Process for the synthesis of pyrazolyl derivatives useful as anticancer agents

Abstract

The present invention relates to novel processes, novel process steps, and novel intermediates useful for the synthesis of pharma- ceutical active compounds, especially KRAS G12C inhibitors.The present invention relates to a direct enantioselective chemical process for making compound A: (I) or a pharma- ceutical acceptable hydrate or solvate thereof.The present invention provides a process for the preparation of intermediate B6*, comprising reacting intermediate B4* with intermediate B5* in an atropselective coupling reaction using a chiral catalyst. [Case 1] JPEG2025503168000072.jpg43170

Description

[Technical field]

[0001] The present invention relates to pyrazolyl compounds and methods for preparing the same, more specifically, the compounds described in WO 2021 / 124222A1, which are useful for the treatment of cancer, particularly KRAS G12C mutant cancer. Thus, the present invention provides processes, process steps, and intermediates useful for the preparation of pyrazolyl compounds such as compound A, which are useful for the treatment of cancer, particularly KRAS G12C mutant cancer. The process of the present invention is suitable for the preparation of large scale, e.g., 500 g, 1 kg, or more, of the compounds described herein.

[0002] introduction RAS is a small GTPase that acts as a molecular on / off switch, adopting active / inactive states when bound to GTP / GDP, respectively. In response to growth factors, guanine exchange factors exchange GDP for GTP to turn on Ras. GTP-bound RAS adopts a conformation that recruits effector proteins to the plasma membrane, thereby activating a signaling cascade leading to cell growth, proliferation, and survival. These cancer-promoting signals are highly transient and tightly regulated, mainly due to a 100,000-fold acceleration by GTPase-activating proteins (GAPs), which are immediately switched off by the GTPase activity of RAS itself (Bos JL et al., Cell, Volume 129, Issue 5, 1 June 2007, pp 865-877). In contrast, RAS mutants are insensitive to these GAPs, causing them to reside longer in the GTP-bound state and shifting the GTP / GDP cycle according to their intrinsic hydrolysis rate toward the on-state.

[0003] The most frequently mutated gene family in cancer consists of the three RAS genes, and RAS mutations are found in approximately 25% of human tumors. Of the three paralogs, KRAS mutations are the most frequent (85% of all RAS-driven cancers), while NRAS and HRAS mutations are reported to be less frequent (12% and 3%, respectively). The majority of KRAS mutations occur at hotspot residues G12, G13, and Q61. KRAS G12C mutations account for approximately 12% of all KRAS mutations and predominate in lung cancer patients (approximately 13% of lung adenomatous carcinomas (LUAC)), approximately 3-5% of colon adenocarcinomas, smaller proportions of other cancer types, and approximately 20% of MYH polyposis colorectal adenomas (COSMIC v80 database; A. Aime'et al, Cancer genet. 2015,208:390-5).

[0004] Several orally bioavailable small molecule KRAS G12C covalent inhibitors are in clinical development, including sotorasib (AMG510) and adagrasib (MRTX-849), both of which have shown antitumor activity against KRAS G12C mutant tumors in early-phase clinical trials, with sotorasib receiving accelerated approval by the U.S. FDA in January 2022 and conditional marketing authorization by the European Commission in May 2021. Nevertheless, there remains a continuing need for improved clinical outcomes as data emerge suggesting multiple acquired resistance mechanisms in patients treated with sotorasib or adagrasib.

[0005] WO 2021 / 124222A1 discloses compounds useful for inhibiting G12C mutant KRAS, HRAS, or NRAS proteins by forming an irreversible covalent bond with the cysteine ​​at position 12. Compound A is a highly potent, selective, oral covalent inhibitor of KRASG12C and is described in Example 1a of WO 2021 / 124222A1. Compound A has the formula (Ia): [ka] It is a compound of the formula:

[0006] The chemical name of Compound A is "(Ra)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one". Alternatively, the chemical name of Compound A may be written as "a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one". Compound A is also known as "JDQ443" or "NVP-JDQ443" or "1-{6-[(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one."

[0007] Compound A is in clinical development as monotherapy and in combination with TNO155, with both strategies showing antitumor activity in patients with KRAS G12C mutant tumors.

[0008] WO 2021 / 124222 A1 is incorporated herein in its entirety, and is incorporated herein in its entirety, particularly with respect to processes and intermediates useful for the preparation of Compound A and analogs thereof. WO 2021 / 124222 A1 describes the synthesis of Compound A as follows: [ka]

[0009] Thus, the prior art shows that separation of the atropisomers by chiral chromatography is required at the very end of the synthesis. This leads to a rather low yield of the desired atropisomer (only about half of the product at the end of the multi-step synthesis route is the target atropisomer). In addition, the syntheses disclosed in the prior art require the use of special columns for chiral separation and large amounts of solvent for elution. Chiral separation results in significant costs and solvent usage as well as large amounts of waste. This makes the prior art processes environmentally unsustainable and requires long cycle times. Summary of the Invention

[0010] The present invention provides a more efficient and convenient process for the preparation of compound A. The process can be carried out on a large industrial scale and produces compound A in the required atropisomeric purity and in good yield.

[0011] In particular, the present inventors have discovered a process that allows for the synthesis of compound A in high enantiomeric excess by introducing atropeselectivity very early in the multi-step synthesis of compound A.

[0012] Thus, valuable intermediates can now be produced in good yields and atropeselectivities and used to form final products.

[0013] In an important aspect of the present invention, the present invention provides a process for preparing intermediate B6*, comprising coupling intermediate B4* and intermediate B5* using a chiral catalyst, wherein intermediates B4*, B5*, and B6* are as described herein. [ka]

[0014] The above process may be a palladium catalyzed atropselective coupling of intermediate B4* and intermediate B5*.

[0015] Thus, according to the present invention, compounds of formula (Ia) may be prepared according to the following synthetic scheme: Scheme 1 [ka]

[0016] Thus, the present invention provides a process for preparing a compound of formula (Ia), comprising one or more of steps 1, 2, 3, 4a, 4b, 5, 6, and 7, and combinations thereof, wherein steps 1 to 7 are as described in Scheme 1.

[0017] Additionally, the present invention provides a process for the preparation of a compound selected from intermediate B1*, intermediate B2*, intermediate B3*, intermediate B4*, intermediate B5*, intermediate B6*, intermediate B7*, intermediate B8*, intermediate B9*, intermediate B10*, and intermediate B11* according to Scheme 1 as defined herein.

[0018] The present invention also provides a compound selected from intermediate B1*, intermediate B2*, intermediate B3*, intermediate B4*, intermediate B5*, intermediate B6*, intermediate B7*, intermediate B8*, intermediate B9*, intermediate B10*, and intermediate B11* described herein.

[0019] The present invention also provides the use of a compound selected from intermediate B1*, intermediate B2*, intermediate B3*, intermediate B4*, intermediate B5*, intermediate B6*, intermediate B7*, intermediate B8*, intermediate B9*, intermediate B10* and intermediate B11* as set forth in Scheme 1 as defined herein for use in the process for the preparation of a compound of formula (Ia) or a salt, or hydrate or solvate thereof.

[0020] A first embodiment of the present invention is a process for the preparation of a compound of formula (Ia) or a salt, hydrate or solvate thereof, comprising [ka] A compound of formula B11b* or a salt thereof [ka] with acrylic acid or a reactive derivative of acrylic acid to form a compound of formula (I), and optionally subsequently forming a salt, hydrate or solvate of a compound of formula (Ia).

[0021] A second embodiment of the method (hereinafter also referred to as step A) comprises the step of converting compound B11* with acrylic acid or a reactive derivative thereof. [ka] (wherein r is 1, 2, 3, 4, or 5, particularly 1 to 3, e.g., 1 or 2; q is 1, 2, 3, 4, or 5, particularly 1 to 3, e.g., 1 or 2; and A is an acid anion of an organic or inorganic acid. or acylation of the deprotonated free form without its acid anion (which may be obtained, for example, by treatment with a base such as an alkali metal hydroxide, e.g. sodium hydroxide or ammonia, at a basic pH, e.g. pH 14), to yield a compound of formula (Ia) in the free form or as a hydrate or solvate.

[0022] Compound B11* can be prepared according to another embodiment of the present invention from intermediate B10* [ka] where Pr1 is a nitrogen protecting group. The compound is prepared by a process which includes deprotection of the compound designated as:

[0023] The removal of the protecting group in compound B11* can be carried out under acidic conditions, i.e. in the presence of an acid. For example, the acid can be acid H qA, where H is hydrogen capable of dissociating to form a proton, q is 1, 2, 3, 4, or 5, especially 1 to 3, e.g., 1 or 2, and A is a group capable of forming an acid anion, i.e., an acidic group.

[0024] Intermediate B10* can be, in another embodiment of the present invention, a mixture of hydrazine or a hydrate or solvate thereof and intermediate B8* [ka] (wherein Pr1 is a nitrogen protecting group, Pr2 is a protected hydroxyl group or an unsubstituted or substituted amino group, and Xc is halogeno or pseudohalogeno.) and (hereinafter also referred to as Step C) reacting

[0025] Intermediate B8* may, in another embodiment of the present invention, be intermediate B7* [ka] The compound is prepared by a process (also referred to as Step D below) comprising reacting Xc, wherein Pr1 is a nitrogen protecting group and Xc is halogeno or pseudohalogeno, with a hydroxylamine derivative of formula Pr2-NH2, wherein Pr2 is a protected hydroxyl group or an unsubstituted or substituted amino group.

[0026] Intermediate B7* may, in another embodiment of the present invention, be intermediate B6* [ka] (wherein Q is formyl or, in particular, in acetal or (further) Schiff base form, a formyl group; Pr1 is a nitrogen protecting group; and Xc is halogeno or pseudohalogeno. in the presence of an acid to convert the formyl acetal group Q to a free formyl group (also referred to below as step E).

[0027] Intermediate B6* may, in another embodiment of the present invention, be intermediate B4* [ka] (wherein Pr1 is a nitrogen protecting group; Xb is (a) (particularly) hydrogen, halogeno, -OSO2RA (wherein RA is C1-C4-alkyl, fluoro-C1-C6-alkyl or substituted phenyl) or ORB (wherein RB is C1-C4-alkyl) when Lb is borono(-B(OH)2) (preferred), a boronic acid diester moiety (preferred), BF3K, MgX (wherein X is Cl, Br or I), Zn(RZ) (wherein RZ is halogen or alkyl), Sn(RD)(RE)(RF) (wherein RD, RE and RF are each methyl, n-butyl), Si(RG)(RH)(RI) (wherein RG, RH and RI are each hydrogen, fluoro, hydroxy, alkyl, alkoxy or Li), or (b) (also) when Lb is hydrogen, halogeno, -OSO2RA (wherein R is C1-C4-alkyl, fluoro-C1-C6-alkyl or substituted phenyl) or ORB (wherein R is C1-C4-alkyl), Xb is borono (-B(OH)2) (preferred), a boronic acid diester moiety (preferred), (BF3K), MgX (wherein X is Cl, Br or I), Zn(Rz) (wherein Rz is halogen or alkyl), Sn(RD)(RE)(RF) (wherein each of R, RE and R is methyl, n-butyl), Si(RG)(RH)(RI) (wherein each of R, RH and R is hydrogen, fluoro, hydroxy, alkyl, alkoxy or Li); However, in each of (a) and (b), the moieties Xb and Lb do not have exactly the same meaning, preferably one (especially Lb) is a borono or especially a boronic acid diester moiety and the other (especially Xc) is -OSO2RA (wherein RA is C1-C4-alkyl, fluoro-C1-C6-alkyl or substituted phenyl), ORB (wherein RB is C1-C4-alkyl) or especially halogeno, especially iodo. and intermediate B5* [ka] wherein Q is formyl or a formyl group, particularly in acetal or Schiff base form; L is (a') (particularly) where X is as exactly above defined for X under (a), borono (-B(OH)2), a boronic acid diester moiety, BF3K, MgX (wherein X is Cl, Br or I), Zn(RZ) (wherein RZ is halogen or alkyl), Sn(RD)(RE)(RF) (wherein each of RD, RE and RF is methyl, n-butyl), Si(RG)(RH)(RI) (wherein each of RG, RH and RI is hydrogen, fluoro, hydroxy, alkyl, alkoxy or Li); or (b') (further) if Xb is exactly as defined above for Xb under (b), then Lb is hydrogen, halogeno, -OSO2RA (wherein RA is C1-C4-alkyl, fluoro-C1-C6-alkyl or substituted phenyl), or ORB (wherein RB is C1-C4-alkyl), Xc is a halogen or pseudohalogen; However, Lb and Xc are not exactly the same, and preferably one of them, especially Lb, is a borono or especially a boronic ester moiety, whereas the other, especially Xc, is -OSO2RA (wherein RA is C1-C4-alkyl, fluoro-C1-C6-alkyl, or substituted phenyl), ORB (wherein RB is C1-C4-alkyl), or especially halogeno, preferably fluoro. via atropselective coupling (also referred to below as Step F).

