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CN110156656B - Five-membered heteroaromatic ring derivative, preparation method thereof, pharmaceutical composition and application - Google Patents

Five-membered heteroaromatic ring derivative, preparation method thereof, pharmaceutical composition and application Download PDF

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CN110156656B
CN110156656B CN201910062130.0A CN201910062130A CN110156656B CN 110156656 B CN110156656 B CN 110156656B CN 201910062130 A CN201910062130 A CN 201910062130A CN 110156656 B CN110156656 B CN 110156656B
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CN110156656A (en
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高大新
杨伟
李国成
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Shanghai de Novo Pharmatech Co Ltd
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Abstract

The invention discloses a five-membered heteroaromatic ring derivative, a preparation method, a pharmaceutical composition and application thereof. The five-membered heteroaromatic ring derivative (I), an isomer, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof has the following structure. The five-membered heteroaromatic ring derivative has good IDO inhibition effect, and can effectively treat, relieve and/or prevent various related diseases caused by immunosuppression, such as tumors, virus infection or autoimmune diseases.

Description

Five-membered heteroaromatic ring derivative, preparation method thereof, pharmaceutical composition and application
Technical Field
The invention relates to a five-membered heteroaromatic ring derivative, a preparation method, a pharmaceutical composition and application thereof.
Background
Indoleamine 2,3-dioxygenase (IDO), an immunomodulatory enzyme produced by a number of alternatively activated macrophages and other immunoregulatory cells (also used by many tumors as a strategy to destroy immunity), is encoded by the IDO gene in humans. Its function is to break down the essential L-tryptophan to kynurenine (kynurenine). Depletion of tryptophan and its metabolites results in strong suppression of the immune response, resulting in the cessation of T cell growth, blocking T cell activation, inducing T cell apoptosis and increasing the production of regulatory T cells. The pathway from tryptophan to kynurenine metabolism is now established as a key regulatory pathway for innate and adaptive immunity.
Numerous preclinical studies have shown that this immune tolerance pathway is active in tumor immunity, autoimmunity, infection, transplant rejection, and allergy. The increased activity of IDO in cancer cells is now recognized as an important factor in cancer proliferation and metastasis. Studies have shown that IDO inactivates tumor-specific cytotoxic T lymphocyte functions or is no longer able to attack cancer cells of patients, and in fact, many human cancers, such as prostate, colorectal, pancreatic, cervical, gastric, ovarian, brain, lung, etc., overexpress human IDO. The inhibition of IDO can reverse the inhibition of tumor to human immune function, thereby generating an effective anti-tumor immune response. Since IDO inhibitors can activate T cells and thereby enhance immune function in humans, IDO inhibitors have therapeutic effects on a number of diseases, including tumor resistance and rejection, chronic infections, HIV infection and aids, autoimmune diseases or disorders, such as rheumatoid arthritis, immune tolerance and prevention of intrauterine fetal rejection. Inhibitors of IDO may also be useful in the treatment of neurological or neuropsychiatric diseases or disorders, such as depression (Protula et al, 2005, blood, 106.
A large number of preclinical and clinical studies have shown that IDO inhibition can enhance the immune competence of the body and significantly improve the antitumor efficacy of various chemotherapeutic drugs and the efficacy against diseases caused by other immunosuppressions (c.j.d.austin and l.m.rendina, drug Discovery Today 2014,1-9). IDO-/-mouse gene knockouts are feasible and mice are healthy, meaning that IDO inhibition may not cause serious mechanism-of-action toxicity.
Small molecule inhibitors of IDO currently under development to treat and prevent the above diseases associated with IDO, for example, PCT patent application WO99/29310 discloses methods of altering T cell mediated immunity, including altering extracellular concentrations of local tryptophan and tryptophan metabolites by administering an amount of 1-methyl DL tryptophan or p- (3 benzofuranyl) -DL-alanine (Munn, 1999). WO2004/0234623 discloses compounds capable of inhibiting indoleamine 2,3-dioxygenase (IDO) activity; U.S. patent application 2004/0234623 discloses a method of treating patients with cancer or infections by administering an IDO inhibitor in combination with other treatment modalities.
In view of the large number of experimental data showing that IDO inhibitors have a good therapeutic and prophylactic effect on immunosuppression, tumor suppression, chronic infections, viral infections including HIV infection, autoimmune diseases or disorders and intra-uterine fetal rejection, etc., it is desirable to use a therapeutic approach that inhibits tryptophan degradation by inhibiting IDO activity. When T cells are inhibited by a virus such as a malignant tumor or HIV, IDO inhibitors can be used to enhance the activity of T cells. Furthermore, IDO chemistry has been studied more clearly and its x-ray crystal structure is also resolved, which helps to better exploit structure-based drug design and structural optimization of drugs. IDO is currently an attractive target for therapeutic intervention.
Disclosure of Invention
The invention aims to solve the technical problem of providing a novel five-membered heteroaromatic ring derivative, a preparation method, a pharmaceutical composition and application thereof. The five-membered heteroaromatic ring derivative has good IDO inhibition effect, and can effectively treat, relieve and/or prevent various related diseases caused by immunosuppression, such as tumors, infectious diseases, autoimmune diseases and the like.
Although the activity of the compounds of formula (I) disclosed in the present invention is shown by the inhibition of IDO, the mechanism of inhibiting IDO activity is not well studied and the possibility of inhibiting TDO (tryptophan 2,3-dioxygenase) activity is not excluded. Thus, all references to "IDO inhibitors" in the present invention can include the following meanings: IDO inhibitors, TDO inhibitors, or dual IDO and TDO inhibitors.
The invention provides a five-membered heteroaromatic ring derivative (I), an isomer, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof;
Figure BDA0001954485700000021
wherein the ring A is pyrrole ring, and X, Y, Z is selected from the following combinations:
1) X is NR 1 Y is CR 2 And Z is CR 3
2) X is CR 2 Y is NR 1 And Z is CR 3
3) X is CR 3 Y is CR 2 And Z is NR 1 (ii) a Or
4) X is CR 3 Y is NR 1 And Z is CR 2
Alternatively, the a ring is an imidazole ring, and X, Y, Z is selected from the group consisting of:
5) X is NR 1 Y is CR 2 And Z is N; or
6) X is N, Y is CR 2 And Z is NR 1
L is CH 2 、CH(CH 3 )、C(CH 3 ) 2 Or CH 2 CH 2
U and V are each independently selected from N or CR 4
Cy is a benzene ring or a 5-10 membered heteroaromatic ring, said Cy is unsubstituted or further substituted by 1 to 4 groups selected from halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halo C 1-6 Alkyl, halo C 1-6 Alkoxy radical, C 2-6 Alkynyl, C 2-6 Alkenyl radical, C 3-6 Cycloalkyl, -OH, -SH, -CN, -NO 2 、-OC(O)R a 、-OC(O)OR b 、-OC(O)N(R b ) 2 、-C(O)OR b 、-C(O)R a 、-C(O)N(R b ) 2 、-NR b C(O)R a 、-N(R b ) 2 、-NR b C(O)R a 、-S(O) 0-2 R a and-S (O) 2 N(R b ) 2 Is substituted at any position with one or more substituents of (a);
r is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; when R is substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl, the substituents can be substituted as follows 1-3R is A The group is substituted at any position: -CN, -OR a 、-C(O)N(R b ) 2 、-OC(O)R a 、-OC(O)OR b 、-OC(O)N(R b ) 2 、-C(O)OR b 、-C(O)R a 、-C(O)N(R b ) 2 、-N(R b ) 2 、-NR b C(O)R a 、-NR b C(O)OR a 、-NR b C(O)N(R b ) 2 、-NR b C(O)N(R b ) 2 、-NR b S(O) 2 R a 、-NR b S(O) 2 N(R b ) 2 、-S(O) 0-2 R a 、-S(O) 2 N(R b ) 2 Halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl; r A Wherein when said alkyl, alkoxy, aryl, heteroaryl, cycloalkyl or heterocycloalkyl group is substituted, it may be further substituted by 1 to 3 groups selected from halogen, hydroxy, amino and C 1-4 Alkyl, or halo C 1-3 The substituent of the alkoxy is substituted at any position;
R 1 is H or C 1-6 An alkyl group; or, R 1 is-C (O) N (R) b ) 2 、-C(O)R a 、-C(O)OR a 、-S(O) 2 N(R b ) 2 、-S(O) 2 R a Substituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; said C is 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl when substituted is preferably substituted with 1 to 3 substituents selected from: deuterium, halogen, hydroxy, mercapto, amino, cyano, C 1-3 Alkyl radical, C 1-3 Alkoxy radical, C 1-3 Alkylamino radical, halogeno C 1-3 Alkoxy, halo C 1-3 Alkyl, carboxylic acid, ester group, amide group, -NH (CO) -C 1-6 Alkyl, -C (O) -C 1-6 Alkyl, -S (O) 0-2 -C 1-6 Alkyl radical, C 3-8 Cycloalkyl, or 3-8 membered heterocycloalkyl, at any position;
R 2 is substituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl; when said C is 1-6 When the alkyl group is substituted, it is preferably substituted by 1 to 3 groups selected from halogen and C 1-4 Alkoxy radical, C 1-4 Alkylamino radical, halogeno C 1-4 Alkoxy, -OH, -NH 2 And one or more substituents in-CN at any position; when said C is 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl when substituted is preferably selected from 1 to 3 deuterium, halogen, C 1-4 Alkyl radical, C 1-4 Alkoxy, halo C 1-4 Alkyl, halo C 1-4 Alkoxy radical, C 1-4 Alkylamino, -OH, -NH 2 And one or more substituents in-CN at any position; or R 2 Is halogen, -CN, -OR a 、-C(O)N(R b ) 2 、-C(O)R a 、-C(O)OR a 、-S(O) 2 N(R b ) 2 、-S(O) 2 R a 、-N(R b ) 2 or-NR b C(O)R a
R 1 And R 2 Is independently substituted, or R 1 And R 2 Are linked to each other to form a 5-10 membered heterocycloalkyl or 5-6 membered heteroaryl; the 5-10 membered heterocycloalkyl may further comprise 1 to 3 members selected from N, O, S (O) 0-2 A heteroatom or group of C (O); the 5-10 membered heterocycloalkyl or 5-6 membered heteroaryl is unsubstituted or further substituted by 1 to 3 substituents selected from the group consisting of halogen, C 1-4 Alkyl radical, C 1-4 Alkoxy, halo C 1-4 Alkyl, halo C 1-4 Alkoxy radical, C 1-4 Alkylamino, -OH, -NH 2 And one or more substituents in-CN at any position;
R 3 is H, deuterium, halogen, cyano, amide, ester group, or C 1-3 An alkyl group;
R 4 is H, -OH, -CN, C 1-6 Alkyl, or C 1-6 An alkoxy group;
each R a And each R b Each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocycloalkylalkyl, cycloalkylalkyl, arylalkyl, or heteroarylalkyl, or alternatively, two R' s b Together with the N atom to which they are commonly attached form a 3-8 membered monocyclic heterocycloalkyl;
m is 1,2 or 3;
n is 0, 1 or 2.
All embodiments described below, as well as combinations of any of the embodiments, are included within the scope of the present invention as shown in formula I.
In some embodiments, the L is CH 2
In some embodiments, the U is CH.
In some embodiments, the V is CH.
In some embodiments, n is 1.
In some embodiments, m is 1.
In some embodiments, in the Cy, the 5-10 membered heteroaryl is 5-6 membered heteroaryl.
In some embodiments, the 5-10 membered heteroaryl in the Cy is thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl; the thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazoleThe group 1,2,5-thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl is unsubstituted or further substituted at any position with 1 to 3 substituents, the substituents being as defined above; the substituents are preferably: deuterium, halogen, amino, cyano, C 1-3 Alkyl (e.g. methyl), C 1-3 Alkoxy (e.g. methoxy, ethoxy) and halo C 1-3 Alkoxy (such as trifluoromethoxy and difluoromethoxy) is one or more.
In some embodiments, in the Cy, the 5-10 membered heteroaryl is pyridinyl, pyrimidinyl, or pyrazinyl; the pyridyl, pyrimidinyl, or pyrazinyl group is unsubstituted or further substituted at any position with 1 to 2 substituents, the substituents being as defined above; the substituents are preferably: deuterium, halogen, amino, cyano, C 1-3 Alkyl (e.g. methyl), C 1-3 Alkoxy (e.g. methoxy, ethoxy) and halo C 1-3 Alkoxy (such as trifluoromethoxy and difluoromethoxy) group.
In some embodiments, in the Cy, the 5-10 membered heteroaryl is pyridinyl; the pyridyl group is unsubstituted or further substituted at any position by 1 to 2 substituents, the substituents being as defined above; the substituents are preferably: deuterium, halogen, amino, cyano, C 1-3 Alkyl (e.g. methyl), C 1-3 Alkoxy (e.g. methoxy, ethoxy) and halo C 1-3 Alkoxy (such as trifluoromethoxy and difluoromethoxy) is one or more.
In some embodiments, the Cy is any one of the following structures:
Figure BDA0001954485700000041
Figure BDA0001954485700000051
Figure BDA0001954485700000052
or->
Figure BDA0001954485700000053
Wherein R is 5 And R 6 Each independently selected from H, halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halogeno C 1-6 Alkyl, halo C 1-6 Alkoxy radical, C 2-6 Alkynyl, C 2-6 Alkenyl radical, C 3-6 Cycloalkyl, -OH, -SH, -CN, -NO 2 、-OC(O)R a 、-OC(O)OR b 、-OC(O)N(R b ) 2 、-C(O)OR b 、-C(O)R a 、-C(O)N(R b ) 2 、-NR b C(O)R a 、-N(R b ) 2 、-NR b C(O)R a 、-S(O) 0-2 R a or-S (O) 2 N(R b ) 2 ;R a And R b Is as defined above. Said R is 5 Preferably hydrogen, methyl, methoxy, cyano, trifluoromethoxy, ethoxy, or difluoromethoxy; the R is 6 Preferably hydrogen, deuterium, halogen, amino, cyano, C 1-3 Alkyl radical, C 1-3 Alkoxy, or halo C 1-3 An alkoxy group.
In some embodiments, the Cy is any one of the following structures:
Figure BDA0001954485700000054
or
Figure BDA0001954485700000055
Wherein R is 5 And R 6 As defined above.
In some embodiments, the Cy is any one of the following structures:
Figure BDA0001954485700000056
or>
Figure BDA0001954485700000057
Wherein R is 5 And R 6 As defined above.
In some embodiments, in the Cy, the R is 5 Is H.
In some embodiments, in the Cy, the R is 5 Is methoxy, difluoromethoxy or trifluoromethoxy.
In some embodiments, in the Cy, the R is 5 Is a trifluoromethoxy group.
In some embodiments, in said R, said substituted or unsubstituted aryl is substituted or unsubstituted C 6-10 Aryl (e.g., substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl).
