Methods for the synthesis of complement factor D inhibitors

Abstract

The present disclosure provides a method for the synthesis of complement factor D inhibitors and intermediates thereof, the method comprising subjecting an intermediate in the synthesis of a complement factor D inhibitor to a t-butyl ester deprotection reaction using a mild base.

Description

[Background technology]

[0001] The complement system is part of the innate immune system, which does not adapt to changes throughout the host's life, but is recruited and used by the adaptive immune system. For example, the complement system assists or complements the ability of antibodies and phagocytes to eliminate pathogens. This elaborate regulatory pathway allows for a rapid response to pathogens while protecting host cells from destruction. More than 30 proteins and protein fragments make up the complement system. These proteins act through opsonization (enhancing phagocytosis of antigens), chemotaxis (attraction of macrophages and neutrophils), cytolysis (rupture of the membrane of foreign cells), and agglutination (clustering and binding of pathogens to each other).

[0002] The complement system has three pathways, the classical pathway, the alternative pathway, and the lectin pathway. Complement factor D plays an early and central role in the activation of the alternative pathway of the complement cascade. Activation of the alternative pathway is initiated by spontaneous hydrolysis of a thioester bond in the C3 protein to generate C3(H2O), which binds to factor B to form the C3(H2O)B complex. Complement factor D acts to cleave factor B in the C3(H2O)B complex to form Ba and Bb. The Bb fragment remains bound to C3(H2O) to form the alternative pathway C3 convertase C3(H2O)Bb. In addition, C3b generated by any of the C3 convertases also binds to factor B to form C3bB, which is cleaved by factor D to generate the late alternative pathway C3 convertase C3bBb. This latter form of the alternative pathway C3 convertase may provide important downstream amplification within all three defined complement pathways, ultimately leading to the recruitment and assembly of additional factors into the complement cascade pathway, including cleavage of C5 to C5a and C5b, which acts in the assembly of factors C6, C7, C8, and C9 into the membrane attack complex, which can destroy pathogenic cells by lysing the cells.

[0003] Complement dysfunction or excessive activation is associated with certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury, and cancer. For example, activation of the alternative pathway of the complement cascade contributes to the generation of C3a and C5a, both of which are potent anaphylatoxins and are also involved in many inflammatory diseases. Therefore, in some instances, it is desirable to reduce the response of the complement pathway, including the alternative pathway. Some examples of disorders mediated by the complement pathway include age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), multiple sclerosis, and rheumatoid arthritis.

[0004] Additional complement-mediated disorders include those classified as C3 nephropathy (C3G), a recently defined subtype of dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) that encompasses a group of chronic kidney diseases in which increased activity of the alternative and terminal complement pathways leads to glomerular deposits of only complement C3, without immunoglobulin (Ig).

[0005] Immune complex membranoproliferative glomerulonephritis (IC-MPGN) is a renal disease that shares many clinical, pathological, genetic, and laboratory features with C3G and can therefore be considered a sister disease of C3G. In the majority of patients with IC-MPGN, an underlying disease or disorder (most commonly an infection, autoimmune disease, or monoclonal gammopathy) has been identified that causes renal disease. Patients with idiopathic IC-MPGN may have similar low C3 and normal C4 levels as observed in C3G, as well as many of the same genetic or acquired factors associated with abnormal alternative pathway activity. Although the current hypothesis suggests that the majority of IC-MPGN results from excessive classical pathway activity, patients with low C3 and normal C4 are likely to have significantly excessive alternative pathway activity. Patients with IC-MPGN who have low C3 and normal C4 may benefit from inhibiting the alternative pathway.

[0006] Other disorders that are associated with the complement cascade include atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), abdominal aortic aneurysm, hemodialysis complications, hemolytic anemia, or hemodialysis, neuromyelitis optica (NMO), myasthenia gravis (MG), fatty liver, nonalcoholic steatohepatitis (NASH), hepatitis, cirrhosis, liver failure, dermatomyositis, and amyotrophic lateral sclerosis.

[0007] Factor D is an attractive target for inhibition or modulation of the complement cascade because of its early essential role in the alternative pathway and its potential role in signal amplification within the classical and lectin complement pathways. Inhibition of factor D effectively blocks the pathway and attenuates formation of the membrane attack complex.

[0008] To this end, a number of small molecule Factor D inhibitors have been developed and investigated for potential therapeutic applications. Examples of methods for preparing these Factor D inhibitor compounds are described in PCT Patent Publications WO2015 / 130838, WO2017 / 035353, WO2017 / 035409, WO2018 / 160891, and WO2018 / 160892. New methods for the synthesis of small molecule Factor D inhibitors and intermediates therefor are desirable. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2015 / 130838 [Patent Document 2] International Publication No. 2017 / 035353 [Patent Document 3] International Publication No. 2017 / 035409 [Patent Document 4] International Publication No. 2018 / 160891 [Patent Document 5] International Publication No. 2018 / 160892 Summary of the Invention [Means for solving the problem]

[0010] The present disclosure relates generally to improved methods for preparing compounds useful in the treatment of disorders mediated by complement factor D and its intermediates.

[0011] Provided herein is a process for preparing a compound of formula (I), comprising reacting a compound of formula (II) with a weak base in a water-miscible organic solvent: [ka] In the formula, R 1 is H, halo, OH, NH2, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted 3-8 membered heterocyclyl, -C(O)NR a R a ' and R a and R a ’ each independently represents H, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, or an optionally substituted C3-C8 cycloalkyl, -C(O)R b , -OC(O)R b , or -C(O)OR b where R b are each selected from H, optionally substituted C-C alkyl, optionally substituted C-C alkoxy, and optionally substituted C-C carbocyclyl; R 2 and R 3 is independently H or an optionally substituted C1-C6 alkyl; 1 is N or CR c and R c is H, halo, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 alkoxy; X 2 and X 5 each independently represents N or CR d And each R dis independently selected from H, halo, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C3-C8 carbocyclyl, and optionally substituted 5-8 membered heteroaryl; X 3 and X 4 Each of the groups is independently N, CR e , and C.R. f Selected from R e is H, halo, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and -C(O)OR g wherein R g is H or optionally substituted C1-C6 alkyl, R f is an optionally substituted C4-C 10 aryl, optionally substituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, and optionally substituted 4-10 membered saturated or unsaturated non-aromatic heterocyclic groups containing 1-4 heteroatoms selected from N, O and S; X 3 and X 4 At least one of the following is CR f It is.