[0028] The atropselective coupling can be carried out in the presence of a palladium catalyst with a chiral additive or in the presence of a chiral (enantiomerically pure) mono- or (especially) bisphosphine ligand catalyst and a palladium source reagent. The palladium source reagent is a palladium catalyst in some embodiments. This step is very important because it serves to stereospecifically introduce the required atropisomerism as the basis for all subsequent steps leading to the compound of formula (Ia).

[0029] Intermediate B4* can be, in another embodiment of the invention, intermediate B3* when Xb is not hydrogen. [ka] (wherein Pr1 is a nitrogen protecting group). and a reagent capable of inserting a group Xb as defined above, except for hydrogen, to intermediate B4* (also referred to below as Step G).

[0030] Intermediate B3* (which is also intermediate B4* in which Xb is hydrogen and Pr1 is a nitrogen protecting group, so that in its synthesis step G above for inserting a group Xb other than hydrogen can be omitted) can be prepared as intermediate B2* in another embodiment of the present invention. [ka] (In the formula, La is (A) (particularly) Xa is hydrogen, halogeno, -OSO2RA (wherein RA is C1-C4-alkyl, fluoro-C1-C6-alkyl or substituted phenyl), or ORB (wherein RB is C1-C4-alkyl, borono, a boronic acid diester moiety, BF3K, MgX (wherein X is Cl, Br or I), Zn(RZ) (wherein RZ is halogen, alkyl or aryl), Sn(RD)(RE)(RF) (wherein each of RD, RE and RF is methyl, n-butyl), Si(RG)(RX)(RY) (wherein each of RG, RX and RY is hydrogen, fluoro, hydroxy, alkyl, alkoxy or Li); or La is hydrogen, halogeno, -OSO2RA (wherein RA is C1-C4-alkyl, fluoro-C1-C6-alkyl, or substituted phenyl), or ORB (wherein RB is C1-C4-alkyl) when (B)Xb is borono, a boronic acid diester moiety, BF3K, MgX (wherein X is Cl, Br, or I), Zn(RZ) (wherein RZ is halogen, alkyl, or aryl), Sn(RD)(RE)(RF) (wherein each of RD, RE, and RF is methyl, n-butyl), Si(RG)(RX)(RY) (wherein each of RG, RX, and RY is hydrogen, fluoro, hydroxy, alkyl, alkoxy, or Li); and intermediate B1* [ka] (wherein Pr1 is a nitrogen protecting group; Xa is (A') (especially) hydrogen, halogeno, -OSO2RA, where RA is C1-C4-alkyl, fluoro-C1-C6-alkyl or substituted phenyl, or ORB, where RB is C1-C4-alkyl, if La is exactly as defined for La under (A), or Xa is borono, a boronic acid diester moiety, BF3K, MgX (where X is Cl, Br, or I), Zn(RZ) (where RZ is halogen, alkyl, or aryl), Sn(RD)(RE)(RF) (where each of RD, RE, and RF is methyl, n-butyl), Si(RG)(RX)(RY) (where each of RG, RX, and RY is hydrogen, fluoro, hydroxy, alkyl, alkoxy, or Li) when (B')La is exactly as defined for La under (B). in the presence of a cross-coupling catalyst to give intermediate B3* (also referred to below as Step H).

[0031] The present invention also provides, in another embodiment, a process for the preparation of a compound of formula (Ia) or a hydrate or solvate thereof, comprising first step B and then step A, each as described above or specifically below.

[0032] The present invention also provides, in another embodiment, a process for the preparation of a compound of formula (Ia) or a hydrate or solvate thereof, comprising first step C, then step B and then step A, each as described above or specifically below.

[0033] The invention also provides, in another embodiment, a process for the preparation of a compound of formula (Ia) or a hydrate or solvate thereof, comprising first step D, then step C, then step B and then step A, each as set out above or as specifically described below.

[0034] The invention also provides, in another embodiment, a process for the preparation of a compound of formula (Ia) or a hydrate or solvate thereof, comprising step E, then step D, then step C, then step B, then step A, each successively as described above or as specifically described below.

[0035] The invention also provides, in another embodiment, a process for the preparation of a compound of formula (Ia) or a hydrate or solvate thereof, comprising first step F, then step E, then step D, then step C, then step B and then step A, each as set out above or as specifically described below.

[0036] The invention also provides, in another embodiment, a process for the preparation of a compound of formula (Ia) or a hydrate or solvate thereof, comprising step H, then step G, then step F, then step E, then step D, then step C, then step B, then step A, each as described above or below.

[0037] The invention also provides, in another embodiment, a process for the preparation of a compound of formula (Ia) or a hydrate or solvate thereof, comprising step H, then step G, then step F, then step E, then step D, then step C, then step B, then step A, each as described above or below.

[0038] The present invention also provides, in another embodiment, a process for the manufacture of intermediate B8* as defined above or below, comprising step E, then step D, then step C, each as described above or specifically described below.

[0039] The present invention also provides, in another embodiment, a process for the preparation of intermediate B10* as defined above or below, comprising step F, then step E, then step D, then step C, each as described above or specifically described below.

[0040] The present invention also provides, in another embodiment, a process for the preparation of a compound of formula B11* as defined above or below, comprising step F, then step E, then step D, then step C, then step B, each as described above or specifically described below.

[0041] Another embodiment of the present invention relates to intermediate B6*, especially intermediate B6, as defined above or specifically below.

[0042] Another embodiment of the present invention relates to intermediate B7*, especially intermediate B7, as defined above or specifically below.

[0043] Another embodiment of the present invention relates to intermediate B8*, especially intermediate B8, as defined above or specifically below.

[0044] Another embodiment of the present invention relates to intermediate B10*, especially intermediate B10, as defined above or specifically below.

[0045] Another embodiment of the present invention relates to intermediate B11*, especially intermediate B11, as defined above or below.

[0046] A particular embodiment of the present invention is represented by the following reaction scheme: [ka] (wherein in intermediate B1', Xa and Pr1 are as defined above or below for intermediate B1*, in intermediate B2', La is as defined above or below for intermediate B2*, in intermediate B3', Pr1 is as defined above for intermediate B3*, in intermediate B4', Xb and Pr1 are as defined above or below for intermediate B4*, in intermediate B5', Q, Xc, and Lb are as defined above or below for intermediate B5*, and in intermediate B6 in intermediate B6', Q, Pr1, and Xc are as defined above or below for intermediate B6*; in intermediate B7', Pr1 and Xc are as defined above or below for intermediate B7*; in intermediate B8', Pr1, Xc, and Pr2 are as defined above or below for intermediate B8*; in intermediate B10', Pr1 is as defined above or below for intermediate B10*; and in intermediate B11', A, q, and r are as defined above for intermediate B11*. Preferably, all moieties are as defined below for compounds B1-B11 of the "Special Scheme" given in the Examples section. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] The present invention relates to any of the embodiments set forth above, below, or as defined in the claims.

[0048] The following definitions also apply unless otherwise specified or clear from the context, and in each embodiment may replace one or more or all of the general definitions, thereby resulting in other embodiments of the invention that should thus be considered as specifically disclosed herein: The compounds of formula (Ia) are atropisomers (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., pp. 1142-55).

[0049] Enantiomeric purity is typically expressed in terms of enantiomeric excess ("ee" or "ee"), which is herein represented by the following formula: ee(%)=(|F R -F S |×100)% (In the formula, F R is the mole fraction of the desired enantiomer and F S is the mole fraction of the other enantiomer) It is expressed as a percentage (%) as defined by .

[0050] As used herein, the terms "halogeno", "halogen", or "halo" refer to fluoro, bromo, chloro, or iodo. Halogen substituents and moieties such as alkyl substituted with halogens (halo-alkyl or halogeno-alkyl) can be mono-, poly-, or perhalogenated. Chloro or especially bromo or iodo are particularly advantageous when these moieties are to be displaced in coupling reactions.

[0051] As used herein, the term "pseudohalogeno" or "pseudohalogen" is used to mean a strongly bonded linear or planar monovalent radical capable of forming anions, hydroacids, neutral dipseudohalogens, and interpseudohalogens. Examples are the monovalent radical "Y" (e.g., Y=CN, OCN, N) capable of forming the anion "Y-", hydroacids HY, dipseudohalogens Y2, and interpseudohalogens XY (X=halogen or pseudohalogen).

[0052] The substituents and features represented by the variables in intermediates B11* to B1* described above (and defined in more detail below) preferably have the following meanings:

[0053] acid H q and acid anion H in A q-r A r(-) A in the formula (I) is preferably an acid H qIn the case of A, it is an acid group that, when deprotonated, forms an acid anion group together with the proton. q A can be an inorganic acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfinic acid, pyrosulfuric acid, phosphoric acid, pyrophosphoric acid, as well as acidic resins. q A can be an inorganic acid such as acetic acid, propionic acid, glycolic acid, oxalic acid, acrylic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, or a sulfonic acid such as an alkylsulfonic acid, such as methanesulfonic acid or ethanesulfonic acid, an arylsulfonic acid, such as phenylsulfonic acid or toluenesulfonic acid, sulfosalicylic acid, trifluoroacetic acid, trifluoroethanesulfonic acid, etc. q A can also be an acid selected from the group consisting of sulfuric acid, nitric acid, phosphoric acid, acetic acid, and trifluoroacetic acid.

[0054] r protons acid H q When removed from A, the result is an anion with qr hydrogens and r negative charges.

[0055] The number "q" is an integer 1, 2, 3, 4, or 5, especially 1 to 3, e.g., 1 or 2.

[0056] The number "r" is an integer 1, 2, 3, 4, or 5, especially 1 to 3, e.g., 1 or 2.