In some embodiments, in said R, said substituted or unsubstituted heteroaryl is preferably a substituted or unsubstituted 5-to 10-membered heteroaryl group which is a substituted or unsubstituted pyridyl, substituted or unsubstituted N-pyridyloxy, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted quinolyl or substituted or unsubstituted isoquinolyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl;
in some embodiments, in said R, said substituted or unsubstituted cycloalkyl is substituted or unsubstituted C 3-8 A cycloalkyl group.
In some embodiments, in said R, said substituted or unsubstituted cycloalkyl is substituted or unsubstituted C 3-8 A monocyclic cycloalkyl group.
In some embodiments, in said R, said substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5-8 membered heterocycloalkyl.
In some embodiments, in said R, said substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5-8 membered monocyclic heterocycloalkyl.
In some embodiments, when R is substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl, the following 1 to 3R groups can be substituted A The group is substituted at any position: -OH, -SH, -CN, -NO 2 、-NH 2 、-C(O)N(R b ) 2 、-OC(O)R a 、-OC(O)OR b 、-OC(O)N(R b ) 2 、-C(O)OR b 、-C(O)R a 、-C(O)N(R b ) 2 、-N(R b ) 2 、-NR b C(O)R a 、-NR b C(O)R a 、-NR b C(O)OR a 、-NR b C(O)N(R b ) 2 、-NR b C(O)N(R b ) 2 、-NR b S(O) 2 R a 、-NR b S(O) 2 N(R b ) 2 、-S(O) 0-2 R a 、-S(O) 2 N(R b ) 2 Halogen, alkylthio, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl.
In some embodiments, the R is A Wherein the halogen is F, cl, br, I; more preferably F or Cl.
In some embodiments, the R is A Wherein the substituted or unsubstituted alkyl is substituted or unsubstituted C 1-4 An alkyl group; more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.
In some embodiments, the R is A Wherein the substituted or unsubstituted alkoxy is substituted or unsubstituted C 1-4 An alkoxy group; more preferably methoxy group or ethoxy group.
In some embodiments, the R is A Wherein the substituted or unsubstituted aryl group is a substituted or unsubstituted phenyl group.
In some embodiments, the R is A The substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5-6 membered heteroaryl group.
In some embodiments, the R is A Wherein said substituted or unsubstituted cycloalkyl is substituted or unsubstituted C 3-8 A cycloalkyl group.
In some embodiments, the R is A Wherein said substituted or unsubstituted heterocycloalkyl is substituted or unsubstitutedSubstituted 5-8 membered heterocycloalkyl.
In some embodiments, the R is A Wherein said alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, when substituted, may be further substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxy, amino, C 1-3 Alkyl, or halo C 1-3 The substituent of the alkoxy group is substituted at an arbitrary position.
In some embodiments, the R is a And R b Each independently is hydrogen, C 1-4 Alkyl, halo C 1-3 Alkyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 3-8 membered heterocycloalkyl C 1-3 Alkyl radical, C 3-8 Cycloalkyl radical C 1-3 Alkyl, phenylalkyl, or 5-6 membered heteroaryl C 1-3 Alkyl, or, two R b Together with the N atom to which they are commonly attached form a 3-8 membered monocyclic heterocycloalkyl group.
In some embodiments, the R is a Is hydrogen, methyl, ethyl, n-propyl, or isopropyl.
In some embodiments, the R is b Is hydrogen, methyl, ethyl, n-propyl, or isopropyl.
In some embodiments, said R is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyridinyloxy, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrrolyl; the substituted R may be represented by 1 to 3R A The group is substituted at any position: c 1-3 Alkyl (e.g. methyl, ethyl, isopropyl), C 1-3 Alkoxy (e.g. methoxy, ethoxy), F, cl, br, -OH, -NH 2 and-CN.
In some embodiments, the R is a substituted or unsubstituted phenyl, substituted or unsubstituted quinolinyl, or substituted or unsubstituted isoquinolinyl; the substituted R may be substituted at any position with 1F as follows.
In some embodiments, R is
Figure BDA0001954485700000071
In some embodiments, the R is 1 Is H.
In some embodiments, the R is 1 Is a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted isopropyl group, or a substituted or unsubstituted cyclopropyl group. The methyl, ethyl, isopropyl or cyclopropyl group is unsubstituted or optionally substituted by 1-OH at any position.
In some embodiments, R 1 Is methyl, ethyl, isopropyl, or cyclopropyl. Said ethyl group being unsubstituted or optionally substituted at any position by 1-OH.
In some embodiments, R 1 Is H, methyl, ethyl, isopropyl, or cyclopropyl. The ethyl group is unsubstituted or optionally substituted at any position by 1-OH.
In some embodiments, the R is 2 In (1), the substituted C 1-6 Alkyl being substituted C 1-4 Alkyl, the substituent is F or-OH.
In some embodiments, the R is 2 In (1), the substituted C 1-6 Alkyl being C substituted by 1 hydroxy 1-4 An alkyl group.
In some embodiments, the R is 2 In (1), the substituted C 1-6 Alkyl is substituted methyl, the substituent preferably being-OH.
In some embodiments, the R is 2 In (1), the substituted C 1-6 Alkyl is substituted ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; the substituent is F or-OH.
In some embodiments, the R is 2 In (1), the substituted C 1-6 The alkyl is trifluoromethyl, difluoromethyl, 2-fluoroprop-2-yl, 2,2-difluoroethyl, 1,1-difluoroethyl, hydroxymethyl (-CH) 2 OH), 2-hydroxyPhenylprop-2-yl (-C (CH) 3 ) 2 OH), or 1-hydroxy-2-methylpropan-2-yl (-C (CH) 3 ) 2 CH 2 OH)。
In some embodiments, the R is 2 In (1), the substituted C 1-6 Alkyl is hydroxymethyl (-CH) 2 OH), 2-hydroxypropan-2-yl (-C (CH) 3 ) 2 OH), or 1-hydroxy-2-methylpropan-2-yl (-C (CH) 3 ) 2 CH 2 OH)。
In some embodiments, the R is 2 In (1), the substituted or unsubstituted C 3-8 Cycloalkyl being substituted or unsubstituted C 3-6 Cycloalkyl radicals, for example: cyclopropyl, 1-methylcyclopropyl
Figure BDA0001954485700000072
1-hydroxycyclopropyl->
Figure BDA0001954485700000073
Cyclobutyl, cyclopentyl, cyclohexyl or 1-fluorocyclopropyl->
Figure BDA0001954485700000081
In some embodiments, the R is 2 Wherein said substituted or unsubstituted C 3-8 Cycloalkyl being substituted or unsubstituted C 3-6 Cycloalkyl radicals, for example: cyclopropyl, 1-methylcyclopropyl
Figure BDA0001954485700000082
1-hydroxycyclopropyl->
Figure BDA0001954485700000083
Cyclobutyl, cyclopentyl, or cyclohexyl.
In some embodiments, the R is 2 The substituted or unsubstituted 3-8 membered heterocycloalkyl group is a substituted or unsubstituted 3-6 membered heterocycloalkyl group, for example: 3-oxetanyl, 2-oxetanyl, 3-azetidinyl, 2-azetidinyl.
In some embodiments, the R is 2 Is halogen, C 2-4 Alkenyl, C substituted by 1 hydroxy 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl; said C is 3-6 Cycloalkyl or 3-to 6-membered heterocycloalkyl being unsubstituted or optionally substituted by 1F, -CH 3 or-OH in any position.
In some embodiments, the R is 2 Is fluorine, chlorine, trifluoromethyl, difluoromethyl, 2-fluoroprop-2-yl, 2,2-difluoroethyl, 1,1-difluoroethyl, hydroxymethyl, 1-methylcyclopropyl, 1-hydroxycyclopropyl, 1-fluorocyclopropyl, cyclobutyl, cyclopropyl, 3-oxetanyl, or 2-oxetanyl.
In some embodiments, the R is 2 Is 1-hydroxy-2-methylpropan-2-yl, 3-azetidinyl, or 2-azetidinyl.
In some embodiments, the R is 2 Is fluorine, chlorine, prop-1-en-2-yl, hydroxymethyl, 1-methylcyclopropyl, 1-hydroxycyclopropyl, cyclobutyl, cyclopropyl, 3-oxetanyl, 2-oxetanyl, 1-hydroxy-2-methylpropan-2-yl, 3-azetidinyl, or 2-azetidinyl.
In some embodiments, the R is 2 Is fluorine, chlorine, prop-1-en-2-yl, hydroxymethyl, 1-methylcyclopropyl, 1-hydroxycyclopropyl, cyclobutyl, cyclopropyl, 3-oxetanyl, 2-oxetanyl, or 1-hydroxy-2-methylprop-2-yl.
In some embodiments, the R is 3 Is H, deuterium, fluorine, chlorine, bromine, cyano, or methyl.
In some embodiments, the R is 3 Is H.
In some embodiments, the R is 4 Is H.
In some embodiments, the five-membered heteroaromatic ring derivative (I), isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt thereof, may be defined as follows, and non-described groups may be defined as in any one of the above embodiments:
wherein the ring A is pyrrole ring, and X, Y, Z is selected from the following combinations:
1) X is NR 1 Y is CR 2 And Z is CR 3
2) X is CR 2 Y is NR 1 And Z is CR 3
Alternatively, the a ring is an imidazole ring, and X, Y, Z is selected from the group consisting of:
5) X is NR 1 Y is CR 2 And Z is N; or
L is CH 2
U and V are each independently selected from N;
cy is
Figure BDA0001954485700000091
Or->
Figure BDA0001954485700000092
R 5 Is methoxy, difluoromethoxy or trifluoromethoxy;
r is
Figure BDA0001954485700000093
R 1 Is a substituted or unsubstituted methyl group, a substituted or unsubstituted ethyl group, a substituted or unsubstituted isopropyl group, or a substituted or unsubstituted cyclopropyl group. The methyl, ethyl, isopropyl or cyclopropyl group is unsubstituted or optionally substituted by 1-OH at any position.
R 2 Is halogen, C 2-4 Alkenyl, C substituted by 1 hydroxy 1-4 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl; said C is 3-6 Cycloalkyl or 3-to 6-membered heterocycloalkyl being unsubstituted or optionally substituted by 1F, -CH 3 or-OH is substituted at any position;
R 3 is H;
m is 1; n is 1.
In some embodiments, the five-membered heteroaromatic ring derivative (I), isomers, prodrugs, stable isotopic derivatives, or pharmaceutically acceptable salts thereof, may be defined as follows, and non-described groups may be defined as in any one of the above embodiments:
said
Figure BDA0001954485700000094
Is composed of
Figure BDA0001954485700000095
Or->
Figure BDA0001954485700000096
In some embodiments, the five-membered heteroaromatic ring derivative (I), isomers, prodrugs, stable isotopic derivatives, or pharmaceutically acceptable salts thereof, may be defined as follows, and non-described groups may be defined as in any one of the above embodiments:
said
Figure BDA0001954485700000097
Is->
Figure BDA0001954485700000098
Or
Figure BDA0001954485700000099
In some embodiments, the five-membered heteroaromatic ring derivative (I), isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt thereof is a compound of formula (II):
Figure BDA0001954485700000101
wherein Cy, R 1 、R 2 And R 3 As defined above.
The following preferred embodiments are included in the definition of the compounds represented by formula (II):
in some preferred embodiments, cy is
Figure BDA0001954485700000102
Or
Figure BDA0001954485700000103
In some preferred embodiments, cy is
Figure BDA0001954485700000104
Or>
Figure BDA0001954485700000105
In some preferred embodiments, R is
Figure BDA0001954485700000106
In some preferred embodiments, R 1 Is H.
In some preferred embodiments, R 1 Is methyl, or hydroxyethyl.
In some preferred embodiments, R 1 Is H or methyl.
In some preferred embodiments, R 2 Is hydroxymethyl, prop-1-en-2-yl, 1-methylcyclopropyl, 1-hydroxycyclopropyl, cyclobutyl, cyclopropyl, 3-oxetanyl, 2-oxetanyl, 1-hydroxy-2-methylpropan-2-yl, 3-azetidinyl, or 2-azetidinyl.
In some preferred embodiments, R 3 Is H or D.
In some preferred embodiments, R 3 Is H.
In some embodiments, the five-membered heteroaromatic ring derivative (I), isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt thereof is a compound of formula (III):
Figure BDA0001954485700000107
wherein, Cy、R、R 1 、R 2 And R 3 As defined above.
The following preferred embodiments are included in the definition of the compounds represented by formula (III):
in some preferred embodiments, cy is
Figure BDA0001954485700000111
Or
Figure BDA0001954485700000112
In some preferred embodiments, cy is
Figure BDA0001954485700000113
Or->
Figure BDA0001954485700000114
In some preferred embodiments, R is
Figure BDA0001954485700000115
In some preferred embodiments, R 1 Is H.
In some preferred embodiments, R 1 Is methyl.
In some preferred embodiments, R 2 Substituted F, cl, hydroxymethyl.
In some preferred embodiments, R 3 Is H or D.
In some preferred embodiments, R 3 Is H.
In some embodiments, the five-membered heteroaromatic ring derivative (I), isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt thereof is a compound of formula (IV):
Figure BDA0001954485700000116
wherein Cy, R 1 、R 2 And R 3 As defined above.
The following preferred embodiments are included in the definition of the compounds represented by formula (IV):
in some preferred embodiments, cy is
Figure BDA0001954485700000117
Or
Figure BDA0001954485700000118
In some preferred embodiments, cy is
Figure BDA0001954485700000119
Or->
Figure BDA00019544857000001110
In some preferred embodiments, R is
Figure BDA0001954485700000121
In some preferred embodiments, R 1 Is H.
In some preferred embodiments, R 2 Is cyclopropyl or cyclobutyl.
In some embodiments, the five-membered heteroaromatic ring derivative (I), isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt thereof is a compound of formula (V) or (VI):
Figure BDA0001954485700000122
wherein X, Y, Z, cy, L and R are as defined above.