[0012] In some embodiments, the method further comprises reacting a compound of formula (III): [ka] or a pharma- ceutically acceptable salt thereof from a compound of formula (I), wherein R 4 , R 4’ , R 5 , R 5’ , R 6 , R 6’ , and R 7 each independently represents H, cyano, halo, OH, nitro, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 thioalkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C3-C8 carbocyclyloxy, -NR g R g’ , -C(O)NR g R g ’ , -OC(O)NR g R g ’ , -NR g C(O)R h , -NR g C(O)OR h , -C(O)R h , -C(O)OR h , or -C=NR h where R g , R g ’ , and R h Each of, in each instance, is independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, and optionally substituted C 3- C carbocyclyl, or R 4 and R 5 together with the atoms to which they are attached form an optionally substituted C-C cycloalkyl, or R 5 and R 6 together with the atoms to which they are attached form an optionally substituted C-C cycloalkyl, or R 4 and R 6 or R 5 and R 7 combine to form an optionally substituted C1-C2 alkylene, or R 4 and R 4’ , R 5 and R 5’ , or R 6 and R 6’ combine to form oxo, and R 8 is H or optionally substituted C1-C6 alkyl, R 9 and R 10 is independently H or methyl; 11 is H, or R 5 and R 11 are combined to give the formula -Y 1 -Y 2 -Y 3 - group, and Y1 and Y 2 each of which is an optionally substituted methylene, an optionally substituted ethylene, -CH2O-, -CH2NR i , -CH2NR i C(O)-, -CHNR i S(O)2-, -CH2S(O)2NR i -, -CH2(4- to 6-membered heterocyclylene)-, -CH2O(4- to 6-membered heterocyclylene)-, wherein R i are each H or an optionally substituted C1-C6 alkyl; Y 3 is an optionally substituted C1-C6 alkylene or an optionally substituted C2-C6 alkenylene, m is 0, 1, or 2, B is an optionally substituted C1-C6 alkylene, an optionally substituted C2-C6 alkenylene, an optionally substituted C3-C 10 Carbocyclylene, optionally substituted C6-C 14 arylene, or optionally substituted 5-10 membered heterocyclylene, and all other variables are as defined above for formula (I).

[0013] In some embodiments, preparing the compound of formula (III) or a pharma- ceutically acceptable salt thereof comprises reacting a compound of formula (I) with a compound of formula (IV): [ka] or a salt thereof, wherein all variables are as defined for formula (III). In some embodiments, preparing the compound of formula (III) or a pharma- ceutically acceptable salt thereof comprises coupling the compound of formula (I) to the hydrochloride salt of the compound of formula (IV) in the presence of, for example, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate and N,N-diisopropylethylamine in dimethylformamide. In some embodiments, preparing the compound of formula (III) or a pharma- ceutically acceptable salt thereof comprises coupling the compound of formula (I) to the hydrobromide salt of the compound of formula (IV) in the presence of, for example, propanephosphonic anhydride and N,N-diisopropylethylamine in acetonitrile. In some embodiments, preparing the compound of formula (III) or a pharma- ceutically acceptable salt thereof comprises coupling the compound of formula (I) to the trifluoroacetate salt of the compound of formula (IV), for example, in the presence of N,N-diisopropylethylamine and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate in dimethylformamide.

[0014] In some embodiments, R 8 is H.

[0015] In some embodiments, R 8 is CH3.

[0016] In some embodiments, m is 1.

[0017] In some embodiments, m is 2.

[0018] In some embodiments, m is 0.

[0019] In some embodiments, R 9 and R 10 Each of is H.

[0020] In some embodiments, R 9 is H and R 10 is CH3.

[0021] In some embodiments, R 9 and R 10 Each of these is CH3.

[0022] In some embodiments, R 5 is fluoro. In some embodiments, R 5 is fluoro and R 4 , R 4’ , R 6 , R 6’ , and R 7 are each hydrogen, for example: [ka] teeth, [ka] In some embodiments, [ka] teeth [ka] In some embodiments, R 5 is fluoro and R 5’ is an optionally substituted C1-C6 alkyl, for example: [ka] teeth, [ka] R 5 In some embodiments, where is fluoro, [ka] teeth, [ka] It is.

[0023] In some embodiments, R 4 and R 5 together with the atoms to which they are attached form an optionally substituted C-C cycloalkyl (e.g., an optionally substituted cyclopropyl), and R 4’ , R 6 , R 6’ , and R 7 Each of R is H. 5’ is H, for example, [ka] teeth, [ka] In some embodiments, R 5’ is an optionally substituted C1-C6 alkyl, for example: [ka] teeth, [ka] [ka] [ka] [ka] In some embodiments, [ka] teeth [ka] In some embodiments, [ka] teeth, [ka] It is.

[0024] In some embodiments, R 5 and R 6 together with the atoms to which they are attached form an optionally substituted C-C cycloalkyl (e.g., an optionally substituted cyclopropyl), and R 4 , R 4’ , R 5’ , R 6’ , and R 7 Each of is H, for example: [ka] teeth, [ka] It is.

[0025] In some embodiments, R 5 and R 7 combine to form an optionally substituted C1-C2 alkylene, such as [ka] teeth [ka] It is.

[0026] In some embodiments, [ka] teeth, [ka] It is.

[0027] In some embodiments, the BR 11 is an optionally substituted 5-10 membered heteroaryl, e.g., a 6 membered heteroaryl, e.g., an optionally substituted pyridyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, or an optionally substituted pyrazinyl.

[0028] In some embodiments, the BR 11 is an optionally substituted pyridyl, e.g. [ka] [ka] [ka] In some embodiments, BR 11 teeth [ka] In some embodiments, BR 11 teeth [ka] It is.

[0029] In some embodiments, the BR 11 is an optionally substituted pyrazinyl, e.g. [ka] It is.

[0030] In some embodiments, the BR 11 is an optionally substituted pyrimidinyl, e.g. [ka] It is.

[0031] In some embodiments, the BR 11 is an optionally substituted pyridazinyl, e.g. [ka] It is.

[0032] In some embodiments, the BR 11 is an optionally substituted 5-membered heteroaryl, e.g. [ka] It is.

[0033] In some embodiments, the BR 11 is a bicyclic 9- or 10-membered bicyclic heteroaryl, such as [ka] It is.

[0034] In some embodiments, the BR 11 is an optionally substituted C6-C 14 Aryl, for example optionally substituted phenyl, for example [ka] It is.

[0035] In some embodiments, the BR 11 is an optionally substituted 5-9 membered unsaturated heterocyclyl, for example [ka] It is.

[0036] In some embodiments, the BR 11 is an optionally substituted C3-C 10 Cycloalkyl, for example [ka] It is.

[0037] In some embodiments, the BR 11 is an optionally substituted C2-C6 alkenyl, for example, [ka] It is.

