LC/MS ESI 480.2(M+H)⁺。¹H NMR (400MHz, MeOD) δ 7.44(d, J ═ 6.4Hz,1H),7.23(t, J ═ 8.0Hz,1H),7.01(d, J ═ 7.6Hz,1H), 6.92-6.83 (m,2H),6.24(d, J ═ 7.6Hz,1H),4.89(s,1H),4.04(s,1H), 3.82-3.77 (m,2H), 3.45-3.35 (m,6H), 2.98-2.90 (m,2H),2.59(t, J ═ 6.4Hz,2H),2.41(t, J ═ 7.2Hz,2H), 1.94-1.17 (m,9H), 0.49-0.27 (m,4H), chiral SFC (45% MeOH): ee 100%, Rt 4.49 min.

2- (2-cyclopropyl-4-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 23-E1 and 23-E2)

Compound 23-E1 LC/MS ESI 468.6(M + H) +.¹H NMR(400MHz,MeOD)δ7.54(d,J＝8.5Hz,1H),7.06(d,J＝7.3Hz,1H),6.93–6.69(m,2H),6.27(d,J＝7.3Hz,1H),5.05(s,1H),4.07(s,1H),3.47–3.25(m,5H),3.21–3.13(m,2H),2.60(t, J ═ 6.2Hz,2H),2.44(t, J ═ 7.5Hz,2H), 2.23-2.01 (m,3H), 1.85-1.71 (m,2H), 1.66-1.44 (m,4H), 1.02-0.78 (m,3H), 0.54-0.52 (m,1H), chiral SFC a (45% MeOH): ee 100%, Rt 3.11 min.

Compound 23-E2 LC/MS ESI 468.6(M + H) +.¹H NMR (400MHz, MeOD) δ 7.53(d, J ═ 8.4,1H),7.03(d, J ═ 7.3Hz,1H), 6.88-6.64 (m,2H),6.27(d, J ═ 7.3Hz,1H),4.95(s,1H),4.06(s,1H), 3.50-3.22 (m,5H), 3.06-2.71 (m,3H),2.60(t, J ═ 6.2Hz,2H),2.42(t, J ═ 7.5Hz,2H), 2.22-2.04 (m,1H), 2.05-1.95 (m,2H), 1.85-1.69 (m,2H), 1.68-1.39 (m,4H), 0.96-0.72 (m,3H), chiral MeOH (sfh), 0.46-1H, 45% chiral MeOH): ee 100%, Rt 2.31 min.

2- (2-Cyclopropylphenyl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetic acid (diastereomer compounds 24-E1 and 24-E2)

Compound 24-E1 LC/MS ESI 447(M + H)⁺ ¹H NMR(400MHz,MeOD)δ7.61(d,J＝8.0Hz,1H),7.32-7.25(m,2H),7.16-7.10(m,2H),6.33(d,J＝7.2Hz,1H),5.25(s,1H),3.75-3.36(m,3H),3.33-3.31(m,2H),2.71–2.68(m,3H),2.51-2.18(m,5H),1.90-1.84(m,2H),1.68–1.58(m,3H),1.46-1.33(m,6H),1.09–1.07(m,3H),0.59-0.55-(m,1H).

Compound 24-E2 LC/MS ESI 447(M + H)⁺ ¹H NMR(400MHz,MeOD)δ7.61(d,J＝8.0Hz 1H),7.33-7.24(m,2H),7.16-7.10(m,2H),6.34(d,J＝7.2Hz,1H),5.24(s,1H),3.85-3.36(m,3H),3.33-3.11(m,2H),2.81–2.68(m,3H),2.52-2.17(m,5H),1.91-1.85(m,2H),1.72-1.3(m,9H),1.11–1.00(m,3H),0.58-0.54(m,1H).

2- (2-Isopropoxyphenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 25)

Compound 25 LC/MS ESI 468.2(M + H)⁺。¹H NMR(400MHz,MeOD)δ7.53–7.35(m,2H),7.14(d,J＝7.2Hz,1H),7.08(d,J＝8.4Hz,1H),6.97(t,J＝7.6Hz,1H),6.39–6.36(m,1H),5.10–4.90(m,1H),4.74–4.72(m,1H),4.25(s,1H),3.55–3.35(m,6H),3.28–3.02(m,2H),2.71(t,J＝6.0Hz,2H),2.20–1.51(m,8H),1.40–1.35(m,6H).

2- (4-Cyclopropylpyridin-3-yl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetic acid (Compound 26)

Compound 26 LC/MS ESI 449.4(M + H)⁺。¹H NMR(400MHz,MeOD)δ8.73(d,J＝4.4Hz,1H),8.36(t,J＝5.6Hz,1H),7.13-7.10(m,1H),7.01(d,J＝5.2Hz,1H),6.37-6.33(m,1H),5.02-4.95(m,1H),3.65-3.35(m,3H),3.25-2.95(m,2H),2.75-2.65(m,3H),2.55–2.10(m,5H),1.91-1.85(m,2H),1.70-1.60(m,3H),1.50-1.18(m,8H),1.06-1.03(m,1H),0.78-0.74(m,1H).

2- (2-Cyclopropylphenyl) -2- ((S) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 27-E1 and 27-E2)

Compound 27-E1 LC/MS ESI 450.2(M + H)⁺。¹H NMR (400MHz, MeOD) δ 7.61(d, J ═ 7.6Hz,1H), 7.31-7.14 (m,4H),6.37(d, J ═ 7.2Hz,1H),5.26(s,1H),4.17(s,1H), 3.60-3.25 (m,8H),2.71(t, J ═ 6.4Hz,2H),2.54(t, J ═ 7.2Hz,2H), 2.20-1.55 (m,9H), 1.00-0.90 (m,3H), 0.58-0.55 (m,1H), chiral SFC a (35% MeOH): ee 100%, Rt 3.45 min.

Compound 27-E2 LC/MS ESI 450.2(M + H)⁺。¹H NMR(400MHz,MeOD)δ7.60(d,J＝7.6Hz,1H),7.33–7.13(m,4H),6.37(d,J＝7.2Hz,1H),5.31(s,1H),4.22(s,1H),3.60–3.05(m,8H),2.71(t,J＝6.4Hz,2H),2.54(t,J＝7.2Hz,2H),2.20–1.55(m,9H), 1.00-0.92 (m,3H), 0.58-0.55 (m,1H). chiral SFC A (35% MeOH): ee 100%, Rt 4.18 min.

2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (2,2, 2-trifluoroethoxy) phenyl) acetic acid (Compound 28)

Compound 28 LC/MS ESI 508.4(M + H)⁺。¹H NMR(400MHz,MeOD)δ7.64-7.60(m,1H),7.45-7.43(m,1H),7.18-7.12(m,3H),6.38-6.35(m,1H),5.10-4.95(m,1H),4.72-4.60(m,2H),4.17(s,1H),3.60-3.35(m,6H),3.20-3.00(m,2H),2.75-2.68(m,2H),2.56-2.50(m,2H),2.43-1.85(m,4H),1.75-1.50(m,4H).

2- (2-Isobutoxy-phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 29-E1 and 29-E2)

Compound 29-E1 LC/MS ESI 482.4(M + H)⁺。¹H NMR(400MHz,MeOD)δ8.54(s,1H),7.54(d,J＝7.6Hz,1H),7.46–7.38(m,2H),7.12–7.02(m,2H),6.51(d,J＝7.6Hz,1H),5.25(s,1H),4.18(s,1H),3.87–3.80(m,2H),3.64–3.32(m,7H),3.12–3.06(m,1H),2.82–2.57(m,4H),2.18–1.57(m,9H),1.10–1.02(m,6H).

Compound 29-E2 LC/MS ESI 482.4(M + H)⁺。¹H NMR(400MHz,MeOD)δ8.54(s,1H),7.53(d,J＝7.6Hz,1H),7.46–7.38(m,2H),7.10–7.01(m,2H),6.49(d,J＝7.6Hz,1H),5.05(s,1H),4.21(s,1H),3.87–3.85(m,2H),3.60–3.22(m,8H),2.82–2.57(m,4H),2.22–1.57(m,9H),1.10–1.02(m,6H).

2- (2-Isopropoxypyridin-3-yl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetic acid (diastereomer compounds 30-E1 and 30-E2)

Compound 30-E1 LC/MS ESI 467.2(M + H)⁺。¹H NMR(400MHz,MeOD)δ8.21-8.19(m,1H),7.91-7.88(m,1H),7.12(d,J＝7.6Hz,1H),7.02-6.98(m,1H),6.34(d,J＝7.2Hz,1H),5.45-5.41(m,1H),3.55-3.36(m,3H),3.25-2.95(m,3H),2.70(t,J＝6.4Hz,2H),2.49(t,J＝7.6Hz,2H),2.45-2.15(m,2H),1.91-1.85(m,2H),1.69-1.59(m,3H),1.42-1.33(m,13H).

Compound 30-E2 LC/MS ESI 467.2(M + H)⁺。¹H NMR(400MHz,MeOD)δ8.21-8.19(m,1H),7.92-7.89(m,1H),7.12(d,J＝7.6Hz,1H),7.02-6.98(m,1H),6.35(d,J＝7.2Hz,1H),5.45-5.39(m,1H),3.60-3.36(m,3H),3.18-3.13(m,1H),2.85-2.65(m,3H),2.53-2.35(m,3H),2.21-2.17(m,1H),1.91-1.85(m,2H),1.71-1.58(m,3H),1.48-1.32(m,13H).

2- (2-Cyclopropylphenyl) -2- ((S) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyloxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 31-E1 and 31-E2)

Compound 31-E1 LC/MS ESI 464.3(M + H)⁺。¹H NMR(400MHz,MeOD)δ8.48(s,1H),7.71–7.29(m,4H),7.20(d,J＝7.6Hz,1H),6.53(d,J＝7.2Hz,1H),5.62(s,1H),4.22(s,1H),3.60–3.05(m,8H),2.83–2.65(m,4H),2.38–2.05(m,3H),1.96–1.48(m,8H),1.15–0.90(m,3H),0.58–0.55(m,1H).

Compound 31-E2 LC/MS ESI 464.3(M + H)⁺。¹H NMR(400MHz,MeOD)δ8.48(s,1H),7.68(d,J＝6.8Hz,1H),7.45(d,J＝7.6Hz,1H),7.39–7.19(m,3H),6.52(d,J＝7.2Hz,1H),5.33(s,1H),4.22(s,1H),3.58–3.05(m,8H),2.81–2.62(m,4H),2.45–1.78(m,8H),1.56–1.42(m,3H),1.15–0.90(m,3H),0.58–0.55(m,1H).

2- (4-isopropylpyrimidin-5-yl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetic acid (compound 32)

Compound 32 LC/MS ESI 452.6(M + H) +.¹H NMR(400MHz,MeOD)δ8.99–8.94(m,2H),7.26(d,J＝6.8Hz,1H),6.41(d,J＝7.2Hz,1H),4.67–4.62(m,1H),3.71–3.69(m,1H),3.47–3.32(m,4H),3.16–2.85(m,2H),2.73–2.63(m,5H),2.41–2.03(m,2H),1.96–1.80(m,2H),1.73–1.52(m,3H),1.52–1.24(m,12H).

2- (2-Cyclobutoxyphenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 33-E1 and 33-E2)

Compound 33-E1 LC/MS ESI 480.4(M + H)⁺。¹H NMR (400MHz, MeOD) δ 7.50(d, J ═ 6.8Hz,1H), 7.38-7.33 (m,1H),7.13(d, J ═ 7.2Hz,1H), 7.00-6.90 (m,2H),6.37(d, J ═ 7.2Hz,1H),5.08(s,1H), 4.82-4.76 (m,1H),4.19(s,1H), 3.62-3.05 (m,8H), 2.78-2.40 (m,6H), 2.25-1.55 (m,12H), chiral SFC a (45% MeOH): ee 99%, Rt 1.82 min.

Compound 33-E2 LC/MS ESI 480.4(M + H)⁺。¹H NMR (400MHz, MeOD) δ 7.42(d, J ═ 7.2Hz,1H), 7.28-7.22 (m,1H),7.03(d, J ═ 7.6Hz,1H), 7.90-6.79 (m,2H),6.26(d, J ═ 7.6Hz,1H),4.95(s,1H), 4.75-4.66 (m,1H),4.06(s,1H), 3.52-3.05 (m,8H),2.60(t, J ═ 6.0Hz,2H), 2.44-2.30 (m,4H), 2.20-1.98 (m,4H), 1.80-1.45 (m,8H), chiral SFC a (45% MeOH): ee 94%, Rt 2.77 min.

2- (2- (pyrrolidin-1-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 34-E1 and 34-E2)

Compound 34-E1LC/MS ESI 479.4(M+H)⁺。¹H NMR(400MHz,CDCL3)δ7.50(d,J＝6.8Hz,1H),7.28–7.02(m,4H),6.27(d,J＝7.2Hz,1H),4.68(s,1H),3.94–3.91(m,1H),3.49–3.17(m,10H),2.72–2.49(m,6H),2.06–1.55(m,12H).

Compound 34-E2 LC/MS ESI 479.4(M + H)⁺。¹H NMR(400MHz,CDCL3)δ7.55(s,1H),7.28–7.02(m,4H),6.27(d,J＝7.2Hz,1H),4.55(s,1H),3.98–3.95(m,1H),3.50–3.07(m,10H),2.85–2.49(m,6H),2.06–1.55(m,12H).

2- (2-Cyclopropylphenyl) -2- ((R) -3- (3- ((5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) methoxy) propyl) pyrrolidin-1-yl) acetic acid (Compound 35)

Compound 35 LC/MS ESI 450(M + H)⁺ ¹H NMR(400MHz,MeOD)δ8.50(brs,1H),7.62-7.60(m,1H),7.41-7.21(m,4H),6.60-6.58(m,1H),5.30-5.28(m,1H),4.37-4.35(m,2H),3.36-3.31(m,5H),3.30-3.11(m,2H),2.85-2.75(m,3H),2.50–1.50(m,10H),1.10–0.50(m,4H).

2- (2-Cyclopropylphenyl) -2- (cis-3-fluoro-4- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 36-E1 and 36-E2)

Compound 36-E1 LC/MS ESI 468.3(M + H) +.¹H NMR(400MHz,MeOD)δ8.53(s,1H),7.70–7.07(m,5H),6.49(d,J＝8.3Hz,1H),5.32–5.19(m,2H),4.30–4.04(m,1H),3.84–3.36(m,6H),3.33–3.24(m,1H),3.00(t,J＝9.7Hz,1H),2.77–2.64(m,4H),2.36–2.18(m,1H),1.98–1.83(m,2H),1.80–1.52(m,4H),1.16–0.87(m,3H),0.58–0.54(m,1H).