The following preferred embodiments are included in the definition of the compounds represented by the formula (V) or (VI):
in some preferred embodiments, L is CH 2
In some preferred embodiments, cy is
Figure BDA0001954485700000123
Or
Figure BDA0001954485700000124
In some preferred embodiments, R is
Figure BDA0001954485700000125
In some embodiments, the five-membered heteroaromatic ring derivative (I), isomers, prodrugs, stable isotopic derivatives, or pharmaceutically acceptable salts thereof, may be defined as follows, and non-described groups may be defined as in any one of the above embodiments:
Figure BDA0001954485700000126
wherein ring a is a pyrrole ring and X, Y, Z is selected from the group consisting of:
1) X is NR 1 Y is CR 2 And Z is CR 3
2) X is CR 2 Y is NR 1 And Z is CR 3
3) X is CR 3 Y is CR 2 And Z is NR 1 (ii) a Or
4) X is CR 3 Y is NR 1 And Z is CR 2
L is CH 2 、CH(CH 3 )、C(CH 3 ) 2 Or CH 2 CH 2
U and V are each independently selected from N or CR 4
Cy is a benzene ring or a 5-10 membered heteroaromatic ring, said Cy is unsubstituted or further substituted by 1 to 4 groups selected from halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halo C 1-6 Alkyl, halo C 1-6 Alkoxy radical, C 2-6 Alkynyl, C 2-6 Alkenyl radical, C 3-6 Cycloalkyl, -OH, -SH, -CN, -NO 2 、-OC(O)R a 、-OC(O)OR b 、-OC(O)N(R b ) 2 、-C(O)OR b 、-C(O)R a 、-C(O)N(R b ) 2 、-NR b C(O)R a 、-N(R b ) 2 、-NR b C(O)R a 、-S(O) 0-2 R a and-S (O) 2 N(R b ) 2 Is substituted at any position with one or more substituents of (a);
r is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; said R is unsubstituted or further substituted by 1 to 3R A The group is substituted at any position: -CN, -OR a 、-C(O)N(R b ) 2 、-OC(O)R a 、-OC(O)OR b 、-OC(O)N(R b ) 2 、-C(O)OR b 、-C(O)R a 、-C(O)N(R b ) 2 、-N(R b ) 2 、-NR b C(O)R a 、-NR b C(O)R a 、-NR b C(O)OR a 、-NR b C(O)N(R b ) 2 、-NR b C(O)N(R b ) 2 、-NR b S(O) 2 R a 、-NR b S(O) 2 N(R b ) 2 、-S(O) 0-2 R a 、-S(O) 2 N(R b ) 2 Halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl; r is A Wherein when said alkyl, alkoxy, aryl, heteroaryl, cycloalkyl or heterocycloalkyl group is substituted, it may be further substituted by 1 to 3 groups selected from halogen, hydroxy, amino and C 1-4 Alkyl, or halo C 1-3 The substituent of the alkoxy is substituted at any position;
R 1 is H or C 1-6 An alkyl group;
R 2 is substituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstitutedC 3-8 Cycloalkyl, or substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl; when said C is 1-6 The alkyl group is optionally substituted by 1 to 3 groups selected from halogen, C 1-4 Alkoxy, halo C 1-4 Alkoxy, -OH, -NH 2 And one or more substituents in-CN at any position; when said C is 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl optionally substituted with 1 to 3 substituents selected from deuterium, halogen, C 1-4 Alkyl radical, C 1-4 Alkoxy, halo C 1-4 Alkyl, halo C 1-4 Alkoxy, -OH, -NH 2 And one or more substituents in-CN at any position;
R 3 is H, deuterium, halogen, cyano, amide, ester group, or C 1-3 An alkyl group;
R 4 is H, -OH, -CN, C 1-6 Alkyl, or C 1-6 An alkoxy group;
each R a And each R b Each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocycloalkylalkyl, cycloalkylalkyl, arylalkyl, or heteroarylalkyl, or alternatively, two R' s b Together with the N atom to which they are both attached form a 3-8 membered monocyclic heterocycloalkyl;
m is 1,2 or 3;
n is 0, 1 or 2.
In some embodiments, the five-membered heteroaromatic ring derivative (I), isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt thereof is any one of the following structures:
Figure BDA0001954485700000141
in some embodiments, the five-membered heteroaromatic ring derivative (I), isomer, prodrug, stable isotopic derivative, or pharmaceutically acceptable salt thereof is any one of the following structures:
Figure BDA0001954485700000142
Figure BDA0001954485700000151
in some embodiments, the five-membered heteroaromatic ring derivative (I), isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt thereof is any one of the following structures:
Figure BDA0001954485700000152
Figure BDA0001954485700000161
in some embodiments, the five-membered heteroaromatic ring derivative (I), isomer, prodrug, stable isotopic derivative or pharmaceutically acceptable salt thereof is any one of the following structures:
Figure BDA0001954485700000162
the invention also provides a preparation method of the five-membered heteroaromatic ring derivative (I), an isomer, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof, which is any one of the following methods.
The method comprises the following steps: in a solvent, carrying out condensation reaction on a compound I-b and a compound X-1 under the action of alkali;
Figure BDA0001954485700000163
wherein Cy, X, Y, Z, L, R, U, V, m and n are as defined above.
In the method shown in the reaction formula 1, the conditions and steps of the condensation reaction may be those conventional in the art, and the following reaction conditions are particularly preferred in the present invention: the solvent is preferably dichloromethane or N, N-dimethylformamide; the dosage of the solvent is preferably 5-20 mL/mmol of the compound I-b; the alkali is preferably N, N-diisopropylethylamine, N-methylmorpholine or triethylamine; the molar ratio of the alkali to the compound I-b is preferably 1:1-5:1; in order to accelerate the reaction speed, a catalytic amount of 4-dimethylaminopyridine can be added into the reaction system, and the molar ratio of the 4-dimethylaminopyridine to the compound I-b is preferably 0.05. The condensing agent in the condensation reaction is preferably 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC) or N, N' -Diisopropylcarbodiimide (DIC), more preferably EDCI, and the molar ratio of the condensing agent to the compound I-b is preferably 1:1-3:1; the reaction temperature is preferably 0-30 ℃; the reaction can be detected by TLC, and the end point of the reaction is generally the time when the compound I-b disappears, preferably 0.5 to 24 hours; after the reaction is finished, the product can be further purified by post-treatment, and the method preferably comprises the following steps: after quenching the reaction system with ice water, diluting with a solvent, separating the organic phase, drying the organic phase, removing the organic solvent under reduced pressure, and purifying the residue by a conventional purification means such as silica gel column chromatography, flash column chromatography or prep-HPLC. The steps and conditions for silica gel column chromatography, flash column chromatography or prep-HPLC purification may be those conventionally used in the art.
The preparation of said compounds I-b may be conventional in the art for such reactions, preferably comprising the steps of: in a solvent, carrying out deprotection reaction on the compound I-a;
Figure BDA0001954485700000171
wherein Pg is a carboxyl protecting group, preferably C 1-6 Alkyl, more preferably methyl or ethyl; cy, X, Y and Z are as defined above.
In the process shown in the reaction formula 2, the deprotection reaction of the compound I-a can be carried out under acidic conditions or basic conditions. The acidic conditions are preferably a hydrochloric acid/alcohol system, or a hydrogen chloride/alcohol system, the alcohol preferably being methanol or ethanol. In alkaline conditions: the solvent can be a solvent commonly used in the reaction in the field, preferably ethanol, methanol, tetrahydrofuran, water, or a mixed solvent of any 2 to 4 of ethanol, methanol, tetrahydrofuran and water, more preferably an ethanol/water mixed solvent, wherein the volume ratio of the ethanol to the water is preferably 1. The amount of the solvent does not generally affect the reaction, and is preferably 5 to 15mL/mmol of the compound I-a. The alkali is preferably sodium hydroxide, potassium hydroxide or lithium hydroxide, more preferably sodium hydroxide, the molar ratio of the alkali to the compound I-a is preferably 2:1-10, and the alkali can be usually dissolved in water in a mixture solvent to prepare an aqueous solution of the alkali. The temperature of the deprotection reaction is preferably 20 to 100 ℃, more preferably 60 to 100 ℃, and still more preferably 80 to 100 ℃. The progress of the reaction can be checked by TLC, and it is generally preferable that the end point of the reaction is 10 minutes to 2 hours, when the compound I-a disappears. After the reaction is finished, the product can be further purified by post-treatment, and the method preferably comprises the following steps: concentrating under reduced pressure to remove organic solvent, acidifying residue, filtering the obtained solid, and vacuum drying the filter cake to obtain compound I-b.
The second method comprises the following steps: in a solvent, under the action of trimethylaluminum, carrying out amine ester exchange reaction on a compound I-a and a compound X-1;
Figure BDA0001954485700000172
wherein Pg is a carboxyl protecting group, preferably C 1-6 Alkyl, more preferably methyl or ethyl; cy, X, Y, U, V, m, n, Z, L and R are as defined above.
In the process shown in the reaction formula 3, the conditions and steps of the condensation reaction may be those of amine transesterification reaction which is conventional in the art, and the following reaction conditions are particularly preferred in the present invention: the solvent is preferably toluene, and the dosage of the solvent is preferably 5-20 mL/mmol of the compound I-a; the molar ratio of trimethylaluminum to the compound X-1 is preferably 2:1 to 3:1. The molar ratio of the compound X-1 to the compound I-a is preferably 1:1-3:1; the reaction temperature is preferably between room temperature and solvent reflux; the reaction temperature is more preferably 90-110 ℃; the reaction can be detected by TLC, and the end point of the reaction is generally determined as the disappearance of the compound I-a, preferably 1 to 24 hours; after the reaction is finished, the product can be further purified through post-treatment, and the purification method comprises silica gel column chromatography, flash column chromatography or prep-HPLC purification. The steps and conditions for silica gel column chromatography, flash column chromatography or prep-HPLC purification may be those conventionally used in the art.
The compound I-a can be synthesized by the method shown in the reaction formulas 4 to 6:
Figure BDA0001954485700000181
wherein Pg is a carboxyl protecting group, preferably C 1-6 Alkyl, more preferably methyl or ethyl; x is iodine, bromine or chlorine; cy, R 1 And R 2 Is as defined above.
Figure BDA0001954485700000182
Wherein Pg is a carboxyl protecting group, preferably C 1-6 Alkyl, more preferably methyl, ethyl or tert-butyl; r 2 Is Cl or Br; cy is as defined above.
Figure BDA0001954485700000183
Wherein Pg is a carboxyl protecting group, preferably C 1-6 Alkyl, more preferably methyl or ethyl; cy and R 2 Is as defined above.
Figure BDA0001954485700000184
Wherein Pg is a carboxyl protecting group, preferably C 1-6 Alkyl, more preferably methyl or ethyl; cy and R 2 Is as defined above.
In the above reaction formulae 1 to 7, when an amino group, a hydroxyl group or a carboxyl group which does not participate in the reaction is present, the amino group, the hydroxyl group or the carboxyl group is preferably protected by a protecting group to avoid any side reaction. If the amino protecting group or the hydroxyl protecting group exists, the compound shown as the formula I is obtained after subsequent deprotection steps. Any suitable amino protecting group, for example: a tert-butyloxycarbonyl (Boc) group, both of which can be used to protect the amino group. If Boc is used as the protecting group, the subsequent deprotection reaction can be carried out under standard conditions, for example, in a p-toluenesulfonic acid/methanol system, a dichloromethane/trifluoroacetic acid system, a saturated ethereal hydrogen chloride solution, or trimethylsilyl trifluoromethanesulfonate/2,6-lutidine/dichloromethane system; any suitable hydroxyl protecting group, for example: tert-butyldimethylsilyl groups, all of which can be used to protect hydroxyl groups, and subsequent deprotection reactions can be carried out under standard conditions, for example, in the sodium hydroxide/methanol/water system; any suitable carboxyl protecting group, for example: the formation of carboxylate groups (e.g., methyl carboxylate, ethyl carboxylate) can all be used to protect carboxyl groups, and subsequent deprotection reactions can be performed under standard conditions, e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide in tetrahydrofuran, water, and/or methanol solvents.
The pharmaceutically acceptable salt of the five-membered heteroaromatic ring derivative (I) can be synthesized by a general chemical method.
In general, salts can be prepared by reacting the free base or acid with a stoichiometric equivalent or excess of the acid (inorganic or organic) or base (inorganic or organic) in a suitable solvent or solvent composition.
The invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of active components and pharmaceutically acceptable auxiliary materials; the active component comprises one or more of five-membered heteroaromatic ring derivatives (I), isomers, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts thereof.
In the pharmaceutical composition, the active ingredient may also include other therapeutic agents for cancer, viral infections or autoimmune diseases.
In the pharmaceutical composition, the pharmaceutically acceptable adjuvant may include a pharmaceutically acceptable carrier, diluent and/or excipient.
The pharmaceutical composition may be formulated into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (solutions and suspensions), and the like, preferably liquids, suspensions, emulsions, suppositories, injections (solutions and suspensions), and the like, according to the therapeutic purpose.
For shaping the pharmaceutical composition in the form of tablets, any excipient known and widely used in the art may be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and the like; binders such as water, ethanol, propanol, common syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.; disintegrators such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch, lactose and the like; disintegration inhibitors such as white sugar, glycerol tristearate, coconut oil and hydrogenated oil; adsorption promoters such as quaternary ammonium hydroxide and sodium lauryl sulfate; humectants such as glycerin, starch, and the like; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; and lubricants such as pure talc, stearates, boric acid powder, polyethylene glycol, and the like. Optionally, conventional coating materials can be selected to make into sugar-coated tablet, gelatin film-coated tablet, enteric coated tablet, film-coated tablet, double-layer film tablet and multilayer tablet.
For shaping the pharmaceutical composition in the form of pellets, any of the excipients known and widely used in the art may be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin, talc and the like; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol and the like; disintegrating agents, such as agar and kelp powder.
For shaping the pharmaceutical composition in the form of suppositories, any excipient known and widely used in the art may be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides and the like.
For preparing the pharmaceutical composition in the form of injection, the solution or suspension can be sterilized (preferably, appropriate amount of sodium chloride, glucose or glycerol, etc.) to make into injection with blood isotonic pressure. In the preparation of ampoules, any of the carriers commonly used in the art may also be used. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan, and the like. In addition, conventional lytic agents, buffers, analgesics, and the like may be added.
In the present invention, the content of the composition in the pharmaceutical composition is not particularly limited, and can be selected from a wide range, and usually 5 to 95% by mass, preferably 30 to 80% by mass.
In the present invention, the method of administration of the pharmaceutical composition is not particularly limited. The formulation of various dosage forms can be selected for administration according to the age, sex and other conditions and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules are administered orally; the injection can be administered alone or mixed with injectable delivery solution (such as glucose solution and amino acid solution) for intravenous injection; suppositories are administered rectally.
The invention also provides the five-membered heteroaromatic ring derivative (I), an isomer, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof, or an application of the pharmaceutical composition in preparation of indoleamine 2,3-dioxygenase inhibitor. The indoleamine 2,3-dioxygenase inhibitor (IDO 1 inhibitor) is a compound which can inhibit IDO1 activity or expression (including abnormal activity or overexpression of IDO 1) and reverse IDO 1-mediated immunosuppression. The IDO1 inhibitor can inhibit IDO1.
The invention also provides the five-membered heteroaromatic ring derivative (I), an isomer, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof, or an application of the pharmaceutical composition in preparing a medicament for stimulating T cell proliferation.
The use of the five-membered heteroaromatic ring derivative of formula (I) and/or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any embodiment of the invention, for the manufacture of a medicament for the treatment, alleviation and/or prevention of a related disorder mediated by IDO1, comprising administering to the individual (e.g. patient) a therapeutically required amount of a compound or pharmaceutical composition of the invention. By IDO1 mediated related disease is meant any disease, condition or disorder that can be treated, ameliorated and/or prevented with an IDO1 inhibitor. In particular said diseases caused by IDO1 mediated immunosuppression, said diseases including but not limited to: viral, or other infections (e.g., skin infections, gastrointestinal tract infections, urogenital infections, systemic infections, etc.), cancer, or autoimmune diseases (e.g., rheumatoid arthritis, lupus erythematosus, psoriasis, etc.).