[0057] Q is formyl or (a) [ka] wherein R1 and R2 are independently selected from alkyl or arylalkyl, or together form an alkenyl bridge which may be unsubstituted or substituted with one or more moieties selected from alkyl, aryl, and arylalkyl, some preferred moieties being: [ka] wherein R1 and R2 are independently selected from hydrogen, alkyl, and aryl; [ka] wherein R1 and R2 are independently selected from hydrogen, alkyl, and aryl. and The following group: [ka] is a special case) and (b) -CH=N-R', where R' is selected from the group consisting of alkyl, aryl, alkoxy, and -S(=O)-R'', where R'' is selected from alkyl, aryl, and alkoxy, e.g., -S(=O)-alkyl (e.g., tert-butyl) or -S(=O)phenyl. The formyl group is an acetal or Schiff base form selected from the group consisting of:

[0058] When the group at position Q is formyl (-CHO), the corresponding compound is intermediate B7*.

[0059] Pr1 is a nitrogen protecting group (meaning a nitrogen protecting group that protects a secondary amino moiety), particularly one that can be removed by not too harsh acidic conditions and maintains the integrity of the remaining part of the molecule to be deprotected. As used herein, the term "nitrogen protecting group" (PG) in the compounds described herein means a group that should protect the corresponding functional group from undesired secondary reactions, such as acylation, etherification, esterification, oxidation, solvolysis, and similar reactions. It can be removed under deprotection conditions. Depending on the protecting group used, the skilled person will be familiar with how to remove the protecting group to obtain the free amino moiety by reference to known procedures. These include organic chemistry textbooks and literature procedures, such as J.F.W.M.Omie, "Protective Groups in Organic Chemistry" (1973), Springer, "Methoden der organischen Chemie" (Methods of organic chemistry), Houben-Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974, or P.G.M.Wuts, "Greene's Protective Groups in Organic Synthesis" (eg 5 th ed., 2014) and “Methoden der organischen Chemie” (Methods of Organic Chemistry).

[0060] Preferred nitrogen protecting groups include the following: C1-C6 alkyl (e.g., tert-butyl), preferably C1-C4 alkyl, more preferably C1-C2 alkyl, most preferably C1-alkyl mono-, di-, or tri-substituted with trialkylsilyl-C1-C7 alkoxy (e.g., trimethylsilylethoxy); aryl, preferably phenyl, or a heterocyclic group (e.g. benzyl, cumyl, benzhydryl, pyrrolidinyl, trityl, pyrrolidinylmethyl, 1-methyl-1,1-dimethylbenzyl, (phenyl)methylbenzene), where the aryl ring or the heterocyclic group is unsubstituted or substituted by one or more, e.g. two or three, residues selected from the group consisting of C1-C7 alkyl, hydroxy, C1-C7 alkoxy (e.g. para-methoxybenzyl (PMB)), C2-C8-alkanoyl-oxy, halogen, nitro, cyano, and CF3; arylalkyl, e.g., benzyl or methoxybenzyl) (MPM=PMB) Aryl-C1-C2-alkoxycarbonyl (preferably phenyl-C1-C2-alkoxycarbonyl (e.g. benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), Pivaloyloxymethyl (POM), C1-C 10 -alkenyloxycarbonyl, C1-C6 alkylcarbonyl (e.g., acetyl or pivaloyl), C6-C 10 -arylcarbonyl, C1-C6-alkoxycarbonyl (e.g., tert-butoxycarbonyl (Boc), methylcarbonyl, trichloroethoxycarbonyl (Troc), pivaloyl (Piv), allyloxycarbonyl), C6-C 10 -aryl C1-C6-alkoxycarbonyl (e.g., 9-fluorenylmethyloxycarbonyl (Fmoc)), allyl or cinnamyl, sulfonyl or sulfenyl, succinimidyl group, silyl group (e.g., triarylsilyl, trialkylsilyl, triethylsilyl (TES), trimethylsilylethoxymethyl (SEM), trimethylsilyl (TMS), triisopropylsilyl, or tertbutyldimethylsilyl) Examples include:

[0061] In an embodiment of the invention, the nitrogen protecting group is C1-C6-alkoxycarbonyl (e.g., tert-butoxycarbonyl (Boc), methyloxycarbonyl, trichloroethoxycarbonyl (Troc), pivaloyl (Piv), allyloxycarbonyl). More preferably, the nitrogen protecting group is tert-butoxycarbonyl.

[0062] Particularly preferred Pr1 is selected from the group consisting of tert-butoxycarbonyl (Boc), carbobenzoxycarbonyl (Cbz), benzyl (Bn), methoxybenzyl (MPM), trifluoroacetyl, acetyl, fluoren-9-yl-methoxycarbonyl (Fmoc), and trityl (Tr).

[0063] More preferably, the nitrogen protecting group is tert.-butoxycarbonyl (Boc).

[0064] In any of the intermediates, functional groups may be optionally protected (e.g., the free NH group in intermediates B10*, B10', and B10 and in intermediates B11*, B11', and B11) and the protecting groups may be removed at any desired stage so that the final compounds of formula (Ia) are obtained in free, hydrated or solvated form.

[0065] Xc is a halogen or pseudohalogeno, particularly selected from the group consisting of F, Cl, Br, I, CN, and NO2.

[0066] Pr2 is preferably (a) Alkyloxy and (b) unsubstituted or substituted amino, particularly NR″′R″″, where R″′ and R″″ are independently selected from the group consisting of hydrogen and alkyl. is selected from.

[0067] Xb, in the case of (a) as described above under intermediate B4*, is selected from the group consisting of halogeno, especially fluoro or especially chloro, bromo or iodo, and -OSO2RA, where R A is C1-C4-alkyl, such as methyl (thus resulting in a mesylate), fluoro-C1-C6-alkyl, especially perfluoro-C1-C6-alkyl, especially trifluoromethyl, or unsubstituted or (especially C1-C4-alkyl-e.g. methyl-) substituted phenyl, such as toluenesulfonyl, for example o-, m- or p-toluenesulfonyl, for example Xb is a mesylate, triflate or tosylate moiety. Alternatively, it is defined above under (b) under Intermediate B4* as borono (-B(OH)2), a boronic acid diester moiety, BF3K, MgX (where X is Cl, Br, or I), Zn(RZ) (where RZ is halogen or alkyl), Sn(RD)(RE)(RF) (where each of RD, RE, and RF is methyl, n-butyl), Si(RG)(RH)(RI) (where each of RG, RH, and RI is hydrogen, fluoro, hydroxy, alkyl, alkoxy, or Li) (see specific definitions below under Lb).

[0068] Lb is preferably (in case (a') described above under formula B5*) (I) borono or boronic acid diester moieties BR*R**, where R* and R** are independently selected from the group consisting of alkyl and alkoxy, or taken together form an unsubstituted or (e.g. methyl or ethyl) substituted alkylene bridge, the most commonly used boronate groups being of the formula [ka] (selected from those having (II) BF3K, (III) MgX, where X is preferably selected from Cl, Br, and I; (IV) ZnR***, where R*** is halogen or alkyl; (V) SnR1*R2*R3*, where R1*, R2*, and R3* are independently selected from alkyl, in particular methyl and n-butyl; and (VI) SiR1**R2**R3**, where R1**, R2**, and R3** are independently selected from hydrogen, fluoro, hydroxyl, alkyl, especially methyl and ethyl, and alkoxy, especially methoxy or ethoxy; is selected from the group consisting of:

[0069] Alternatively, Lb is hydrogen, halogeno, -OS2RA (wherein RA is C1-C4-alkyl, fluoro-C1-C6-alkyl or substituted phenyl) or ORB (wherein RB is C1-C4-alkyl as defined below for Xb), as defined in the case of (b') under formula B5* above, in particular as defined under (a) under intermediate B5*.

[0070] Most preferred are borono or boronic acid diester moieties as defined for Lb under (I).

[0071] La is preferably independently selected from the moieties defined for Lb, especially the more specific groups such as borono and boronic acid diester moieties defined under (I) for Lb, which may further be defined as under its definition under (B) under intermediate B2* above.

[0072] Lc is preferably (a) alkoxy, such as methoxy and ethoxy, and (b) NR'*R*', where R'* and R*' are independently selected from hydrogen and alkyl, such as methyl and ethyl. is selected from the group consisting of:

[0073] Xa is preferably independently selected from the groups defined for Xb, in particular the groups defined as under (A') above under intermediate B1* or the groups defined as under (B') above under intermediate B1*.

[0074] Where a chiral mono- or (especially) bisphosphine ligand catalyst (and palladium source reagent) is mentioned, this is preferably a chiral bisphosphine ligand or its monooxide, such as (R)H8-BINAP ([(1R)-5,5',6,6',7,7',8,8'-octahydro-[1,1'-binaphthalene]-2,2'-diyl]-bis-[diphenylphosphine]), (R)-H8-BINAPO, (R)-BINAP ((R)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthalene), (R)-BINAPO, (R)-BINAPOXyl(R)-(+)-2,2-bis(di-3,5-xylylphosphino)-1,1-binaphthyl, T-BINAP ((R)-(+)-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl), SEGPhos ([4(R)-(4,4'-bi- 1,3-benzodioxole)-5,5'-diyl]-bis-[diphenylphosphine]), SynPhos ((R)-[5-(6-diphenylphosphanyl-2,3-dihydro-1,4-benzodioxin-5-yl)-2,3-dihydro-1,4-benzodioxin-6-yl]-diphenylphosphine), TrostPhos, MeOBIPHEP ligands (e.g., (R)-(6,6'-dimethoxybiphenylphosphine), or chiral monophosphine ligands, such as MOP (chiral monodentate phosphine ligands) or ligands selected from those described in WO 2011 / 126917 A1 having the following general formula Ia, Ib, or mixtures thereof (biaryl monodentate phosphine ligands): [ka] (In the formula, R is (C1-C6)-alkyl, CF3, (C3-C10 )-carbocyclyl, (5-11 membered)heterocarbocyclyl, (C6-C 10 )aryl, (5-11 membered)heteroaryl, or ferrocenyl, provided that each of such (C 10 ) carbocyclyl group, (5-11 membered) heterocarbocyclyl group, (C6-C 10 ) an aryl group or a (5-11 membered) heteroaryl group is optionally substituted with 1-3 substituents independently selected from the group consisting of -O(C1-C6)alkyl, (C1-C6)alkyl, and CF3; R 1 , R 2 , R 3 , R 4 , R 5 are each independently H, halo, CF3, -O(C1-C6)alkyl, (C1-C6)alkyl, (C3-C 10 )carbocyclyl, (5-11 membered)heterocarbocyclyl, (C6-C 10 )aryl, (5-11 membered)heteroaryl, -NR 11 R 12 , -Si(R 11 )3, and -SR 11 wherein each of said (C3 to C 10 ) carbocyclyl group, (5-11 membered) heterocarbocyclyl group, (C6-C 10 )aryl group, or (5-11 membered)heteroaryl group is optionally substituted with 1-3 substituents independently selected from the group consisting of -O(C1-C6)alkyl, (C1-C6)alkyl, and CF3, or R 1 , R 2 , R 3 , R 4 , R 5 any two adjacent instances of are taken together with the carbons to which they are attached to form a 5- or 6-membered substituted or unsubstituted aryl or heteroaryl ring, with the proviso that R 1 , R 2 , R 3 , R 4 , R 5 At least one of is OR 11 and R 6, R 7 , R 8 are each independently H, CF3, -O(C1-C6)alkyl, (C1-C6)alkyl, (C3-C 10 )carbocyclyl, (5-11 membered)heterocarbocyclyl, (C6-C 10 )aryl, (5-11 membered)heteroaryl, and -NR 11 R 12 wherein each of said (C3 to C 10 ) carbocyclyl group, (5-11 membered) heterocarbocyclyl group, (C6-C 10 ) an aryl group or a (5-11 membered) heteroaryl group is optionally substituted with 1-3 substituents independently selected from the group consisting of -O(C1-C6)alkyl, (C1-C6)alkyl, and CF3; R 9 , R 10 are each independently H, (C1-C6) alkyl, (C3-C6) cycloalkyl, (3-6 membered) heterocycloalkyl, (C6-C 10 )aryl, (5-6 membered)heteroaryl, and -SiR 5 3, provided that each of such (C3-C6)cycloalkyl groups, (3-6 membered)heterocycloalkyl groups, (C6-C 10 ) an aryl group or a (5- to 6-membered) heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of -O(C1-C6)alkyl, (C1-C6)alkyl, and CF3; R 11 and R 12 are each independently H, (C1-C6) alkyl, CF3, (C3-C 10 )carbocyclyl, (5-11 membered)heterocarbocyclyl, (C6-C 10 )aryl, and (5-11 membered)heteroaryl, provided that each of said (C3-C 10 ) carbocyclyl group, (5-11 membered) heterocarbocyclyl group, (C6-C 10The aryl group or the (5-11 membered) heteroaryl group is optionally independently substituted with 1-3 substituents independently selected from the group consisting of halo, -O(C1-C6)alkyl, (C1-C6)alkyl, and -CF3. is involved as a ligand.