[0038] In some embodiments, the BR 11 is optionally substituted C1-C6 alkyl, e.g., [ka] It is.

[0039] In some embodiments, R 5 and R 11 are combined to give the formula -Y 1 -Y 2 -Y 3 -,for example, [ka] [ka] Form.

[0040] In some embodiments, [ka] teeth [ka] It is.

[0041] In some embodiments, [ka] teeth [ka] It is.

[0042] In some embodiments, the BR 11 teeth [ka] It is.

[0043] In some embodiments, the BR 11 teeth [ka] It is.

[0044] In some embodiments, X 1 is N.

[0045] In some embodiments, X 1 is CR c For example, C(CH3) or CH.

[0046] In some embodiments, X 2 is CR d In some embodiments, R d is H or optionally substituted C1-C6 alkyl, e.g., X 2 is CH or C(CH3).

[0047] In some embodiments, X 5 is CR d , for example CH.

[0048] In some embodiments, X 3 is CR f For example, X 3 CR f and X 4 is N or X 3 CR f and X 4 CR e , for example CH.

[0049] In some embodiments, X 4 is CR fFor example, X 4 CR f and X 3 is N or X 4 CR f and X 3 CR e , for example CH.

[0050] In some embodiments, R f is an optionally substituted 5-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, e.g., a 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, S.

[0051] In some embodiments, R f is an optionally substituted pyrimidinyl, e.g. [ka] [ka] In some embodiments, R f teeth [ka] It is.

[0052] In some embodiments, R f teeth, [ka] It is.

[0053] In some embodiments, R f is an optionally substituted 8-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, e.g., R fare optionally substituted pyrazolo[1,5-a]pyrimidinyl, optionally substituted [1,2,4]triazolo[1,5-a]pyridinyl, optionally substituted thiazolo[5,4-b]pyridinyl, optionally substituted imidazo[1,2-a]pyrimidinyl, optionally substituted 3H-imidazo[4,5-b]pyridinyl, 1H-thieno[3,2-c]pyrazolyl, imidazo[1,2-b]pyridazinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, and 1H-benzo[d]imidazolyl, such as [ka] In some embodiments, R f teeth [ka] In some embodiments, R f teeth [ka] It is.

[0054] In some embodiments, R f is an optionally substituted C6-C 14 Aryl. For example, R f is optionally substituted phenyl, e.g. [ka] It is.

[0055] In some embodiments, R f is an optionally substituted 6-9 membered unsaturated heterocyclyl having 1-4 heteroatoms selected from N, O, or S. In some embodiments, R f is attached to a carbon atom that is bonded through a carbon ring atom contained therein, e.g., R f teeth, [ka] In some embodiments, Rf teeth, [ka] It is.

[0056] In some embodiments, R f is an optionally substituted 5-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, e.g., [ka] It is.

[0057] In some embodiments, R 1 is -C(O)R b ,for example, [ka] In some embodiments, R 1 teeth [ka] It is.

[0058] In some embodiments, R 1 is -C(O)NR a R a ’ ,for example, [ka] In some embodiments, R 1 teeth [ka] It is.

[0059] In some embodiments, R 1 is -C(O)OR b , for example, -C(O)OCH3 or -C(O)OH.

[0060] In some embodiments, R1 is optionally substituted C1-C6 alkyl, e.g., [ka] It is.

[0061] In some embodiments, R 1 teeth [ka] It is.

[0062] In some embodiments, R 1 is cyano.

[0063] In some embodiments, R 1 is a halo.

[0064] In some embodiments, R 2 is H.

[0065] In some embodiments, R 3 is H.

[0066] In some embodiments, the compound of formula (III) is [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0067] In some embodiments, the weak base is at least one of potassium carbonate or cesium carbonate. For example, the weak base is potassium carbonate.

[0068] In some embodiments, the water-miscible organic solvent is selected from 1,2-propanediol, dimethylformamide, di-isopropylethylamine, or dimethylsulfoxide. For example, the water-miscible organic solvent is 1,2-propanediol.

[0069] definition To facilitate understanding of this disclosure, certain terms are defined below. Terms defined herein have the meanings commonly understood by those skilled in the art to which this disclosure pertains. Terms such as "a", "an", and "the" are not intended to refer to a singular entity only, but include a general class for which a specific example may be used for illustration. Terms in this specification are used to describe specific embodiments of the invention, but their usage does not limit the invention, except as outlined in the claims.

[0070] As used herein, the term "about" refers to a value within 10% above or below the stated value.

[0071] As used herein, any value provided in a range of values ​​includes both the upper and lower limits, as well as any value subsumed within the upper and lower limits.

[0072] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound that is described within the normal scope of sound medical judgment as being suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. These salts may be acid addition salts, including inorganic or organic acids. Salts may be prepared in situ during the final isolation and purification of the compounds described herein, or may be prepared separately by reacting the free base group with a suitable acid.

[0073] As used herein, the term "alkyl" refers to a branched or straight chain monovalent saturated aliphatic radical that, when unsubstituted, contains only C and H. The monovalency of an alkyl group does not include optional substituents on the alkyl group. For example, if an alkyl group is attached to a compound, the monovalency of the alkyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkyl group. In some embodiments, an alkyl group can contain, for example, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 2 carbon atoms (e.g., C1-C 12 , C1-C 10 , C1-C8, C1-C6, C1-C4, or C1-C2). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, and tert-butyl.

[0074] The term "alkylene," as used herein, refers to a divalent radical obtained by removing a hydrogen atom from a carbon atom of an alkyl group. The divalency of the alkylene group does not include optional substituents on the alkylene group.

[0075] As used herein, the term "alkenyl" refers to a branched or straight-chain monovalent unsaturated aliphatic radical that contains at least one carbon-carbon double bond, no carbon-carbon triple bonds, and, if unsubstituted, contains only C and H. The monovalency of an alkenyl group does not include optional substituents on the alkenyl group. For example, if an alkenyl group is attached to a compound, the monovalency of the alkenyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkenyl group. In some embodiments, an alkenyl group can contain, for example, 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms (e.g., C2-C3). 12 , C2-C 10 , C2-C8, C2-C6, or C2-C4). Examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, and the like.

[0076] The term "alkenylene," as used herein, refers to a divalent radical obtained by removing a hydrogen atom from a carbon atom of an alkenylene group. The divalency of the alkenylene group does not include optional substituents on the alkenylene group.

[0077] As used herein, the term "alkenyloxy" refers to a monovalent radical having the structure -O-alkenyl, where "alkenyl" is as defined herein. Examples include, but are not limited to, ethenyloxy, propenyloxy, and the like.