The invention also provides the application of the five-membered heteroaromatic ring derivative (I), the isomer, the prodrug, the stable isotope derivative or the pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing medicines for treating, relieving and/or preventing related diseases mediated by indoleamine 2,3-dioxygenase. The five-membered heteroaromatic ring derivatives (I), isomers, prodrugs, solvates, hydrates, stable isotopic derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions may also be used in combination with one or more other types of therapeutic agents and/or methods for the treatment of cancer for the treatment, alleviation and/or prevention of related disorders mediated by indoleamine 2,3-dioxygenase. The 2,3-dioxygenase mediated related diseases refer to diseases caused by 2,3-dioxygenase mediated immunosuppression, and the diseases can comprise: viral, or other infections (e.g., skin infections, gastrointestinal tract infections, urogenital infections, systemic infections, etc.), cancer, or autoimmune diseases (e.g., rheumatoid arthritis, lupus erythematosus, psoriasis, etc.).
The other therapeutic agents for treating cancer may be administered in a single dosage form with the five-membered heteroaromatic ring derivative (I) or in separate sequential dosage forms.
Such other classes of therapeutic agents and/or methods of treatment for treating cancer may include, but are not limited to: one or more of tubulin inhibitors, alkylating agents, topoisomerase I/II inhibitors, platinum-based compounds, antimetabolites, hormones and hormone analogs, signal transduction pathway inhibitors, angiogenesis inhibitors, targeted therapies (e.g., specific kinase inhibitors), immunotherapeutic agents, pro-apoptotic agents, cell cycle signaling pathway inhibitors, and radiation therapy.
The tubulin inhibitor may be selected from, but not limited to: vinblastine series (e.g., vinblastine, vincristine, vinorelbine, vindesine), taxanes (docetaxel, paclitaxel) and methanesulfonic acid Ai Ribu forest.
The alkylating agent may be selected from, but not limited to: nitrogen mustards, ethylene imine derivatives, methane sulfonates, nitrosoureas, and triazenes.
The topoisomerase I/II inhibitor may be selected from, but is not limited to: one or more of irinotecan, topotecan, doxorubicin and dexrazoxane.
The platinum-based compound may be selected from, but is not limited to: cisplatin and/or carboplatin.
The antimetabolite may be selected from, but not limited to: folic acid antagonists, pyrimidine analogs, purine analogs, adenosine deaminase inhibitors, such as: one or more of methotrexate, 5-fluorouracil, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin and gemcitabine.
The immunotherapeutic agent may be selected from, but is not limited to: anti-tumor vaccines (e.g., synthetic peptides, DNA vaccines, and recombinant viruses), oncolytic viruses, immunostimulatory antibodies, novel adjuvants, cytokine therapy (e.g., IL2 and GM-CSF), chimeric antigen receptor T-cell therapy (CAR-T), small molecule immunomodulators, tumor microenvironment modulators, and anti-angiogenic factors. The immunostimulatory antibodies may include, but are not limited to: 1) Protein antagonists that inhibit T cell activity (e.g.: immune checkpoint inhibitors): CTLA4 (e.g., ipilimumab and tremelimumab), PD-1 (e.g., pembrolizumab and nivolumab), PD-L1 (e.g., durvalumab, avelumab, and atezolizumab), PD-L2, LAG3, TIM1, TIM3, TIM4, CD73, galectin9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, and LAIR 1; 2) Protein agonists that stimulate T cell activity: one or more of B7-1, B7-2, CD28, ICOS-L, GITR, GITRL, CD70, DR3, CD28H, GITR, OX40L, 4-1BB (CD 137), CD27, and CD 40. 3) Receptor antagonists acting on NK cells: KIR (e.g., iilumab); 4) Receptor antagonists that inhibit or deplete macrophages or monocytes: CSF-1R.
The signal transduction pathway inhibitor (STI) may be selected from, but is not limited to: BCR/ABL kinase inhibitors, epidermal growth factor receptor inhibitors, her-2/neu receptor inhibitors, AKT family kinase inhibitors, PI3K signaling pathway inhibitors, and cell cycle checkpoint inhibitors.
The angiogenesis inhibitor may be selected from, but not limited to: one or more of a VEGF/VEGFR signaling pathway inhibitor, a Src family kinase inhibitor, a Src signaling pathway inhibitor, and a c-Fes kinase inhibitor.
The viral infection may include: infections caused by viruses such as influenza, hepatitis B Virus (HBV), hepatitis C Virus (HCV), human Papilloma Virus (HPV), cytomegalovirus (CMV), epstein-barr virus (EBV), poliovirus, varicella-zoster virus, coxsackie virus, or Human Immunodeficiency Virus (HIV).
The cancer may comprise a solid tumor or a liquid tumor.
In some embodiments, the solid tumor can include, but is not limited to, related tumors of the eye, bone, lung, stomach, pancreas, breast, prostate, brain (including glioblastomas and medulloblastomas), ovary (including those stromal, germ, and stromal cells produced from epithelial cells), bladder, testis, spinal cord, kidney (including adenocarcinomas, wilms), mouth, lip, throat, oral cavity (including squamous cell carcinoma), nasal cavity, small intestine, colon, rectum, parathyroid, gallbladder, bile duct, cervix, heart, hypopharynx, bronchus, liver, ureter, vagina, anus, laryngeal gland, thyroid (including thyroid and medullary carcinoma), esophagus, nasopharyngeal pituitary, salivary gland, adrenal gland, head and neck intraepithelial neoplasia (including Bowen's disease and Paget's disease), sarcoma (including leiomyosarcoma, rhabdomyosarcoma, fibrosarcoma, osteosarcoma), skin (including melanoma, kaposi's sarcoma, solvacel cancer, and squamous cell carcinoma), and the like.
In some embodiments, the liquid tumor can include, but is not limited to, tumors associated with lymphoid tissues (including acute lymphocytic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia, hodgkin's disease, non-hodgkin's lymphoma and lymphocytic lymphoma, T-cell and B-cell chronic lymphocytic leukemia), chronic lymphocytic leukemia, myeloid leukemia and aids-related leukemia.
In some embodiments, the autoimmune disease may include, but is not limited to: rheumatoid arthritis, systemic lupus erythematosus, mixed Connective Tissue Disease (MCTD), systemic scleroderma (including CREST syndrome), dermatomyositis, nodular vasculitis, nephropathy (including hemorrhagic nephritis syndrome, acute glomerulonephritis, primary membranous proliferative glomerulonephritis, etc.), endocrine-related diseases (including type I diabetes, gonadal insufficiency, pernicious anemia, hyperthyroidism, etc.), liver diseases (including primary biliary cirrhosis, autoimmune cholangitis, autoimmune hepatitis, primary sclerosing cholangitis, etc.), and autoimmune reactions due to infection (e.g., AIDS, malaria, etc.).
The invention also provides a method for inhibiting the degradation of tryptophan in a system by using the five-membered heteroaromatic ring derivative (I), an isomer, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition, which comprises the following steps: inhibiting degradation of tryptophan in a mammal by administering to the mammal a therapeutically effective amount of a compound of formula (I); the system is tissues, mammals or cell tissues expressing IDO.
The mammal, preferably a human.
In the present invention, when the bond to a substituent exhibits an intersection with a bond linking two atoms in the ring, then such substituent may be bonded to any bondable ring atom on the ring.
Unless otherwise indicated, the following terms appearing in the specification and claims of the invention have the following meanings:
the term "alkyl" refers to a saturated straight or branched chain hydrocarbon group containing 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6,1 to 5, 1 to 4,1 to 3, or 1 to 2 carbon atoms, representative examples of alkyl groups including but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl, and their various isomers, and the like.
The term "cycloalkyl" refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) monocyclic or polycyclic group containing 3 to 20 carbon atoms. "monocyclic cycloalkyl" is preferably 3-10 membered monocyclic cycloalkyl, more preferably 3-8 membered monocyclic cycloalkyl, more preferably 3-6 membered monocyclic cycloalkyl, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl. "polycyclic cycloalkyl" includes "fused cycloalkyl" and "spirocycloalkyl," fused cycloalkyl "comprising a monocyclic cycloalkyl ring fused to an aryl, cycloalkyl, or heteroaryl, and fused bicyclic cycloalkyl including, but not limited to: benzocyclobutene, 2,3-dihydro-1-H-indene, 2,3-cyclopentenopyridine, 5,6-dihydro-4H-cyclopentyl [ B ] thiophene, decahydronaphthalene and the like. "spirocycloalkyl" refers to a bicyclic group formed by two cycloalkyl groups sharing a common carbon atom, and includes, but is not limited to: spiro [2.4] heptyl, spiro [4.5] decane, and the like. The monocyclic cycloalkyl or bicyclic cycloalkyl can be linked to the parent molecule through any carbon atom in the ring.
The term "heterocycloalkyl" refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) 3-to 20-membered non-aromatic cyclic group consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen or sulfur, which cyclic group may be a monocyclic or bicyclic group, in the present invention, the number of heteroatoms in the heterocycloalkyl is preferably 1,2,3 or 4, and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl may be optionally oxidized. The nitrogen atom may optionally be further substituted with other groups to form tertiary amines or quaternary ammonium salts. "monocyclic heterocycloalkyl" is preferably 3-to 10-membered monocyclic heterocycloalkyl, more preferably 5-to 8-membered monocyclic heterocycloalkyl. For example: aziridinyl, tetrahydrofuran-2-yl, morpholin-4-yl, thiomorpholin-S-oxide-4-yl, piperidin-1-yl, N-alkylpiperidin-4-yl, pyrrolidin-1-yl, N-alkylpyrrolidin-2-yl, piperazin-1-yl, 4-alkylpiperazin-1-yl, and the like. "polycyclic heterocycloalkyl" includes "fused heterocycloalkyl" and "spiroheterocyclyl". "fused heterocycloalkyl" includes a monocyclic heterocycloalkyl ring fused to a phenyl, heterocycloalkyl, cycloalkyl or heteroaryl group, including, but not limited to: 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, indolinyl, 2,3-dihydrobenzo [ b ] thienyl, dihydrobenzopyranyl, and 1,2,3,4-tetrahydroquinolinyl, and the like. "spiroheterocyclyl" refers to a bicyclic group formed by two heterocycloalkyl groups or one cycloalkyl group and one heterocycloalkyl group sharing a carbon atom. Monocyclic heterocycloalkyl and polycyclic heterocycloalkyl can be linked to the parent molecule through any ring atom in the ring. The above ring atoms particularly denote carbon atoms and/or nitrogen atoms constituting the ring skeleton.
The term "cycloalkylalkyl" refers to a cycloalkyl group attached to the parent nuclear structure through an alkyl group. Thus, "cycloalkylalkyl" encompasses the definitions of alkyl and cycloalkyl above.
The term "heterocycloalkylalkyl" refers to a linkage between a heterocycloalkyi and the parent core structure through an alkyl group. Thus, "heterocycloalkylalkyl" embraces the definitions of alkyl and heterocycloalkyl described above.
The term "alkoxy" refers to a cyclic or acyclic alkyl group having the indicated number of carbon atoms attached through an oxygen bridge, including alkyloxy, cycloalkyloxy, and heterocycloalkyloxy. Thus, "alkoxy" encompasses the above definitions of alkyl, heterocycloalkyl, and cycloalkyl.
The term "alkylthio" means a cyclic or acyclic alkyl group interconnected through the sulfur atom and the parent molecule, and includes alkylmercapto, cycloalkylmercapto, and heterocycloalkylmercapto. Thus, "alkylthio" encompasses the definitions of alkyl, heterocycloalkyl, and cycloalkyl above.
The term "alkenyl" refers to a straight, branched, or cyclic non-aromatic hydrocarbon group containing at least 1 carbon-carbon double bond. Wherein 1-3 carbon-carbon double bonds, preferably 1 carbon-carbon double bond, may be present. The term "C 2-4 Alkenyl "means an alkenyl group having 2 to 4 carbon atoms, the term" C 2-6 Alkenyl "means alkenyl having 2 to 6 carbon atoms and includes ethenyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl.
The term "alkynyl" refers to a straight, branched, or cyclic hydrocarbon group containing at least 1 carbon-carbon triple bond. Wherein 1-3 carbon-carbon triple bonds may be present, preferably 1 carbon-carbon triple bond is present. The term "C 2-6 Alkynyl "refers to alkynyl groups having 2 to 6 carbon atoms and includes ethynyl, propynyl, butynyl, and 3-methylbutynyl.
The term "aryl" refers to any stable 6-10 membered monocyclic or bicyclic aromatic group, for example: phenyl, naphthyl, tetrahydronaphthyl, 2,3-indanyl, biphenyl, or the like.
The term "heteroaryl" refers to an aromatic ring group formed by replacement of at least 1 ring carbon atom with a heteroatom selected from N, O or S, wherein the N atom may be further oxidized. The heteroaryl group may be a 5-7 membered monocyclic ring structure or a 7-12 membered bicyclic ring structure, preferably a 5-10 membered heteroaryl group, more preferably a 5-6 membered heteroaryl ring. In the present invention, the number of heteroatoms is preferably 1,2 or 3, including but not limited to: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridazin-3 (2H) -onyl, furyl, thienyl, thiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, triazolyl (1,2,4-triazolyl, 1,2,3-triazolyl), tetrazolyl, indazolyl, isoindolyl, benzofuranyl, benzothienyl, benzo [ d ] [1,3] dioxolanyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, and the like.
The term "arylalkyl" refers to an aryl group attached to the parent core structure through an alkyl group. Thus, "arylalkyl" encompasses the above definitions of alkyl and aryl groups.
The term "heteroarylalkyl" refers to a heterocycloalkyl group attached to the parent nucleus structure through an alkyl group. Thus, "heteroarylalkyl" embraces the definitions of alkyl and heteroaryl as described above.
The term "halogen" denotes fluorine, chlorine, bromine or iodine.
The term "haloalkyl" refers to an alkyl group optionally substituted with a halogen. Thus, "haloalkyl" encompasses the above definitions of halogen and alkyl.
The term "haloalkoxy" refers to an alkoxy group optionally substituted with a halogen. Thus, "haloalkoxy" encompasses the above definitions of halogen and alkoxy.
The term "cyano" refers to — CN.
The term "amino" refers to the group-NH 2 . The term "alkylamino" refers to an amino group wherein at least one hydrogen atom is replaced with an alkyl group, including, but not limited to: -NHCH 3 、-N(CH 3 ) 2 、-NHCH 2 CH 3 、-N(CH 2 CH 3 ) 2
The term "amido" refers to-C (O) N (R') 2 Wherein each R' is independently hydrogen or C 1-6 An alkyl group.
The term "ester group" refers to-C (O) OR ', wherein each R' is independently hydrogen OR C 1-6 An alkyl group.
(symbol)
Figure BDA0001954485700000241
Indicates the position at which the substituent is attached to the parent molecule.