Compound 36-E2 LC/MS ESI 468.3(M + H) +.¹H NMR(400MHz,MeOD)δ8.50(s,1H),7.68–7.06(m,5H),6.52(d,J＝7.2Hz,1H),5.42–5.08(m,2H),4.44–4.01(m,1H),3.81–3.33(m,6H),3.33–3.24(m,2H),2.77–2.64(m,4H),2.36–2.18(m,1H),1.98–1.83(m,2H),1.84–1.53(m,4H),1.24–0.85(m,3H),0.58–0.54(m,1H).

2- (2-cyclopropyl-5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 37)

Compound 37 LC/MS ESI 468.3(M + H) + 1H NMR (400MHz, MeOD) Δ 8.52(s,1H),7.48-7.01(M,4H),6.49-6.46(M,1H),5.41-5.28(M,1H),4.24-4.20(M,1H),3.55-3.10(M,8H),2.77-2.61(M,4H),2.29-2.05(M,3H),1.92-1.55(M,6H),1.05-0.80(M,3H),0.55-0.50(M,1H).

2- (2-cyclopropyl-6-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 38)

Compound 38 LC/MS ESI 468.4(M + H) + 1H NMR (400MHz, MeOD) Δ 8.49(s,1H),7.45-7.37(M,2H),7.09-7.03(M,2H),6.54-6.50(M,1H),5.60-5.52(M,1H),4.24-4.20(M,1H),3.59-3.15(M,8H),2.80-2.63(M,4H),2.23-2.13(M,3H),1.92-1.55(M,6H),1.08-0.65(M,4H).

2- (2- (methoxymethyl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 39-E1 and 39-E2)

Compound 39-E1 LC/MS ESI 454.2(M + H) + 1H NMR (400MHz, MeOD) δ 7.66-7.64 (M,1H), 7.43-7.39 (M,3H),7.13(d, J ═ 7.2Hz,1H),6.36(d, J ═ 7.2Hz,1H),4.89(s,1H),4.44(d, J ═ 8.0Hz,1H),4.17(s,1H),3.49-3.36(M,8H), 3.14-3.13 (M,2H),2.70(t, J ═ 6.4Hz,2H),2.55(t, J ═ 7.6Hz,2H), 2.14-2.13 (M,2H), 1.96-1.84 (M,2H), chiral MeOH (M, 1.74, 1.59, 5M, 40% SFC): ee 100%, Rt 2.64 min.

Compound 39-E2 LC/MS ESI 454.2(M + H) + 1H NMR (400MHz, MeOD) δ 7.67-7.65 (M,1H), 7.42-7.38 (M,3H),7.13(d, J ═ 7.6Hz,1H),6.36(d, J ═ 7.2Hz,1H),4.81(s,1H),4.45(s,1H),4.17(s,1H), 3.36-3.27 (M,8H), 3.19-3.13 (M,2H),2.70(t, J ═ 6.4Hz,2H),2.55(t, J ═ 7.6Hz,2H), 2.18-2.14 (M,2H), 1.90-1.84 (M,2H), 1.73-1.58 (M,5H), chiral MeOH (SFC) (40%): ee 100%, Rt 4.68 min.

2- (2- (cyclopropylmethyl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 40-E1 and 40-E2)

Compound 40-E1 LC/MS ESI 464.4(M + H)⁺。¹H NMR(400MHz,MeOD)δ8.45(s,1H),7.66-7.30(m,5H),6.54(d,J＝7.2Hz,1H),5.18-4.93(m,1H),4.21(m,1H),3.61-3.41(m,6H),3.28-3.24(m,2H),2.94-2.64(m,6H),2.22-2.18(m,2H),1.94-1.65(m,6H),1.17-1.11(m,1H),0.58-0.52(m,2H),0.27-0.24(m,2H).

Compound 40-E2 LC/MS ESI 464.4(M + H)⁺。¹H NMR(400MHz,MeOD)δ8.46(s,1H),7.63-7.31(m,5H),6.57(d,J＝7.6Hz,1H),5.13(s,1H),4.24(m,1H),3.59-3.42(m,6H),3.18-3.11(m,2H),2.86-2.61(m,6H),2.16-2.13(m,2H),1.93-1.68(m,6H),1.17-1.11(m,1H),0.56-0.51(m,2H),0.27-0.23(m,2H).

2- (2-isopropylphenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 41-E1 and 41-E2)

Compound 41-E1 LC/MS ESI 452.2(M + H)⁺ ¹H NMR(400MHz,MeOD)δ7.61(d,J＝7.2Hz,1H),7.41(d,J＝6.4Hz,1H),7.38(t,J＝7.2Hz,1H),7.22(t,J＝7.0Hz,1H),7.14(d,J＝72Hz,1H),6.37(d, J ═ 7.2Hz,1H),4.92(s,1H),4.18(s,1H), 3.49-3.36 (m,6H), 3.32-3.03 (m,3H),2.70(t, J ═ 6.4Hz,2H),2.55(t, J ═ 7.6Hz,2H), 2.21-2.02 (m,2H), 1.89-1.84 (m,2H), 1.71-1.69 (m,2H), 1.62-1.58 (m,2H), 1.30-1.27 (m,6H), chiral SFC F (45% MeOH): ee 100%, Rt 3.67 min.

Compound 41-E2 LC/MS ESI 452.2(M + H) + 1H NMR (400MHz, MeOD) δ 7.60(d, J ═ 7.0Hz,1H),7.41(d, J ═ 6.0Hz,1H),7.38(t, J ═ 7.2Hz,1H),7.23(t, J ═ 8.0Hz,1H),7.17(d, J ═ 7.2Hz,1H),6.40(d, J ═ 7.6Hz,1H),5.03(s,1H),4.20(s,1H), 3.56-3.54 (M,3H), 3.39-3.36 (M,3H), 3.08-3.01 (M,3H),2.72(t, J ═ 6.4Hz,2H), 2H (t, 7, 88H), 2.19 (M, 1H), 2.19H, 1H), 2.19-19H, 1H: ee 96.7%, Rt 8.03 min.

2- (2-cyclopropyl-6- (cyclopropylmethyl) pyridin-3-yl) -2- ((R) -3- (3- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) propoxy) pyrrolidin-1-yl) acetic acid (Compound 42)

Compound 42 LC/MS ESI 491.6(M + H) +.¹H NMR(400MHz,MeOD)δ7.67(d,J＝8.1Hz,1H),6.92(d,J＝7.5Hz,2H),6.16(d,J＝7.3Hz,1H),4.78–4.72(m,1H),4.11–3.81(m,1H),3.39–3.13(m,5H),2.97–2.72(m,3H),2.55–2.47(m,2H),2.43–2.19(m,5H),2.05–1.78(m,2H),1.78–1.58(m,4H),1.14–0.98(m,1H),0.94–0.63(m,4H),0.31–0.27(m,2H),0.22–0.18(m,2H).

2- (2-Cyclopropoxyphenyl) -2- ((3R,4S) -3-fluoro-4- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 43-E1 and 43-E2)

Compound 43-E1 LC/MS ESI 484.4(M + H)⁺。¹H NMR(400MHz,MeOD)δ7.49(d,J＝7.5Hz,1H),7.40-7.39(m,2H),7.20-7.18(m,1H),7.06–6.96(m,1H),6.39(d,J＝7.3Hz,1H),5.20(d,J＝54.2Hz,1H),4.89(s,1H),4.10-4.02(m,1H),3.90(s,1H),3.80–3.33(m,6H),3.20-3.03(m,2H),2.71(t,J＝6.2Hz,2H),2.56(t,J＝7.6Hz,2H),1.90–1.82(m,2H),1.75-1.55(m,4H),0.96–0.63(m,4H).

Compound 43-E2 LC/MS ESI 484.4(M + H)⁺。¹H NMR(400MHz,MeOD)δ7.51(d,J＝7.5Hz,1H),7.39-7.37(m,2H),7.20-7.18(m,1H),7.06–6.96(m,1H),6.41(d,J＝7.3Hz,1H),5.12(d,J＝54.2Hz,1H),4.84(s,1H),4.10-4.02(m,1H),3.87(s,1H),3.65–3.33(m,6H),3.20-3.01(m,2H),2.72(t,J＝6.2Hz,2H),2.59(t,J＝7.6Hz,2H),1.90–1.82(m,2H),1.75-1.55(m,4H),0.96–0.63(m,4H).

2- (5-fluoro-2- (isopropoxymethyl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 44-E1 and 44-E2)

Compound 44-E1 LC/MS ESI 500.3(M + H) + 1H NMR (400MHz, MeOD) δ 7.55-7.41(M,3H),7.25-7.19(M,1H),6.61(d, J ═ 7.2Hz,1H),5.29(s,1H),4.83-4.79(M,1H),4.51-4.47(M,1H),4.26(s,1H),3.83-3.23(M,9H),2.84-2.71(M,4H),2.29-1.55(M,8H),1.35-1.20(M,6H).

Compound 44-E2 LC/MS ESI 500.3(M + H) + 1H NMR (400MHz, MeOD) δ 7.59-7.41(M,3H),7.25-7.19(M,1H),6.60(d, J ═ 7.2Hz,1H),5.19(s,1H),4.83-4.79(M,1H),4.51-4.47(M,1H),4.28(s,1H),3.83-3.23(M,9H),2.84-2.71(M,4H),2.29-1.55(M,8H),1.35-1.20(M,6H).

2- (2, 4-Dicyclopropylpyrimidin-5-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compound 45)

Compound 45 LC/MS ESI 492(M + H)⁺ ¹H NMR(400MHz,MeOD)δ8.60-8.57(m,1H),8.46(bs,1H),7.52(d,J＝7.2Hz,1H),6.59(d,J＝7.6Hz,1H),5.21-5.10(m,1H),4.23-4.21(m,1H),3.70-2.50(m,12H),2.50-1.55(m,10H),1.50-1.00(m,8H).

2- (2- (Cyclobutoxymethyl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 46-E1 and 46-E2)

Compound 46-E1 LC/MS ESI 494.3(M + H) + 1H NMR (400MHz, MeOD) δ 8.51(s,1H),7.68-7.66(M,1H),7.45-7.41(M,4H),6.53(d, J ═ 7.2Hz,1H),5.06(s,1H),4.82-4.79(M,1H),4.40-4.36(M,1H),4.21-4.09(M,2H),3.63-3.33(M,7H),3.18-3.14(M,1H),2.79-2.68(M,4H),2.24-1.50(M,14H).

Compound 46-E2 LC/MS ESI 494.3(M + H) + 1H NMR (400MHz, MeOD) δ 8.49(s,1H),7.66(s,1H),7.48-7.42(M,4H),6.54(d, J ═ 7.2Hz,1H),4.94(s,1H),4.80-4.45(M,2H),4.24-4.10(M,2H),3.58-3.15(M,8H),2.80-2.62(M,4H),2.24-1.50(M,14H).

2- (2- (3-fluoro-3-methylbutyl) pyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 47)

Compound 47 LC/MS ESI 498.9(M + H) + 1H NMR (400MHz, MeOD) Δ 8.43-8.42(M,1H),8.31-8.08(M,1H),7.32-7.23(M,2H),6.44-6.41(M,1H),4.69-4.57(M,1H),4.13-4.12(M,1H),3.49-3.32(M,4H),3.24-2.90(M,6H),2.75-2.56(M,4H),2.25-1.52(M,10H),1.48-1.35(M,6H).

2- (3-cyano-2-cyclopropylphenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 48)

Compound 48 LC/MS ESI 475.3(M + H) + 1H NMR (400MHz, MeOD) δ 7.85-7.81(M,2H),7.60-7.55(M,2H),6.01(d, J ═ 7.2Hz,1H),5.90-5.78(M,1H),4.28-4.26(M,1H),3.62-3.46(M,7H),3.28-3.20(M,1H),2.84-2.72(M,4H),2.27-1.67(M,9H),1.26-0.88(M,4H).

2- (1-isopentyl-6-oxo-1, 6-dihydropyridin-2-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 49)

Compound 49 LC/MS ESI 497(M + H)⁺ ¹H NMR(400MHz,MeOD)δ8.41(s,2H),7.71(t,J＝7.6Hz,1H),7.52(d,J＝7.6Hz,1H),7.14(d,J＝6.8Hz,1H),6.78(d,J＝8.4Hz,1H),6.55(d,J＝7.6Hz,1H),4.85(d,J＝9.6Hz,1H),4.40-4.21(m,3H),3.70-2.50(m,12H),2.50-1.55(m,11H),0.96-0.94(m,6H).

2- (6-cyclopropyl-4- (isopropoxymethyl) pyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 50-E1 and 50-E2)

Compound 50-E1 LC/MS ESI 523.3(M + H) +.¹H NMR(400MHz,MeOD)δ8.58(s,1H),8.50(s,1H),7.41(d,J＝7.3Hz,1H),7.32(s,1H),6.51(d,J＝7.3Hz,1H),4.78–4.75(m,1H),4.62–4.59(m,1H),4.20(s,1H),3.84–3.76(m,1H),3.69–3.32(m,8H),3.24–3.07(m,1H),2.83–2.39(m,4H),2.12–2.02(m,3H),1.97–1.87(m,2H),1.84–1.61(m,4H),1.27–1.25(m,6H),1.21–0.83(m,4H).

Compound 50-E2 LC/MS ESI 523.3(M + H) +.¹H NMR(400MHz,MeOD)δ8.57–8.49(m,2H),7.40(d,J＝7.3Hz,1H),7.32(s,1H),6.51(d,J＝7.3Hz,1H),4.89–4.69(m,2H),4.23(s,1H),3.81–3.76(m,1H),3.60–3.32(m,7H),3.24–3.10(m,2H),2.78–2.66(m,4H),2.12–2.02(m,3H),1.97–1.87(m,2H),1.74–1.51(m,4H),1.27–1.25(m,6H),1.21–0.83(m,4H).

2- (3-fluoro-2- (isopropoxymethyl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 51)

Compound 51 LC/MS ESI 500(M + H) +. 1H NMR (500MHz, MeOD) δ 7.52(d, J ═ 8.0Hz,1H),7.45-7.41(m,1H),7.20-7.15(m,1H),6.39-6.37(m,1H),4.84-4.76(m,1H),4.18(s,1H),3.85-3.81(m,1H),3.49-3.40(m,6H),3.33-3.12(m,2H),2.73-2.70(m,2H),2.56-2.53(m,2H),2.12-2.06(m,2H),1.90-1.58(m,6H),1.26-1.21(m,6H).