[0078] As used herein, the term "alkoxy" refers to a monovalent radical having the structure -O-alkyl, where "alkyl" is as defined herein. Examples include, but are not limited to, methoxy, ethoxy, and n-butoxy, i-butoxy, t-butoxy, and the like.

[0079] As used herein, the term "alkynyl" refers to a branched or straight-chain monovalent unsaturated aliphatic radical that contains at least one carbon-carbon triple bond and, if unsubstituted, contains only C and H. The monovalency of an alkynyl group does not include optional substituents on the alkynyl group. For example, if an alkynyl group is attached to a compound, the monovalency of the alkynyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkynyl group. In some embodiments, an alkynyl group can contain, for example, 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms (e.g., C2-C3). 12 , C2-C 10 , C2-C8, C2-C6, or C2-C4). Examples include, but are not limited to, ethynyl, 1-propynyl, and 3-butynyl.

[0080] As used herein, the term "aryl" refers to a monocyclic or fused ring bicyclic or polycyclic system having aromatic character with respect to the distribution of electrons throughout the ring system, e.g., phenyl, naphthyl, or phenanthryl. Aryl groups can have, for example, 6 to 16 carbons (e.g., C6-C 16 Aryl, C6-C 14 Aryl, C6-C 13 Aryl, or C6-C 10 aryl).

[0081] As used herein, the term "arylene" refers to a divalent radical obtained by removing a hydrogen atom from a carbon atom of an aryl group. The divalency of the arylene group does not include the optional substituents on the alkenylene group.

[0082] As used herein, the term "carbocyclyl" refers to a monovalent, saturated or unsaturated, non-aromatic cyclic group that, when unsubstituted, contains only C and H. A carbocyclyl (e.g., cycloalkyl or cycloalkenyl) can have, for example, 3 to 14 carbons (e.g., C3-C7, C3-C8, C3-C9, C3-C 10 , C3-C 11 , C3-C 12 , C3-C 14 The term "carbocyclyl" also includes bicyclic and polycyclic (eg, tricyclic and tetracyclic) fused ring structures.

[0083] The term "carbocyclylene," as used herein, refers to a divalent radical obtained by removing a hydrogen atom from a carbon atom of a carbocyclyl group. The divalency of the carbocyclylene group does not include optional substituents on the carbocyclylene group.

[0084] As used herein, the term "carbocyclyloxy" refers to a monovalent radical having the structure -O-carbocyclyl, e.g., an -O-cycloalkyl or an -O-cycloalkenyl radical. Included in -O-carbocyclyl, -O-cycloalkyl, and -O-cycloalkenyl are the terms "carbocyclyl," "cycloalkyl," and "cycloalkenyl," as defined herein.

[0085] As used herein, the term "cycloalkyl" refers to saturated carbocyclyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "cycloalkyl" also includes cyclic groups having bridged polycyclic structures in which one or more carbons bridge two non-adjacent members of a monocyclic ring, such as bicyclo[2.2.1]heptyl and adamantyl. The term "cycloalkyl" also includes bicyclic, tricyclic, and tetracyclic fused ring structures, such as decalin and spirocyclic compounds.

[0086] As used herein, the term "cycloalkylene" refers to a divalent radical obtained by removing a hydrogen atom from a carbon atom of a cycloalkylene group. The divalency of the cycloalkylene group does not include optional substituents on the cycloalkylene group.

[0087] As used herein, the term "cyano" refers to a monovalent radical having the structure --CN.

[0088] As used herein, the term "cycloalkenyl" refers to a monovalent unsaturated carbocyclyl group that contains at least one carbon-carbon double bond, no carbon-carbon triple bonds, and, if unsubstituted, contains only C and H and is not fully aromatic. Cycloalkenyls can have, for example, 4 to 14 carbons (e.g., C4-C7, C4-C8, C4-C9, C4-C 10 , C4-C 11 , C4-C 12 , C4-C 13 , or C4-C14 Cycloalkenyl). Exemplary cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and cycloheptenyl. The term "cycloalkenyl" also includes cyclic groups having bridged polycyclic structures in which one or more carbons bridge two non-adjacent members of a monocyclic ring, such as bicyclo[2.2.2]oct-2-ene. The term "cycloalkenyl" also includes fused ring bicyclic and polycyclic systems containing one or more double bonds, such as fluorene.

[0089] As used herein, the term "cycloalkenylene" refers to a divalent radical obtained by removing a hydrogen atom from a carbon atom of a cycloalkenylene group. The divalency of the cycloalkenylene group does not include optional substituents on the cycloalkenylene group.

[0090] As used herein, the term "halo" refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0091] As used herein, the term "heterocyclyl" refers to one or more carbon atoms and at least one heteroatom, e.g., 1 to 4 heteroatoms (e.g., 1 to 4, 1 to 3, 1 or 2, 1, 2, 3, or 4 heteroatoms) selected from N, O, and S. Heterocyclyl groups include both non-aromatic and aromatic systems. Aromatic heterocyclyl groups are referred to as "heteroaryl" groups. In some embodiments, heterocyclyl groups are 3-8 membered ring systems, 3-6 membered ring systems, 4-6 membered ring systems, 4-10 membered ring systems, 6-10 membered ring systems, 6-12 membered ring systems, 5 membered rings, or 6 membered rings, or rings or ring systems having numbers of ring atoms included within the aforementioned ranges. Exemplary 5 membered heterocyclyl groups can have 0 to 2 double bonds, and exemplary 6 membered heterocyclyl groups can have 0 to 3 double bonds. Exemplary five-membered groups include, for example, optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazole, optionally substituted thiophene, optionally substituted thiolane, optionally substituted furan, optionally substituted tetrahydrofuran, optionally substituted diazole, optionally substituted triazole, optionally substituted tetrazole, optionally substituted oxazole, optionally substituted 1,3,4-oxadiazole, optionally substituted 1,3,4-thiadiazole, optionally substituted 1,2,3,4-oxatriazole, and optionally substituted 1,2,3,4-thiatriazole. Exemplary 6-membered heterocyclyl groups include, but are not limited to, optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted 2H-pyran, optionally substituted 4H-pyran, and optionally substituted tetrahydropyran. Exemplary 7-membered heterocyclyl groups include, but are not limited to, optionally substituted azepine, optionally substituted 1,4-diazepine, optionally substituted thiepine, and optionally substituted 1,4-thiazepine.Exemplary 8-10 membered bicyclic groups include, but are not limited to, optionally substituted pyrazolo[1,5-a]pyrimidinyl, optionally substituted [1,2,4]triazolo[1,5-a]pyridinyl, optionally substituted thiazolo[5,4-b]pyridinyl, optionally substituted imidazo[1,2-a]pyrimidinyl, optionally substituted 3H-imidazo[4,5-b]pyridinyl, optionally substituted 1H-thieno[3,2-c]pyrazolyl, optionally substituted imidazo[1,2-b]pyridazinyl, optionally substituted quinazolinyl, optionally substituted quinolinyl, and optionally substituted 1H-benzo[d]imidazolyl.