The isotopically substituted derivatives include: an isotopically substituted derivative in which any hydrogen atom in formula I is substituted with 1 to 5 deuterium atoms, an isotopically substituted derivative in which any carbon atom in formula I is substituted with 1 to 3 carbon 14 atoms, or an isotopically substituted derivative in which any oxygen atom in formula I is substituted with 1 to 3 oxygen 18 atoms.
By "prodrug" is meant a compound that is metabolized in vivo to the original active compound. Prodrugs are typically inactive substances or less active than the active parent compound, but may provide convenient handling, administration, or improved metabolic properties.
The "Pharmaceutically acceptable salts" of the present invention are discussed in Berge, et al, "pharmaceutical acceptable salts", j.pharm.sci.,66,1-19 (1977), and are readily apparent to the pharmaceutical chemist, are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion, etc. The compounds of the present invention may have an acidic group, a basic group or an amphoteric group, and typical pharmaceutically acceptable salts include salts prepared by reacting the compounds of the present invention with an acid, for example: hydrochloride, hydrobromide, sulphate, pyrosulphate, hydrogen sulphate, sulphite, bisulphite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, nitrate, acetate, propionate, decanoate, octanoate, formate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, suberate, benzoate, methylbenzoate, phthalate, maleate, methanesulfonate, p-toluenesulfonate, (D, L) -tartaric acid, citric acid, maleic acid, (D, L) -malic acid, fumaric acid, succinic acid, succinate, lactate, trifluoromethanesulfonate, naphthalene-1-sulfonate, mandelate, pyruvate, stearate, ascorbate, salicylate. When the compound of the present invention contains an acidic group, pharmaceutically acceptable salts thereof may further include: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; examples of the organic base salt include salts with ammonia, alkylamines, hydroxyalkylamines, amino acids (lysine and arginine), and N-methylglucamine.
The term "isomers" as used herein means that the compounds of formula (I) of the present invention may have asymmetric centers and racemates, racemic mixtures and individual diastereomers, and all such isomers, including stereoisomers and geometric isomers, are encompassed by the present invention. In the present invention, when a compound of formula I or a salt thereof exists in stereoisomeric forms (e.g., which contain one or more asymmetric carbon atoms), individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are included within the scope of the invention. The invention also includes individual isomers of the compounds or salts represented by formula I, as well as mixtures of isomers with one or more chiral centers reversed therein. The scope of the invention includes: mixtures of stereoisomers, and purified enantiomerically or enantiomerically/diastereomerically enriched mixtures. The present invention includes mixtures of stereoisomers in all possible different combinations of all enantiomers and diastereomers. The present invention includes all combinations and subsets of stereoisomers of all specific groups defined above. The invention also includes geometric isomers, including cis and trans isomers, of the compounds of formula I or salts thereof. The "isomer" according to the present invention is preferably a "stereoisomer".
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The structures of all compounds of the invention can be determined by nuclear magnetic resonance 1 H NMR) and/or mass spectrometric detection (MS).
1 H NMR chemical shifts (. Delta.) are recorded in PPM (1)0 -6 ). NMR was performed on a Bruker AVANCE-400 spectrometer. A suitable solvent is deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), deuterated dimethylsulfoxide (DMSO-d) 6 ) Tetramethylsilane was used as internal standard (TMS).
Low resolution Mass Spectrometry (MS) was determined by an Agilent 1200HPLC/6120 mass spectrometer with the ion source being an ESI source using XBridge C18,4.6 x 50mm,3.5 μm, acid method: solvent A:0.01% trifluoroacetic acid (TFA) in water; solvent B:0.01% trifluoroacetic acid in acetonitrile; the percentages are the volume percent of solute in solution. An alkaline method: solvent A:10mM ammonium bicarbonate in water; solvent B: and (3) acetonitrile.
All compounds of the invention can be separated by a high performance liquid chromatograph, silica gel column chromatography, a thin layer silica gel plate and a rapid separator.
Flash system/Cheetah Flash column chromatography TM ) Agela Technologies MP200 is used, and Flash column Silica-CS (80 g) and Cat No. CS140080-0 are used as a matched separation column.
High performance liquid chromatograph (prep-HPLC) liquid chromatography was prepared using shimadzu LC-20, and detection wavelength: 214nm and 254nm; flow rate: 9.0 mL/min. The chromatographic column comprises: waters xbridge Pre C18, 10um,19mm × 260mm. Elution conditions (alkaline method): solvent A:10mM aqueous ammonium bicarbonate solution, solvent B: acetonitrile, elution gradient 1: a mobile phase A: 80-25% (v/v%), elution gradient 2: mobile phase B: 15-65% (v/v%); elution conditions (acid method): solvent A:0.05% aqueous trifluoroacetic acid, mobile phase B: acetonitrile; elution gradient: mobile phase B: 90-30% (v/v%).
The thin-layer silica gel plate is a tobacco stage yellow sea HSGF254 or Qingdao GF254 silica gel plate. The column chromatography is carried out by using 200-300 mesh silica gel of the yellow sea of Taiwan tobacco as carrier.
All compounds of the invention can be analyzed by Ultra Performance Liquid Chromatography (UPLC) using a Waters acquisition Hclass platform, columns: waters acquisition UPLC beam Shield RP 18.1 mm x 100mm,1.7 μm, mobile phase a: acetonitrile, mobile phase B:5mm potassium dihydrogen phosphate in water (pH adjusted to 2.5 with phosphoric acid). Gradient elution time 15min, flow rate: 0.4mL/min, detection wavelength: 214nm and 254nm; column temperature: 40 ℃; the sample volume is 1 mu L; gradient elution conditions are as follows:
time (minutes) Velocity phase A (%) Velocity phase B (%)
0.00 10 90
5.00 40 60
7.00 90 10
13.00 90 10
13.10 10 90
15.00 10 90
Example 1: synthesis of Compound 1a/1b
Figure BDA0001954485700000261
Step 1: to a solution of 1,4-dioxaspiro [4.5] decan-8-one (6.0g, 38.4 mmol), N-phenylbis (trifluoromethanesulfonimide) (16.5g, 46.1 mmol) in methyl tert-butyl ether (95 mL) at-78 ℃ under nitrogen protection was added dropwise a solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran (2.0M, 23mL) and, after completion, the reaction was stirred for 1 hour. The reaction was then warmed to room temperature and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate = 10/1) to give compound 1.1 (10.8 g, yield: 97%) as a yellow oil.
Step 2: compound 1.1 (8.0g, 27.8mmol), bis-pinacolborate (9.17g, 36.1mmol), potassium acetate (8.18g, 83.3mmol), sodium bromide (1.14g, 11.1mmol) and Pd (dppf) Cl 2 (1.0 g,1.4 mmol) of a 1,4-dioxane (100 mL) mixture was stirred at reflux overnight. The reaction system was then cooled to room temperature, the solvent was removed under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate = 8/1) to obtain compound 1.2 (4.7 g, yield: 55%) as a yellow oil.
And step 3: under nitrogen protection, compound 1.2 (3.22g, 12.1mmol), 4-chloro-6-fluoroquinoline (2.1g, 13.8mol), potassium carbonate (3.85g, 27.3mmol) and Pd (PPh) 3 ) 4 (0.22g, 0.19mmol) of water/1,4-dioxane (50ml, 4.
And 4, step 4: to a solution of compound 1.3 (2.0 g, 7.02mmol) in isopropanol (30 mL) was added Pd/C (200mg, 10%), and the reaction was stirred under a hydrogen atmosphere (hydrogen balloon) at 55 ℃ overnight. However, the device is not suitable for use in a kitchenThereafter, the reaction system was filtered through Celite to remove Pd/C, and the filtrate was concentrated under reduced pressure to give compound 1.4 (1.9 g, yield: 90%) as a yellow oil. M/z [ M + H ]] + 288.0。
And 5: a mixture of compound 1.4 (2.0 g, 6.97mmol) and hydrochloric acid (6.0M, 5 mL) in acetone (20 mL) was stirred at 45 ℃ for 48 hours. Then, the reaction system was concentrated under reduced pressure, the residue was adjusted to pH =8 to 9 with an aqueous solution of sodium hydroxide (6M), the mixture was extracted with ethyl acetate (30 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate =4/1 to 2/1) to obtain compound 1.5 (750 mg, yield: 44%) as a yellow solid.
Step 6: to a mixed solution of compound 1.5 (750mg, 3.09mmol) and p-toluenesulfonylmethylitrile (TosMIC) (784mg, 4.02mmol) in ethylene glycol dimethyl ether (20 mL) and ethanol (2 mL) under ice-bath conditions was added potassium tert-butoxide (943mg, 7.73mmol). The reaction was stirred at room temperature overnight, quenched with aqueous ammonium chloride solution, and then extracted with ethyl acetate (30 mL. Times.3) to separate the organic phase. The organic phase was washed with saturated brine, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate = 3/1) to give compound 1.6a (263 mg, less polar, single stereoisomer) and 1.6b (300 mg, more polar, single stereoisomer) as colorless oils.
And 7: to a solution of compound 1.6a (300mg, 1.18mmol) in methanol (12 mL) was added Raney nickel (wet weight, 0.5 g) under nitrogen, and the reaction system was replaced with hydrogen gas for 3 times, followed by stirring at 45 ℃ for 7 hours. After TLC (petroleum ether/ethyl acetate = 3/1) monitored disappearance of the reaction raw material, the system was filtered with celite, and the filtrate was concentrated under reduced pressure to give compound 1a (280 mg, yield: 92%) as a pale yellow oil. M/z: [ M + H] + 259.0。
Example 2: synthesis of Compound 2
Figure BDA0001954485700000271
Figure BDA0001954485700000281
Step 1: to a mixed solution of methyl 3- (6-chloro-2- (trifluoromethoxy) pyridin-3-yl) -3-oxopropanoate (2.2 g, 7.39mmol) in tetrahydrofuran (10 mL) and methanol (10 mL) was added sodium borohydride (84mg, 2.22mmol) portionwise under ice bath conditions, the reaction system was stirred at 0 ℃ for 30 minutes, then the reaction was quenched with water (10 mL), extracted with ethyl acetate (50mL. Times.2), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 2.1 (2.2 g, yield: 99%) as an off-white solid. M/z [ M + H ]] + 300.0。
Step 2: compound 2.1 (2.2 g, 7.34mmol) was dissolved in toluene (50 mL), p-toluenesulfonic acid monohydrate (1.4 g, 7.34mmol) was added, the reaction was refluxed at 150 ℃ for 10 hours, most of toluene was removed by concentration under reduced pressure, ethyl acetate (200 mL) was added, and the mixture was washed with saturated sodium bicarbonate solution (50 mLx 2) and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1) to give compound 2.2 (400 mg, yield: 19%) as a pale yellow solid. 1 H NMR(400MHz,CDCl 3 ):δ7.90(d,J=8.4Hz,1H),7.73(d,J=16.4Hz,1H),7.28(d,J=8.4Hz,1H),6.52(d,J=16.4Hz,1H),3.84(s,3H)。
And step 3: compound 2.2 (200mg, 0.71mmol) and p-toluenesulfonylmethylisocyanogen (208mg, 1.07mmol) were dissolved in anhydrous tetrahydrofuran (15 mL), potassium tert-butoxide (239mg, 2.13mmol) was added in portions under ice-bath conditions, the resulting mixture was stirred at 0 ℃ for 3 hours, quenched with water, extracted with ethyl acetate (20 mLx 2), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified with silica gel preparation plates (petroleum ether/ethyl acetate = 10/1-1/1) to give compound 2.3 (138 mg, yield: 61%) as an off-white solid. M/z [ M + H ]] + 321.0。
And 4, step 4: compound 2.3 (138mg, 0.43mmol) was dissolved in methanol (5 mL), ammonium formate (109mg, 1.73mmol) and 10% palladium on carbon (20 mg) were added, the reaction system was heated under reflux under a hydrogen atmosphere (1 atmosphere) for 16 hours, then the reaction solution was filtered with celite, the filter cake was sufficiently washed with ethyl acetate, and the filtrate was concentrated to give compound 2.4 (64 mg, crude) as an off-white solid.
And 5: compound 2.4 (64 mg, crude) was dissolved in tetrahydrofuran (5 mL), N-chlorodicarboximide (27mg, 0.20mmol) was added, the reaction system was stirred at 80 ℃ for 6 hours, then the reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate =10/1 to 3/1) to give compound 2.5 (40 mg, yield: 57%) as a white solid. M/z: [ M + H] + 321.0。
Step 6: a solution of Compound 2.5 (40mg, 0.13mmol) and aqueous sodium hydroxide (4M, 3mL) in ethanol (3 mL) was stirred under reflux for 1 hour. The reaction was then cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was adjusted to pH 4-5 with hydrochloric acid (1M), filtered, and the filter cake was dried under vacuum to give 5-chloro-4- (2- (trifluoromethoxy) pyridin-3-yl) -1H-pyrrole-3-carboxylic acid (compound 2, 30mg, crude) as a white solid. M/z [ M + H ]] + 327.0。
Example 3: synthesis of Compound 3
Figure BDA0001954485700000291
Step 1: bromoacetone (2.0g, 14.7mmol), ethyl cyanoacetate (1.66g, 14.7mmol), sodium ethoxide (1 g, 14.7mmol) and diisopropylethylamine (1.89g, 14.7mmol) were dissolved in anhydrous tetrahydrofuran (40 mL), and the reaction solution was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Flash column chromatography (30% ethyl acetate/petroleum ether) to give compound 3.1 (1.5 g, yield: 60%) as a yellow oil.
Step 2: compound 3.1 (1.2g, 7.09mmol) was dissolved in a mixed solvent of methyl t-butyl ether (3 mL) and methylene chloride (2 mL), and the above solution was slowly added dropwise to a solution of hydrobromic acid (33%, 12 mL) in acetic acid at 5 ℃The resulting mixture was stirred at this temperature for 15 minutes. TLC (petroleum ether/ethyl acetate = 4/1) detects compound 8.1 reaction completion. The reaction mixture was extracted with dichloromethane, the organic phase was separated and concentrated. The residue was purified by Flash column chromatography (30% ethyl acetate/petroleum ether) to give compound 3.2 (900 mg, yield: 56%) as a yellow solid. M/z: [ M + H] + 233.0。
And 3, step 3: a suspension of compound 3.2 (200mg, 0.86mmol), (2-methoxypyridin-3-yl) boronic acid (263mg, 1.72mmol), potassium carbonate (356mg, 2.58mmol), palladium tetrakistriphenylphosphine (92.4mg, 0.08mmol) in 1,4 dioxane (3 mL) and water (1 mL) was reacted with microwave at 120 ℃ for 1 hour. The reaction solution was then filtered, and the filtrate was extracted with ethyl acetate, the organic phase was separated and concentrated. The residue was purified by Flash column chromatography (30% ethyl acetate/petroleum ether) to give compound 3.3 (200 mg, yield: 81%) as a yellow solid. M/z [ M + H ]] + 261.0。
And 4, step 4: a solution of compound 3.3 (200mg, 0.77mmol) and aqueous sodium hydroxide (4M, 3mL) in ethanol (3 mL) was stirred at 100 ℃ for 6 hours. Then, the pH =3 to 4 was adjusted with hydrochloric acid (2M), the mixture was extracted with ethyl acetate, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by Flash column chromatography (60% ethyl acetate/petroleum ether) to give 4- (2-methoxypyridin-3-yl) -5-methyl-1H-pyrrole-3-carboxylic acid (compound 3, 53mg, yield: 30%) as a yellow oil. M/z [ M + H ]] + 233.2。
Example 4: synthesis of Compound 11
Figure BDA0001954485700000292
Step 1: to a mixed solution of 6-chloro-3- (trifluoromethoxy) pyridine-2-carboxylic acid (108mg, 0.45mmol) in tetrahydrofuran (3 mL) and acetonitrile (12 mL) was added N, N' -carbonyldiimidazole (146mg, 0.90mmol) under nitrogen protection, and the reaction was stirred at room temperature for 0.5 hours. Then, potassium monomethyl malonate (141mg, 0.90mmol), triethylamine (137mg, 1.35mmol) and magnesium chloride (190mg, 2.03mmol) were added to the reaction solution, and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness, and then quenched with hydrochloric acid (1M) and adjusted to PH =7 to 8. Extraction was performed with ethyl acetate (100 mL. Times.3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate =4/1 to 1/1) to give compound 11.1 (60 mg, yield: 45%) as a pale yellow oil.