2- (2, 4-Dicyclopropylpyrimidin-5-yl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetic acid (compound 52)

Compound 52 LC/MS ESI 490(M + H)⁺ ¹H NMR(400MHz,MeOD)δ8.61-8.59(m,1H),8.36(bs,2H),7.51(d,J＝7.2Hz,1H),6.55(d,J＝7.2Hz,1H),5.11-5.10(m,1H),3.50-2.50(m,8H),2.50-1.55(m,9H),1.50-1.00(m,15H).

2- (2- ((cyclopropylmethoxy) methyl) -5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 53-E1 and 53-E2)

Compound 53-E1 LC/MS ESI 512.3(M + H) +¹H NMR(400MHz,MeOD)δ8.51(s,1H),7.49-7.41(m,3H),7.20-7.15(m,1H),6.52(d,J＝7.2Hz,1H),5.07(s,1H),4.86-4.84(m,1H),4.48-4.45(m,1H),4.22(s,1H),3.62-3.12(m,10H),2.79-2.65(m,4H),2.24-1.55(m,8H),1.08-1.01(m,1H),0.54-0.49(m,2H),0.27-0.24(m,2H).

Compound 53-E2 LC/MS ESI 512.3(M + H) + 1H NMR (400MHz, MeOD) δ 8.51(s,1H),7.49-7.46(M,3H),7.20-7.16(M,1H),6.54(d, J ═ 7.2Hz,1H),4.98(s,1H),4.85-4.52(M,2H),4.24(s,1H),3.60-3.12(M,10H),2.81-2.65(M,4H),2.29-1.55(M,8H),1.16-1.13(M,1H),0.54-0.49(M,2H),0.27-0.24(M,2H).

2- (5-fluoro-2- ((1-methylcyclopropoxy) methyl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 54-E1 and 54-E2)

Compound 54-E1 LC/MS ESI 512.3(M + H) +¹H NMR(400MHz,MeOD)δ8.51(s,1H),7.49-7.38(m,3H),7.17-7.11(m,1H),6.50(d,J＝7.6Hz,1H),4.93-4.90(m,2H),4.53-4.50(m,1H),4.21(s,1H),3.66-3.09(m,8H),2.78-2.65(m,4H),2.18-1.62(m,8H),1.50(s,3H),0.87-0.84(m,2H),0.49-0.45(m,2H).

Compound 54-E2 LC/MS ESI 512.3(M + H) +¹H NMR(400MHz,MeOD)δ8.51(s,1H),7.47-7.36(m,3H),7.15-7.11(m,1H),6.48(d,J＝7.2Hz,1H),4.85-4.80(m,2H),4.60-4.57(m,1H),4.20(s,1H),3.62-3.09(m,8H),2.77-2.64(m,4H),2.20-1.64(m,8H),1.50(s,3H),0.91-0.88(m,2H),0.49-0.47(m,2H).

2- (5-fluoro-2- (isopropoxymethyl) phenyl) -2- ((3R) -3- (4- (7-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 55-E1 and 55-E2)

Compound 55-E1 (mixture of 2 stereoisomers) LC/MS ESI 514(M + H)⁺ ¹H NMR(400MHz,MeOD)δ8.35(s,2H),7.54-7.47(m,3H),7.19-7.15(m,1H),6.57(d,J＝7.2Hz,1H),5.07-5.05(m,1H),4.85(d,J＝7.6Hz,1H),4.50-3.31(m,9H),3.30-2.00(m,8H),1.96-1.20(m,14H).

Compound 55-E2 (mixture of 2 stereoisomers) LC/MS ESI 514(M + H)⁺ ¹H NMR(400MHz,MeOD)δ8.31(s,2H),7.54-7.47(m,3H),7.19-7.15(m,1H),6.58(d,J＝8.8Hz,1H),5.07-5.05(m,1H),4.87-4.35(m,3H),3.80-3.31(m,5H),3.30-2.25(m,8H),2.15-1.20(m,16H).

2- (2- ((S) -1-Isopropoxyethyl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 56-E1 and 56-E2)

Compound 56-E1 LC/MS ESI 496.3(M + H) +¹H NMR (400MHz, MeOD) δ 8.56(s,1H),7.71(d, J ═ 7.2Hz,1H),7.47(d, J ═ 7.2Hz,1H),7.24-7.19(m,1H),7.11(d, J ═ 7.6Hz,1H),6.34(d, J ═ 7.6Hz,1H),5.44-5.42(m,1H),4.19(s,1H),4.02(s,1H),3.56-3.31(m,4H),2.95-2.48(m,8H),2.14-1.81(m,4H),1.68-1.52(m,4H),1.41-1.02(m,9H), SFC F (45% MeOH): ee 100%, Rt 3.77 min.

Compound 56-E2 LC/MS ESI 496.3(M + H) +¹H NMR (400MHz, MeOD) δ 7.65-7.61(m,2H),7.42-7.31(m,2H),7.17(d, J ═ 7.6Hz,1H),6.40(d, J ═ 7.2Hz,1H),5.06-5.04(m,1H),4.20(s,1H),3.53-3.31(m,7H),3.08-2.98(m,2H),2.72(t, J ═ 6.4Hz,2H),2.57(t, J ═ 7.2Hz,2H),2.18-1.82(m,4H),1.78-1.50(m,4H),1.45-1.42(m,3H),1.20-1.08(m,6H), chiral F (45% MeOH): ee 100%, Rt 5.60 min.

2- (2- ((R) -1-Isopropoxyethyl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 57-E1 and 57-E2)

Compounds 57-E1 LC/MS ESI 496.4(M + H) + 1H NMR (400MHz, MeOD) δ 8.47(s,1H),7.70(d, J ═ 7.6Hz,1H),7.65(d, J ═ 8.0Hz,1H),7.45-7.34(M,3H),6.53(d, J ═ 7.2Hz,1H),5.11-5.09(M,1H),4.94(s,1H),4.23(s,1H),3.59-3.28(M,9H),2.78(t, J ═ 6.4Hz,2H),2.69(t, J ═ 7.6Hz,2H),2.27-2.14(M,2H),1.93-1.65(M,6H),1.49(d, J ═ 6, 1.12H), 1.3.27-2H).

Compound 57-E2 LC/MS ESI 496.4(M + H) +¹H NMR(400MHz,MeOD)δ8.46(s,1H),7.62(d,J＝8.0Hz,1H),7.53(d,J＝7.2Hz,1H),7.46-7.34(m,3H),6.53(d,J＝7.2Hz,1H),5.23(s,1H),5.10-5.05(m,1H),4.25(s,1H),3.66-3.20(m,9H),2.80-2.67(m,4H),2.17-2.10(m,2H),1.93-1.65(m,6H),1.50-1.47(m,3H),1.21-1.02(m,6H).

2- (5-fluoro-2- (isopropoxymethyl) phenyl) -2- ((R) -3- (4- (4-fluoro-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 58)

Compound 58 LC/MS ESI 518(M + H)⁺ ¹H NMR(400MHz,MeOD)δ8.50(bs,1H),7.45-7.43(m,2H),7.18-7.14(m,1H),6.25(d,J＝7.6Hz,1H),4.90-4.80(m,2H),4.52-4.48(m,1H),4.22(s,1H),3.80-3.05(m,9H),2.70-2.55(m,4H),2.22-1.54(m,8H),1.25-1.18(m,6H).

2- (5-fluoro-2- (isopropoxymethyl) phenyl) -2- ((R) -3- (4- (4-methoxy-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compound 59)

Compound 59 LC/MS ESI 530(M + H)⁺ ¹H NMR(400MHz,MeOD)δ8.54(bs,1H),7.48-7.45(m,2H),7.13-7.12(m,1H),6.40(d,J＝8.8Hz,1H),4.90-4.83(m,2H),4.52-4.48(m,1H),4.19(s,1H),3.81-3.75(m,4H),3.55-3.02(m,8H),2.68-2.52(m,4H),2.20-1.54(m,8H),1.28-1.20(m,6H).

2- (5-fluoro-2- ((3-methyloxetan-3-yloxy) methyl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 60)

Compound 60LC/MS ESI 528.3(M + H) + 1H NMR (400MHz, MeOD) δ 7.52-7.46(M,2H),7.19-7.11(M,2H),6.39(d, J ═ 7.2Hz,1H),4.88-4.72(M,4H),4.54-4.42(M,3H),4.17(s,1H),3.48-3.31(M,6H),3.18-3.03(M,2H),2.73-2.55(M,4H),2.20-1.84(M,4H),1.78-1.55(M,8H).

2- (3-fluoro-2- (((R) -tetrahydrofuran-3-yloxy) methyl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 61)

Compound 61 LC/MS ESI 528.3(M + H)⁺ ¹H NMR(400MHz,MeOD)δ7.56–7.46(m,1H),7.43–7.38(m,1H),7.21–7.18(m,2H),6.41–6.38(m,1H),4.86(m,1H),4.81–4.68(m,2H),4.39–4.35(m,1H),4.30–4.14(m,1H),3.98–3.65(m,4H),3.50–3.39(m,5H),3.18–3.00(m,2H),2.75–2.71(m,2H),2.58–2.55(m,2H),2.21–2.02(m,4H),1.92–1.80(m,2H),1.76–1.65(m,2H),1.62–1.58(m,3H).

2- (3-fluoro-2- (((R) -tetrahydrofuran-3-yloxy) methyl) phenyl) -2- ((3R) -3- (1-hydroxy-5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetic acid (Compound 62)

Compound 62 LC/MS ESI 542.4(M + H) + 1H NMR (500MHz, MeOD) δ 7.42-7.34(M,2H),7.19-7.08(M,2H),6.36-6.33(M,1H),4.68-4.60(M,1H),4.28-4.23(M,1H),3.98-3.50(M,5H),3.44-3.31(M,6H),3.15-2.84(M,2H),2.64-2.45(M,4H),2.20-1.75(M,5H),1.60-1.22(M,8H).

2- (3-fluoro-2- ((3-methyloxetan-3-yloxy) methyl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 63)

Compound 63 LC/MS ESI 528.3(M + H) +¹H NMR(400MHz,MeOD)δ7.57-7.45(m,2H),7.24-7.16(m,2H),6.41-6.37(m,1H),4.94-4.71(m,4H),4.47-4.41(m,2H),4.20-4.18(m,1H),3.74-3.02(m,8H),2.72(t,J＝6.4Hz,2H),2.56(t,J＝7.2Hz,2H),2.20-1.84(m,4H),1.78-1.51(m,7H).

2- (5-fluoro-2- (((R) -tetrahydrofuran-3-yloxy) methyl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 64)

Compound 64 LC/MS ESI 528.4(M + H) +¹H NMR(500MHz,MeOD)δ8.43(s,1H),7.52-7.49(m,3H),7.19-7.17(m,1H),6.57(d,J＝7.0Hz,1H),5.03-4.83(m,2H),4.57-4.49(m,1H),4.38-4.28(m,2H),3.98-3.22(m,12H),2.82-2.72(m,4H),2.30-2.04(m,4H),1.98-1.58(m,6H).

2- (2-Cyclobutylphenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 65)

Compound 65 LC/MS ESI 528.4(M + H) +¹H NMR(500MHz,MeOD)δ7.62-7.59(m,1H),7.51-7.27(m,4H),6.59-6.55(m,1H),5.05-4.91(m,1H),4.30-4.28(m,1H),4.02-3.90(m,1H),3.68-3.05(m,8H),2.81-2.70(m,4H),2.44-1.58(m,14H).

2- (2-cyclopropyl-3-methoxyphenyl) -2- [ (3R) -3- [4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy ] pyrrolidin-1-yl ] acetic acid (diastereomer compounds 66-E1 and 66-E2)

Compound 66-E1 LC/MS ESI 480(M + H)⁺ ¹H NMR(400MHz,MeOD)δ7.46(d,J＝7.2Hz,1H),7.32-7.28(m,1H),7.19(d,J＝7.6Hz,1H),6.99(d,J＝8.4Hz,1H),6.53(d,J＝8.4Hz,1H),5.58(s,1H),4.21-4.18(m,1H),3.86(s,3H),3.61-3.24(m,8H),2.81-2.66(m,4H),2.18–1.61(m,9H),1.11–0.67(m,4H).

Compound 66-E2 LC/MS ESI 480(M + H)⁺ ¹H NMR(400MHz,MeOD)δ7.47(d,J＝7.2Hz,1H),7.34-7.17(m,2H),7.02(d,J＝8.4Hz,1H),6.55(d,J＝7.2Hz,1H),5.76(s,1H),4.21-4.18(m,1H),3.86(s,3H),3.65-3.24(m,8H),2.78-2.54(m,4H),2.22–1.51(m,9H),1.15–0.60(m,4H).

2- (2- (cis-2-methoxycyclopropyl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 67-E1 and 67-E2)

Compound 67-E1 LC/MS ESI 480.3(M + H) +.¹H NMR (400MHz, MeOD) δ 7.69-7.58 (m,1H), 7.29-7.23 (m,2H), 7.15-7.09 (m,2H),6.37(d, J ═ 7.3Hz,1H),5.19(d, J ═ 7.8Hz,1H), 4.18-4.17 (m,1H), 3.70-3.34 (m,9H), 3.27-3.24 (m,3H),2.70(t, J ═ 6.2Hz,2H), 2.61-2.37 (m,3H), 2.25-2.05 (m,2H), 1.96-1.79 (m,2H), 1.79-1.47 (m,4H), 1.42-0.84 (m,2H), chiral K: (45% MeOH): ee 98.4%, Rt 2.78 min.

Compound 67-E2 LC/MS ESI 480.3(M + H) +.¹H NMR (400MHz, MeOD) delta 7.68-7.56 (m,1H), 7.49-7.26 (m,4H),6.51-6.49(m,1H),5.31-5.26(m,1H), 4.18-4.17 (m,1H), 3.72-3.34 (m,12H), 2.75-2.55 (m,4H),2.50-2.42(m,1H), 2.25-2.05 (m,2H), 1.96-1.52 (m,6H), 1.12-1.04 (m,2H) chiral K: (45% MeOH): ee 38%, Rt 5.26 min.