[0075] Suitable ligands in R or S configuration may be used as desired, as well as other ligands described below, to produce the desired result (desired atropisomer), which is achievable, for example, by simple pilot experiments.

[0076] The ligand may be, for example, [ka] can be selected from:

[0077] Some of the most preferred ligands are, for example: [ka] [ka] and further comprising Group 3: [ka] is selected from.

[0078] The ligands or chiral additives are available in the literature or can be purchased from vendors. For example:

[0079] [Table 1]

[0080] [Table 2]

[0081] Strem website: https: / / www.strem.com / index.php (e.g. Strem (Europe), Bischheim, France) Daicel website: https: / / www.daicelchiraltech.cn / (Daicel Chiral Technologies, China) Co., Ltd.) Shanghai, China), Sigma-Aldrich website: https: / / www.sigmaaldrich.cn / (Sigma-Aldrich,China) Synthesized according to M. Batuecas et al., ACS Catal. 2019, 9, 5268-5278.

[0082] Palladium sources include Pd(OAc)2, Pd(OPiv)2, Pd(OCOEt)2, PdCl2, PdBr2, PdI2, Pd(OH)2, PdSO4, Pd(TFA)2, Pd(dba)2, Pd2(dba)3, Pd(acac)2, Pd2(dba)3·CHCl3, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(CH3CN)2Cl2, Pd(PhCN)2Cl2, [Pd(π-allyl)Cl]2, [Pd(π-cinnamyl)Cl]2, Pd[P(o-Tol)3]2, Pd / C, Pd(OH)2 / C, [Pd-G1]2, [Pd-G2]2, [Pd-G3]2, [Pd-G1]2, [Pd-G2 ... ]2, [Pd-G3]2, [Pd-G4]2. Any Pd salt or complex can be used, such as Pd(BINAP)Cl2, Pd(dppe)Cl2, Pd(dppp)Cl2, Pd(dppb)Cl2, Pd(dppf)Cl2, for example, a Pd(II) salt or complex selected for the bisphosphone ligand, such as Pd(II) selected from Pd(OAc)2, Pd(TFA)2, and Pd(PhCN)2Cl2, or Pd(0), such as Pd2(dba)3 or Pd(dba)2, for the bisphosphine monoxide.

[0083] Other suitable Pd sources are possible and can be found, for example, in https: / / www.strem.com / uploads / resources / documents / buchwaldligprecat.pdf, “Pd Metal Catalysts for Cross-Couplings and Related Reactions in the 21st Century: A Critical Review” Chemical Reviews (acs.org), or “The 2-Pyridyl Problem: Challenging Nucleophiles in Cross-Coupling Arylations”-Cook-2021-Angewandte Chemie International Edition-Wiley Online Library.

[0084] "Piv" means pivaloyl, "Et" means ethyl, "TFA" means trifluoroacetate, "acac" means acetoacetonyl, "Ac" means acetyl, "Tol" means tolyl, "dppe" means 1,2-bis(diphenylphosphino)ethane, "dppp" means 1,3-bis(diphenylphosphino)propane, "TFA" means trifluoroacetyl, "dppb" means 1,4-bis(diphenylphosphino)butane, "dppf" means 1,1'-bis(diphenylphosphino)ferrocene, "Ph" means phenyl, and "dba" means dibenzylideneacetone.

[0085] The reaction of intermediate B4*, intermediate B4', and especially intermediate B4 with intermediate B5*, intermediate B5', or especially intermediate B5, leading to intermediate B6*, intermediate B6', or intermediate B6, respectively, as hereinbefore or hereinafter defined, is preferably carried out using a base, such as, for example, Cs2CO3, CsOH·H2O, CsHCO3, CsOPiv, CsF, CsOAc, K3PO4, K2CO3, KHCO3, KF, TMSOK, NaOH, NaHCO3, KOH, NaOMe, KOMe, NaOEt, KOEt, KO t Bu, NaO tBu, NaOAc, KOAc, DABCO, DBU, TEA, DIPEA, Cy2NMe, pyridine, 2,6-lutidine, etc. 3、 In particular, the micronized form is a preferred example. "TMSO" means trimethylsilanolate, "DABCO" means 1,4-diazabicyclo[2.2.2]octane, "DBU" means 1,8-diazabicyclo[5.4.0]undec-7-ene, "TEA" means triethylamine, "DIPEA" means N,N-diisopropylethylamine, and "Cy" means cyclohexyl.

[0086] For the key reactions and specific embodiment of the same reactions of the present invention, for example, DMF (dimethylformamide), DMSO (dimethylsulfoxide), NMP (N-methyl-2-pyrrolidone), water, MeOH, EtOH, i-PrOH, tert-amyl alcohol, toluene, o-xylene, m-xylene, p-xylene, 1,3,5-trimethylbenzene, 1,3,5-trifluorobenzene, chlorobenzene, trifluoromethylbenzene, 1,2-difluorobenzene, n-heptane, n-hexane, c-hexane, n-pentane, THF (tetrahydrofuran), 2-MeTHF (2-methyltetrahydrofuran), ), 1,4-dioxane, MTBE (methyl tert-butyl ether), CPME (cyclopentyl methyl ether), i-Pr2O, n-Bu2O, Ph2O, DME (1,2-dimethoxyethane), MeO(CH2CHO)2Me, cyclohexane, acetonitrile, DCM (dichloromethane), Et3N, DIPEA (N,N-diisopropylethylamine), 2,6-lutidine, ethyl acetate, i-propyl acetate, t-butyl acetate, MIBK (methyl isobutyl ketone), and sulfolane, which may form a mixture. The total amount of water in the reaction mixture is preferably kept at about 1.5 (e.g., 1-2, e.g., 1.2-1.8) equivalents. Too much water or too little water (based on intermediate B4* / B4' / B4) may lead to failure of the reaction. The reaction is preferably carried out at an elevated temperature in the range of 0°C to the boiling temperature of the reaction mixture, especially in the range of 25-90°C, such as 50-75°C, for example 60-70°C.

[0087] When multiple substituents are present, the substituents are independently selected unless otherwise specified, so that, for example, when two or three substituents are present, those substituents may be ("independently") the same or different.

[0088] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain radical, containing no unsaturation and consisting solely of carbon and hydrogen atoms, attached to the remainder of the molecule by a single bond, especially C1-C6-alkyl, more especially "C1-C4-alkyl". Examples of (e.g. C1-C4-)alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), and n-butyl. A preferred example is methyl.

[0089] As used herein, the term alkyloxy (=alkoxy) refers to a group of the formula -OR a (In the formula, R a means a group which is alkyl, preferably C1-C6 alkyl, or especially a C1-C4 alkyl group as generally defined above. Examples of C1-C4-alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

[0090] As used herein, the term "fluoro-alkyl" refers to alkyl or perfluoroalkyl as defined herein substituted with one or more fluoro. In particular, non-limiting examples of fluoro-C1-C4-alkyl include trifluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-fluoropropyl, 3,3-difluoropropyl, and 1-fluoromethyl-2-fluoroethyl. Preferred fluoro-alkyl groups, unless otherwise specified, include monofluoro, difluoro, and trifluoro substituted methyl and ethyl groups, such as CF3, CF2H, CFH2, and CH2CF3.

[0091] As used herein, the term "aryl" refers to an aromatic hydrocarbon group having 6 to 14 carbon atoms in the ring portion. Typically, aryl is a monocyclic, bicyclic, or tricyclic aryl having 6 to 14 carbon atoms, often 6 to 10 carbon atoms, such as phenyl, naphthyl, fluoren-9-yl, or tetrahydro-naphthyl. Phenyl may be preferred. Aryl may further include tetrahydronaphthyl.

[0092] When aryl is mentioned, this includes aryl carrying one or more, such as up to three, independently selected substituents, such as alkyl as defined above, in particular methyl or ethyl, or further alkoxy as defined above, such as methoxy or ethoxy, phenyl, phenoxy, alkyl-CO-, in particular acetyl or propionyl, alkyl-C(O)-O-, such as acetyloxy or propionyloxy, or even further carboxyl (-COOH).

[0093] The term "cyano" refers to the group --CN.

[0094] The term "amino" refers to the group -NH2.

[0095] The term "secondary amino" refers to the group -NH-.

[0096] The term "hydroxy" or "hydroxyl" refers to the group --OH.

[0097] When "further" is used in connection with features of embodiments of the present invention, it means that the feature preceding the word is more preferred.

[0098] The term "atropisomer" refers to a stereoisomer resulting from restricted rotation about a single bond where the rotational barrier is high enough that the isomeric species can be isolated. Typically, rotation about a single bond in a molecule is prevented or greatly slowed as a result of steric interactions with other parts of the molecule, resulting in a stereogenic unit referred to as a "chiral axis" due to the unsymmetrical substituents on either end of the single bond.

[0099] The absolute configuration of the chiral axis is assigned, for example, in exemplary compounds, using the Cahn-Ingold-Prelog (CIP) chirality rules with stereodescriptors (aR) or (aS) or using the CIP helicity rules with stereodescriptors (P) or (M) (V. Prelog and G. Helmchen, Angewandte Chemie International Edition, 21(8):567-583, 1982, https: / / doi.org / 10.1002 / anie.198205671, P. Mata, AM Lobo, C. Marshall, and AP Johnson, Tetrahedron: Asymmetry, 4(4):657-688, 1993, https: / / doi.org / 10.1016 / S0957-4166(00)80173-1, both in HA Favre and WH Powell, Nomenclature of Organic Synthesis, 1999, 11, 144-151, 1999). Chemistry: IUPAC Recommendations and Preferred Names 2013 (the IUPAC “Blue Book”), Cambridge, UK: Royal Soc. of Chem., 2014, https: / / doi.org / 10.1039 / 9781849733069, Chapter P-9, “Specification of Configuration and Conformation”, https: / / doi.org / 10.1039 / 9781849733069-01156).

[0100] The compound of formula (Ia) is represented by "(R aThe compound of formula (Ia) may also be represented by the name "1-{6-[(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one". The compound of formula (Ia) may also be represented by the name "1-{6-[(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one".