[0092] As used herein, the term "heterocyclylene" refers to a divalent radical obtained by removing a hydrogen atom from a ring atom of a heterocyclylene group. The divalent value of the heterocyclylene group does not include the optional substituents on the heterocyclylene group. Aromatic heterocyclylene groups are referred to as "heteroarylene" groups.

[0093] As used herein, the term "N-protecting group" refers to a group that protects a nitrogen atom in a molecule from participating in one or more undesired reactions during chemical synthesis (e.g., oxidation reactions, or certain nucleophilic and electrophilic substitutions). Commonly used N-protecting groups are disclosed in Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, 2006.Exemplary N-protecting groups include acyl (e.g., formyl, acetyl, trifluoroacetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl), sulfonyl-containing groups (e.g., benzenesulfonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, and p-nitrobenzenesulfonyl), carbamate-forming groups (e.g., benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, benzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl), arylalkyl (e.g., triphenylmethyl), silyl groups (e.g., trimethylsilyl), and imine-forming groups (e.g., diphenylmethylene). Preferred N-protecting groups are acetyl, benzoyl, phenylsulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, o-nitrobenzenesulfonyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0094] As used herein, the term "oxo" refers to a divalent oxygen atom represented by the structure =O.

[0095] As used herein, the term "thioalkyl" refers to a monovalent radical having the structure -S-alkyl, where "alkyl" is as defined herein.

[0096] As used herein, the phrase "optionally substituted X" is intended to be equivalent to "X, where X is optionally substituted" (e.g., "alkyl, where the alkyl is optionally substituted"). It is not intended to imply that the feature "X" (e.g., alkyl) itself is optional. As used herein, the term "optionally substituted" refers to having 0, 1, or more substituents (e.g., 0-10, 0-9, 0-8, 0-7, 0-6, 0-5, 0-4, 0-3, 0-2, 0, or 1, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents).

[0097] Alkyl, alkylene, alkenyl, alkynyl, carbocyclyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heterocyclylene groups include carbocyclyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, halo, OH, cyano, alkoxy, alkenyloxy, thioalkyl, NO2, N3, NR b R c (In the formula, R b and R c each is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl), SOR d (In the formula, R d is H, alkyl, or aryl), SO2NR e R f (In the formula, R e and R f each is independently H, alkyl, or aryl, or NR b SO2R c (In the formula, R band R c Each of may be substituted with one or more of the following: (as defined above). The aryl, carbocyclyl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclyl groups may also be substituted with alkyl, alkenyl, or alkynyl. The alkyl, alkoxy, carbocyclyl, cycloalkyl, cycloalkenyl, and unsaturated heterocyclyl groups may also be substituted with oxo. In some embodiments, the substituents are further substituted as described herein. For example, a C6 aryl group, i.e., phenyl, may be substituted with an alkyl group, which may be further substituted with a heterocyclyl group.

[0098] As used herein, the term "water-miscible organic solvent" refers to an organic solvent that can form a homogeneous mixture with water and a weak base. Examples of such solvents include, but are not limited to, dimethylsulfoxide, dimethylformamide, 1,2-propanediol, and other alcohol solvents, such as methanol, ethanol, and 1,4-butanediol, or alcohol solvents having a boiling point of about 90 to about 100°C. "Water-miscible" means that up to 80%, 90%, 95%, or more of the organic solvent is soluble in water.

[0099] As used herein, the term "weak base" refers to an organic or inorganic base whose conjugate acid has a pKa of about 7 to about 12 in aqueous solution. Exemplary inorganic weak bases include, but are not limited to, alkali metal carbonates (e.g., Na2CO3, K2CO3, Cs2CO3), alkali metal bicarbonates (e.g., NaHCO3, KHCO3), alkali metal phosphates (e.g., Na3PO4, Na2HPO4, NaH2PO4, K3PO4, K2HPO4, KH2PO4). Exemplary organic weak bases include, but are not limited to, alkylamines (e.g., triethylamine, diethylamine, t-butylamine, n-butylamine, di-isopropylethylamine, and dimethylethylamine), pyridine, piperidine, morpholine, and DABCO. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0100] The present disclosure provides methods for the synthesis of small molecule inhibitors of Factor D and intermediates thereto. The small molecule inhibitors are compounds of formula (III): [ka] or a pharma- ceutically acceptable salt thereof. Exemplary compounds of formula (III) are described, for example, in U.S. Patent Nos. 9,796,741, 10,011,612, and 10,662,675, and U.S. Patent Publication Nos. 2019 / 0382376A1, 2020 / 0002347A1, and 2020 / 0071301A1, the disclosures of which are incorporated herein by reference.

[0101] The method comprises deprotecting a compound of formula (II) to give a compound of formula (I): [ka] by reacting a compound of formula (II) with a weak base (e.g., potassium carbonate or cesium carbonate) in a water-miscible solvent (e.g., 1,2-propanediol), where the variables of formulas (I), (II), and (III) are as defined above. The successful removal of the t-butyl group of the compound of formula (I) is unexpected, since it is well known in the art that t-butyl esters are stable to weak basic hydrolysis and are usually cleaved by moderately acidic hydrolysis (see, e.g., Chapter 5, pages 584-586 of Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, 2006), or by the use of a strong base such as KOH (see, e.g., E. Filali, et al., Synlett, 2009, 205-208). Indeed, prior to the present disclosure, deprotection of a compound of formula (II) was typically accomplished by treating it with an acid, e.g., trifluoroacetic acid in dichloromethane, or methanesulfonic acid or sulfuric acid in a mixture of water and acetonitrile, and in certain cases, a strong base, such as NaOH in a mixture of tetrahydrofuran and water, or LiOH in a mixture of methanol and water. Replacing the use of an acid or strong base with deprotection with a weak base offers advantages including (i) the use of safer, lower-cost solvents, (ii) easier work-up procedures, and / or (iii) improved yield and purity of the final product, which may be less susceptible to decomposition from weak bases compared to strong bases. These advantages provided by the methods described herein are useful in scaling up the synthetic process for preparing a compound of formula (III).