2- (2- (trans-2-methoxycyclopropyl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 68-E1 and 68-E2)

Compound (I)68-E1 LC/MS ESI 480.3(M+H)+.¹H NMR (400MHz, MeOD) δ 7.69-7.58 (m,1H), 7.29-7.23 (m,2H), 7.15-7.09 (m,2H),6.37(d, J ═ 7.3Hz,1H),5.24(d, J ═ 7.8Hz,1H), 4.18-4.17 (m,1H), 3.70-3.34 (m,9H), 3.27-3.24 (m,3H),2.70(t, J ═ 6.2Hz,2H), 2.61-2.37 (m,3H), 2.25-2.05 (m,2H), 1.96-1.79 (m,2H), 1.79-1.47 (m,4H), 1.42-0.84 (m,2H), chiral K: (45% MeOH): ee 98.4%, Rt 2.72 min.

Compound 68-E1 LC/MS ESI 480.3(M + H) +.¹H NMR (400MHz, MeOD) δ 7.62-7.59 (m,1H), 7.33-7.24 (m,2H), 7.16-7.07 (m,2H),6.37(d, J ═ 7.3Hz,1H),5.30-5.23(m,1H),4.21(s,1H), 3.65-3.02 (m,12H),2.70(t, J ═ 6.2Hz,2H), 2.56-2.30 (m,3H), 2.16-1.98 (m,2H), 1.96-1.80 (m,2H), 1.79-1.49 (m,4H), 1.38-1.05 (m,2H), chiral K: (45% MeOH): ee 38%, Rt 5.22 min.

2- (3-fluoro-2- ((3-methyloxetan-3-yloxy) methyl) phenyl) -2- ((R) -3- (4- (4-methoxy-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 69)

Compound 69 LC/MS ESI 558(M + H) ⁺ ¹H NMR(400MHz,MeOD)δ7.62-7.60(m,1H),7.43-7.41(m,1H),7.19-7.14(m,1H),6.28(s,1H),4.90-4.71(m,7H),4.46-4.41(m,2H),4.17-4.12(m,1H),3.87(s,3H),3.55-3.30(m,4H),3.22-2.95(m,2H),2.64-2.52(m,4H),2.20-1.55(m,11H).

2- (4- ((3-Methyloxyoxetan-3-yl) methoxy) pyrimidin-5-yl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetic acid (compound 70)

Compound 70LC/MS ESI 510.3(M + H)⁺ ¹H NMR(400MHz,MeOD)δ8.74–8.69(m,2H),7.13–7.11(m,1H),6.36–6.33(m,1H),4.80–4.72(m,1H),4.70–4.50(m,6H),3.50–3.30(m,3H),3.22–3.00(m,2H),2.80–2.60(m,3H),2.50–2.40(m,2H),2.35–2.00(m,2H),1.92–1.82(m,2H),1.62–1.48(m,3H),1.42–1.22(m,9H).

2- (4-Cyclopropoxypyrimidin-5-yl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetic acid (Compound 71)

Compound 71 LC/MS ESI 466.3(M + H)⁺ ¹H NMR(400MHz,MeOD)δ8.75(d,J＝8.4Hz,1H),8.69(d,J＝8.4Hz,1H),7.13–7.11(m,1H),6.36–6.33(m,1H),4.54–4.49(m,2H),3.39–3.37(m,3H),3.18–2.90(m,2H),2.71–2.68(m,2H),2.51–2.47(m,2H),2.30–2.20(m,1H),2.19–2.04(m,1H),1.92–1.82(m,2H),1.62–1.24(m,10H),0.94–0.80(m,4H).

2- (2- (Cyclopropoxyphenyl) -2- ((R) -3- (4- (4-methoxy-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 72-E1 and 72-E2)

Compound 72-E1 LC/MS ESI 496.3(M + H)⁺。¹H NMR(500MHz,MeOD)δ7.42-7.40(m,1H),7.36–7.30(m,2H),6.97-6.95(m,1H),6.20(s,1H),4.91-4.85(m,1H),4.10(s,1H),3.78-3.71(m,4H),3.43-3.38(m,4H),3.22-2.94(m,3H),2.51-2.48(m,4H),2.03-1.57(m,8H),0.73-0.62(m,3H).

Compound 72-E2 LC/MS ESI 496.3(M + H)⁺。¹H NMR(500MHz,MeOD)δ7.44-7.42(m,1H),7.35-7.33(m,2H),6.96-6.94(m,1H),6.17(s,1H),4.85-4.82(m,1H),4.09(s,1H),3.86-3.77(m,4H),3.40-3.37(m,3H),3.25-3.13(m,5H),2.52-2.48(m,4H),2.12–1.51(m,8H),0.81–0.64(m,4H).

2- (5-fluoro-2- ((3-methyloxobutan-3-yloxy) methyl) phenyl) -2- ((R) -3- (4- (4-methoxy-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 73-E1 and 73-E2)

Compound 73-E1 LC/MS ESI 558.2(M + H)⁺ ¹H NMR(400MHz,MeOD)δ8.50(br,1H),7.54–7.48(m,2H),7.19–7.15(m,1H),6.52(s,1H),5.00(s,1H),4.87(d,J＝10.8Hz,1H),4.76–4.70(m,2H),4.49–4.40(m,3H),4.22(s,1H),3.97(s,3H),3.66–3.60(m,1H),3.58–3.42(m,3H),3.40–3.37(m,3H),3.13–3.10(m,1H),2.74–2.59(m,4H),2.21–2.15(m,2H),1.92–1.62(m,9H).

Compound 73-E2 LC/MS ESI 558.2(M + H)⁺ ¹H NMR(400MHz,MeOD)δ8.50(br,1H),7.54–7.48(m,2H),7.20–7.16(m,1H),6.55(s,1H),5.02–5.00(s,1H),4.93–4.76(m,3H),4.57–4.48(m,1H),4.46–4.40(m,2H),4.23(s,1H),3.98(s,3H),3.80–3.19(m,6H),3.15–3.08(m,2H),2.76–2.60(m,4H),2.27–2.05(m,2H),1.89–1.62(m,9H).

2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (tetrahydrofuran-3-yl) phenyl) acetic acid (Compound 74)

Compound 74: LC/MS ESI 480.2(M + H)⁺,¹H NMR(500MHz,MeOD)δ7.63(dd,J＝13.4,7.8Hz,1H),7.47(d,J＝7.2Hz,1H),7.39(t,J＝7.6Hz,1H),7.28(t,J＝7.6Hz,1H),7.17(d,J＝7.3Hz,1H),6.40(dd,J＝7.3,5.4Hz,1H),4.99(s,1H),4.23–4.14(m,2H),4.13–4.06(m,1H),4.06–3.96(m,1H),3.95–3.80(m,2H),3.75(m,1H),3.52(m,2H),3.40(m,3H),3.30–2.99(m,3H),2.72(t,J＝6.2Hz,2H),2.57(m,2H),2.38(m,1H),2.06(m,3H),1.89(m,2H),1.79–1.68(m,2H),1.67–1.57(m,2H).

2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) -2- (2- (tetrahydro-2H-pyran-3-yl) phenyl) acetic acid (Compound 75)

Compound 75: LC/MS ESI 494.2(M + H)⁺,¹H NMR(500MHz,MeOD)δ7.67(t,J＝7.9Hz,1H),7.41(d,J＝7.9Hz,1H),7.35(t,J＝7.5Hz,1H),7.27(t,J＝7.5Hz,1H),7.16(d,J＝7.3Hz,1H),6.44–6.35(m,1H),4.84(s,1H),4.17(d,J＝23.7Hz,1H),3.94(m,2H),3.66–3.35(m,8H),3.10(m,3H),2.74–2.67(m,2H),2.61–2.52(m,2H),2.21–2.01(m,3H),1.88(m,2H),1.84–1.59(m,7H).

2- (2- (3, 3-Difluorocyclobutyl) pyridin-2-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 76)

Compound 76 LC/MS ESI 501.2(M + H)⁺。¹H NMR(500MHz,MeOD)δ8.62–8.58(m,1H),8.04–7.99(m,1H),7.34–7.29(m,2H),6.48(d,J＝7.3Hz,1H),4.84-4.70(m,1H),4.17(s,1H),4.12–3.95(m,1H),3.45-3.32(m,4H),3.28–2.61(m,12H),2.17–1.62(m,8H).

2- (2- (trans-3-methoxycyclobutyl) pyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 77)

Compound 77 LC/MS ESI 495.3(M + H)⁺。¹H NMR(500MHz,MeOD)δ8.59-8.57(m,1H),8.03–7.98(m,1H),7.32-7.28(m,2H),6.48(t,J＝7.3Hz,1H),4.84-4.71(m,1H),4.26–4.15(m,3H),3.54-3.40(m,5H),3.28(s,3H),3.13-3.10(m,2H),2.78–2.60(m,6H),2.48–2.36(m,2H),2.17–1.64(m,8H).

2- (2- (cis-3-methoxycyclobutyl) pyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 78)

Compound 78 LC/MS ESI 495.3(M + H)⁺。¹H NMR(500MHz,MeOD)δ8.58-8.56(m,1H),8.00(dd,J＝17.8,7.9Hz,1H),7.31-7.29(m,2H),6.49-6.46(m,1H),4.91-4.79(m,1H),4.21-4.18(m,1H),3.90-3.87(m,1H),3.71-3.40(m,6H),3.30–3.00(m,6H),2.78–2.59(m,6H),2.51–1.60(m,10H).

2- (2- (tert-butoxymethyl) phenyl) -2- ((R) -3- (4- (4-methoxy-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 79-E1 and 79-E2)

Compound 79-E1 LC/MS ESI 526.2(M + H)⁺ ¹H NMR(400MHz,MeOD)δ7.67–7.65(m,1H),7.44–7.38(m,3H),6.36(s,1H),4.96(s,1H),4.83(d,J＝10.4Hz,1H),4.47(d,J＝10.4Hz,1H),4.20(s,1H),3.91(s,3H),3.79–3.42(m,4H),3.39–3.36(m,2H),3.35–3.31(m,1H),3.09–3.07(m,1H),2.64–2.58(m,4H),2.20–2.12(m,2H),1.86–1.62(m,6H),1.29(s,9H).

Compound 79-E2 LC/MS ESI 526.2(M + H)⁺ ¹H NMR(400MHz,MeOD)δ7.62(s,1H),7.42(s,3H),6.49(s,1H),4.96(s,1H),4.76–4.75(m,1H),4.61–4.55(m,1H),4.24(s,1H),3.96(s,3H),3.64–3.42(m,3H),3.40–3.30(m,3H),3.25–3.15(m,2H),2.79–2.58(m,4H),2.29–2.21(m,1H),2.13–2.02(m,1H),1.96–1.62(m,6H),1.33(s,9H).

2- (5-fluoro-2- ((1-methylcyclopropyl) methoxy) phenyl) -2- ((R) -3- (4- (4-methoxy-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 80-E1 and 80-E2)

Compound 80-E1 LC/MS ESI 542.2(M + H) +.¹H NMR(400MHz,MeOD)δ7.37–7.34(m,1H),7.15–6.93(m,2H),6.31–6.21(m,1H),5.04(s,1H),4.24–3.96(m,1H),3.93–3.74(m,5H),3.56–3.36(m,3H),3.35–3.17(m,4H),3.08–2.88(m,1H),2.59–2.55(m,4H),2.16–1.96(m,2H),1.93–1.48(m,6H),1.24(s,3H),0.79–0.32(m,4H).

Compound 80-E2 LC/MS ESI 542.2(M + H) +. ¹H NMR(400MHz,MeOD)δ7.35–7.33(m,1H),7.18–7.03(m,2H),6.55(s,1H),5.05(s,1H),4.31(s,1H),3.98–3.81(m,5H),3.58–3.31(m,8H),2.82–2.55(m,4H),2.40–2.06(m,2H),1.98–1.52(m,6H),1.24(s,3H),0.55–0.38(m,4H).

2- (2-Cyclopropoxy-5-fluorophenyl) -2- ((R) -3- (4- (4-methoxy-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 81)

Compound 81 LC/MS ESI 514(M + H) +.¹H NMR(500MHz,MeOD)δ7.41-7.39(m,1H),7.35-7.32(m,1H),7.17-7.13(m,1H),6.28(s,1H),4.81(s,1H),4.16(s,3H),3.91-3.90(m,1H),3.87(s,3H),3.50-3.36(m,3H),3.22-3.30(m,3H),3.18-3.14(m,2H),2.62-2.58(m,4H),2.17-2.10(m,2H),1.78-1.72(m,2H),1.66-1.62(m,2H),0.86-0.77(m,4H).

2- (2- (2, 2-dimethyltetrahydro-2H-pyran-4-yl) pyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereoisomeric compounds 82-E1 and 82-E2)

Compound 82-E1 LC/MS ESI 523.3(M + H)⁺。¹H NMR(500MHz,MeOD)δ8.52–8.47(m,1H),8.03-8.01(m,1H),7.31-7.24(m,2H),6.46(t,J＝6.8Hz,1H),4.81-4.76(m,1H),4.16(s,1H),3.88–3.72(m,3H),3.56–3.38(m,4H),3.31–2.99(m,4H),2.78–2.60(m,4H),2.11–1.62(m,12H),1.40-1.38(m,3H),1.26(s,3H).

Compound 82-E2 LC/MS ESI 523.3(M+H)+。¹H NMR(500MHz,MeOD)δ8.52–8.46(m,1H),8.08–8.02(m,1H),7.30-7.24(m,2H),6.46-6.44(m,1H),4.76-4.66(m,1H),4.14(s,1H),3.81-3.64(m,3H),3.54–3.37(m,4H),3.15-2.95(m,4H),2.78–2.59(m,4H),2.06–1.59(m,12H),1.39-1.36(m,3H),1.27-1.26(m,3H).

2- (5-fluoro-2- ((oxetan-3-yloxy) methyl) phenyl) -2- ((R) -3- ((S) -1-fluoro-5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetic acid (Compound 83)

Compound 83 LC/MS ESI 526(M + H)⁺ ¹H NMR(400MHz,MeOD)δ7.49-7.44(m,2H),7.15-7.11(m,2H),6.36-6.33(m,1H),4.85-4.82(m,1H),4.50-4.35(m,2H),4.10-3.39(m,8H),3.22-2.98(m,2H),2.71-2.68(m,2H),2.52-2.02(m,6H),1.90-1.86(m,2H),1.71-1.24(m,10H).