[0101] The structure of compound A is as follows: [ka]

[0102] Intermediates B2*, particularly B2', more particularly B2, and intermediates B5*, particularly B5', more particularly B5, are known or can be prepared according to methods known in the art or using methods described herein or analogous to those described herein.

[0103] For example, intermediate B5* may be prepared by the methods disclosed in US Patent Application Publication No. 2004 / 44258A1 or by analogy therewith (e.g., compounds of this intermediate B5* type are described on page 165).

[0104] With respect to intermediate B5*, where Lb is a boronic acid diester moiety, intermediate B5″ as defined below can be prepared by the following method, among other methods readily available to the skilled artisan: [ka] where Q is 1,3-dioxolanyl (or any other additional formyl group in acetal form); Xc is a halogen or pseudohalogen; Xd is a halogen (especially Cl, Br or I). Or a similar method may be used.

[0105] Various embodiments or aspects of the invention are described herein, particularly in the claims. It will be understood that the features specifically recited in each embodiment may be combined with other specifically recited features to provide specific embodiments of the invention. In particular, it will be understood that the features recited in a particular embodiment or aspect are preferred aspects of the invention. The following enumerated embodiments are representative of the invention.

[0106] For any of the intermediates, all tautomeric forms thereof are intended to be included, where possible, particularly when the heteroaryl ring containing N as a ring atom is a 2-pyridone, for example, the tautomer in which the carbonyl is depicted as a hydroxy (e.g., 2-hydroxypyridine) is included.

[0107] When reference is made in this document to "about", this means, for example, the respectively stated numerical value ±15%, such as ±10%, in particular ±5%.

[0108] As used herein, the term "salt" or "salts" refers to an acid or base addition salt of an intermediate prepared or used in accordance with the present invention. In many cases, the intermediates are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0109] Salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfinic acid, pyrosulfuric acid, phosphoric acid, pyrophosphoric acid, as well as acidic resins. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, acrylic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, or sulfonic acids, such as alkylsulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, arylsulfonic acids, such as phenylsulfonic acid, toluenesulfonic acid, sulfosalicylic acid, trifluoroacetic acid, trifluoroethanesulfonic acid, and the like. In the case of intermediates B11* / B11' / B11, the anion H q-r A r(-) It should be noted that the acid forming may be acrylic acid itself, which can then be reacted to give a compound of formula (Ia) or a hydrate or solvate thereof.

[0110] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0111] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I-XII of the periodic table, in certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly suitable salts including ammonium, potassium, sodium, calcium, and magnesium salts.

[0112] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0113] In another aspect, the present invention provides an agonist, an anti-inflammatory agent ... These include intermediates in the salt form of lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate or xinafoate.

[0114] In the reactions of the above-described method embodiments, the following conditions constitute specific embodiments.

[0115] In the reaction of intermediate B11* to compounds of formula (Ia), acylation is carried out either with acrylic acid or preferably with a reactive derivative thereof.

[0116] The reaction with acrylic acid is carried out under known condensation conditions between compounds bearing carboxylic acid groups and compounds bearing amino groups, for example similar to those customary in peptide synthesis. For in situ formation customary coupling agents can be applied. Such agents are known to the skilled artisan and can be deduced accordingly from many sources. Possible coupling agents for the synthesis of amide and ester bonds can include: triazole, uronium or hexafluorophosponium derivatives, such as 1-hydroxy-benzotriazole (HOBt), 1-hydroxy-7-aza-benzotriazole (HOAt), ethyl 2-cyano-2-(hydroxyimino)acetate, 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium ...1-hydroxy-benzotriazole (HOBt), 1-hydroxy-7-aza-benzotriazole (HOAt), ethyl 2-cyano-2-(hydroxyimino)acetate, 1-hydroxy-benzotriazole (HOBt), 1-hydroxy-7- benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole (MSNT), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(1H-benzotriazol-1-yl)-1,1, 3,3-Tetramethyluronium hexafluoroborate (TBTU), 2-succinimido-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), 2-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate (TNTU), O-[(cyano(ethoxycarbonyl)methylidene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU), O -(Benzotriazol-1-yl)-1,3-dimethyl-1,3-dimethyleneuronium hexafluorophosphate (HBMDU), O-(benzotriazol-1-yl)-1,1,3,3-bis(tetramethylene)uronium hexafluorophosphate (HBPyU), O-(benzotriazol-1-yl)-1,1,3,3-bis(pentamethylene)uronium hexafluorophosphate (HBPipU), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-Benzotriazine (HODhbt), 1-hydroxy-7-azabenzotriazole and its corresponding uronium or phosphonium salts designated HAPyU and AOP, 1-cyano-2-ethoxy-2-oxoethylideneaminooxy-dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), chlorotripyrrolidinophosphonium hexafluorophosphate (PyCloP), etc. Carbodiimides, such as dicyclohexylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide=EDC, particularly preferred), 1-tert-butyl-3-ethylcarbodiimide, N-cyclohexyl-N'-2-morpholinoethyl)carbodiimide, or diisopropylcarbodiimide (especially for ester formation via O-acylurea formation of carboxylic acid groups), or Active ester forming agents, such as 2-mercaptobenzothiazole (2-MBT); Azide-forming agents, such as diphenylphosphoryl azide; Acid anhydrides, such as propanephosphonic anhydride, Acid halogenating agents, such as 1-chloro-N,N,2-trimethyl-1-propenylamine, chloro-N,N,N',N'-bis(tetramethylene)formamidinium tetrafluoroborate or hexafluorophosphate, chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, fluoro-N,N,N',N'-bis(tetramethylene)formamidinium hexafluorophosphate, etc. or a mixture of two or more such agents.

[0117] The reaction may optionally be carried out in the presence of a mild base (e.g., N-methylmorpholine, a trialkylamine such as ethyldiisopropylamine, a di-(alkyl)aminopyridine such as N,N-dimethylaminopyridine and the like (taking care that the conditions are not so basic as to permit hydrolysis of ester groups present in the precursor of the compound of formula I, e.g., depsipeptide ester groups), optionally or optionally in the presence of a suitable solvent or mixture of solvents, such as N,N dialkylformamide such as dimethylformamide, a halogenated hydrocarbon such as dichloromethane, an N-alkylpyrrolidone such as N-methylpyrrolidone, a nitrile such as acetonitrile, or even an aromatic hydrocarbon such as toluene, or a mixture of two or more (although water may also be present if an excess of coupling agent is present). The temperature may be below or above ambient temperature, for example in the range of -20°C to 50°C.

[0118] If an activated (= reactive) derivative of acrylic acid is used, the activated derivative is preferably a symmetric or mixed anhydride of the acid, for example an anhydride with an inorganic acid, for example an acrylic acid halide, especially an acrylic acid chloride (which can be obtained, for example, by the acid chloride method by treatment of the acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride), an azide (which can be obtained, for example, by the azide method from the corresponding acid ester via treatment with the corresponding hydrazide and its nitrous acid), a carbonic acid semi-derivative, for example an anhydride with the corresponding ester, for example a lower alkyl carbonate semi-ester (which can be obtained, for example, by treatment of the corresponding acid with a haloformic acid, for example a lower alkyl ester of chloroformic acid or a 1-lower alkoxycarbonyl-2-lower alkoxy-1,2-dihydroquinoline, for example 1-lower alkoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, in the mixed O-alkyl carbonic acid anhydride method), or an anhydride with a dihalogenated, especially dichlorinated phosphoric acid (which can be obtained, for example, by treatment of the corresponding acid with phosphorus oxychloride). the phosphorus oxychloride method), or anhydrides of organic acids, such as mixed anhydrides of organic carboxylic acids (which may be obtained, for example, by the mixed carboxylic acid anhydride method by treatment of the corresponding acid with an unsubstituted or substituted lower alkane- or phenylalkane-carboxylic acid halide, such as phenylacetic acid chloride, pivalic acid chloride, or trifluoroacetic acid chloride), anhydrides of organic sulfonic acids (which may be obtained, for example, by treatment of a salt, such as an alkali metal salt, of the corresponding acid with a suitable organic sulfonic acid halide, such as a lower alkane- or aryl-, such as methane- or p-toluene-sulfonic acid chloride, in the mixed sulfonic acid anhydride method), or anhydrides of organic phosphonic acids (which may be obtained, for example, by treatment of the corresponding acid with a suitable organic phosphonic acid anhydride or phosphonic acid cyanide, in the mixed phosphonic acid anhydride method), and especially symmetrical anhydrides (which may be obtained, for example, by condensation of the corresponding acid in the presence of a carbodiimide or 1-diethylaminopropyne, in the symmetrical anhydride method). Preferably, an activated acid derivative selected from acrylic acid chloride or acrylic acid anhydride is used.The reaction can be carried out in a manner known per se, usually in the presence of a suitable solvent or diluent or a mixture thereof, with cooling or heating, for example in a temperature range from approximately -30°C to approximately +150°C, in particular from approximately 0°C to +100°C, preferably from room temperature (approximately +20°C) to +70°C, in an open or sealed reaction vessel and / or in an atmosphere of an inert gas such as nitrogen.

[0119] In the deprotection reaction intermediate B10* → intermediate B11* (especially B10' → B11', more particularly B10 → B11), the protecting group Pr1 in compound B10* is preferably removed under standard conditions for deprotection of (here secondary) nitrogen, for example under the definition of Pr1 described below or in the standard textbook and literature procedures cited therein, and the removal of the protecting group can typically be achieved by solvolysis (especially hydrolysis by acid), reduction (including hydrogenation), photolysis, electrolysis, or even by enzymatic activity under conditions similar to physiological conditions and not present in the final product, for example. Which protecting groups are suitable in the reactions described above or below are familiar to those skilled in the art or can be easily established.

[0120] The protection of such functional groups by such protecting groups, the protection of the protecting groups themselves, and their removal reactions are described, for example, in the previously cited standard reference books for peptide synthesis and in special books on protecting groups, such as J.F.W. MacOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in "Methoden der organischen Chemie" (Methods of organic chemistry), Houben-Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974, and T.W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York.

[0121] For example, Boc, Tr, SEM can be removed under acid hydrolysis conditions, while benzyl, MPM, or Cbz can be removed by hydrogenolysis, for example, using Pd / C and hydrogen gas.

[0122] In the case of acidic conditions, the acid is preferably of the formula H q A (wherein q is 1, 2, 3, 4 or 5, preferably 1, 2 or 3, and A is an acid anion, preferably an anion of a strong organic acid, such as trifluoroacetic acid or especially acrylic acid, or especially an inorganic acid, such as a monoprotic acid, such as a halogen acid, for example HCl or HBr, a diprotic acid, such as sulfuric acid, or a triprotic acid, such as a phosphate anion, etc.), so that intermediate B10* presents the advantage that it can be formed directly in the salt form of the corresponding acid. q Depending on the number of protons dissociable from A, the anion obtained in intermediate 10* has the formula H q-r A r(-) in which q is as defined above and r is 1, 2, 3, 4 or 5, especially 1, 2 or 3, more especially 1 or 2.

[0123] The acid hydrolysis can be preferably carried out at a temperature in the range of 0° C. to the boiling temperature of the reaction mixture, preferably under moderate temperature conditions which avoid decomposition of intermediate B10* and the resulting intermediate B11*, for example at a temperature in the range of 5-30° C., preferably at a temperature of around 20° C., for example at 15-25° C. The reaction is preferably carried out in a solvent or solvent mixture, for example in water or an organic solvent, for example in a cyclic ether, such as tetrahydrofuran, dioxane, etc., in dimethylformamide, in an alcohol, such as methanol, ethanol, isopropanol, or ethylene glycol, or in a mixture of two or more, for example in an aqueous solution comprising one or more of the mentioned organic solvents.

