阅读说明：本技术 非天然氨基酸类衍生物、包含其的药物组合物及其制备方法和用途 (Non-natural amino acid derivative, pharmaceutical composition containing same, and preparation method and application thereof ) 是由 田强 宋帅 赵明亮 王太津 孙启正 蔡家强 王利春 王晶翼 于 2019-04-16 设计创作，主要内容包括：<Image he="416" wi="539" file="DDA0002652598410000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>一种式(I)的非天然氨基酸类衍生物、包含其的药物组合物、其制备方法及其作为精氨酸酶抑制剂的用途。更具体地,涉及一种非天然氨基酸类衍生物,其能够抑制精氨酸的水解,从而可用于预防或治疗与精氨酸酶活性有关的疾病或病况。(A non-natural amino acid derivative of formula (I), pharmaceutical compositions comprising the same, methods of making the same, and uses thereof as an arginase inhibitor. More particularly, it relates to a non-natural amino acid derivative which is capable of inhibiting the hydrolysis of arginine and is thus useful for the prevention or treatment of diseases or conditions associated with arginase activity.)

A compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof, wherein the compound has the structure of formula (I):

wherein:

R¹is selected from-OR^aand-NR^bR^c；

R²Selected from hydrogen, C_1-6Alkyl, saturated or partially unsaturated C_3-10Cycloalkyl, -OR^a、-NR^bR^c、-C(＝O)-R^a、-S(＝O)₂-R^a、-C(＝NR^a)NR^bR^c、-C(＝O)NR^bR^cand-C (═ O) CH (NH)₂)R^a；

R³And R⁴Each independently selected from hydrogen and C_1-6Alkyl, saturated or partially unsaturated C_3-10Cycloalkyl, saturated or partially unsaturated 3-to 10-membered heterocyclyl, C_6-10Aryl, 5-14 membered heteroaryl, C_6-12Aralkyl and-C (═ O) -R^a(ii) a Or R³And R⁴Together with the group to which they are attached form a 5-8 membered ring (e.g.Or)；

D is selected from C_2-6Alkylene radical, -CH₂-C_3-10Cycloalkylene, -CH₂- (3-to 10-membered heterocyclylene), -CH₂-C_6-10Arylene radical, C_2-6Alkenylene radical, C_2-6Alkynylene, saturated or partially unsaturated C_3-10Cycloalkylene, saturated or partially unsaturated 3-to 10-membered heterocyclylene, C_6-10Arylene and 5-14 membered heteroarylene, and when D is C_2-6Alkylene radical, C_2-6Alkenylene or C_2-6When alkynylene, the hydrocarbon chain of the group is optionally interrupted by one or more groups selected from: -NR' "-, -O-, -S (═ O)_p-, saturated or partially unsaturated C_3-10Cycloalkylene, saturated or partially unsaturated 3-to 10-membered heterocyclylene, C_6-10Arylene and 5-14 membered heteroarylene;

x, Y and Z are each independently selected from-C (R ') (R ') -, -C (═ O) -, -C (═ S) -, -N (R ') -, -O-and-S (═ O)_p-；

R 'and R' are each independently selected from hydrogen, halogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, saturated or partially unsaturated C_3-10Cycloalkyl, saturated or partially unsaturated 3-to 10-membered heterocyclyl, C_6-10Aryl, 5-14 membered heteroaryl, C_6-12Aralkyl, -OR^a、-NR^bR^c、-O-C(＝O)-C_1-6Alkyl, -C_1-6alkylene-NR^bR^cand-C_1-6alkylene-CO₂-C_1-6An alkyl group;

r' "is selected from hydrogen and C_1-6Alkyl, saturated or partially unsaturated C_3-10Cycloalkyl, saturated or partially unsaturated 3-to 10-membered heterocyclyl, C_6-10Aryl, 5-14 membered heteroaryl, C_6-12Aralkyl, -OR^a、-C(＝O)-R^a、-S(＝O)₂-R^a、-C_1-6alkylene-CO₂-C_1-6Alkyl, -C (═ O) OC_1-6Alkyl and-C (═ O) NHC_1-6An alkyl group;

R^aselected from hydrogen, C_1-6Alkyl, saturated or partially unsaturated C_3-10Cycloalkyl, saturated or partially unsaturated 3-to 10-membered heterocyclyl, C_6-10Aryl, 5-14 membered heteroaryl, C_6-12Aralkyl, -C (═ O) C_1-6Alkyl, -C (═ O) OC_1-6Alkyl, -C (═ O) NHC_1-6Alkyl and-C_1-6alkylene-CO₂-C_1-6An alkyl group;

R^band R^cEach independently selected from hydrogen and C_1-6Alkyl, saturated or partially unsaturated C_3-10Cycloalkyl, saturated or partially unsaturated 3-to 10-membered heterocyclyl, C_6-10Aryl, 5-14 membered heteroaryl, C_6-12Aralkyl, -OR^a、-S(＝O)₂-R^a、-C_1-6alkylene-CO₂-C_1-6Alkyl, -C (═ O) C_1-6Alkyl, -C (═ O) OC_1-6Alkyl and-C (═ O) NHC_1-6An alkyl group;

k. m, n and p are each independently 0, 1 or 2, provided that k, m and n are not simultaneously 0; and is