2- (2-Cyclopropylphenyl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyloxy) pyrrolidin-1-yl) acetic acid (Compound 84)

Compound 84 LC/MS ESI 464.2(M + H)⁺ ¹H NMR(500MHz,MeOD)δ7.70–7.57(m,2H),7.35–7.24(m,4H),7.21–7.10(m,4H),6.38(dd,J＝7.3,5.5Hz,2H),5.35(s,1H),5.21(s,1H),4.20(d,J＝23.0Hz,2H),3.66–3.35(m,10H),3.28–3.01(m,6H),2.75–2.63(m,4H),2.60–2.46(m,4H),2.30–2.01(m,6H),1.93–1.83(m,4H),1.74–1.53(m,8H),1.53–1.36(m,4H),1.08–0.92(m,6H),0.65–0.54(m,2H).

2- (4-Cyclopropylpyridin-3-yl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentoxy) pyrrolidin-1-yl) acetic acid (Compound 85)

Compound 85 LC/MS ESI 464.9(M + H)⁺。¹H NMR(500MHz,MeOD)δ8.74(d,J＝22.7Hz,1H),8.24(d,J＝5.3Hz,1H),7.14(m,1H),6.92(d,J＝4.6Hz,1H),6.35(m,1H),4.55(d,J＝47.6Hz,1H),4.05(d,J＝18.7Hz,1H),3.38(m,4H),2.84–2.37(m,8H),2.15–1.99(m,1H),1.84(s,3H),1.72–1.42(m,5H),1.37(d,J＝6.0Hz,2H),1.18–1.04(m,2H),1.01–0.89(m,1H),0.69–0.57(m,1H).

2- (2- (1, 1-difluoroethyl) phenyl) -2- ((R) -3- ((5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) oxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 86-E1 and 86-E2)

Compound 86-E1 LC/MS ESI 488.2(M + H)⁺ ¹H NMR(500MHz,MeOD)δ7.87(d,J＝7.7Hz,1H),7.67(d,J＝7.8Hz,1H),7.55(m,2H),7.16(d,J＝7.3Hz,1H),6.39(d,J＝7.3Hz,1H),5.09(s,1H),4.20(s,1H),3.62(s,1H),3.50–3.42(m,2H),3.38(m,2H),3.21(m,2H),3.03(s,1H),2.71(m,2H),2.61–2.50(m,2H),2.19(m,4H),2.04(s,1H),1.94–1.80(m,2H),1.76–1.53(m,4H),1.44(m,2H).

Compound 86-E2 LC/MS ESI 488.2(M + H)⁺ ¹H NMR(500MHz,MeOD)δ7.95(d,J＝7.6Hz,1H),7.66(d,J＝7.7Hz,1H),7.53(m,2H),7.24(d,J＝7.2Hz,1H),6.42(d,J＝7.3Hz,1H),4.17(s,1H),3.59(s,1H),3.49–3.42(m,2H),3.41–3.36(m,2H),3.09(d,J＝12.7Hz,3H),2.73(t,J＝6.2Hz,2H),2.58(m,2H),2.20(m,4H),2.06(s,1H),1.94–1.84(m,2H),1.80–1.63(m,2H),1.58(s,3H),1.50–1.36(m,2H).

2- (2-cyclopropyl-5-methylpyridin-3-yl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (Compound 87)

Compound 87: LC/MS ESI 465.2(M + H) +,¹H NMR(500MHz,MeOD)δ8.21(dd,J＝5.4,1.7Hz,1H),7.86(dd,J＝15.8,1.6Hz,1H),7.26–7.16(m,1H),6.40(d,J＝7.3Hz,1H),5.00(s,1H),4.93(s,1H),4.20–4.11(m,1H),3.47(m,2H),3.38(m,2H),3.33(m,1H),3.19–2.88(m,3H),2.72(t,J＝6.1Hz,2H),2.58(m,2H),2.54–2.40(m,1H),2.28(d,J＝5.5Hz,3H),2.20–2.01(m,2H),1.92–1.84(m,2H),1.75–1.66(m,2H),1.59(m,2H),1.20(m,1H),1.04–0.92(m,2H),0.91–0.82(m,1H).

2- (5-fluoro-2- (2-methoxyethoxy) phenyl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetic acid (Compound 88)

Compound 88 LC/MS a: 95% purity, UV 214nm, Rt 1.406 min, ESI 500.7(M + H) +.¹H NMR(500MHz,MeOD)δ7.32(td,J＝9.0,3.0Hz,1H),7.21-7.03(m,3H),6.36(dd,J＝7.3,4.1Hz,1H),4.98(s,1H),4.29-4.16(m,2H),3.81(t,J＝4.3Hz,2H),3.46(d,J＝2.2Hz,3H),3.41-3.37(m,2H),3.32(s,2H),3.16(d,J＝31.1Hz,2H),2.71(t,J＝6.2Hz,2H),2.51(td,J＝7.6,4.4Hz,2H),2.45-2.16(m,2H),1.98-1.84(m,2H),1.64(m,3H),1.40(m,6H).

2- (2- (2-methoxyethoxy) phenyl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyl) pyrrolidin-1-yl) acetic acid (Compound 89)

Compound 89: LC/MS ESI 482.2(M + H)⁺,¹H NMR(500MHz,MeOD)δ7.56(s,1H),7.51(d,J＝7.5Hz,1H),7.48–7.42(m,1H),7.18(dd,J＝8.2,4.6Hz,1H),7.12(t,J＝7.5Hz,1H),6.59(s,1H),5.43(s,1H),4.31–4.25(m,2H),4.19–3.96(m,1H),3.82–3.77(m,2H),3.48(m,6H),3.35–3.30(m,1H),3.23–2.92(m,2H),2.81(d,J＝5.3Hz,2H),2.74–2.62(m,2H),2.25(m,2H),1.99–1.90(m,2H),1.80–1.63(m,3H),1.57–1.29(m,6H).

2- (5-fluoro-2- (tetrahydrofuran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 90-E1 and 90-E2)

Compound 90-E1 (mixture of 2 isomers) LC/MS ESI 498.1(M + H)⁺。¹H NMR(500MHz,MeOD)¹H NMR(500MHz,MeOD)δ7.46(dd,J＝8.8,5.9Hz,1H),7.38–7.26(m,1H),7.12–6.97(m,2H),6.30(d,J＝7.3Hz,1H),5.13(m,1H),4.90(s,1H),4.07(d,J＝15.0Hz,1H),3.95(m,1H),3.83–3.70(m,1H),3.46–3.31(m,3H),3.27(m,2H),3.14–2.88(m,2H),2.61(t,J＝6.2Hz,2H),2.47(m,2H),2.33(m,1H),2.08–1.83(m,5H),1.77(m,2H),1.63(m,2H),1.55–1.45(m,2H).

Compound 90-E2 (mixture of 2 isomers) LC/MS ESI 498.1(M + H)⁺。¹H NMR(500MHz,MeOD¹H NMR(500MHz,MeOD)δ7.46–7.31(m,2H),7.00(dd,J＝30.9,7.6Hz,1H),6.87(d,J＝7.7Hz,1H),6.27(d,J＝7.3Hz,1H),5.22(m,1H),4.53(m,1H),4.29(m,1H),4.05–3.92(m,1H),3.77(d,J＝6.5Hz,1H),3.71–3.55(m,2H),3.32(m,5H),3.06(t,J＝9.7Hz,1H),2.63(m,5H),2.48–2.26(m,3H),1.93(m,2H),1.85–1.73(m,4H),1.52–1.48(m,2H).

2- (5-fluoro-2- (tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (4-methoxy-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 91-a-E1, 91-a-E2, 91-B-E1 and 91-B-E2)

Compound 91-A-E1 LC/MS A: 99% purity, UV 214nm, Rt 1.64 min, ESI 542.7(M + H) +.

¹H NMR(500MHz,MeOD)δ7.53(m,2H),7.09(d,J＝2.6Hz,1H),6.30(s,1H),4.87(s,1H),4.60(s,1H),4.12(s,1H),4.03(s,1H),3.87(s,3H),3.72(d,J＝2.5Hz,1H),3.55-3.40(m,2H),3.30(m,4H),3.07-2.95(m,2H),2.74-2.53(m,4H),2.18-2.09(m,1H),2.08-1.93(m,3H),1.74(m,10H).

Compound 91-B-E1 LC/MS A: 100% purity, UV 214nm, Rt 1.62 min, ESI 542.7(M + H) +.¹H NMR(500MHz,MeOD)δ7.52(m,2H),7.11(d,J＝2.7Hz,1H),6.30(s,1H),4.89–4.72(m,3H),4.16(d,J＝2.7Hz,1H),4.02(s,1H),3.87(s,3H),3.70(d,J＝2.2Hz,1H),3.48(m,3H),3.25(m,1H),3.13(d,J＝12.2Hz,1H),2.99–2.85(m,1H),2.60(m,4H),2.08–1.96(m,4H),1.88–1.60(m,11H).

Compound 91-B-E2 LC/MS A: 95% purity, UV 214nm, Rt 1.66 min, ESI 542.7(M + H) +.¹H NMR(500MHz,MeOD)δ7.47–7.41(m,2H),7.06(m,1H),6.33(s,1H),4.86(dd,J＝13.9,10.6Hz,3H),4.15–4.06(m,2H),3.73–3.64(m,1H),3.55–3.39(m,3H),3.29(m,2H),3.09–2.92(m,3H),2.71–2.56(m,4H),2.19–1.56(m,16H).

2- (2- (6, 6-dimethyltetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereoisomeric compounds 103-E1 and 103-E2)

Compound 103-E1 (mixture of 2 stereoisomers) LC/MS ESI 522(M + H) +. 1H NMR (500MHz, MeOD) Δ 7.72-7.70(m,1H),7.62-7.59(m,1H),7.45-7.35(m,2H),7.21-7.19(m,1H),6.38-6.35(m,1H),5.21-5.19(m,1H),4.92-4.90(m,1H),4.23-4.21(m,1H),3.81-3.61(m,1H),3.51-2.91(m,7H),2.62-2.59(m,2H),2.51-2.49(m,2H),2.18-1.48(m,14H),1.31-1.29(m,3H),1.23-1.21(m,3H).

Compound 103-E2 (mixture of 2 stereoisomers) LC/MS ESI 522(M + H) +. 1H NMR (500MHz, MeOD) δ 7.70-7.65(m,1H),7.35-7.32(m,3H),7.14(d, J ═ 7.2Hz,1H),6.37-6.35(m,1H),5.51-5.49(m,1H),4.98-4.92(m,1H),4.18-4.16(m,1H),3.51-3.31(m,4H),3.29-2.81(m,4H),2.72-2.68(m,2H),2.54-2.51(m,2H),2.18-1.48(m,14H),1.34-1.31(m,6H).

2- (2- (4, 4-dimethyltetrahydrofuran-2-yl) -5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 104-E1 and 104-E2)

Compound 104-E1 (mixture of 2 stereoisomers) LC/MS ESI 526(M + H) +.¹H NMR (400MHz, MeOD) δ 7.63-7.59(m,1H),7.48-7.45(dd, J ═ 2.8Hz, J ═ 10.4Hz 1H),7.18-7.14(m,2H),6.38(d, J ═ 7.1Hz, J1H),5.46-5.42(m,1H),4.82(m,1H),4.15-4.14(m,1H),3.75-3.73(m,1H),3.63-3.61(m,1H),3.49-3.32(m,5H),3.23-3.12(m,2H),2.75-2.71(m,2H),2.57-2.54(m,2H),2.37-2.33(m,1H),2.14(m,2H), 2.75-2.71(m,2H), chiral MeOH (m,1H), 1H, 5H, 1H, 8H, 1: ee 100%, Rt 3.86 min.

Compound 104-E2 (mixture of 2 stereoisomers) LC/MS ESI 526(M + H) +.¹H NMR (400MHz, MeOD) δ 7.61-7.58(m,1H),7.47-7.44(dd, J ═ 2.8Hz, J ═ 10.4Hz 1H),7.16-7.11(m,2H),6.38(d, J ═ 7.1Hz, J1H),5.46-5.42(m,1H),4.81(m,1H),4.16-4.15(m,1H),3.75-3.73(m,1H),3.63-3.61(m,1H),3.47-3.31(m,5H),3.22-3.11(m,2H),2.94(m,1H),2.72-2.69(m,1H),2.56-2.53(m,2H),2.35-2.31(m,1H), 2.65 (m,1H), 1H: ee 98%, Rt 4.89 min.

2- (4-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereoisomeric compounds 105-E1 and 105-E2)

Compound 105-E1 (mixture of 2 stereoisomers) LC/MS ESI 512.3(M + H) +.¹H NMR(400MHz,MeOD)δ7.80-7.70(m,1H),7.27-7.24(m,1H),7.13(d,J＝8.0Hz,1H),7.10-7.05(m,1H),6.38-6.36(m,1H),4.87-4.65(m,2H),4.16-4.03(m,2H),3.70-3.67(m,1H),3.49-3.36(m,5H),3.25-3.15(m,1H),3.10-2.85(m,2H),2.70(t,J＝6.4Hz,2H),2.54(t,J＝8.0Hz,2H),2.20-1.80(m,6H),1.78-1.55(m,8H).

Compound 105-E2 (mixture of 2 stereoisomers) LC/MS ESI 512.3(M + H) +.¹H NMR(400MHz,MeOD)δ7.75-7.60(m,1H),7.22-7.18(m,2H),7.17-7.00(m,1H),6.39-6.36(m,1H),5.25-4.94(m,1H),4.81-4.58(m,1H),4.20-4.05(m,2H),3.80-3.36(m,7H),3.25-2.95(m,2H),2.71(t,J＝6.4Hz,2H),2.56(t,J＝3.6Hz,2H),2.20-2.00(m,2H),1.99-1.80(m,5H),1.98-1.54(m,7H).

2- (2-fluoro-6- (tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereoisomeric compounds 106-E1 and 106-E2)

Compound 106-E1 (mixture of 2 stereoisomers) LC/MS ESI 512.3(M + H) +.¹H NMR(400MHz,MeOD)δ7.35-7.29(m,2H),7.13-7.05(m,2H),6.35(d,J＝8.0Hz,1H),5.18-5.12(m,1H),4.74(s,1H),4.70(s,1H),4.01(d,J＝12.0Hz,1H),3.78-3.61(m,1H),3.54-3.36(m,4H),3.24-2.82(m,3H),2.71-2.68(m,2H),2.53-2.48(m,2H),2.19-2.17(m,2H),2.03-2.00(m,1H),1.94-1.84(m,4H),1.72-1.52(m,8H).