[0124] In the reaction of intermediate B8* (especially B8', more particularly B8) with hydrazine or a hydrate or solvate thereof, more particularly hydrazine or hydrazine monohydrate, leading to intermediate B10*, intermediate B8* is reacted with hydrazine or a hydrate or solvate thereof under standard conditions for cyclization of the group C(H)=N-Lc (wherein Lc is as defined for intermediate B8*, especially B8', more particularly B8, more particularly benzyloxy) by the group Xc (as defined for intermediate B8*, especially B8', more particularly B8, more particularly F) in the ortho position, as defined above or below. The reaction is preferably carried out in the presence of a (e.g. mild or strong) base, e.g. an alkali or alkaline earth metal salt of an alkanoic acid (especially up to C6), such as acetic acid, especially sodium acetate (although it can also be carried out without a base), in an aprotic polar organic solvent or solvent mixture, e.g. a cyclic ether, e.g. dioxane or tetrahydrofuran, N,N-alkaline formamide, e.g. dimethylformamide, an alcohol, e.g. a C1-C6 alkanol, e.g. ethanol, or (especially) an N-alkylpyrrolidone, e.g. N-methyl-2-pyrrolidone. The reaction is preferably carried out at a temperature between 20°C and the boiling temperature of the reaction mixture, e.g. 50-90°C, e.g. about 80°C.

[0125] In the reaction from intermediate B7* (especially B7', more especially B7) to intermediate B8*, more especially B8', more especially B8, a compound of formula Lc-NH2 (wherein Lc is as defined for compounds of formula B8*) or in particular of formula benzyl-O-NH2 or a salt thereof, for example a salt of an organic or inorganic acid, for example sulfuric acid or a hydrogen halide, for example HCl, is reacted under standard conditions for the formation of a Schiff base. For example, the reaction is preferably carried out in the absence of a (for example mild or strong) base, for example an alkali or alkaline earth metal salt of an alkanoic acid (especially up to C6), such as acetic acid, especially sodium acetate (although it can also be carried out without a base), in the presence of a protic solvent, for example acetic acid, in water, or in an aprotic polar organic solvent or solvent mixture, for example a cyclic ether, for example dioxane or tetrahydrofuran, N,N-alkaline formamide, for example dimethylformamide, N-alkylpyrrolidone, for example N-methyl-2-pyrrolidone, or especially an alcohol, for example a 1-C6 alkanol, for example ethanol, preferably in the presence of water. The reaction is preferably carried out at a temperature of -20°C to 30°C, for example at -5 to 10°C, for example at about 0°C of the reaction mixture, for example at 50 to 90°C, for example at about 80°C.

[0126] The reaction from intermediate B6* (wherein Q is preferably as defined above or below, in particular a formyl group in (preferably cyclic) acetal form) to intermediate B7* (in particular B6'→B7', more particularly B6→B7) can utilize conventional (in particular hydrolytic) conditions for liberating a formyl group from an acetal or Schiff base derivative, such as acetal cleavage in the presence of an acid, for example an organic acid, for example an alkanoic acid (in particular up to C6), for example acetic acid, in an aqueous solvent or solvent mixture. The reaction is preferably carried out at a temperature in the range of 0° C. to the boiling point of the reaction mixture, for example in the range of 20 to 50° C., for example at about 35° C.

[0127] The reactions in the above paragraphs are preferably carried out sequentially in a "one-pot" synthesis.

[0128] The reaction of intermediate B4*, intermediate B4', and especially intermediate B4 with intermediate B5*, intermediate B5', or especially intermediate B5 to intermediate B6*, intermediate B6', or especially intermediate B6, respectively, as defined herein above or below, is preferably carried out using a base, such as, for example, Cs2CO3, CsOH·H2O, CsHCO3, CsOPiv, CsF, CsOAc, Na2CO3, K3PO4, K2CO3, KHCO3, KF, TMSOK, NaOH, NaHCO3, KOH, NaOMe, KOMe, NaOEt, KOEt, KO t Bu, NaO t Bu, NaOAc, KOAc, DABCO, DBU, TEA, DIPEA, Cy2NMe, pyridine, 2,6-lutidine, etc. 3、 In particular, the micronized form is a preferred example. "TMSO" means trimethylsilanolate, "DABCO" means 1,4-diazabicyclo[2.2.2]octane, "DBU" means 1,8-diazabicyclo[5.4.0]undec-7-ene, "TEA" means triethylamine, "DIPEA" means N,N-diisopropylethylamine, and "Cy" means cyclohexyl.

[0129] For the key reactions and the specific embodiment of the same reaction of the present invention, for example, DMF (dimethylformamide), DMSO (dimethylsulfoxide), NMP (N-methyl-2-pyrrolidone), water, alcohols such as MeOH, EtOH, i-PrOH, or tert-amyl alcohol, aromatic solvents (preferred), such as toluene, o-xylene, m-xylene, p-xylene, 1,3,5-trimethylbenzene, 1,3,5-trifluorobenzene, chlorobenzene, trifluoromethylbenzene, 1,2-difluorobenzene, or even benzene, alkanes (preferred), such as heptanes, for example n-heptane, n-hexane, c-hexane, or n-pentane, cyclic ethers such as THF (tetrahydrofuran), 2-MeTHF (2-methyltetrahydrofuran), or 1,4-dioxane. Any one or more solvents (in which case forming a mixture) selected from the group consisting of benzene, alkyl, cycloalkyl, or aryl ethers such as MTBE (methyl tert-butyl ether), CPME (cyclopentyl methyl ether), i-PrO, n-BuO, PhO, DME (1,2-dimethoxyethane), MeO(CHCHO)Me, cyclic hydrocarbons such as cyclohexane, alkyl nitriles such as acetonitrile, haloalkanes such as DCM (dichloromethane), amines such as EtN, DIPEA (N,N-diisopropylethylamine), or 2,6-lutidine, alkyl esters such as ethyl acetate, i-propyl acetate, or t-butyl acetate, ketones such as MIBK (methyl isobutyl ketone), and sulfolane can be used. The total amount of water in the reaction mixture is preferably kept at about 1.5 (e.g. 1.2-1.8) equivalents (defined based on 1 mole of intermediate B4* / B4' / B4), too much or too little water can lead to failure of the reaction. The reaction is preferably carried out at an elevated temperature in the range of 0°C to the boiling temperature of the reaction mixture, in particular in the range of 25-90°C, e.g. 50-75°C, e.g. 60-70°C.

[0130] Depending on the moiety Lb under (a) to (f) above, for example, Suzuki coupling may be used in the case of (a), coupling under appropriate conditions with a coupling aryl-BF3K reagent in the case of (b), Kumada coupling in the case of (c), Negishi coupling in the case of (d), Stille or Hiyama coupling in the case of (e), and desilylation coupling in the case of (f).

[0131] In the reaction of intermediates B3*→B4* (especially B3'→B4', more particularly B3→B4), a reagent capable of carrying out a substitution reaction to introduce a group Xb as defined above (other than hydrogen) or below is reacted under conditions known in the art for introducing a group Xb. As reagents, halogens such as Br2, Cl2 or even Cl2, or even tetrabutylammonium bromide, pyridinium hydrobromide perbromide, 1,3-dibromo-5,5-dimethylhydantoin, 2,4,4,6-tetrabromocyclohexa-2,5-dienone, or analogues thereof, or in particular N-halogenosuccinimides (e.g. iodosuccinimide, bromosuccinimide or chlorosuccinimide), or reactive derivatives of compounds of formula HO-SO2RA (RA is as defined above or below), such as acid halides thereof (halogeno instead of HO), may be used.

[0132] The reaction is preferably carried out in an inert organic protic or aprotic solvent or solvent mixture, such as a nitrile, for example acetonitrile, or acetic acid. The T temperature is preferably in the range of 0° C. to the boiling point of the reaction mixture, for example in the range of 25 to 80° C., for example about 50° C.

[0133] For example, -OTf or -OSO2(CF2)3CF3 can be inserted as follows: [ka]

[0134] Testing Procedure: [ka] To a solution of compound 1 (2 mmol) in 6 mL of anhydrous THF was added i-PrMgCl-LiCl (2.6 mmol, 1.3 M in THF) dropwise at -10 °C under N2 atmosphere. The resulting solution was stirred at -10 °C for 60 min until complete conversion of the starting material was indicated by UPLC. B(OMe)3 (2.6 mmol) was added at -10 °C. o The cold bath was removed and the resulting mixture was stirred at room temperature (rt) for about 3 h, then quenched with saturated NH4Cl(aq). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. The crude mixture after concentration was further purified by slurrying in heptane to give the desired product. [ka]

[0135] To a vigorously stirred solution of 2 (0.66 mmol) in 10 mL of THF at 0 °C was added NaOH (25 wt% aq.) (1.3 mmol) and H2O2 (30% aq.) (2.0 mmol). After 30 min, additional 2O2 (30% aq.) (2.0 mmol) was added and the mixture was stirred at 0 °C for about 2 h until UPLC indicated complete conversion. The resulting mixture was quenched with saturated NH4Cl (aq), diluted with water, and then extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography to give the desired product. [ka]

[0136] To a solution of 3 (2 mmol) and TEA (3 mmol) in 5 mL of DCM was added Tf2O (trifluoromethanesulfonic anhydride) or nonafluoro-n-butanesulfonyl fluoride (2.4 mmol) dropwise at 0° C. The resulting suspension was stirred at room temperature until complete conversion of the starting material. The suspension was filtered and concentrated. The crude product was purified by column to give the desired product.

[0137] The reactions from intermediates B1* and B2* to intermediate B3* (particularly B1' and B2' → B3', more particularly B2 and B3 → B4) use reaction conditions that support cross-coupling of intermediates B1* and B2* (particularly B1' and B2', more particularly B1 and B2). Coupling reaction of intermediate B2* with intermediate B1* in the presence of a cross-coupling catalyst (especially in a Suzuki or Stille type cross-coupling reaction, the coupling partners B2* and B1* are preferably reacted in the presence of a palladium catalyst, such as RuPhos-Pd-G3 / RuPhos, in a suitable solvent, such as 1,4-dioxane (or toluene), in the presence of a base (e.g. as defined above for the reaction of intermediates B4* and B5*), especially K3PO4 or Na2CO3. Depending on the moiety La used as defined for moiety Lb under (a) to (f) above, for example Suzuki coupling may be used in the case of (a), coupling aryl-BF3K reagents under suitable conditions in the case of (b), Kumada coupling in the case of (c), Negishi coupling in the case of (d), Stille or Hiyama coupling in the case of (e) and desilylation coupling in the case of (f). For example, Pd Metal Catalysts for Cross-Couplings and Related Reactions in the 21st Century:A Critical Please see Review|Chemical Reviews (acs.org) or The 2-Pyridyl Problem: Challenging Nucleophiles in Cross-Coupling Arylations-Cook-2021-Angewandte Chemie International Edition-Wiley Online Library.

[0138] - in intermediate B4* / B4' / B4, Xb and Lb are as defined under (b) above under the formula of intermediate B4*, and for the reaction in which in the intermediate B2* / B2' / B2, La and Xb are as defined above under (B) under the formula of intermediate B2*, Each of the above reactions is carried out using the corresponding exchange reactions just described.