The above-mentioned alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, heterocyclic, aromatic hydrocarbonEach of the group, arylene, heteroaryl, heteroarylene, and aralkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: halogen, hydroxy, oxo, cyano, -NH₂Nitro, mercapto, -CO₂H、-CO₂C_1-6Alkyl radical, C_1-6Alkyl, halo C_1-6Alkyl, -O-C_1-6Alkyl, -O-halo C_1-6Alkyl radical, C_3-6Cycloalkyl, halo C_3-6Cycloalkyl, -NH-C_1-6Alkyl, -N- (C)_1-6Alkyl radical)₂、-C_1-6alkylene-OH, -C_1-6alkylene-CN, -C_1-6alkylene-O-C_1-6Alkyl, -C_1-6alkylene-CO₂-C_1-6Alkyl, 3-to 10-membered heterocyclic group, C_6-10Aryl, 5-14 membered heteroaryl and C_6-12An aralkyl group.

The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof, wherein R is^aSelected from hydrogen, C_1-6Alkyl (preferably methyl) and-CH (NH)₂)CH₃。

The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof, wherein R is^bAnd R^cEach independently selected from hydrogen and C_1-6Alkyl (preferably methyl), -C (═ O) -CH (NH)₂)CH₃and-CH (CH)₃)-CO₂-CH₃。

A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labelled compound, metabolite or prodrug thereof, wherein R¹is-OH.

A compound according to any one of claims 1 to 4 orA pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labelled compound, metabolite or prodrug thereof, wherein R is²Selected from hydrogen and C_1-6Alkyl, preferably, R²Selected from hydrogen and methyl.

The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein R³And R⁴Are all hydrogen.

The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein- (X)_k-(Y)_m-(Z)_nThe group-is selected from-CH₂-CR’R”-CH₂-、-CH₂-CH₂-CR’R”-CH₂-、-CH₂-CR’R”-CH₂-CH₂-、-CH₂-CH₂-NR”’-CH₂-and-CH₂-NR”’-CH₂-CH₂-。

The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein R' and R "are each independently selected from the group consisting of hydrogen, -NH₂、-NHCH₃、-N(CH₃)₂、-CH₂NH₂、-CH₂NHCH₃、-CH₂N(CH₃)₂、-OH、-OCH₃、

The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein R' and R "are each independently selected from the group consisting of hydrogen, -NH₂、-NHCH₃、-N(CH₃)₂、-CH₂NH₂、-CH₂NHCH₃、-CH₂N(CH₃)₂、-OH、-OCH₃、

The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein R '"is selected from hydrogen, a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein R'" is selected from the group consisting of,

The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein R '"is selected from hydrogen, a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein R'" is selected from the group consisting of,

The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein D is C_2-6Alkylene, preferably butylene.

The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of formula (II):

preferably, the compound has the structure of any of the following formulae:

wherein q is 2, 3, 4, 5 or 6, preferably q is 4.

The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein the compound is selected from the group consisting of:

a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1-14, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and a pharmaceutically acceptable carrier, preferably in a solid, semi-solid, liquid or gaseous formulation.

Use of a compound of any one of claims 1-14, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of claim 15, in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with arginase activity.

The use of claim 16, wherein the disease or condition is selected from cardiovascular disorders, sexual dysfunction, wound healing disorders, gastrointestinal disorders, autoimmune disorders, immune disorders, infections, lung disorders, liver disorders, inflammation, hemolytic disorders, and cancer, preferably gastric, colon, breast and lung cancer (including non-small cell lung cancer), renal cell carcinoma, prostate cancer, multiple myeloma, acute myelogenous leukemia, neuroblastoma, glioblastoma or melanoma.

A process for preparing a compound of formula (II) as described in claim 13, comprising the steps of:

wherein:

hal is halogen, preferably chlorine, bromine or iodine;

q' is an integer of q-2;

when R is^aWhen it is hydrogen, R^a’Is a carboxyl protecting group, preferably C_1-6Alkyl groups such as methyl; and when R is^aWhen not hydrogen, R^a’And R^aThe same;

when R is²When it is hydrogen, R^2’Is an amino protecting group such as tert-butyloxycarbonyl (Boc) or benzyloxycarbonyl (Cbz); and when R is²When not hydrogen, R^2’And R²The same;

when R is³Or R⁴When it is hydrogen, R^3’Or R^4’Each independently is C_1-6Alkyl, or R^3’And R^4’Together with the group to which they are attached form a 5-8 membered ring (e.g.Or

The remaining groups are as defined in claim 13;

the reaction conditions for each step were as follows:

the method comprises the following steps: reacting compound (II) -a with compound Reg-1 in the presence of a base to prepare compound (II) -b;

step two: reacting compound (II) -b with compound Reg-2 in the presence of a catalyst/promoter, optionally with the addition of a phosphine ligand to produce compound (II) -c; and

step three: reacting the compounds (II) -c in the presence of an acid or a base to prepare the compound of formula (II), with the proviso that when R is^a’And R^aSame as R^2’And R²Are identical and R^3’And R^4’Are each independently of R³And R⁴If so, step three is absent.