Compound 106-E2 (mixture of 2 stereoisomers) LC/MS ESI 512.3(M + H) +.¹H NMR(400MHz,MeOD)δ7.35-7.29(m,2H),7.13-7.05(m,2H),6.35(d,J＝8.0Hz,1H),5.18-5.12(m,1H),4.72(s,1H),4.05-3.99(m,2H),3.78-3.61(m,1H),3.44-3.36(m,4H),3.24-2.82(m,2H),2.71-2.68(m,3H),2.53-2.48(m,2H),2.19-2.18(m,2H),2.03-2.00(m,1H),1.90-1.86(m,4H),1.69-1.54(m,8H).

2- (5-fluoro-2- (5-oxaspiro [2.4] heptan-6-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereoisomeric compounds 107-E1 and 107-E2)

Compound 107-E1 (mixture of 2 stereoisomers) LC/MS ESI 524(M + H) +.¹H NMR(500MHz,MeOD)δ8.30(bs,1H),7.58-754(m,1H),7.40-7.35(m,2H),7.11-7.06(m,1H),6.46(d, J ═ 7.2Hz,1H),5.43-5.40(m,1H),4.95(s,1H),4.13-4.11(m,1H),3.86-3.84(m,1H),3.66-3.64(m,1H),3.50-3.31(m,6H),3.31-3.20(m,2H),2.72-2.51(m,4H),2.18-2.03(m,4H),1.81-1.59(m,6H),0.60-0.48(m,4H), chiral SFC E (45% MeOH): ee 100%, Rt 4.74 min.

Compound 107-E2 (mixture of 2 stereoisomers) LC/MS ESI 524(M + H) +.¹H NMR (500MHz, MeOD) δ 8.53(bs,1H),7.70-7.67(m,1H),7.52-7.46(m,2H),7.24-7.20(m,1H),6.58(d, J ═ 7.2Hz,1H),5.49-5.45(m,1H),5.20(s,1H),4.23-4.21(m,1H),3.96-3.91(m,1H),3.75-3.71(m,1H),3.71-3.31(m,7H),3.31-3.20(m,1H),2.82-2.61(m,4H),2.18-2.03(m,4H),1.81-1.59(m,6H),0.70-0.58(m,4H), chiral E (SFC 45%) as: ee 100%, Rt 6.51 min.

2- (5-fluoro-2- (6-oxaspiro [2.5] octan-5-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereoisomeric compounds 108-E1 and 108-E2)

Compound 108-E1 (mixture of 2 stereoisomers) LC/MS ESI 538.2(M + H) +,¹h NMR (400MHz, MeOD) δ 7.55-7.40(m,1H),7.39-7.31(m,1H),7.15-7.01(m,2H),6.28(d, J ═ 7.2Hz,1H),4.84(s,1H),4.18-4.14(m,1H),4.00-3.85(m,1H),3.80-3.60(m,1H),3.58-3.43(m,1H),3.42-3.35(m,2H),3.33-3.23(m,3H),3.20-3.11(m,1H),2.95-2.90(m,1H),2.60(t, J ═ 6.4Hz,2H),2.45(t, J ═ 7.6, 2H), 2.95-2.85 (m,1H), 0.85-0.0.0 (m,1H), 0.83-1H, 0.70 (m,1H),0.39-0.20(m,3H). chiral SFC H (40% EtOH): ee 100%, Rt 2.10 min.

Compound 108-E2 (mixture of 2 stereoisomers) LC/MS ESI 538.2(M + H) +,¹H NMR(400MHz,MeOD)δ7.55-7.43(m,1H),7.41-7.30(m,1H),7.20-6.90(m,2H),6.40-6.20(m,1H),4.70(s,1H),4.20-4.05(m,1H),4.00-3.85(m,1H),3.80-3.60(m,1H),3.58-3.22(m,6H),3.20-2.90(m,2H),2.70-2.55(m,2H),2.50-2.38(m,2H),2.20-1.90(m,4H),1.83-1.73(m,2H),1.70-1.40(m,4H),1.25-1.15(m,2H), 0.80-0.60 (m,1H),0.50-0.40(m,1H),0.39-0.20(m,3H), chiral SFC H (40% EtOH): ee 100%, Rt 2.51 min.

2- (2- (1, 4-dioxan-2-yl) -5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 109-E1 and 109-E2)

Compound 109-E1 (mixture of 2 stereoisomers) LC/MS ESI 514(M + H) +.¹H NMR(400MHz,MeOD)δ7.61-7.59(m,1H),7.52-7.48(m,1H),7.22-7.20(m,1H),7.16-7.14(m,1H),6.42-6.40(m,1H),5.21-5.02(m,1H),4.78-4.75(m,1H),4.30-4.26(m,1H),4.20-4.17(m,1H),3.81-3.75(m,2H),3.73-3.68(m,2H),3.50-3.31(m,6H),3.20-2.98(m,3H),2.72-2.68(m,2H),2.54-2.51(m,2H),2.18-2.03(m,2H),1.81-1.59(m,6H).

Compound 109-E2 (mixture of 2 stereoisomers) LC/MS ESI 514(M + H) +.¹H NMR(400MHz,MeOD)δ7.51-7.49(m,2H),7.32-7.29(m,1H),7.22-7.18(m,1H),6.42-6.39(m,1H),5.30-4.96(m,2H),4.20-4.17(m,1H),3.91-3.70(m,6H),3.52-3.31(m,6H),3.20-2.98(m,3H),2.72-2.68(m,2H),2.54-2.51(m,2H),2.18-2.03(m,2H),1.81-1.56(m,6H).

2- (2- (4, 4-Difluorotetrahydrofuran-2-yl) -5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereoisomeric compounds 110-E1 and 110-E2)

Compound 110-E1 (mixture of 2 stereoisomers) LC/MS ESI 534.2(M + H) +,¹H NMR(400MHz,MeOD)δ7.80-7.60(m,1H),7.55-7.45(m,1H),7.35-7.15(m,2H),6.43(d,J＝7.2Hz,1H),5.75-5.60(m,1H),4.77(s,1H),4.30-4.05(m,2H),4.04-3.90(m,1H),3.60-3.50(m,1H),3.45-3.30(m,4H),3.25-2.95(m,4H),2.80-2.70(m,2H),2.65-2.30(m,3H),2.25-2.05(m,2H),1.95-1.85(m,2H)1.80-1.55(m,4H). chiral SFC F (30% MeOH): ee 100%, Rt 4.16 min.

Compound 110-E2 (mixture of 2 stereoisomers) LC/MS ESI 534.2(M + H) +,¹h NMR (400MHz, MeOD) delta 7.75-7.68(m,1H),7.65-7.40(m,1H),7.35-7.15(m,2H),6.50-6.40(m,1H),5.70-5.40(m,1H),4.78(s,1H),4.40-4.10(m,2H),4.05-3.80(m,1H),3.60-3.45(m,2H),3.42-3.38(m,3H),3.30-2.80(m,4H),2.78-2.70(m,2H),2.65-2.40(m,3H),2.20-2.00(m,2H),1.95-1.85(m,2H),1.80-1.55(m,4H), chiral SFC (30% MeOH): ee 100%, Rt 5.04 min.

2- (5-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((S) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereoisomeric compounds 111-E1 and 111-E2)

Compound 111-E1 LC/MS ESI 512.3(M + H) +,¹H NMR(500MHz,MeOD)δ7.62-7.58(m,1H),7.48-7.46(m,1H),7.22-7.15(m,2H),6.41(d,J＝7.0Hz,1H),4.85-4.79(m,2H),4.18(s,1H),4.05-4.02(m,1H),3.75–3.71(m,1H),3.56–3.31(m,6H),3.21-3.16(m,2H),2.74–2.57(m,4H),2.18–1.62(m,14H).

compound 111-E2 LC/MS ESI 512.3(M + H) +,¹H NMR(500MHz,MeOD)δ7.62-7.58(m,1H),7.48-7.46(m,1H),7.22-7.15(m,2H),6.62-6.60(m,1H),6.00(br,1H),4.65-4.61(m,1H),4.25-4.12(m,2H),3.55-3.31(m,8H),2.84–2.65(m,5H),2.18–1.62(m,14H).

2- (5-fluoro-2- (tetrahydrofuran-2-yl) phenyl) -2- ((R) -3- (4- (4-methoxy-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (THF stereoisomer a, diastereomer compounds 112-a-E1 and 112-a-E2)

Compound 112-A-E1 LC/MS ESI 528.2(M + H) +,¹H NMR(400MHz,MeOD)δ8.53(s,1H),7.60-7.58(m,1H),7.47-7.45(m,1H),7.19-7.15(m,1H),6.49(s,1H),5.20-5.09(m,2H),4.20(s,1H),4.10-4.05(m,1H),3.96(s,3H),3.90–3.81(m,1H),3.56–3.31(m,6H),3.16-3.10(m,1H),2.74–2.69(m,4H),2.40(s,1H),2.08–1.62(m,12H).

compound 112-A-E2 LC/MS ESI 528.2(M + H) +,¹H NMR(400MHz,MeOD)δ8.59(s,4H),7.50-7.40(m,2H,7.19-7.15(m,1H),6.49(s,1H),5.16-5.12(m,1H),4.20-4.10(m,2H),3.96(s,3H),3.90–3.81(m,1H),3.56–3.31(m,4H),3.19–3.01(m,4H),2.75–2.69(m,4H),2.40(s,1H),2.20(s,1H),2.09–1.98(m,4H),1.92–1.62(m,7H).

2- (5-fluoro-2- ((R) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((S) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereoisomeric compounds 113-E1 and 113-E2)

Compound 113-E1 LC/MS ESI 512.3(M + H) +.¹H NMR(400MHz,MeOD)δ8.45(s,1H),7.63-7.59(m,1H),7.46(d,J＝8.0Hz,2H),7.21-7.19(m,1H),6.55(d,J＝8.0Hz,1H),5.11(s,1H),4.74(d,J＝8.0Hz,1H),4.34(s,1H),4.06(d,J＝8.0Hz,1H),3.72-3.71(m,1H),3.58-3.33(m,6H),3.15(s,1H),2.81-2.67(m,4H),2.18(s,2H),2.03-1.58(m,13H).

Compound 113-E2 LC/MS ESI 512.3(M + H) +. 1H NMR (400MHz, MeOD) δ 8.45(s,1H),7.47-7.45(m,2H),7.21-7.19(m,1H),7.16-7.11(m,1H),6.43(d, J ═ 8.0Hz,1H),5.25(s,1H),4.89(d, J ═ 8.0Hz,1H),4.19(s,1H),4.10(d, J ═ 8.0Hz,1H),3.58-3.33(m,6H),3.15-3.12(m,2H),2.75-2.72(m,2H),2.63-2.59(m,2H),2.18-2.16(m,2H),2.03-1.58(m,13H).

2- (5-fluoro-2- (tetrahydrofuran-2-yl) phenyl) -2- ((R) -3- (4- (7-methyl-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (THF stereoisomer A, Me stereoisomer Compounds A and B, diastereomer Compounds 114-A-E1, 114-A-E2, 114-B-E1 and 114-B-E2)

Compound 114-A-E1 LC/MS ESI 512.3(M + H) +.¹H NMR(400MHz,MeOD)δ7.56-7.49(m,2H),7.18(d,J＝8.0Hz,1H)7.08-7.06(m,1H),6.41(d,J＝8.0Hz,1H),5.33-5.30(m,1H),4.95(s,2H),4.59(s,1H),4.16-4.05(m,2H),3.92–3.85(m,1H),3.59–3.40(m,3H),3.03-2.82(m,2H),2.75-2.72(m,3H),2.57-2.42(m,3H),2.07-2.01(m,3H),2.00–1.82(m,3H),1.75–1.65(m,2H),1.62–1.59(m,2H),1.57–1.55(m,1H),1.22(d,J＝10.8Hz,3H).

Compound 114-A-E2 LC/MS ESI 512.3(M + H) +.¹H NMR(400MHz,MeOD)δ7.51-7.41(m,2H),7.22(d,J＝8.0Hz,1H)7.11-7.08(m,1H),6.42(d,J＝8.0Hz,1H),5.23-5.21(m,1H),4.95(s,1H),4.79(s,1H),4.16-4.05(m,2H),3.92–3.85(m,1H),3.59–3.40(m,3H),3.13-3.03(m,3H),2.75-2.72(m,2H),2.64-2.58(m,2H),2.47-2.42(m,1H),2.07-1.82(m,6H),1.75–1.65(m,2H),1.62–1.59(m,2H),1.57–1.55(m,1H),1.22(d,J＝10.8Hz,3H).

Compound 114-B-E1 LC/MS ESI 512.3(M + H) +. 1H NMR (400MHz, MeOD) δ 7.56-7.49(m,2H),7.18(d, J ═ 8.0Hz,1H)7.08-7.06(m,1H),6.41(d, J ═ 8.0Hz,1H),5.33-5.30(m,1H),4.95(s,2H),4.59(s,1H),4.16-4.05(m,2H), 3.92-3.85 (m,1H), 3.59-3.40 (m,3H),3.03-2.82(m,2H),2.75-2.72(m,3H),2.57-2.42(m,3H),2.07-2.01(m,3H), 2.00-1.82 (m,3H), 1.75-1.65 (m,2H), 1.59-1.55H, 1H), 1.55H (m,1H), 1H).

Compound 114-B-E2 LC/MS ESI 512.3(M + H) +.¹H NMR(400MHz,MeOD)δ7.51-7.41(m,2H),7.22(d,J＝8.0Hz,1H)7.11-7.08(m,1H),6.42(d,J＝8.0Hz,1H),5.23-5.21(m,1H),4.95(s,1H),4.79(s,1H),4.16-4.05(m,2H),3.92–3.85(m,1H),3.59–3.40(m,3H),3.13-3.03(m,3H),2.75-2.72(m,2H),2.64-2.58(m,2H),2.47-2.42(m,1H),2.07-1.82(m,6H),1.75–1.65(m,2H),1.62–1.59(m,2H),1.57–1.55(m,1H),1.22(d,J＝10.8Hz,3H).

2- (2- (2, 2-difluoro-6-oxaspiro [3.5] nonan-7-yl) -5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 115-A-E1, 115-A-E2, 115-B-E1 and 115-B-E2)

Compounds 115-a-E1 LC/MS ESI 588.3(M + H) +,1H NMR (400MHz, MeOD) δ 7.60-7.55(M,1H),7.50-7.20(M,1H),7.20-7.05(M,2H),6.39(d, J ═ 7.2Hz,1H),4.88-4.80(M,1H),4.75(s,1H),4.25-4.15(M,1H),3.90-3.75(M,1H),3.70-3.60(M,1H),3.58-3.45(M,3H),3.42-3.38(M,2H),3.35-3.18(M,1H),3.17-3.05(M,1H),3.00-2.85(M,1H),2.80-2.70(M,2H), 2.35-3.18 (M,1H),3.17-3.05(M,1H),3.00-2.85(M, 2.80, 2.70-2H), 2.65 (M, 2.50-2H), 2.85(M, 2.50-2.50H), 7H) 1.83-1.55(m,5H).