Step 2: under ice-bath conditions, sodium hydrogen (60%, 12mg, 0.30mmol) was added in portions to a solution of compound 11.1 (60mg, 0.20mmol) in tetrahydrofuran (5 mL) under nitrogen protection, and the reaction was stirred at 0 ℃ for 0.5 h. Then, 2-bromo-1-cyclopropylethanone (50mg, 0.30mmol) was added to the reaction solution, which was then heated under reflux for 2 hours. The reaction solution was then quenched by pouring it into saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined and washed with brine. The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 11.2 (76 mg, yield: 100%) as a yellow oil.
And step 3: compound 11.2 (76mg, 0.20 mmol) and ammonium acetate (46mg, 0.60mmol) were added to ethanol (3 mL) under reflux for 6 hours under nitrogen, then the reaction was concentrated, ethyl acetate was added to the residue, and then washed with saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate = 10/1) to give compound 11.3 (37 mg, yield: 51%) as a yellow oil.
And 4, step 4: compound 11.3 (37mg, 0.10mmol), ammonium formate (25mg, 040mmol) and palladium on charcoal (20mg, 10%) were added to methanol (3 mL), the reaction system was replaced with hydrogen gas 3 times, and then refluxed under a hydrogen atmosphere for 1 hour, after which the reaction system was cooled to room temperature and filtered with celite, and the filtrate was concentrated. To the residue was added ethyl acetate, which was washed with water and saturated brine, respectively, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 11.4 (33.5 mg, yield: 100%) as a yellow oil.
And 5: a solution of Compound 11.4 (33.5mg, 0.10mmol) and an aqueous sodium hydroxide solution (4M, 3mL) in methanol (3 mL) was addedThe mixture was stirred under reflux for 2 hours. Then, the reaction system was cooled to room temperature, and water (40 mL) was added to the reaction system, followed by concentration under reduced pressure to remove the organic solvent. The residue was adjusted to pH 3 to 4 with hydrochloric acid (1M), stirred for 30 minutes, and then the aqueous phase was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 5-cyclopropyl-2- (3- (trifluoromethoxy) pyridin-2-yl) -1H-pyrrole-3-carboxylic acid (compound 11, 33mg, yield: 100%) as a yellow oil. M/z [ M + H ]] + 313.2。
Example 5: synthesis of Compound 12
Figure BDA0001954485700000301
Synthesis of 2-bromo-1- (1-methylcyclopropyl) ethanone: 1-methylcyclopropylmethyl ketone (1.0 g, 10.2mmol) was dissolved in methanol (10 mL), and the reaction was cooled to 0 ℃. Liquid bromine (1.6 g, 10.2mmol) was slowly added dropwise. The reaction solution was stirred at 0 ℃ for 2 hours. The reaction was quenched by the addition of water (10 mL). Extraction with dichloromethane was performed, organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by Flash column chromatography (petroleum ether/ethyl acetate =100/1 to 10/1) to give 2-bromo-1- (1-methylcyclopropyl) ethanone (compound 12, 790mg, yield: 44%) as a pale yellow oil.
Figure BDA0001954485700000302
By using the synthesis method of the compound 11.3, 6-chloro-3- (trifluoromethoxy) pyridine-2-carboxylic acid in the step 1 is replaced by 3- (trifluoromethoxy) pyridine-2-carboxylic acid, 2-bromo-1-cyclopropylethanone in the step 2 is replaced by 2-bromo-1- (1-methylcyclopropyl) ethanone to obtain a compound 12.3, and by using the synthesis method of the compound 11, the compound 12.3 is reacted to obtain 5- (1-methylcyclopropyl) -2- (3- (trifluoromethoxy) pyridine-2-yl) -1H-pyrrole-3-carboxylic acid (the compound 12) as a white solid.
Example 6: synthesis of Compound 13
By using the synthesis method of the compound 12, 2-bromo-1- (1-methylcyclopropyl) ethanone in the step 2 is replaced with 2-bromo-1-cyclobutylethylketone to obtain 5-cyclobutyl-2- (3- (trifluoromethoxy) pyridin-2-yl) -1H-pyrrole-3-carboxylic acid (compound 13) as a white solid.
Example 7: synthesis of Compound 14
Figure BDA0001954485700000311
Step 1: compound 11.4 (155mg, 0.48mmol) was dissolved in acetone (4 mL), potassium carbonate (133mg, 0.96mmol) and methyl iodide (82 mg) were added, respectively, and the reaction solution was heated to 60 ℃ and stirred for 12 hours. The reaction was quenched with water and extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate = 4/1) to give compound 14.1 (45 mg, yield: 28%) as a brown oil.
Step 2: compound 14.1 (45mg, 0.13mmol) was added to a mixed solution of ethanol (2 mL) and aqueous sodium hydroxide (4M, 2mL), and the reaction was stirred under reflux for 1 hour. The reaction solution was concentrated to remove the solvent, and then pH =3 to 4 was adjusted with hydrochloric acid (6M). The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 5-cyclopropyl-1-methyl-2- (3- (trifluoromethoxy) pyridin-2-yl) -1H-pyrrole-3-carboxylic acid (compound 14, 30mg, yield: 71%) as a brown oil. M/z [ M + H ]] + 313.2。
Example 8: synthesis of Compound 15
Synthesis of 1-bromo-3-hydroxy-3-methylbutan-2-one: after 3-hydroxy-3-methylbutan-2-one (1.0g, 9.8mmol) was dissolved in diethyl ether (20 mL), a solution of bromine in diethyl ether (5 mL,1.25g, 7.8mmol) was slowly dropped at room temperature, and after completion of the addition, the reaction mixture was stirred at room temperature for 10 minutes, whereupon the color of the solution changed from dark red to light yellow. The reaction solution was concentrated to give 1-bromo-3-hydroxy-3-methylbutan-2-one (1.8 g) as a yellow oil. 1 H NMR(400MHz,CDCl 3 ):δ4.71(s,2H),1.25(s,6H)。
The 2-bromo-1-cyclopropyl group in the step 2 is synthesized by using a compound 11 synthesis methodThe replacement of the ethanone by 1-bromo-3-hydroxy-3-methylbutan-2-one gave a mixture of 5- (2-hydroxypropan-2-yl) -2- (3- (trifluoromethoxy) pyridin-2-yl) -1H-pyrrole-3-carboxylic acid and 5- (prop-1-en-2-yl) -2- (3- (trifluoromethoxy) pyridin-2-yl) -1H-pyrrole-3-carboxylic acid (1/2, compound 15, partial elimination of the 2-hydroxypropan-2-yl group under basic conditions in the last step) as a white solid. M/z: [ M + H] + 313.2,331.2。
Example 9: synthesis of Compound 16
Synthesis of 2-bromo-1- (oxetan-3-yl) ethanone: a synthesis method of 2-bromo-1- (1-methylcyclopropyl) ethanone comprises reacting 1- (oxetan-3-yl) ethanone to obtain 2-bromo-1- (oxetan-3-yl) ethanone. 1 H NMR(400MHz,CDCl 3 ):δ4.87-4.76(m,4H),3.97-3.87(m,1H),2.18(s,3H)。
Using the synthesis method of compound 11, 2-bromo-1-cyclopropylethanone in step 2 was replaced with 2-bromo-1- (oxetan-3-yl) ethanone to give 5- (oxetan-3-yl) -2- (3- (trifluoromethoxy) pyridin-2-yl) -1H-pyrrole-3-carboxylic acid (compound 16) as a white solid. M/z: [ M + H] + 329.0。
Example 10: synthesis of Compound 17
Using the synthetic method of compound 14, the iodomethane in step 1 was replaced with 2-iodopropane to give 5-cyclopropyl-1-isopropyl-2- (3- (trifluoromethoxy) pyridin-2-yl) -1H-pyrrole-3-carboxylic acid (compound 17) as a white solid. M/z: [ M + H] + 355.2。
Example 11: synthesis of Compound 18
By using the synthesis method of compound 11, 2-bromo-1-cyclopropylethanone in step 2 was replaced with 4-hydroxy-3,3-dimethyl-butan-2-one to give 5- (1-hydroxy-2-methylpropan-2-yl) -2- (3- (trifluoromethoxy) pyridin-2-yl) -1H-pyrrole-3-carboxylic acid (compound 18) as a white solid. M/z: [ M + H] + 359.2。
Example 12: synthesis of Compound 19
Figure BDA0001954485700000321
Synthesis of 1-Cbz-3- (2-bromoacetyl) azetidine:
step 1&2: under ice-bath conditions, 2 drops of N, N-dimethylformamide were added dropwise to a solution of 1-Cbz-azetidine-3-carboxylic acid (1.0 g,4.5 mmol) and oxalyl chloride (1.62g, 12.8 mmol) in dichloromethane (20 mL), and after completion of addition, the reaction was stirred at 0 ℃ for 15 minutes, then warmed to room temperature and stirred for 2 hours. The reaction solution was directly concentrated under reduced pressure, the residue was dissolved in anhydrous tetrahydrofuran (20 mL), trimethylsilyldiazomethane (5.4 mL,2.5M in n-hexane) was added dropwise under ice-bath conditions, and the reaction system was stirred at room temperature overnight. The reaction solution was then concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and saturated brine, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1-Cbz-3- (2-diazoacetyl) azetidine (1.3 g, crude) as a yellow oil. M/z: [ M + H] + 260.0。
And step 3: hydrobromic acid (0.6 mL of a 48% aqueous solution) was added dropwise to a solution of 1-Cbz-3- (2-diazoacetyl) azetidine (1.3 g) in diethyl ether (20 mL) under ice-bath conditions, and the reaction was stirred at 0 ℃ for 1 hour. The reaction solution was adjusted to pH 8 with saturated sodium bicarbonate. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate =8/1 to 2/1) to give 1-Cbz-3- (2-bromoacetyl) azetidine (980 mg, yield: 73%) as a colorless oil. M/z [ M + H ]] + 312.0。
Figure BDA0001954485700000322
Figure BDA0001954485700000331
Step 1: under nitrogen, compound 11.1 (500mg, 1.70mmol) was added to acetone (20 mL) and the reaction was cooled to 0 ℃. Potassium carbonate (705mg, 5.1mmol) and 1-Cbz-3- (2-bromoacetyl) azetidine (575mg, 1.87mmol) were added to the above reaction in that orderThe mixture was stirred at room temperature for 1 hour. The reaction was quenched with water and extracted three times with ethyl acetate. The organic phases were combined and washed with brine. The organic phase was separated and concentrated to give compound 19.1 (980 mg, crude) as a yellow oil. M/z [ M + H ]] + 529.0。
Step 2: under nitrogen, compound 19.1 (980 mg) and ammonium acetate (525mg, 6.8mmol) were added to ethanol (20 mL) and stirred at reflux for 4 hours, then the reaction mixture was concentrated, ethyl acetate was added to the residue, and the organic phase was washed with saturated brine. The organic phase was separated and concentrated. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate =8/1 to 2/1) to give compound 19.2 (345 mg, yield: 40%) as a yellow oil. M/z: [ M + H] + 510.2。
And step 3: compound 19.2 (115mg, 0.23mmol) was added to a mixed solution of ethanol (2.5 mL) and aqueous sodium hydroxide (2.5 mL, 4M), and the reaction mixture was stirred under reflux for 1 hour. After cooling to room temperature, di-tert-butyl dicarbonate (100mg, 0.46mmol) was added to the reaction mixture. After the reaction system was further stirred at room temperature for 1 hour, the reaction mixture was concentrated to remove ethanol and adjusted to pH =3 to 4 with hydrochloric acid (2M). The aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 5- (1- (tert-butoxycarbonyl) azetidin-3-yl) -2- (6-chloro-3- (trifluoromethoxy) pyridin-2-yl) -1H-pyrrole-3-carboxylic acid (compound 19, 120 mg) as a yellow oil.