[0139] In all reactions, the resulting compound can preferably be isolated, for example, by standard procedures such as solvent partition, centrifugation, or other precipitation, precipitation such as crystallization, chromatography, filtration, and the like.

[0140] The reaction can be carried out under an inert gas, such as nitrogen, argon or helium, or carbon dioxide, as appropriate or necessary.

[0141] If appropriate, the reaction may be quenched by the addition of a base such as, for example, sodium carbonate.

[0142] For any formula given herein, unlabeled forms of the compounds as well as isotopically labeled compounds have the structure depicted by the formula given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, for example, 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 17 O. 18 O. 18 F, 35 S, 36 The present invention includes various isotopically labeled compounds as defined herein, such as 3 H and 14 Those containing radioactive isotopes such as C, or 3 H, 14 These include those in which non-radioactive isotopes such as C are present. Such isotope-labeled compounds are useful for metabolic studies ( 14 C), reaction kinetic studies (e.g. 2 H and 13C), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including tissue distribution assays of drugs or substrates, or radiation treatment of patients. 18 F may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of formula (Ia) can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described in the accompanying examples, substituting the appropriate isotopically labeled reagent for the non-labeled reagent previously utilized.

[0143] Alternatively, heavier isotopes, particularly deuterium (i.e. 2 Substitution with heavier isotopes (H or D) may confer certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or improved therapeutic index. In this context, it is understood that deuterium is considered as a substituent of the compound of formula (Ia). The concentration of such heavier isotopes, specifically deuterium, may be defined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a specific isotope. When deuterium is recited as a substituent in a compound of the invention, such compounds have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0144] The invention also relates to compounds of any of the described embodiments in which one or more hydrogen atoms in one or more substituents are replaced with deuterium, for example, all hydrogens in one or more alkyl substituents are replaced with deuterium (in which case one or more moieties of each are perdeuterated).

[0145] In embodiments of the present invention, alkyl (or methyl) may be deuterated or perdeuterated, particularly when alkyl (or methyl) is present as a substituent in an intermediate of the present invention and / or when alkyl (or methyl) is present as a substituent.

[0146] The present invention also provides the preparation of crystalline forms of the compound of formula (Ia) as defined herein, such as the hydrate (modified HA) crystalline form of the compound of formula (Ia), or the isopropyl alcohol (IPA) solvate crystalline form, or the ethanol (EtOH) solvate crystalline form, or the propylene glycol solvate 30 crystalline form, the preparation of which is described in WO 2021 / 24222 A1.

[0147] As described therein, the hydrate (modified HA) crystalline form of the compound of formula (Ia) can be obtained, for example, from an isopropyl (IPA) solvate, an ethanol (EtOH) solvate, a methanol solvate, and a propylene glycolate solvate of the compound of formula (Ia). The hydrate (modified HA) crystalline form of the compound of formula (Ia) can be characterized by an X-ray powder diffraction pattern (XRPD) (measured as described in WO 2021 / 24222 A1) that includes at least one, two, three, or four peaks having a refraction angle 2θ value selected from the group consisting of 8.2 °, 11.6 °, 12.9 °, and 18.8 ° (CuKαλ=1.5418 Å) measured at a temperature of about 25 ° C. and an X-ray wavelength λ of 1.5418 Å. The hydrate (modified HA) crystalline form may also be characterized by an X-ray powder diffraction pattern (XRPD) that includes at least one, two, three, or four, or all, peaks having refraction angle 2θ values ​​(CuKαλ=1.5418 Å) selected from the group consisting of 8.2°, 11.6°, 12.1°, 12.9°, 14.6°, 16.2°, 18.8°, 20.4°, and 24.1°, measured at a temperature of about 25° C. and an X-ray wavelength λ of 1.5418 Å. For example, the hydrate modified HA may be obtained as described in Example 97 of WO 2021 / 24222 A1 and may be characterized in more detail as described in said document.

[0148] The isopropyl alcohol (IPA) solvate of the compound of formula (Ia) may be characterized by an X-ray powder diffraction pattern (XRPD) that includes at least one, two, or three peaks having refractive angle 2θ values ​​selected from the group consisting of 7.5°, 12.5°, and 17.6° (CuKαλ=1.5418Å) measured at a temperature of about 25° C. and an X-ray wavelength λ of 1.5418Å. The isopropyl alcohol solvate of the compound of formula (Ia) may be characterized by an X-ray powder diffraction pattern (XRPD) that includes at least one, two, three, or four or more peaks having refractive angle 2θ values ​​selected from the group consisting of 7.5°, 12.5°, 15.5°, 16.4°, 17.6°, 21.4°, and 24.4° (CuKαλ=1.5418Å) measured at a temperature of about 25° C. and an X-ray wavelength λ of 1.5418Å.

[0149] The ethanol (EtOH) solvate of the compound of formula (Ia) may be characterized by an X-ray powder diffraction pattern (XRPD) comprising at least one, two, or three, or four peaks having refraction angle 2θ values ​​selected from the group consisting of 7.9°, 12.7°, 18.2°, and 23.1° (CuKαλ=1.5418 Å) measured at a temperature of about 25° C. and an X-ray wavelength λ of 1.5418 Å. The ethanol solvate of the compound of formula (Ia) may be characterized by an X-ray powder diffraction pattern (XRPD) that includes at least one, two, three, or more than four, or all, peaks having refraction angle 2θ values ​​selected from the group consisting of 7.9°, 12.7°, 13.1°, 15.5°, 15.9°, 16.9°, 18.2°, 18.6°, and 23.1° (CuKαλ=1.5418 Å) measured at a temperature of about 25° C. and an X-ray wavelength λ of 1.5418 Å. The propylene glycol solvate of the compound of formula (Ia) may be characterized by an X-ray powder diffraction pattern (XRPD) comprising at least one, two, or three, or four peaks having refraction angle 2θ values ​​selected from the group consisting of 7.3°, 13.2°, 18.0°, and 22.5° (CuKαλ=1.5418 Å) measured at a temperature of about 25° C. and an X-ray wavelength λ of 1.5418 Å. The propylene glycol solvate of the compound of formula (Ia) may be characterized by an X-ray powder diffraction pattern (XRPD) that includes at least one, two, three, or more than four, or all, peaks having refraction angle 2θ values ​​selected from the group consisting of 7.3°, 13.2°, 15.6°, 16.2°, 18.0°, 22.5°, 22.8°, 23.2°, and 25.1° (CuKαλ=1.5418 Å) measured at a temperature of about 25° C. and an X-ray wavelength λ of 1.5418 Å.

[0150] Any resulting isomeric mixtures can be separated into pure or substantially pure optical isomers, diastereoisomers, atropisomers, racemates, based on the physicochemical differences of the components, for example, by chromatography and / or fractional crystallization. For example, any one or more of the chiral intermediates B6* / B6' / B6, B7* / B7' / B7, B8* / B8' / B8, B10* / B10' / B10, and B11* / B11' / B11 can be further purified from their enantiomers by conventional methods, for example, as described in the following paragraphs:

[0151] Any racemic final product or intermediate obtained can be resolved into its optical enantiomers by known methods, for example by separation of its diastereomeric salts obtained with optically active acids or bases followed by liberation of the optically active acid or base compound. In particular, for this purpose, the base moiety can be utilized to resolve the compounds of the present invention into their optical enantiomers by fractional crystallization of salts formed with optically active acids, for example tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, camphor-10-sulfonic acid, etc. Racemic or enantiomerically impure products can also be resolved by chiral chromatography, such as high pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0152] Traces or small amounts of the undesired enantiomer can be removed, for example, by recrystallization using the pure enantiomer (obtained, for example, by chiral chromatography) as seed material.

[0153] Typically, intermediates and compounds of formula (Ia) can be prepared according to the schemes provided above and below. The more specific descriptions and examples outlining specific synthetic routes and the generic schemes below are intended to provide guidance to synthetic chemists of ordinary skill in the art, who will readily recognize that modifications of solvents, concentrations, reagents, protecting groups, synthetic step order, times, temperatures, and the like can be made as necessary.

[0154] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound of the present invention and a pharma- ceutically acceptable carrier, obtained by synthesizing a compound of formula (Ia) according to the present invention or a pharma- ceutically acceptable hydrate or solvate thereof, and in particular, the preparation of such pharmaceutical compositions comprising synthesizing a compound of formula (Ia) or a pharma- ceutically acceptable hydrate or solvate thereof and combining it with one or more pharma- ceutical acceptable carriers. In another embodiment, the composition comprises at least two pharma- ceutical acceptable carriers, such as those described herein. For the purposes of the present invention, solvates and hydrates are also generally considered to be compositions, unless otherwise specified.

[0155] Compound A (wherever mentioned, referring to the compound in free or hydrated or solvated form) is useful for treating cancers selected from, for example, lung cancer (e.g., lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic adenocarcinoma), uterine cancer (including endometrial adenocarcinoma), and rectal cancer (including rectal adenocarcinoma), more preferably, lung cancer, colorectal cancer, or pancreatic cancer, or solid tumors, with the proviso that the cancer is KRAS G12C mutant. More preferably, the cancer to be treated by the compound of the present invention is KRAS G12C mutant lung cancer, including KRAS G12C mutant non-small cell lung cancer.

[0156] The present invention also relates to embodiments set forth in the claims, which are therefore considered to be included herein as part of the description.

[0157] The following examples serve to illustrate the invention without limiting its scope, while also defining specific embodiments of the invention.

[0158] The abbreviations used are those conventional in the art.

[0159] [Table 3]

[0160] [Table 4]

[0161] General methods and conditions: Temperatures are given in degrees Celsius. Unless otherwise stated, all evaporations are carried out under reduced pressure, typically between about 15 mmHg and 100 mmHg (=20 to 133 mbar).

[0162] Mass spectra were obtained on an LC-MS, SFC-MS, or GC-MS system using electrospray ionization, chemical ionization, and electron impact ionization with the following configuration: Waters Acquity UPLC series with a Waters SQ detector, or Mass spectra were obtained on an LCMS system using ESI with the following configuration: Waters Acquity LCMS series with a PDA detector. [M+H] + refers to the protonated molecular ion of a chemical species.

[0163] NMR spectra were measured using Bruker Ultrashield™ 400 (400 MHz), Bruker Ultrashield™ 600 (600 MHz), and Bruker Ascend™ 400 (400 MHz) spectrometers, both with and without tetramethylsilane as an internal standard. Chemical shifts (δ values) are reported in ppm downfield from tetramethylsilane, and spectral splitting patterns are designated as singlet (s), doublet (d), triplet (t), quartet (q), multiplet, unresolved or more overlapping signals (m), broad signal (br). Solvents are given in parentheses. Only observed proton signals that do not overlap with the solvent peak are reported.

[0164] The X-ray powder diffraction (XRPD) patterns described herein were obtained as described in WO 2021 / 124222 A1.