Compounds 115-a-E2 LC/MS ESI 588.3(M + H) +,1H NMR (400MHz, MeOD) δ 7.60-7.40(M,2H),7.30-7.20(M,1H),7.18-7.05(M,1H),6.42(d, J ═ 7.2Hz,1H),5.04(s,1H),4.75(d, J ═ 10.4Hz,1H),4.20-4.10(M,1H),3.95-3.85(M,1H),3.75-3.60(M,1H),3.59-3.50(M,2H),3.48-3.38(M,3H),3.20-3.18(M,2H),2.80-2.70(M,2H),2.68-2.40(M,4H),2.38 (M,3H), 2.20-3.18 (M,2H),2.80-2.70(M,2H),2.68-2.40(M, 2H), 2.58-1H).

Compound 115-B-E1 LC/MS ESI 588(M + H) +. 1H NMR (400MHz, MeOD) δ 7.58-7.48(m,2H),7.19-7.14(m,2H),6.40(d, J ═ 7.2Hz,1H),4.91-4.77(m,2H),4.16-4.15(m,1H),3.82-3.80(m,1H),3.72-3.70(m,1H),3.50-3.31(m,6H),3.31-3.20(m,2H),2.72-2.41(m,6H),2.31-2.25(m,2H),2.20-1.60(m,12H).

Compound 115-B-E2 LC/MS ESI 588(M + H) +. 1H NMR (400MHz, MeOD) δ 7.46-7.43(m,2H),7.19-7.14(m,2H),6.39(d, J ═ 7.2Hz,1H),5.21-5.19(m,1H),4.71-4.69(m,1H),4.19-4.17(m,1H),3.87-3.84(m,1H),3.66-3.64(m,1H),3.40-3.31(m,4H),3.31-2.98(m,2H),2.76-2.50(m,6H),2.28-2.25(m,2H),2.20-1.60(m,14H).

2- (2- (5, 5-Difluorotetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 116-E1 and 116-E2)

Compound 116-E1 (mixture of 2 stereoisomers) LC/MS ESI 530.2(M + H) +,1H NMR (400MHz, MeOD) δ 7.70-7.55(M,1H),7.50-7.40(M,1H),7.38-7.20(M,2H),7.10-7.00(M,1H),6.26(d, J ═ 7.6Hz,1H),4.90(d, J ═ 10.8Hz,1H),4.72(s,1H),4.10-4.00(M,1H),3.98-3.85(M,1H),3.80-3.65(M,1H),3.60-3.25(M,5H),3.18-3.05(M,2H),2.65-2.55(M,2H),2.50-2.38(M,2H), chiral etf (13-13H), 13% sff): ee 100%, Rt 1.89 min.

Compound 116-E2 (mixture of 2 stereoisomers) LC/MS ESI 530.2(M + H) +,1H NMR (400MHz, MeOD) δ 7.70-7.55(M,1H),7.50-7.40(M,1H),7.38-7.20(M,2H),7.10-7.00(M,1H),6.26(d, J ═ 7.2Hz,1H),5.05-4.82(M,2H),4.10-4.00(M,1H),3.98-3.85(M,1H),3.80-3.65(M,1H),3.60-3.43(M,1H),3.42-3.35(M,2H),3.30-3.25(M,2H),3.18-3.08(M,1H),3.05-2.85(M, 2H), 3.44 (M,2H), 2H, 13.44 (M, 6H), 6H, 13H), 10-4.35 (M, 1H): ee 100%, Rt 4.45 min.

2- (5-fluoro-2- (tetrahydro-2H-pyran-4-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 117-E1 and 117-E2)

Compound 117-E1: (ESI 512.63(M + H) ⁺),¹H NMR(500MHz,MeOD)δ7.39–7.26(m,2H),7.10(d,J＝7.3Hz,1H),7.01(m,1H),6.31(d,J＝7.3Hz,1H),4.80(s,1H),4.09(s,1H),3.95–3.85(m,2H),3.49–3.33(m,5H),3.31–3.26(m,2H),3.20–3.13(m,2H),2.97–2.86(m,2H),2.62(t,J＝6.2Hz,2H),2.49(m,2H),2.03–1.93(m,2H),1.87–1.74(m,4H),1.59(m,6H).

Compound 117-E2: (ESI 512.63(M + H) +),¹H NMR(500MHz,MeOD)δ7.49–7.39(m,2H),7.22(d,J＝7.3Hz,1H),7.12(m,1H),6.42(d,J＝7.3Hz,1H),4.84(s,1H),4.17(d,J＝3.3Hz,1H),4.05–3.96(m,2H),3.66–3.49(m,3H),3.46–3.34(m,5H),3.26–3.12(m,3H),2.73(t,J＝6.2Hz,2H),2.61(m,2H),2.21–2.10(m,2H),1.96–1.85(m,4H),1.78–1.59(m,6H).

2- (5-fluoro-2- ((R) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyloxy) pyrrolidin-1-yl) acetic acid (diastereoisomeric compounds 118-E1 and 118-E2)

Compound 118-E1: (ESI 526.65(M + H)⁺),¹H NMR(500MHz,MeOD)δ7.57(m,1H),7.51(m,1H),7.19(d,J＝7.3Hz,1H),7.13(m,1H),6.39(d,J＝7.3Hz,1H),4.87–4.78(m,2H),4.17(d,J＝2.7Hz,1H),4.07(m,1H),3.74(m,1H),3.55(m,1H),3.45(m,2H),3.40–3.35(m,2H),3.24(m,1H),3.13(d,J＝12.5Hz,1H),3.01–2.93(m,1H),2.69(t,J＝6.2Hz,2H),2.56(t,J＝7.6Hz,2H),2.10–1.99(m,4H),1.92–1.83(m,2H),1.74(m,2H),1.64(m,6H),1.43(m,2H).

Compound 118-E2: (ESI 526.65(M + H)⁺),¹H NMR(500MHz,MeOD)δ7.51–7.41(m,2H),7.23(d,J＝7.3Hz,1H),7.08(m,1H),6.40(d,J＝7.3Hz,1H),4.89(s,2H),4.12(m,2H),3.70(t,J＝10.6Hz,1H),3.54–3.45(m,2H),3.44–3.36(m,3H),3.09(s,1H),3.00–2.88(m,2H),2.72(t,J＝6.2Hz,2H),2.66–2.51(m,2H),2.17(m,1H),2.03–1.93(m,2H),1.88(m,4H),1.74(t,J＝10.4Hz,3H),1.69–1.50(m,5H),1.48–1.35(m,1H).

2- (5-fluoro-2- (tetrahydrofuran-2-yl) phenyl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyloxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 119-A-E1, 119-A-E2, 119-B-E1 and 119-B-E2)

Compound 119-a-E1: (ESI 512.63(M + H)⁺),¹H NMR(500MHz,MeOD)δ7.55–7.41(m,2H),7.18(d,J＝7.3Hz,1H),7.10(m,1H),6.39(d,J＝7.3Hz,1H),5.22–5.16(m,1H),4.88(s,1H),4.15(m,2H),3.91(m,1H),3.53–3.42(m,3H),3.41–3.37(m,2H),3.25(d,J＝8.8Hz,1H),3.06(d,J＝12.2Hz,1H),3.00–2.94(m,1H),2.71(t,J＝6.2Hz,2H),2.56(t,J＝7.6Hz,2H),2.42(m,1H),2.16–1.98(m,5H),1.91–1.85(m,2H),1.70–1.59(m,4H),1.44(m,2H).

Compound 119-A-E2：(ESI 512.63(M+H)⁺),¹H NMR(500MHz,MeOD)δ7.55(m,2H),7.23(d,J＝7.3Hz,1H),7.12(m,1H),6.41(d,J＝7.3Hz,1H),5.37(t,J＝7.0Hz,1H),4.68(s,1H),4.12(m,2H),3.94(m,1H),3.51–3.36(m,5H),3.17(s,1H),3.06–2.94(m,2H),2.73(t,J＝6.2Hz,2H),2.57(m,3H),2.18(m,1H),2.12–2.01(m,3H),1.97–1.86(m,3H),1.78–1.55(m,5H),1.48–1.40(m,1H).

Compound 119-B-E1: (ESI 512.63(M + H)⁺),¹H NMR(500MHz,MeOD)δ7.58(m,1H),7.47(m,1H),7.22–7.09(m,2H),6.39(d,J＝7.3Hz,1H),5.25(t,J＝7.2Hz,1H),4.93(s,1H),4.18(d,J＝3.4Hz,1H),4.11(m,1H),3.94(m,1H),3.56–3.42(m,3H),3.41–3.36(m,2H),3.27–3.11(m,2H),3.07–2.97(m,1H),2.71(t,J＝6.2Hz,2H),2.56(t,J＝7.6Hz,2H),2.49(m,1H),2.14–2.02(m,4H),2.02–1.92(m,1H),1.91–1.83(m,2H),1.71–1.57(m,4H),1.49–1.38(m,2H).

Compound 119-B-E2: (ESI 512.63(M + H)⁺),¹H NMR(500MHz,MeOD)δ7.51(m,2H),7.25(d,J＝7.3Hz,1H),7.07(m,1H),6.41(d,J＝7.3Hz,1H),5.34(t,J＝7.5Hz,1H),4.58(s,1H),4.15(m,2H),3.92(m,1H),3.49(m,1H),3.45–3.35(m,4H),2.96(d,J＝7.2Hz,2H),2.89(m,1H),2.73(t,J＝6.2Hz,2H),2.66–2.52(m,2H),2.46(m,1H),2.10(m,3H),1.97(m,1H),1.90(m,3H),1.78–1.64(m,2H),1.63–1.51(m,3H),1.44(m,1H).

2- (5-fluoro-2- (tetrahydro-2H-pyran-4-yl) phenyl) -2- ((R) -3- (5- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) pentyloxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 120-E1 and 120-E2)

Compound 120-E1: (ESI 526.65(M + H)⁺),¹H NMR(500MHz,MeOD)δ7.44(m,2H),7.18(d,J＝7.3Hz,1H),7.10(m,1H),6.40(d,J＝7.3Hz,1H),4.81(s,1H),4.18(s,1H),4.09–4.00(m,2H),3.62(m,2H),3.47(t,J＝6.4Hz,2H),3.44–3.35(m,4H),3.11(d,J＝12.0Hz,1H),2.94(t,J＝7.8Hz,2H),2.71(t,J＝6.2Hz,2H),2.56(t,J＝7.6Hz,2H),2.12–2.00(m,2H),1.96–1.86(m,4H),1.80–1.60(m,6H),1.44(m,2H).

Compound 120-E2: (ESI 526.65(M + H)⁺),¹H NMR(500MHz,MeOD)δ7.51(d,J＝10.3Hz,1H),7.41(m,1H),7.26(d,J＝7.3Hz,1H),7.09(m,1H),6.42(d,J＝7.3Hz,1H),4.61(s,1H),4.14(s,1H),4.04(d,J＝7.5Hz,2H),3.65(m,2H),3.52(m,2H),3.45–3.37(m,4H),3.19(s,1H),3.02(s,1H),2.92(s,1H),2.73(t,J＝6.2Hz,2H),2.69–2.52(m,2H),2.16(m,1H),2.05(s,1H),1.94–1.86(m,4H),1.81–1.66(m,4H),1.57(d,J＝18.6Hz,3H),1.44(m,1H).

(2S) -2- (4-cyano-2- (tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereoisomeric compounds 121-E1 and 121-E2)

Compound 121-E1 (mixture of 2 stereoisomers) (ESI 519.2(M + H) ⁺),¹H NMR(500MHz,MeOD)δ7.89(dd,J＝12.0,8.2Hz,2H),7.76–7.58(m,1H),7.24(m,1H),6.43(d,J＝7.3Hz,1H),4.81(m,2H),4.16(m,1H),4.09(m,1H),3.77–3.67(m,1H),3.52–3.37(m,5H),3.30–2.88(m,3H),2.73(m,2H),2.68–2.53(m,2H),2.21–1.54(m,15H).

Compound 121-E2 (mixture of 2 stereoisomers) (ESI 519.2(M + H) +),¹H NMR(500MHz,MeOD)δ7.84(dd,J＝8.1,2.7Hz,1H),7.81(t,J＝1.9Hz,1H),7.64(m,1H),7.27(m,1H),6.43(t,J＝6.8Hz,1H),5.02(d,J＝58.4Hz,1H),4.86(m,1H),4.21–4.05(m,2H),3.67(m,1H),3.57–3.34(m,5H),3.30–2.84(m,3H),2.74(m,2H),2.62(m,2H),2.21–1.51(m,15H).

(S) -methyl 2- (3-fluoro-2- ((S) -tetrahydro-2H-pyran-2-yl) phenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetate (122-E1)

Compound 122-E1: LC/MS ESI 512.2(M + H) +.¹H NMR(400MHz,DMSO)δ8.18(s,1H),δ7.26-7.33(m,2H),δ7.03-7.10(m,2H),δ6.58(s,1H),δ6.25(d,J＝6Hz,1H),δ4.96(d,J＝14Hz,1H),δ4.53(s,1H),δ3.95-3.99(m,1H),δ3.91(d,J＝10.8Hz,1H),δ3.44(t,J＝11.2Hz,1H),δ3.30(t,J＝6.4Hz,2H),δ3.22(t,J＝6Hz,2H),δ2.95(dd,J＝6,12Hz,1H),δ2.69-2.80(m,2H),δ2.60(t,J＝6Hz,2H),δ2.53-2.55(m,1H),δ2.43(t,J＝5.6,2H),δ1.90-1.98(m,2H),δ1.47-1.82(m,12H).

2- (5-fluoro-2- (5-oxaspiro [2.5] octan-6-yl) phenyl) -2- ((R) -3- (4- (4-methoxy-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereoisomeric compounds 129-E1 and 129-E2)

Compound 129-E1: LC/MS ESI 568(M + H) +.¹H NMR (400MHz, MeOD) delta 7.63-7.48(m,2H),7.18-7.15(m,1H),6.30(s,1H),4.92-4.85(m,3H),4.77(s,1H),4.20-4.14(m,2H),3.87(s,3H), 3.50-3.32 (m,3H), 3.30-2.85 (m,4H), 2.62-2.55 (m,4H), 2.21-1.60 (m,12H),0.60-0.30(m,4H), chiral SFC C (20% EtOH): ee 100%, Rt 1.35 min.