[0102] Compound of formula (II) The compound of formula (II) can be prepared by first reacting a compound of formula (V): [ka] (In the formula, X 3’ and X 4’One of them is N or CR e and the other is CBr), with potassium carbonate and a compound of formula (VI): [ka] in refluxing acetonitrile to give a compound of formula (VII): [ka] and then reacting a compound of formula (VII) with a group R f Organoboron reagents containing, for example, a compound of formula (VIII): [ka] can be prepared by reacting the above-mentioned amines under Suzuki coupling reaction (e.g., in the presence of Pd(PPh3)4 and cesium carbonate in a 9:1 mixture of DMF and HO) to obtain a compound of formula (II). Suitable reagents for Suzuki coupling reaction (e.g., catalysts, solvents, and reagents such as organoboron reagents) are well known in the art. Exemplary compounds of formula (II) are described, for example, in U.S. Pat. Nos. 9,796,741, 10,011,612, and 10,662,675, and U.S. Patent Publication Nos. 2019 / 0382376A1, 2020 / 0002347A1, and 2020 / 0071301A1, the disclosures of which are incorporated herein by reference.

[0103] Compound of formula (III) In some embodiments, the compound of formula (III) is prepared by reacting a compound of formula (I) with a compound of formula (IV): [ka] or a salt thereof, where all variables are as defined for formula (III), under amidation reaction conditions.

[0104] In some embodiments, the hydrochloride salt of a compound of formula (IV) is coupled to a compound of formula (I), which may be carried out in dimethylformamide in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate and N,N-diisopropylethylamine.

[0105] In some embodiments, the hydrobromide salt of a compound of formula (IV) is coupled to a compound of formula (I). The reaction may be carried out in acetonitrile in the presence of propanephosphonic anhydride and N,N-diisopropylethylamine.

[0106] In some embodiments, the trifluoroacetate salt of a compound of formula (IV) is coupled to a compound of formula (I). This reaction may be carried out in dimethylformamide in the presence of N,N-diisopropylethylamine and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate or 2-(1H0 benzotrizol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate.

[0107] Compound of formula (IV) The compound of formula (IV) can be reacted with a compound of formula (IV) according to the following reaction scheme: [ka] wherein all variables of formulas (IX)-(XII) are as defined in formula (IV) and the variable PG is an N-protecting group. Briefly, a compound of formula (IX) is treated with an amine protecting agent to form a compound of formula (X), which is then coupled to a compound of formula (XI) via an amidation reaction to form a compound of formula (XII). The amine group of the compound of formula (XII) is then deprotected (i.e., the N-protecting group is removed) to provide a compound of formula (IV).

[0108] In some embodiments, the amine protecting reagent is di-tert-butyl dicarbonate (Boc2O), the amine protecting reaction is carried out in an organic solvent (e.g., acetonitrile) in the presence of a base (e.g., 4-dimethylaminopyridine), and the N-protecting group is tert-butyl carbonate (Boc). In some embodiments where the N-protecting group is Boc, the amine deprotection reaction comprises treating the compound of formula (XII) with an acid in the presence of an organic solvent. In some embodiments, the acid is hydrochloric acid. In some embodiments, the organic solvent is dioxane. Other suitable amine protecting reagents and reaction conditions required for the introduction and removal of N-protecting groups are well known in the art (see, for example, Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, 2006).

[0109] In some embodiments, the amidation reaction is carried out in an organic solvent in the presence of a base and a coupling reagent. In some embodiments, the organic solvent is dimethylformamide. In some embodiments, the base is diisopropylethylamine. In some embodiments, the coupling reagent is (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU).

[0110] Exemplary compounds of formula (IV) and methods for their preparation are described, for example, in U.S. Pat. Nos. 9,796,741, 10,011,612, and 10,662,675, and U.S. Patent Publication Nos. 2019 / 0382376A1, 2020 / 0002347A1, and 2020 / 0071301A1, the disclosures of which are incorporated herein by reference. EXAMPLES

[0111] The examples described herein serve to illustrate the invention, and the invention is not limited to the examples given.

[0112] Comparative Example 1. Synthesis of 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid [ka] A 250 mL 3-neck round bottom flask equipped with a heating mantle, overhead stirrer, thermocouple, and distillation head was charged with tert-butyl 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate (6 g, 16 mmol), acetonitrile (8 vol, 48 ml), and 2.6 wt % aqueous sulfuric acid (10 vol, 60 mL). The mixture was heated to 75° C. until complete dissolution and then further heated to 82° C. to initiate distillation. A total of 21 mL of distillate was removed and the condenser was switched from distillation to reflux. The mixture was held at 82° C. for an additional 3 hours during which in-process control (IPC) samples were taken to monitor the reaction progress. After the reaction was complete, the mixture was cooled to 50° C. and additional water (24 mL) was added. The mixture was held at 50° C. for 30 minutes and then cooled to room temperature over 1.5 hours. The mixture was kept at room temperature for 1 hour, filtered, and the solid was washed with water (30 mL) to give 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (4.66 g, 91% yield) as a white solid. The water content was determined to be 0.09% by Karl Fischer titration. The compositions of the IPC sample, the filtered solid obtained after completion of the reaction, and the filtrate (or mother liquor; ML), as determined using ESI-MS, are shown in the table below. [Table 1]

[0113] Example 1. Synthesis of 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid [ka] Experiment 1 A mixture of tert-butyl 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate (0.5 g, 1.365 mmol) and potassium carbonate (0.566, 4.094 mmol) in a mixture of 1,2-propanediol (5 mL) and water (0.5 mL) was heated to approximately 90° C. for 1 h. The reaction mixture was cooled to room temperature and 6 N HCl (aq.) was added until pH 2. The resulting precipitate was collected, washed with water on a disposable polymer filter (Chemrus), and then baked to dryness under vacuum (approximately 30-50 mmHg at 40° C.) to give 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (0.40 g, 1.290 mmol, 94.5% yield, 100% purity). The identity of the product and the completion of the reaction are verified by comparison with known samples. 1 Confirmed by 1 H NMR and HPLC / MS. 1 H NMR (300 MHz, DMSO-d6) δ 13.27 (bs, 1H), 9.04 (s, 2H), 8.43 (s, 1H), 7.94 (m, 1H), 7.88 (m, 1H) 5.50 (s, 2H), 2.66 (m, 6H).