Example 13: synthesis of Compound 20
Figure BDA0001954485700000332
Step 1: dess-Martin oxidant (1.07g, 2.53mmol) was slowly added to a solution of methyl 3- (6-chloro-3- (trifluoromethoxy) pyridin-2-yl) -3-pyruvate (500mg, 1.68mmol) and pyridine (398mg, 5.04mmol) in dichloromethane (30 mL) under ice-bath conditions, and after the addition, the reaction was stirred at room temperature for 3 hours, then a saturated aqueous sodium thiosulfate solution (8 mL) and a saturated aqueous sodium bicarbonate solution (8 mL) were added to the reaction, and stirring was continued at room temperature for 1 hour. Extracting the reaction system with ethyl acetateTake (30 mL. Times.3). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate =6/1 to 2/1) to give compound 20.1 (270 mg, yield: 48%) as a yellow oil. M/z: [ M + H] + 312.0。
And 2, step: a solution of compound 20.1 (220mg, 0.71mmol), ammonium acetate (546mg, 7.10mmol) and cyclopropanecarbaldehyde (149mg, 2.12mmol) in acetic acid (3 mL) was stirred at 150 ℃ for 15 minutes under microwave conditions; concentrated under reduced pressure, and the residue was extracted with ethyl acetate (30 mL. Times.3). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate = 8/1-1/1) to give compound 20.2 (98mg, 31%) as a white solid. M/z [ M + H ]] + 362.0。
And step 3: a mixture of compound 20.2 (98mg, 0.27mmol), palladium on carbon (20mg, 10%) and ammonium formate (68mg, 1.08mmol) in methanol (20 mL) was replaced with hydrogen gas 3 times, and then the reaction system was stirred under reflux under a hydrogen atmosphere for 1 hour. The reaction was cooled to room temperature, filtered through celite to remove palladium on carbon, and the filtrate was concentrated to give compound 20.3 (110 mg, crude) as a white solid. M/z [ M + H ]] + 328.0。
And 4, step 4: a solution of Compound 20.3 (110mg, 0.27mmol) and aqueous sodium hydroxide (2mL, 4M) in ethanol (2 mL) was stirred at 90 ℃ for 1 hour. The organic solvent was removed by concentration under reduced pressure, the aqueous phase was adjusted to pH 4 to 5 with hydrochloric acid (1M), a solid precipitated, and filtered under reduced pressure to give 2-cyclopropyl-5- (3- (trifluoromethoxy) pyridin-2-yl) -1H-imidazole-4-carboxylic acid (compound 20, 20mg, two-step yield: 54%) as a yellow solid. M/z: [ M + H] + 314.0。
Example 14: synthesis of Compound 21
By using the synthesis method of the compound 20, the cyclopropanecarboxaldehyde in the step 2 is replaced by the ring Ding Jiaquan to obtain the 2-cyclobutyl-5- (3- (trifluoromethoxy) pyridine-2-yl) -1H-imidazole-4-carboxylic acid (compound 21) as a white solid. M/z [ M + H ]] + 328.0。
Example 15: synthesis of Compound 22
A synthetic method using compound 12The 3- (trifluoromethoxy) pyridine-2-carboxylic acid in step 1 was replaced with benzoic acid and the 2-bromo-1- (1-methylcyclopropyl) ethanone in step 2 was replaced with 2-bromo-1-cyclopropylethanone to give 5-cyclopropyl-2-phenyl-1H-pyrrole-3-carboxylic acid (compound 22) as a white solid. M/z [ M + H ]] + 228.2。
Example 16: synthesis of Compound 23
Figure BDA0001954485700000341
Step 1: to a solution of methyl 2- (6-chloro-3- (trifluoromethoxy) pyridin-2-yl) -5-methyl-1H-pyrrole-3-carboxylate (using the synthesis method of compound 11.3, 2-bromo-1-cyclopropylethanone in step 2 was replaced with bromoacetone) (280mg, 0.84mmol) in N, N-dimethylformamide (5 mL) was added sodium hydride (67.2 mg,1.68mmol, 60%) under ice bath conditions, the reaction was stirred at 0 ℃ for 30 minutes, and then (2-bromoethoxy) (tert-butyl) dimethylsilane (402mg, 1.68mmol) was added to the above reaction. The reaction system was further stirred at room temperature overnight, water was added to quench the reaction and extracted with ethyl acetate, the combined organic phases were washed with saturated brine, the organic phase was separated and concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate = 10/1-2/1) to give compound 23.1 (450 mg, crude) as a light yellow oil.
Step 2&3: using the synthesis method of compound 11, compound 23.1 is reacted to obtain 1- (2-hydroxyethyl) -5-methyl-2- (3- (trifluoromethoxy) pyridin-2-yl) -1H-pyrrole-3-carboxylic acid (compound 23). M/z [ M + H ]] + 331.2。
Example 17: synthesis of Compound 1-1
Figure BDA0001954485700000351
To a solution of the compound 11 (33mg, 0.10mmol), the compound 1a (30mg, 0.11mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (40mg, 0.21mmol) in N, N-dimethylformamide (5 mL) were slowly added N, N-diisopropylethylamine (41mg, 0.32mmol) and 4-Dimethylaminopyridine (1.3 mg, 0.01mmol), the reaction system was stirred at 45 ℃ for 2 hours, then quenched with ice water (10 mL), diluted with ethyl acetate (30 mL) and the organic phase separated, washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by prep-HPLC (basic method, mobile phase B: 15-65% (v/v%)) to give compound 1-1 (UPLC retention time: 7.125 min, 3.9mg, yield: 7%) as a white solid. M/z: [ M + H] + 553.2, 1 H NMR(400MHz,CD 3 OD):δ8.75(d,J=4.4Hz,1H),8.55-8.56(m,1H),8.05-8.09(m,1H),7.80-7.86(m,2H),7.54-7.61(m,2H),7.43-7.46(m,1H),6.25(s,1H),3.34-3.50(m,3H),2.08-2.09(m,1H),1.77-1.92(m,9H),0.89-0.93(m,2H),0.68-0.72(m,2H)。
Example 18: synthesis of Compound 1-2
Figure BDA0001954485700000352
Compound 1-2 was obtained by replacing compound 11 with compound 12 using the method for the synthesis of compound 1-1 (UPLC retention time: 7.279 min). M/z: [ M + H] + 567.2, 1 H NMR(400MHz,CD 3 OD):δ8.76-8.77(d,J=4.8Hz,1H),8.57-8.59(m,1H),8.07-8.11(m,1H),7.83-7.91(m,2H),7.58-7.63(m,2H),7.46-7.50(m,1H),6.39(s,1H),3.51-3.52(d,J=4.8Hz,2H),3.37-3.38(m,1H),2.07-2.17(m,1H),1.71-1.92(m,8H),1.47(s,3H),0.92-0.96(m,2H),0.73-0.76(m,2H)。
Example 19: synthesis of Compounds 1-3
Figure BDA0001954485700000353
Using the synthesis method of compound 1-1, compound 11 was replaced with compound 13 to give compound 1-3 (UPLC retention time: 7.361 min). M/z: [ M + H] + 567.2, 1 H NMR(400MHz,CD 3 OD):δ8.76-8.77(d,J=4.4Hz,1H),8.58-8.59(d,J=4.4Hz,1H),8.07-8.11(m,1H),7.83-7.90(m,2H),7.56-7.61(m,2H),7.46-7.49(m,1H),6.46(s,1H),3.50-3.57(m,3H),3.33-3.39(m,1H),2.03-2.39(m,6H),1.79-1.91(m,9H)。
Example 20: synthesis of Compounds 1-4
Figure BDA0001954485700000361
Using the synthesis of Compound 1-1, compound 11 was replaced with Compound 14 to give Compound 1-4 (UPLC retention time: 7.321 min). M/z [ M + H ]] + 567.2, 1 H NMR(400MHz,CD 3 OD):δ8.73-8.72(d,J=4.0Hz,1H),8.63-8.62(d,J=4.0Hz,1H),8.08-8.04(m,1H),7.87-7.82(m,2H),7.60-7.51(m,3H),6.29(s,1H),3.48(s,3H),3.42-3.39(m,2H),3.35(m,1H),2.05(m,1H),1.84-1.73(m,8H),1.29(s,1H),1.00-0.88(m,2H),0.66(s,2H)。
Example 21: synthesis of Compounds 1-5 and 1-6
Figure BDA0001954485700000362
By using a synthesis method of a compound 1-1, a compound 11 is replaced by a compound 15 to obtain a mixture of the compounds 1-5 and 1-6, and the mixture is separated by prep-HPLC (alkaline method, mobile phase B: 20-40% (5 min); 40-70% (15 min) (v/v%)) to obtain the compounds 1-5 (peak time: 16-17 min, UPLC retention time: 6.291 min) and 1-6 (peak time: 20-21 min, UPLC retention time: 7.207 min), which are all in single stereo configuration. 1-5: m/z [ M + H ]] + 571.2, 1 H NMR(400MHz,CD 3 OD):δ8.79-8.74(m,1H),8.09-8.06(m,1H),7.86-7.85(m,3H),7.61-7.52(m,3H),6.50(s,1H),3.29-3.27(m,3H),2.17-1.75(m,9H),1.59(s,6H);1-6:m/z:[M+H] + 553.2, 1 H NMR(400MHz,CD 3 OD):δ8.75-8.74(m,1H),8.59-8.58(m,1H),8.08-8.05(m,1H),7.89-7.83(m,2H),7.59-7.48(m,3H),6.69(s,1H),5.40(s,1H),4.96(s,1H),3.50-3.48(m,2H),3.36(s,1H),2.21(s,4H),1.85-1.77(m,8H)。
Example 22: synthesis of Compounds 1-7
Figure BDA0001954485700000363
Using the synthesis of Compound 1-1, compound 11 was replaced with Compound 16 to give Compound 1-7 (UPLC retention time: 6.047 min). M/z [ M + H ]] + 569.2, 1 H NMR(400MHz,CD 3 OD):δ8.75(d,J=4.8Hz,1H),8.58(d,J=4.4Hz,1H),8.11-8.03(m,1H),7.94-7.78(m,2H),7.65-7.45(m,3H),6.65(s,1H),5.04-4.99(m,4H),4.37(q,J=8.0Hz,1H),3.56-3.45(m,3H),2.06-2.00(m,1H),1.93-1.74(m,8H)。
Example 23: synthesis of Compounds 1-8
Figure BDA0001954485700000371
Using the synthesis of compound 1-1, compound 11 was replaced with compound 17 to give compound 1-8 (UPLC retention time: 7.604 min). M/z [ M + H ]] + 595.2, 1 H NMR(400MHz,CD 3 OD):δ8.73-8.72(d,J=4.0Hz,1H),8.59-8.58(d,J=4.0Hz,1H),8.08-8.04(m,1H),7.87-7.82(m,2H),7.60-7.50(m,3H),6.32(s,1H),4.38-4.31(m,1H),3.37-3.35(d,J=8.0Hz,2H),3.33-3.32(m,1H),2.03-2.02(m,1H),1.98-1.91(m,1H),1.79-1.72(m,8H),1.48-1.46(m,3H),1.43-1.41(m,3H),1.00-0.95(m,2H),0.79-0.73(m,2H)。
Example 24: synthesis of Compounds 1-9
Figure BDA0001954485700000372
Using the synthesis of Compound 1-1, compound 11 was replaced with Compound 18 to give Compound 1-9 (UPLC retention time: 6.583 min). M/z [ M + H ]] + 585.2, 1 H NMR(400MHz,CD 3 OD):δ8.98-8.97(m,1H),8.60-8.59(m,1H),8.25-8.15(m,2H),7.92-7.91(m,3H),7.51(m,1H),6.53(s,1H),3.59-3.13(m,5H),2.25-1.75(m,9H),1.33(s,6H)。
Example 25: synthesis of Compounds 1-10
Figure BDA0001954485700000373
Step 1: compound 1-10-1 (obtained by substituting compound 11 for compound 19 using the synthesis method for compound 1-1) (73mg, 0.1mmol), palladium on carbon (10mg, 10%) and ammonium formate (26mg, 0.42mmol) were added to methanol (15 mL) under reflux for 1 hour under hydrogen conditions. Cooled to room temperature, filtered to remove palladium on carbon, and the filtrate was concentrated to give compound 1-10-2 (70 mg) as a white solid. M/z [ M + H ]] + 668.2。
And 2, step: compound 1-10-2 (70 mg, crude) and trifluoroacetic acid (0.5 mL) were dissolved in dichloromethane (5 mL) and stirred at ambient temperature for 1 hour. The organic solvent was removed under reduced pressure, the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (alkaline method, mobile phase B: 80-25% (v/v%)) to give compounds 1-10 (UPLC retention time: 4.304 min, 10.1mg, yield: 17%) as off-white solids. M/z: [ M + H] + 568.2; 1 HNMR(400MHz,CD 3 OD):δ8.76-8.78(d,J=4.8Hz,1H),8.60-8.62(d,J=4.8Hz,1H),8.07-8.11(m,1H),7.85-7.92(m,2H),7.49-7.61(m,3H),6.62(s,1H),3.91-4.13(m,5H),3.51-3.53(d,J=8.0Hz,2H),3.36-3.43(m,1H),2.10-2.18(m,1H),1.75-1.95(m,8H)。
Example 26: synthesis of Compounds 1-11
Figure BDA0001954485700000381
Using the synthesis of Compound 1-1, compound 11 was replaced with Compound 22 to give Compound 1-11 (UPLC retention time: 7.197 min). M/z: [ M + H] + 468.2, 1 H NMR(400MHz,CD 3 OD):δ8.76-8.77(d,J=4.8Hz,1H),8.07-8.09(m,1H),7.87-7.90(m,1H),7.53-7.61(m,4H),7.29-7.39(m,3H),6.12(s,1H),3.45-3.47(d,J=8.0Hz,2H),3.36-3.40(m,1H),2.00-2.09(m,1H),1.74-1.93(m,9H),0.85-0.91(m,2H),0.65-0.71(m,2H)。
Example 27: synthesis of Compounds 1-12 and 1-13
Figure BDA0001954485700000382
Step 1: to a mixed solution of tetrahydrofuran, water and acetic acid (1/1/1.2, 3.2ml) in which compound 1-12-1 (45mg, 0.078mmol) was obtained by replacing compound 11 with compound 23 using the synthesis method of compound 1-1, was added cerium ammonium nitrate (174mg, 0.31mmol), the reaction system was stirred at room temperature for 2 hours, then diluted with ethyl acetate, adjusted to pH. Gtoreq.7 with a saturated aqueous sodium bicarbonate solution, the organic phase was separated and concentrated under reduced pressure to obtain a mixture (38 mg) of compounds 1-12-2 and 1-12-3 as a pale yellow oily liquid.
Step 2: dissolving the mixture (35 mg) obtained in the step 1 in methanol (1 mL), adding sodium borohydride (5 mg, 0.12mmol), adding the sodium borohydride, stirring the obtained mixture for 20 molecules at room temperature, adding hydrochloric acid (2M) to adjust the pH to be approximately equal to 5, adding saturated sodium bicarbonate solution to adjust the pH to be more than or equal to 7, extracting the aqueous phase by dichloromethane, combining the organic phases, drying by anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the residue by prep-HPLC (acid method) to obtain the compounds 1-12 (UPLC retention time: 5.525 minutes, 35mg, two-step yield: 72%) as off-white solids. [ M + H ]] + 587.0, 1 H NMR(400MHz,D 2 O):δ8.83-8.82(m,1H),8.51-8.50(m,1H),8.15-8.10(m,2H),7.90-7.82(m,3H),7.57-7.53(m,1H),6.51(s,1H),4.59(s,2H),4.18-4.14(m,1H),4.00-3.90(m,1H),3.47-3.24(m,5H),1.92(s,1H),1.70-1.61(m,8H)。
And 3, step 3: compounds 1-12 (10mg, 0.017mmol) were dissolved in pyridine (1.0 mL), p-toluenesulfonyl chloride (10mg, 0.051mmol) was added, the reaction system was stirred at 80 ℃ for 6 hours, the reaction system was concentrated to remove the solvent, and the residue was purified by prep-HPLC (acid method) to give compounds 1-13 (UPLC retention time: 4.186 minutes, 4.6mg, yield: 47%) as off-white solids. [ M + H ]] + 569.1, 1 HNMR(400MHz,D 2 O):δ8.79-8.78(m,1H),8.75-8.74(m,2H),8.50-8.46(m,2H),8.12-8.10(m,1H),8.08-8.07(m,1H),8.04-8.00(m,2H),7.98-7.76(m,3H),7.56-7.52(m,1H),6.84(s,1H),5.91(s,1H),4.18-4.10(m,1H),3.60-3.48(m,1H),3.41-3.22(m,1H),1.95-1.90(m,1H),1.69-1.56(m,9H)。
Example 28: synthesis of Compound 2-1
Figure BDA0001954485700000391
Using the method for synthesizing Compound 1-1, compound 11 was replaced with Compound 2 to give Compound 2-1 (UPLC retention time: 7.027 min). M/z [ M + H ]] + 547.2, 1 H NMR(400MHz,CD 3 OD):δ8.75-8.76(d,J=4.4Hz,1H),8.22-8.23(m,1H),8.07-8.11(m,1H),7.85-7.91(m,2H),7.54-7.63(m,2H),7.36-7.39(m,1H),7.33(s,1H),3.44(d,J=7.8Hz,2H),3.33-3.34(m,1H),2.04-2.13(m,1H),1.75-1.90(m,8H)。
Example 29: synthesis of Compound 2-2
Figure BDA0001954485700000392
Compound 2-A is obtained by replacing compound 11 with compound 3 using the synthesis method for compound 1-1.