Compound 129-E2: LC/MS ESI 568(M + H) +.¹H NMR (400MHz, MeOD) Δ 7.46-7.40(m,2H),6.95-6.92(m,1H),6.14(s,1H),4.85-4.80(m,3H),4.37(s,1H),4.02-3.96(m,2H),3.74(s,3H), 3.40-3.22 (m,2H), 2.98-2.65 (m,5H), 2.52-2.41 (m,4H), 2.20-1.40 (m,12H),0.44-0.20(m,4H), chiral SFC C (20% EtOH): ee 100%, Rt 2.02 min.

2- (2- (5, 5-dimethyl-1, 4-dioxan-2-yl) -5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (compound 125)

Compound 125 (mixture of 4 stereoisomers) LC/MS ESI 542(M + H) + +. 1H NMR (400MHz, MeOD) Δ 8.42(s,1H),7.76-7.69(m,1H),7.60-7.45(m,2H),7.29-7.19(m,1H),6.62-6.57(m,1H),5.18(s,1H),4.90-4.81(m,1H),4.28-4.24(m,1H),4.18-3.98(m,1H),3.81-3.38(m,10H),3.32-3.16(m,1H),2.82-2.61(m,4H),2.31-2.20(m,2H),1.98-1.55(m,6H),1.49-1.35(m,3H)),1.20-1.08(m,3H).

2- (2- (5, 5-Difluorotetrahydro-2H-pyran-2-yl) -5-fluorophenyl) -2- ((R) -3- (4- (4-methoxy-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 126-E1 and 126-E2)

Compound 126-E1 (mixture of 2 stereoisomers) LC/MS ESI 578(M + H) +,1H NMR (400MHz, MeOD) δ 7.60-7.49 (M,2H),7.10(t, J ═ 8.0Hz,1H),6.32(s,1H),5.04(d, J ═ 10.8Hz,1H),4.59(s,1H),4.12(s,1H),4.02-3.79(M,5H), 3.52-3.35 (M,4H), 3.30-2.75 (M,6H), 2.68-2.52 (M,4H), 2.35-1.55 (M,12H), chiral SFC a (35% IPA): ee 100%, Rt 4.39 min.

Compound 126-E2 (mixture of 2 stereoisomers) LC/MS ESI 578(M + H) +,1H NMR (400MHz, MeOD) δ 7.62-7.49 (M,2H), 7.12-7.06 (M,1H),6.36(s,1H), 5.12-5.04 (M,1H),4.50(s,1H),4.13(s,1H), 4.02-3.78 (M,5H), 3.57-3.35 (M,4H), 3.27-2.83 (M,6H), 2.79-2.52 (M,4H), 2.38-1.52 (M,12H), chiral SFC a (35% IPA): ee 100%, Rt 5.12 min.

2- (2- (5, 5-Dimethyltetrahydro-2H-pyran-2-yl) -5-fluorophenyl) -2- ((R) -3- (4- (5,6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereoisomeric compounds 127-E1, 127-E2 and 127-E3)

Compound 127-E1 LC/MS ESI 540(M + H) +. 1H NMR (400MHz, MeOD) δ 7.64-7.61(m,1H),7.49-7.47(m,1H),7.19-7.15(m,2H),6.41-6.39(m,1H),4.92-4.90(m,1H),4.72-4.70(m,1H),4.19-4.17(m,1H),3.52-3.32(m,8H),3.16-3.14(m,1H),3.02-3.01(m,1H),2.73-2.70(m,2H),2.59-2.56(m,2H),2.11-1.50(m,12H),1.20(s,3H),0.90(s,3H) chiral SFC H (45% IPA): ee 100%, Rt 2.35 min.

Compound 127-E2 LC/MS ESI 540(M + H) +. 1H NMR (400MHz, MeOD) delta 7.65-7.63(m,1H),7.52-7.49(m,1H),7.21-7.16(m,2H),6.41-6.39(m,1H),4.82-4.70(m,2H),4.17-4.16(m,1H),3.52-3.32(m,8H),3.20-3.16(m,2H),2.73-2.70(m,2H),2.59-2.56(m,2H),2.24-2.08(m,2H),2.01-1.55(m,10H),1.20(s,3H),0.90(s,3H), chiral SFC H (45% IPA): ee 100%, Rt 3.66 min.

Compound 127-E3 (mixture of 2 stereoisomers) LC/MS ESI 540(M + H) +. 1H NMR (400MHz, MeOD). delta.7.66-7.62 (m,1H),7.51-7.49(m,1H),7.41-7.17(m,2H),6.48-6.46(m,1H),4.92-4.90(m,1H),4.72-4.70(m,1H),4.19-4.17(m,1H),3.52-3.32(m,8H),3.16-3.10(m,2H),2.73-2.70(m,2H),2.59-2.56(m,2H),2.11-1.50(m,12H),1.20-1.18(m,3H),0.90-0.84(m,3H).

2- (2- (5, 5-dimethyltetrahydro-2H-pyran-2-yl) -5-fluorophenyl) -2- ((R) -3- (4- (4-methoxy-5, 6,7, 8-tetrahydro-1, 8-naphthyridin-2-yl) butoxy) pyrrolidin-1-yl) acetic acid (diastereomer compounds 128-E1, 128-E2 and 128-E3)

Compound 128-E1 (mixture of 2 stereoisomers) LC/MS ESI 570(M + H) +,1H NMR (400MHz, MeOD) δ 7.65-7.58 (M,1H), 7.53-7.46 (M,1H), 7.15-7.11 (M,1H), 6.32-6.30 (M,1H), 4.83-4.64 (M,2H), 4.20-4.12 (M,1H), 3.88-3.85 (M,3H), 3.58-3.35 (M,6H), 3.32-2.91 (M,4H), 2.75-2.54 (M,4H), 2.20-1.55 (M,12H),1.12(s,3H),0.87(d, J ═ 4.8Hz,3H).

Compound 128-E2 LC/MS ESI 570(M + H) +,1H NMR (400MHz, MeOD) δ 7.47-7.44 (M,2H), 7.12-7.08 (M,1H),6.30(s,1H),5.18(s,1H),4.65(d, J ═ 8.0Hz,1H),4.13(s,1H),3.87(s,3H), 3.61-3.36 (M,7H), 3.28-2.94 (M,3H), 2.69-2.56 (M,4H), 2.19-1.53 (M,12H),1.16(s,3H),0.87(s,3H).

Compound 128-E3 LC/MS ESI 570(M + H) +,1H NMR (400MHz, MeOD) δ 7.51-7.40 (M,2H), 7.09-7.05 (M,1H),6.35(s,1H),4.79(d, J ═ 8.0Hz,1H),4.13(s,1H),3.90(s,3H), 3.62-3.38 (M,5H), 3.31-3.20 (M,2H), 3.02-2.52 (M,8H), 2.21-1.52 (M,12H),1.15(s,3H),0.87(s,3H).

Example 35: fluorescence polarization assay for α v β 6 binding of compounds

The Fluorescence Polarization (FP) assay was used to measure compound activity by binding competition with the fluorescein-labeled peptide GRGDLGRL. In the assay, 10nM integrin α v β 6 was incubated with 2mM manganese chloride, 0.1mM calcium chloride, 20mM HEPES buffer pH 7.3, 150mM sodium chloride, 0.01% Triton X-100, 2% DMSO and 3nM fluorescein labeled peptide containing the test compound. The assay was run in 384-well plates. For both assay versions, the integrin was preincubated with test compound for 15 minutes at 22 ℃ before addition of the fluorescein-labeled peptide. After addition of the fluorescein-labeled peptide, the assay was incubated at 22 ℃ for 1 hour, and the degree of fluorescence polarization was measured. Determination of IC by non-Linear regression (4-parameter Curve fitting)₅₀Values (fig. 1 and 2).

Example 36: MDCK permeability assay

Compounds were tested for permeability in the MDCK permeability assay. This assay measures the ability of a compound to cross the martin-dabigatran dog kidney (MDCK) cell layer from the apical to basolateral side (a- > B). This measurement predicts the ability of a compound to be absorbed in the gut following oral administration, which is an essential feature of orally administered small molecule integrin inhibitor drugs.

The assay was run in two formats. One format uses wild-type MDCK cells without inhibitors. This method is well suited for determining the passive permeability of low efflux compounds by P-glycoprotein (Pgp) and for evaluating the permeability of reference compounds having the formula shown below. The MDCK value of the reference compound obtained using this method is less than 1 (i.e., less than about 0.23); the IC50 value for the reference compound obtained using the fluorescence polarization assay of example 35 was about 96.5 nM.

Reference compound

avb6.(IC50)[nM]	MDCK(A->B)
		96.5	<0.23

However, for compounds with Pgp efflux, Pgp inhibitors must be included in order to determine the passive permeability of a- > B transmission. In this case, a MDCK-MDR1 cell line overexpressing Pgp was used and included Pgp inhibitor GF120918 at a sufficient concentration (10 μ M) to block Pgp activity. This procedure (MDCK-MDR 1(A- > B) [10^6 cm/sec ] with PGP inhibitor) was used to obtain the data presented in the tables shown in FIGS. 3 and 4. MDCK permeability values less than 510 ^6 cm/sec predict low absorption in the intestinal tract, while permeability values greater than 510 ^6 cm/sec predict adequate absorption in the intestinal tract of orally administered small molecule drugs.

The detailed experimental procedure is as follows:

Cell culture and maintenance:

maintenance of cell stock cultures (MDCK or MDCK MDR1) in MEM + 10% FBS + 1% NEAA, over 75cm²Tissue culture treated flasks were grown and split (passaged) 2 times per week to maintain the desired confluence.

For maintenance passages: trypsinized cells are typically distributed into new flasks at a standard passage ratio of 1: 20.

Inoculation assay plate: MDCK assay plates were treated with MDCK or MD 3-4 days before running the assayCK MCR1 cells. Mixing 24-well plate at 0.88 × 10⁵Cell density per well seeded at 400. mu.L apical chamber volume (2.2X 10)⁵/mL), and a volume of 25mL of growth medium is injected into the 24-well basal chamber. The assay plates are typically provided with growth medium changes 24 hours prior to the assay.

Preparation of assay plates and transepithelial electrical resistance (TEER) measurements: before running the assay, MDCK assay plates were rinsed with HBSS +. After rinsing, fresh HBSS + was added to the assay plate at 400 μ L apical volume and 0.8mL HBSS + basal volume. The resistance across the monolayer was measured using a Millicell ERS system ohmmeter. (if TEER is higher than 100ohm x cm²Cells will be used).

Preparation of dosing solutions. Donor solutions were prepared in HBSS + with 0.4% DMSO and 5 μ M test compound. The donor solution contained 5 μ M fluorescein for apical administration, but no fluorescein for basolateral administration. The donor solution may also contain 10 μ M GF120918 for Pgp inhibition. The receptor solution was prepared with HBSS + with 0.4% DMSO. The donor and acceptor solutions were centrifuged at 4000rpm for 5 minutes and the supernatant was used for compound administration.

Preparation of cell plate:

remove buffer from top and base outer sides. Based on the plate map, 600 μ L of donor solution (A to B) or 500 μ L of acceptor solution (B to A) were added to the apical pore.

Fresh basolateral plates were prepared by adding 800 μ L of the receptor solution (a to B) or 900 μ L of the donor solution (B to a) to the wells of a new 24-well plate.

Put the top and base outer panels to 37 ℃ CO₂In an incubator.

Preparation of assay plates:

after 5 minutes, 100. mu.L of sample was transferred from all donors (A to B and B to A) to the appropriate wells of the sample plate for D0. And 100. mu.L of sample was transferred from all apical chambers (donor of A to B and acceptor of B to A) to the appropriate wells of the microplate for fluorescein D0(D0 LY).

Place the top plate on the substrate outer side plate to start the transfer process.

At 90 minutes, the top and bottom outer panels were separated and 100 μ Ι _ of sample was transferred from all donors (a to B and B to a) into the appropriate wells of the new sample plate for D90 and 200 μ Ι _ of sample all acceptors into the appropriate wells of the sample plate for R90. 100 μ L of sample was transferred from all substrate outer compartments (acceptor A to B and donor B to A) to the appropriate wells of a new microplate for fluorescein R90(R90 LY).

The LY permeability was determined by reading D0 LY and R90LY at an excitation wavelength of 485nm and an emission wavelength of 535nm using a fluorescence plate reader.

LC/MS/MS sample preparation:

for the receptor solution: 60 μ L of sample +60 μ L of IS-containing ACN (200ng/mL salsolinol)

For the donor solution: 6 μ L of sample +54 μ L of 0.4% DMSO/HBSS +60 μ L of IS-containing ACN (200ng/mL salsolinol)

Standard curve 20X solutions of compounds (range 0.1-60. mu.M) in MeOH H₂Prepared in O (1: 1). 1 Xconcentrated solutions (range 0.005-3. mu.M) were prepared by mixing 3. mu.L of 20 Xsolution with 57. mu.L of 0.4% DMSO HBSS and 60. mu.L of IS-containing ACN (200ng/mL salbutamol).

Computing

Transepithelial electrical resistance (TEER) — (electrical resistance)_{Sample (I)}Resistance of_{Blank space}) X effective membrane area

Permeability of fluorescent yellow:

P_app＝(V_A/(area × time)) × ([ RFU)]_{A recipient}-[RFU]_{Blank space})/(([RFU]_{Initial, donor}-[RFU]_{Blank space}) X dilution factor) x 100

Plate drug transport assays were performed using the following equation:

transepithelial electrical resistance (TEER) — (electrical resistance)_{Sample (I)}Resistance of_{Blank space}) X effective membrane area

Drug permeability:

P_app＝(V_R/(area × time)) × ([ drug ]]_Receptors/([ drug)]_{Initial, donor}) X dilution factor)

Wherein V_RIs the volume in the receptor well (0.8 mL for A to B and 0.4mL for B to A), the area being the surface area of the membrane (0.7 cm for a Millipop-24 cell culture plate) ²) And time is the total transit time in seconds.

Percent recovery of 100 × (total compounds in donor at 90 min x dilution factor + total compounds in acceptor at 90 min)/(total compounds in donor at 0 min x dilution factor)

Is incorporated by reference

All U.S. patents and U.S. patent applications cited herein are hereby incorporated by reference.

Equivalent forms

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

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Inhibition of alpha v beta 6 integrins

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