[0114] HPLC / MS analysis was carried out on an Acquity UPLC BEH C18 column (50 mm length x 2.1 mm; 1.7 μm particle size) at room temperature under the following conditions: [Table 2]

[0115] Experiment 2 A mixture of tert-butyl 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetate (1.0 g, 2.729 mmol) and potassium carbonate (1.132, 8.187 mmol) in a solvent mixture of n-propanol (10 mL) and water (2.0 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature and 6N HCl (aq) was added to a pH of about 2. The resulting precipitate was collected, washed with water on a disposable polymer filter (Chemrus), and then baked to dryness under vacuum (about 30-50 mmHg at 40° C.) to give 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)acetic acid (0.83 g, 2.674 mmol, 98.0% yield, 100% purity). Product identity and reaction completion were confirmed by comparison with known samples by HPLC / MS. Analyses were carried out on an Acquity UPLC BEH C18 column (50 mm length x 2.1 mm; 1.7 μm particle size) at room temperature under the conditions given in Experiment 1 above.

[0116] Example 2. 2-(3-acetyl-7-methyl-5-(2-methylpyrazolo[1,5-a]pyrimidin-6-yl)-1H-indol-1-yl)acetic acid [ka] Experiment 1 A mixture of tert-butyl 2-(3-acetyl-7-methyl-5-(2-methylpyrazolo[1,5-a]pyrimidin-6-yl)-1H-indol-1-yl)acetate (0.5 g, 1.195 mmol) and potassium carbonate (0.495, 3.584 mmol) in a mixture of DMSO (5 mL) and water (0.5 mL) was heated to approximately 90° C. for 4 hours. The reaction mixture was then cooled to room temperature and 6N HCl (aq) was added to a pH of approximately 2. The resulting precipitate was collected, washed with water on a disposable polymer filter (Chemrus), and then baked dry under vacuum (approximately 30-50 mmHg at 40° C.) to give 2-(3-acetyl-7-methyl-5-(2-methylpyrazolo[1,5-a]pyrimidin-6-yl)-1H-indol-1-yl)acetic acid (0.41 g, 3.394 mmol, 94.7% yield, 100% purity). Product identity and reaction completion were confirmed by HPLC / MS in comparison with known samples. Analysis was performed on an Acquity UPLC BEH C18 column (50 mm length×2.1 mm; 1.7 μm particle size) at room temperature (° C.) under the conditions given in Run 1 of Example 1 above.

[0117] Experiment 2 A mixture of tert-butyl 2-(3-acetyl-7-methyl-5-(2-methylpyrazolo[1,5-a]pyrimidin-6-yl)-1H-indol-1-yl)acetate (0.5 g, 1.195 mmol) and potassium carbonate (0.495, 3.584 mmol) in a mixture of 1,2-propanediol (5 mL) and water (0.5 mL) was heated to approximately 90° C. for 1 hour. The reaction mixture was then cooled to room temperature and 6N HCl (aq) was added to a pH of approximately 2. The resulting precipitate was collected, washed with water on a disposable polymer filter (Chemrus), and then baked dry under vacuum (approximately 30-50 mmHg at 40° C.) to give 2-(3-acetyl-7-methyl-5-(2-methylpyrazolo[1,5-a]pyrimidin-6-yl)-1H-indol-1-yl)acetic acid (0.43 g, 3.559 mmol, 99.3% yield, 100% purity). Product identity and reaction completion were confirmed by HPLC / MS in comparison to known samples. Analysis was performed on an Acquity UPLC BEH C18 column (50 mm length×2.1 mm; 1.7 μm particle size) at room temperature under the conditions given in Run 1 of Example 1 above.

[0118] Example 3. Synthesis of 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indol-1-yl)acetic acid [ka] A 250 mL four-neck round bottom flask equipped with a reflux condenser, stir bar, thermocouple, and gas inlet adapter was charged with 2.8 g of tert-butyl 2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indol-1-yl)acetate (7.4 mmol), followed by 3.1 g (22.4 mmol) of potassium carbonate, 28 mL of propane-1,2-diol, and 2.8 mL of water. The slurry was heated to an internal temperature of 85-90° C. and dissolution was observed. The reaction was held for 1 hour. IPC showed less than 1% starting material. The reaction was cooled to 25° C. and the pH was adjusted to a final pH of 2-2.5 by slow addition of 2N HCl. The solid was then collected by filtration and dried in a vacuum oven at 50° C. overnight to give the title compound (2.47 g, 6.86 mmol, 93% yield, 100% purity as determined by reverse phase HPLC using gradient elution). 1 H NMR (300 MHz, DMSO-d6) δ 13.39 (bs, 1H), 8.97 (s, 2H), 8.37 (m, 2H), 7.38 (s, 1H), 5.31 (s, 2H), 3.37-2.45 (m, 9H).

[0119] Other embodiments Various modifications and variations of the described compositions and methods of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention. Although the present invention has been described in connection with specific embodiments, it should be understood that the present invention as described in the claims should not be unduly limited to such specific embodiments. Indeed, various modifications of the described methods for carrying out the present invention that are apparent to those skilled in the art are intended to be within the scope of the present invention.

[0120] Other embodiments are within the claims.

Claims

1. A process for preparing a compound of formula (I), comprising the step of: 【Chemistry 75】 with a weak base in a water-miscible organic solvent, wherein R １ But, H, halo, OH, NH ２ , cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ alkenyl, optionally substituted 3- to 8-membered heterocyclyl, —C(O)NR ａ R ａ ' and R ａ and R ａ ’ each independently represents H, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl or optionally substituted C ３ -C ８ cycloalkyl, —C(O)R ｂ , -OC(O)R ｂ , or —C(O)OR ｂ and R ｂ are H, optionally substituted C, １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkoxy, and optionally substituted C ３ -C ８ carbocyclyl, R ２ and R ３ each independently represents H or an optionally substituted C １ -C ６ is alkyl, X １ But N or CR ｃ and R ｃ is H, halo, optionally substituted C １ -C ６ alkyl, or optionally substituted C １ -C ６ is an alkoxy, X ２ and X ５ each independently represents N or CR ｄ and each R ｄ are independently H, halo, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkoxy, optionally substituted C ３ -C ８ carbocyclyl, and optionally substituted 5- to 8-membered heteroaryl; and X ３ and X ４ each independently represents N, CR ｅ , and C.R. ｆ and R ｅ is H, halo, cyano, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkoxy, and —C(O)OR ｇ and R ｇ is H or optionally substituted C １ -C ６ alkyl, and R ｆ is optionally substituted C ４ -C １０ aryl, optionally substituted 5- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and optionally substituted 4- to 10-membered saturated or unsaturated non-aromatic heterocyclyl containing 1 to 4 heteroatoms selected from N, O, and S; ３ and X ４ At least one of the following is CR ｆ The preparation method.