Step 1: to a mixed solution of compound 2-A (80mg, 0.17mmol) dissolved in tetrahydrofuran (2 mL), acetic acid (3 mL) and water (2 mL) was added cerium ammonium nitrate (371mg, 0.68mmol), the reaction system was stirred at room temperature for 3 hours, the reaction was quenched with a saturated aqueous solution of sodium carbonate and adjusted to pH 8 or more, the aqueous phase was extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 2-B (80 mg, yield: 97%) as an off-white solid.
And 2, step: to a solution of compound 2-B (80mg, 0.16mmol) in methanol (3 mL) was added sodium borohydride (12mg, 0.32mmol), the reaction was stirred at room temperature for 20 minutes, then quenched with hydrochloric acid (2M) and adjusted to pH =6, adjusted to pH =8 with sodium bicarbonate solid, the aqueous phase was extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by prep-HPLC (basic method, mobile phase B: 15-65% (v/v%)) to give compound 2-2 (UPLC retention time: 4.525 minutes, 10mg, yield: 13%) as a white solid。m/z:[M+H] + 489.2, 1 H NMR(400MHz,CD 3 OD):δ8.78-8.79(m,1H),8.11-8.07(m,2H),7.90-7.87(m,1H),7.67-7.53(m,3H),7.31(s,1H),7.03-7.00(m,1H),4.38(s,2H),3.86(s,3H),3.42-3.40(m,2H),1.84(m,1H),1.82-1.74(m,1H),1.38-1.34(m,8H)。
Example 30: synthesis of Compound 3-2
Figure BDA0001954485700000393
Compound 11 was replaced with Compound 20 using the synthesis of Compound 1-1 to give Compound 3-1 (UPLC retention time: 6.346 min). M/z [ M + H ]] + 554.2, 1 H NMR(400MHz,CD 3 OD):δ8.76-8.77(d,J=4.8Hz,1H),8.62-8.63(d,J=4.8Hz,1H),8.07-8.11(m,1H),7.88-7.91(m,2H),7.56-7.63(m,3H),3.37-3.61(m,3H),2.05-2.12(m,2H),1.76-1.96(m,8H),1.05-1.07(m,4H)。
Example 31: synthesis of Compound 3-2
Figure BDA0001954485700000401
Using the synthesis of compound 1-1, compound 11 was replaced with compound 21 to give compound 3-2 (UPLC retention time: 6.715 min). M/z [ M + H ]] + 568.2, 1 H NMR(400MHz,CD 3 OD):δ8.76-8.77(d,J=4.8Hz,1H),8.64(s,1H),8.07-8.11(m,1H),7.88-7.92(m,2H),7.57-7.61(m,3H),3.69-3.73(m,1H),3.52-3.63(m,2H),3.36-3.44(m,1H),2.40-2.47(m,4H),2.07-2.19(m,2H),1.75-2.04(m,9H)。
Biological test example: determination of IDO biological Activity
Example 1: IDO inhibition activity assay (IC) based on HeLa cells 50 )
HeLa cell line origin: ATCC was cultured in MEM/EBSS liquid medium, and bovine fetal serum (10% FBS), penicillin-streptomycin (100,000U/L), nonessential amino acids (0.1 mM), and sodium pyruvate (Na-pyruvate) (1.0 mM) were added thereto. The cells were maintained in an incubator at 37 deg.C, 95% humidity and 5% carbon dioxide. IDO is expressed by co-incubation with interferon-gamma (IFN. Gamma.), which metabolizes tryptophan to N-formylkynurenine in the medium. The specific experimental method is as follows:
HeLa cells were seeded in a 96-well plate at 25,000 cells/well containing 100 μ L of medium per well, followed by overnight induction of the cells with IFN γ and a specific concentration of test compound (concentration ranging from 10 μ M to 1nM, which is its final volume in conventional medium of 200 μ L) to allow expression of human recombinant IDO. Following incubation, the supernatant (140. Mu.L) was transferred to a 96-well plate and incubation continued at 50 ℃ for 30 minutes after addition of 6.1N TCA (10. Mu.L) to effect complete hydrolysis of the IDO-produced N-formylkynurenine to kynurenine. The reaction solution was then centrifuged at 2500rpm for 10 minutes to remove solid precipitates, after which the supernatant was transferred to another 96-well plate at 100. Mu.L/well and 100. Mu.L of a 2% (w/v) solution of 4- (N, N-dimethylamino) benzaldehyde in acetic acid was added. After incubation for 10 minutes at room temperature, the yellow kynurenine solution may be recorded by a microplate reader (TECAN Infinite M1000 Pro) as its absorbance at 480 nm.
The percent inhibition at each concentration of test compound was determined by evaluating the reduction of kynurenine in the test compound system using a 0.1% DMSO blank as a reference control, and the data was given in Graph Pad
Figure BDA0001954485700000403
4 obtaining IC by non-linear regression 50 The value is obtained.
The five-membered heteroaromatic ring derivative of the present invention shows the result of the activity test, IC 50 The values are shown in the following table:
Figure BDA0001954485700000402
Figure BDA0001954485700000411
example 2: cytochrome oxidase P450 inhibitory Effect test
The inhibition of the CYP3A4 subtype of the compound was assessed by LC-MS/MS. The method comprises mixing test compound with human liver microsome solution containing CYP model substrate, incubating under the condition of adding NADPH, and calculating inhibition IC of the compound on CYP3A4 by measuring the metabolite amount of the model substrate in the reaction solution 50 . The specific experimental method is as follows:
test compounds were prepared as 10mM stock solutions in DMSO, and subsequently diluted to 4mM in acetonitrile. Simultaneously, a corresponding reference inhibitor solution is prepared for CYP subtypes, for example, ketoconazole is used as the reference inhibitor, the reference inhibitor and Ketoconazole are separately prepared (8 mu L inhibitor DMSO stock solution +12 mu L acetonitrile), and the sample prepared under the above conditions is 400X concentration. The above solution was then diluted with DMSO: a mixture of acetonitrile (v/v: 40) was diluted in 3-fold gradient to prepare final test solutions, each test compound was assigned 7 concentration points, and the initial final test concentration was 10uM. NADPH, the CYP enzyme model substrate, and the human liver microsome solution were each diluted to an appropriate concentration with a pre-warmed potassium phosphate buffer (0.1M, pH 7.4). Wherein the human liver microsome solution was purchased from BD Gentest (20 mg/mL, corning, cat # 452161).
Adding 400. Mu.L of human liver microsome solution (0.2 mg/mL) to each well of test compound in a 96-well plate, and then adding 2. Mu.L of the test compound final test sample prepared by gradient dilution; for each well for the reference inhibitor, 200. Mu.L of human liver microsome solution (0.2 mg/mL) and 1. Mu.L of the final test sample were added. The prepared corresponding model substrate is dispensed into a 96-well plate by 15 mu L per well, after the microsome solution is mixed evenly, 30 mu L of test compound/reference inhibitor-human liver microsome mixed solution is taken and transferred into the 96-well plate added with the substrate, mixed evenly and preheated for 5 minutes at 37 ℃, and then 15 mu L of 8mM NADPH solution preheated at 37 ℃ is added for starting the reaction. Each test was provided with a duplicate well control, along with a blank control with no test substance added. Incubating a 96-well plate containing a total volume of 60. Mu.L of the reaction solution at 37 ℃, adding 120. Mu.L of a cold acetonitrile solution containing an internal standard to each well to terminate the reaction after the incubation is finished, and then oscillating the 96-well plate on a microplate oscillator for 5 minutes (600 rpm/min) and placing the plateCentrifuge 6000rpm,4 ℃ and centrifuge for 20 minutes. Then, 40. Mu.L of the supernatant from each well was transferred to another 96-well plate, and 80. Mu.L of ultrapure water was added to each well, and the mixture was mixed by a shaker for 5 minutes (600 rpm/min) and centrifuged at 6000rpm,4 ℃ for 20 minutes. Then LC-MS/MS detection is carried out. The inhibition rate was determined by comparing the amount of model substrate metabolites at each test concentration and without test substance addition, and the IC of the test compound was determined by non-linear regression (non-linear) model analysis in GraphPad Prism 5.0 software with the logarithm of the test concentration as the abscissa and the inhibition rate as the ordinate 50 The value is obtained. The results are given in the following table:
Figure BDA0001954485700000412
note that ref.a (positive control) in the biological test examples is compound 14-1b disclosed in chinese patent application 201710644418.X, chemical name: 5-methyl-N- (((1r, 4r or 1s, 4s) -4- (2-methylpyridin-4-yl) cyclohexyl) methyl) -2- (pyridin-3-yl) -1H-pyrrole-3-carboxamide.

Claims (14)

1. A five-membered heteroaromatic ring derivative (I), a cis-trans isomer or a pharmaceutically acceptable salt thereof;
Figure FDA0004002564010000011
wherein the ring A is a pyrrole ring or an imidazole ring, and X, Y, Z is selected from the following combinations:
x is NR 1 Y is CR 2 And Z is CR 3 (ii) a Or X is NR 1 Y is CR 2 And Z is N;
l is CH 2
U and V are each independently selected from CH;
cy is a benzene ring or pyridyl, and is unsubstituted or substituted by 1 to 4 groups selected from halogen and C 1-6 Alkoxy or halo C 1-6 One or more substituents of alkoxy being substituted inAn arbitrary position;
r is substituted or unsubstituted quinolyl; said substituted quinolinyl is substituted at any position with 1F;
R 1 is H, methyl, ethyl, isopropyl or cyclopropyl;
R 2 is C 2-4 Alkenyl or substituted or unsubstituted C 3-6 A cycloalkyl group; when said C is 3-6 Cycloalkyl when substituted is optionally substituted by 1C 1-4 Alkyl substituted at any position;
R 3 is H;
m is 1;
n is 1.
2. The five-membered heteroaromatic ring derivative (I), a cis-trans isomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein: cy is phenyl or pyridyl; the Cy is unsubstituted or further substituted by 1 to 3 groups selected from halogen and C 1-3 Alkoxy and halogeno C 1-3 One or more substituents in the alkoxy group are substituted at any position;
and/or, R 2 Is prop-1-en-2-yl, 1-methylcyclopropyl, cyclobutyl or cyclopropyl.
3. The five-membered heteroaromatic ring derivative (I), a cis-trans isomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein: cy is
Figure FDA0004002564010000012
Wherein R is 5 And R 6 Each independently selected from H, halogen, C 1-6 Alkoxy or halo C 1-6 An alkoxy group.
4. The five-membered heteroaromatic ring derivative (I), a cis-trans isomer, or a pharmaceutically acceptable salt thereof according to claim 3, wherein: r 5 Is hydrogen, methoxy, trifluoromethoxy, ethoxy or difluoromethoxy;
and/or, R 6 Is hydrogen.
5. The five-membered heteroaromatic ring derivative of claim 1, a cis-trans isomer thereof, or a pharmaceutically acceptable salt thereof, wherein it is a compound represented by general formula (II) or (IV):
a compound represented by the general formula (II):
Figure FDA0004002564010000021
wherein Cy is
Figure FDA0004002564010000022
R 1 Is hydrogen or methyl; r 2 Is prop-1-en-2-yl, 1-methylcyclopropyl, cyclobutyl or cyclopropyl; r 3 Is H;
a compound represented by the general formula (IV):
Figure FDA0004002564010000023
wherein Cy is
Figure FDA0004002564010000024
R is->
Figure FDA0004002564010000025
R 1 Is hydrogen or methyl; r 2 Is cyclopropyl or cyclobutyl.
6. The five-membered heteroaromatic ring derivative (I), a cis-trans isomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein: the structural general formula is any one of the following types:
Figure FDA0004002564010000026
wherein X, Y, Z, cy, L and R are as defined above.
7. The five-membered heteroaromatic ring derivative of claim 1, a cis-trans isomer, or a pharmaceutically acceptable salt thereof, wherein: the compound shown as the formula (I) has any one of the following structures:
Figure FDA0004002564010000027
Figure FDA0004002564010000031
8. a process for the preparation of the five-membered heteroaromatic ring derivative (I), a cis-trans isomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein the process comprises:
in a solvent, carrying out condensation reaction on a compound I-b and a compound X-1 under the action of alkali;
Figure FDA0004002564010000041
wherein Cy, X, Y, Z, L, R, U, V, m and n are as defined in any one of claims 1 to 7.
9. A pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable adjuvant; the active ingredient comprises the five-membered heteroaromatic ring derivative (I), a cis-trans isomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7.
10. The pharmaceutical composition of claim 9, wherein: in the pharmaceutical composition, the pharmaceutically acceptable auxiliary materials are pharmaceutically acceptable carriers, diluents and/or excipients.
11. Use of the five-membered heteroaromatic ring derivative (I), a cis-trans isomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or a pharmaceutical composition according to claim 9 or 10 for the preparation of an indoleamine 2,3-dioxygenase inhibitor.
12. Use of the five-membered heteroaromatic ring derivative (I), a cis-trans isomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or a pharmaceutical composition according to claim 9 or 10 for the manufacture of a medicament for stimulating T cell proliferation.
13. Use of the five-membered heteroaromatic ring derivative (I), a cis-trans isomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or a pharmaceutical composition according to claim 9 or 10 for the manufacture of a medicament for the treatment, alleviation and/or prevention of a related disorder mediated by indoleamine 2,3-dioxygenase; the 2,3-dioxygenase mediated related diseases are viral infections, cancers or autoimmune diseases.
14. The use of claim 13, wherein: the cancer is one or more of bone cancer, liver cancer, esophagus cancer, stomach cancer, rectal cancer, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, bladder cancer, cervical cancer, testicular cancer, kidney cancer, head and neck cancer, lymph cancer, leukemia and skin cancer; the autoimmune disease is one or more of rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease, systemic scleroderma, dermatomyositis, nodular vasculitis, nephropathy, endocrine related diseases, liver disease, psoriasis and autoimmune reaction caused by infection; the viral infection is an infection caused by one or more of influenza, hepatitis b virus, hepatitis c virus, human papilloma virus, cytomegalovirus, epstein-barr virus, poliovirus, varicella-zoster virus, coxsackie virus and human immunodeficiency virus.
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