2. Compounds of formula (III): 【Transformation 76】 or a pharmaceutically acceptable salt thereof from the compound of formula (I), During the ceremony, R ４ , R ４’ , R ５ , R ５’ , R ６ , R ６’ , and R ７ each independently represents H, cyanohalo, OH, nitro, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, C １ -C ６ Alkoxy, C １ -C ６ Thioalkyl, optionally substituted C ３ -C ８ Carbocyclyl, optionally substituted C ３ -C ８ Carbocyclyloxy, —NR ｇ R ｇ ’ , —C(O)NR ｇ R ｇ ’ , —OC(O)NR ｇ R ｇ ’ , -NR ｇ C(O)R ｈ , -NR ｇ C(O)OR ｈ , -C(O)R ｈ , -C(O)OR ｈ , or -C=NR ｈ wherein R ｇ , R ｇ ’ , and R ｈ are each independently H, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, and optionally substituted C ３ -C ８ carbocyclyl, or R ４ and R ５ together with the atoms to which they are attached, optionally substituted C ３ -C ６ forming a cycloalkyl, or R ５ and R ６ together with the atoms to which they are attached, optionally substituted C ３ -C ６ forming a cycloalkyl, or R ４ and R ６ Or R ５ and R ７ are combined to form an optionally substituted C １ -C ２ forming an alkylene, or R ４ and R ４’ , R ５ and R ５’ , or R ６ and R ６’ combine to form oxo, and R ８ is H or optionally substituted C １ -C ６ is alkyl, R ９ and R １０ each is independently H or methyl; R １１ is H, or R ５ and R １１ are combined to form the formula -Y １ -Y ２ -Y ３ - group, Y １ and Y ２ each of which is an optionally substituted methylene, an optionally substituted ethylene, —CH ２ O-, -CH ２ NR ｉ , -CH ２ NR ｉ C(O)-, -CH ２ NR ｉ S (O) ２ -, -CH ２ S (O) ２ NR ｉ -, -CH ２ (4- to 6-membered heterocyclylene)-, —CH ２ O(4- to 6-membered heterocyclylene)-; R ｉ are each H or optionally substituted C １ -C ６ is alkyl, Y ３ is optionally substituted C １ -C ６ Alkylene or optionally substituted C ２ -C ６ is alkenylene, m is 0, 1, or 2; B is optionally substituted C １ -C ６ Alkylene, optionally substituted C ２ -C ６ Alkenylene, optionally substituted C ３ -C １０ Carbocyclylene, optionally substituted C ６ -C １４ arylene, or optionally substituted 5- to 10-membered heterocyclylene; 10. The method of claim 1, wherein all other variables are as defined for formula (I) above.

3. The preparation of the compound of formula (III) or a pharmaceutically acceptable salt thereof comprises converting the compound of formula (I) to the compound of formula (IV): 【Chemical 77】 or a salt thereof, wherein all variables are as defined for formula (III).

4. said preparing said compound of formula (III) or a pharmaceutically acceptable salt thereof, coupling the compound of formula (I) to the hydrochloride salt of the compound of formula (IV), or coupling the compound of formula (I) to the hydrobromide salt of the compound of formula (IV); or coupling the compound of formula (I) to the trifluoroacetate salt of the compound of formula (IV) The method of claim 3, comprising:

5. said coupling of said compound of formula (I) to the hydrochloride salt of said compound of formula (IV) is carried out in dimethylformamide in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate and N,N-diisopropylethylamine; said coupling of said compound of formula (I) to the hydrobromide salt of said compound of formula (IV) is carried out in acetonitrile in the presence of propanephosphonic anhydride and N,N-diisopropylethylamine; 5. The method of claim 4, wherein the coupling of the compound of formula (I) to the trifluoroacetate salt of the compound of formula (IV) is carried out in dimethylformamide in the presence of N,N-diisopropylethylamine and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate.

6. In the formula, R ８ The method of any one of claims 2 to 5, wherein is H and / or m is 0.

7. During the ceremony, 【Transformation 78】 but, 【Chemistry 144】 【Chemistry 145】 【Chemistry 146】 【Chemistry 147】 The method according to any one of claims 2 to 5, wherein

8. During the ceremony, 【Chemistry 80】 but 【Chemistry 81】 or 【Chemistry 91】 The method of claim 7, wherein

9. In the formula, BR １１ The method of any one of claims 2 to 5, wherein is an optionally substituted 6-membered heteroaryl.

10. In the formula, BR １１ but, 【Chemistry 148-1】 【Chemistry 148-2】 【Chemistry 148-3】 The method of claim 9, wherein

11. In the formula, BR １１ but 【Chemistry 101】 or 【Chemical Engineering 102】 The method of claim 10, wherein

12. In the formula, BR １１ The method of any one of claims 2 to 5, wherein is an optionally substituted 5-membered heteroaryl.

13. In the formula, BR １１ but, 【Chemistry 106】 The method of claim 12, wherein

14. In the formula, BR １１ The method of any one of claims 2 to 5, wherein is optionally substituted phenyl.

15. In the formula, BR １１ but, 【Chemistry 108】 The method of claim 14, wherein

16. During the ceremony, X １ is N or CH, and / or X 2 is CH or C(CH 3 ), and / or X 5 is CH, and / or X 3 is N or CH and X 4 is CR f , and / or R 1 is —C(O)R b or —C(O)NR a R a ′; and / or R 2 is H, and / or R 3 is H; The method according to any one of claims 1 to 5.

17. In the formula, R ｆ 17. The method of claim 16, wherein is an optionally substituted 5-10 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S.

18. In the formula, R ｆ 18. The method of claim 17, wherein is a 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S.

19. In the formula, R ｆ but, 【Chemistry 149-1】 【Chemistry 149-2】 19. The method of claim 18, wherein:

20. In the formula, R ｆ but 【Chemistry 121】 20. The method of claim 19, wherein:

21. In the formula, R ｆ 18. The method of claim 17, wherein is an optionally substituted 8-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.

22. In the formula, R ｆ but, 【Chemical 123】 22. The method of claim 21, wherein:

23. In the formula, R １ but, [Chemical 150] 17. The method of claim 16, wherein:

24. In the formula, R １ but 【Chemistry 130】 or 【Chemistry 132】 24. The method of claim 23, wherein:

25. The compound of formula (III) 【Chemistry 151】 The method according to any one of claims 2 to 5, wherein the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

26. 6. The method of claim 1, wherein the weak base is at least one of potassium carbonate or cesium carbonate.

27. 27. The method of claim 26, wherein the weak base is potassium carbonate.

28. The method of any one of claims 1 to 5, wherein the water-miscible organic solvent is selected from 1,2-propanediol, dimethylformamide, di-isopropylethylamine, or dimethylsulfoxide.

29. 29. The method of claim 28, wherein the inert, water-miscible organic solvent is 1,2-propanediol.

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