[0165] The following "Scheme 2" illustrates the steps of the synthesis according to the present invention, which are also described below: Scheme 2 [ka]

[0166] Example 1: Synthesis of compounds of formula (Ia) using steps according to the invention Step 1: tert-Butyl-6-[5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate B3) In a 500 mL three-neck flask equipped with a magnetic stirrer, tert-butyl 6-(3-bromo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (B1, 20.00 g, 56.14 mmol, see WO 2021 / 124222, p. 192), (1-methyl-1H-indazol-5-yl)boronic acid (intermediate B2, 10.08 g, 57.26 mmol, see US 2004 / 44258A, p. 165), RuPhos (0.524 g, 1.12 mmol), and RuPhos-Pd-G3 (0.939 mg, 1.12 mmol) were suspended in 2-MeTHF (86.34 g) under N2. Aqueous K3PO4 solution (prepared by adding 17.88 g of K3PO4 to 100.08 g of water) was added and the resulting mixture was heated for 65-70 minutes. oThe mixture was stirred overnight at 60-70°C. The mixture was cooled to 55-65°C. After phase separation, the organic layer was heated to 60-70°C. Activated carbon (2.00 g) was added to the organic layer, and the resulting suspension was stirred at the same temperature for 4-5 h. After hot filtration, the cake was washed twice with 2-MeTHF (12.87 g x 2). Water (50.00 g) was added to the combined filtrate at 60-70°C, followed by H3PO4 buffer solution (2.50 g). The resulting mixture was stirred for 1 h, and then the aqueous layer was removed at 60-70°C. The mixture was concentrated to about 80 g, heated until a clear solution was obtained, and then cooled to 50-60°C. B3 crystal seeds (seeds could be obtained from the same manufacturing batch) were added, and the resulting suspension was stirred at 50-60°C for 1 h. n-Heptane (137.19 g) was added over 4 h, then the suspension was stirred for 1 h, cooled to 25° C. for 2 h, kept overnight, and then filtered under vacuum. The wet cake was washed twice with n-heptane / 2-MeTHF and dried under vacuum to give the title compound as a beige powder (20.79 g, yield: 91%). The procedure was scaled up to 300 Kg. 1H NMR(400MHz,DMSO-d6)δ 8.08(s,1H),8.04(s,1H),7.86(dd,J1=8.0Hz,J2=1.4Hz,1H),7.62(d,J=8.0Hz,1H),6.47(s,1H),4.71( p,J=8.0Hz,1H),4.04(s,3H),3.98(s,2H),3.91(s,2H),2.78-2.60(m,4H),2.25(s,3H),1.39(s,9H);13C NMR(100MHz,DMSO-d6)δ MS m / z[M+H]+ 408.2.

[0167] Preparation of H3PO4 buffer solution: K3PO4 (14.41 g) was added to deionized water (110.4 g). 85% H3PO4 in H2O (40.4 g) was added and the pH value was confirmed to be 7.31.

[0168] Step 2: tert-Butyl 6-[4-iodo-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate B4) In a 350 ml four-neck round bottom flask equipped with an impeller stirrer, tert-butyl 6-[5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate (B3, 20.38 g, 50.00 mmol) and acetonitrile (40.87 g) were added under N2. The resulting suspension was heated to 50 °C, followed by the addition of a solution of NIS (12.38 g, 55.00 mmol) in acetonitrile (39.31 g) over 1 h. The resulting suspension was stirred at 50 °C until complete conversion of B3 (approximately 1-2 h), after which an aqueous Na2CO3 solution (prepared by dissolving 2.65 g of Na2CO3 in 20.4 g of deionized water) was added dropwise over 30 min. The resulting suspension was then stirred at 50° C. for 15 min, followed by successive dropwise addition of deionized water (61.2 g) at 90 min and Na2SO3 aqueous solution (prepared by dissolving 3.15 g Na2SO3 in 20.4 g deionized water) at 30 min. The resulting suspension was stirred at 50° C. for 15 min, cooled to 25° C. for 2 h, stirred for an extra hour, and then filtered under vacuum. The wet cake was washed with water / acetonitrile=4 / 1 (v / v, 117.19 g) and dried under vacuum to give the title compound as a white powder (25.33 g, yield: 95%). The procedure was scaled up to 400 Kg. 1 H NMR(400MHz,DMSO-d6)δ 7.94(s,1H),7.57(d,J=8.0Hz,1H),7.50(d,J=8.0Hz,1H),4.67(p,J=8.0Hz,1H),3 .89(s,1H),3.79(s,2H),3.68(s,2H),2.35-2.27(m,7H),2.13(s,3H),1.19(s,9H); 13C NMR(100MHz,DMSO-d6)δ 155.3,149.7,149.2,139.1,132.8,126.3,125.7,123.2,119.5,109.3,78.4,61.0,47.8,39.6,35.4,31.2,28.0,11.6.

[0169] Step 3: tert-Butyl 6-[(4M)-4-[2-chloro-6-(1,3-dioxolan-2-yl)-5-fluoro-3-methylphenyl]-5-methyl-3-rea(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate B6) To a 1 L Radley reactor equipped with an impeller stirrer was added tert-butyl 6-[4-iodo-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate (B4, 50.00 g, 93.74 mmol), Pd(OAc)2 (2.10 g, 9.37 mmol), (R)-H8-BINAP (6.50 g, 10.31 mmol), toluene (242.00 g), and n-heptane (85.50 g) under N2. The resulting solution was heated to 65 °C and stirred for 30 min. Micronized Cs2CO3 (91.62 g, 281.21 mmol, 400-600 mesh) was added in one portion and the resulting suspension was stirred at 65 °C for 10 min. A solution of 2-[2-chloro-6-(1,3-dioxolan-2-yl)-5-fluoro-3-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (B5, 48.17 g, 140.60 mmol) in toluene / n-heptane = 2 / 1 (112.00 g) was added slowly via peristaltic pump over 26 h and the resulting suspension was stirred at 65 °C for another 8 h. The total water in the reaction mixture was kept at about 1.5 equiv., too much water or too little water may lead to failure of the reaction. After the reaction was completed, 9% N-acetylcysteine ​​aqueous solution (550.00 g, 163.19 mmol) was added at 65° C., the resulting two-phase solution was stirred for another 7 h, and then cooled to 25° C. The aqueous layer was removed, and the remaining organic layer was filtered through MCC and washed with water (100.00 g). After phase separation, the organic layer was concentrated under vacuum to approximately 200 g. n-heptane (80.00 g) and B6 crystal seeds (obtained from a manufacturing batch) were added in one portion, and the resulting suspension was stirred at 35° C. for 2 h. n-heptane (120.00 g) was added dropwise over 2 h, and the resulting suspension was stirred for 2 h, cooled to 20° C., and filtered under vacuum. The wet cake was washed with toluene / n-heptane=2 / 1 (99.90 g) and dried under vacuum to give the title compound as an off-white powder (45.65 g, yield: 78%, 98.2% ee). The procedure was scaled up to 200 Kg (yield: 79-81%, 99.6% ee). 1H NMR(400MHz,DMSO-d6)δ 7.93(s,1H),7.62(s,1H),7.49(d,J=8.0Hz,1H),7.44-7.33(m,2H),5.60(s,1H),4.83(p,J=8.0Hz,1 H),4.06-3.88(m,7H),3.88-3.66(m,4H),2.90-2.64(m,4H),2.34(s,3H),1.95(s,3H),1.39(s,9H); 13 C NMR(100MHz,DMSO-d6)δ 160.7,158.2,155.4,147.1,139.4(J=9.0Hz),138.8,137.7,134.8(J=5.0Hz),132.6,130.6(J=3.0Hz),126.3,124.9,124.4( MS m / z[M+H]+ 622.3.

[0170] Intermediate B5 is prepared as follows: [ka]

[0171] 2-(2-bromo-3-chloro-6-fluoro-4-methylphenyl)-1,3-dioxolane (Intermediate B5-1) A solution of 2-bromo-3-chloro-6-fluoro-4-methylbenzaldehyde (B5-2, 517.9 Kg, assay: 11.7%, see US Patent Publication No. 2019 / 248767, p. 31) in MTBE was added under N2 to a glass-lined reactor equipped with an impeller agitator and concentrated to 120-180 Kg under vacuum. Toluene (266 Kg) was charged and the mixture was then concentrated to 120-180 Kg. The mixture was cooled to 20-30 °C. p-TsOH·H2O (2.3 Kg), ethylene glycol (25.6 Kg), and toluene (320 Kg) were added sequentially and the resulting solution was heated to 55-62 °C and concentrated to 300-360 Kg at the same temperature. Toluene (320 Kg) was charged and the mixture was concentrated to 300-360 Kg at 55-62 °C. The toluene addition / distillation procedure was repeated until complete conversion of B5-2. The reaction mixture was cooled to 20-30 °C and washed with 7% NaHCO3 aqueous solution (120 Kg) and 5% NaCl aqueous solution (138 Kg). After phase separation, the organic layer was diluted with THF (210 kg) and concentrated to 120-180 Kg under vacuum at <45 °C. The THF addition / distillation procedure was repeated until the water content of the solution was ≦0.2% (KF). The residue was cooled to 20-30 °C to give a THF / toluene solution of the title compound (268.2 Kg, yield: >99%, purity: 92.2%, assay: 26.8%), which was used directly in the next step without further purification.

[0172] 2-[2-chloro-6-(1,3-dioxolan-2-yl)-5-fluoro-3-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate B5) A glass-lined reactor equipped with an impeller agitator was charged with a toluene / THF solution of 2-(2-bromo-3-chloro-6-fluoro-4-methylphenyl)-1,3-dioxolane (B5-1, 268.2 Kg, assay: 26.8%) and THF (345 Kg) under N2. The solution was cooled to -10 to 0 °C and i-PrMgCl·LiCl (2.0 M in THF, 182 Kg) was added slowly below 0 °C. The resulting solution was stirred for an additional 3 to 5 h, after which 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (69 Kg) was added slowly below -10 to 0 °C. The resulting solution was warmed to 20 to 30 °C and stirred for an additional 3 to 5 h. After complete conversion, the mixture was diluted with MTBE (497 Kg) and quenched with 10% citric acid aqueous solution (340 Kg) at 0-10°C. The aqueous layer was then extracted with MTBE (178 Kg) and the combined organic layers were washed successively with 10% citric acid aqueous solution (354 Kg), 12.5% ​​NaCl aqueous solution (284 KgX2), water (284 Kg) and concentrated under vacuum to 140-210 L. MTBE (155-200 Kg) and water (50-100 Kg) were charged and the organic layer was concentrated under vacuum to 70-140 Kg below 45°C. n-Heptane (98 Kg) was charged at 40-50°C and the resulting mixture was cooled to 0-10°C and stirred for 2-5 h. B5 seeds (seeds could be obtained from the same production batch) were added. The suspension was stirred at 0-10°C for 2-5 h and then filtered. The wet cake was washed with n-heptane (50 Kg) and dried under vacuum to give the title compound as a white powder (55.35 Kg, yield: 66%). The procedure was scaled up to 196 Kg. 1 H NMR(400MHz,DMSO-d6)δ 7.29(d,J=12.0Hz,1H),5.97(s,1H),4.03-3.89(m,4H),2.31(s,3H),1.33(s,12H); 13 C NMR(100MHz,DMSO-d6)δ MS m / z[M+H]+ 343.1.

[0173] Step 4. tert-Butyl 6-[(4M)-4-(2-{(E)-[(benzyloxy)imino]methyl}-6-chloro-3-fluoro-5-methylphenyl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate B8) Step 4a: In a 1 L Radley reactor equipped with an impeller stirrer was added tert-butyl 6-[(4M)-4-[2-chloro-6-(1,3-dioxolan-2-yl)-5-fluoro-3-methylphenyl]-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate (B6, 27.87 g, 44.80 mmol), AcOH (126.62 g) and water (59.28 g). The reaction mixture was stirred at 35° C. for 25 h. Step 4b: After cooling to 0 °C, MeOH (260.96 g), NaOAc (4.04 g, 49.28 mmol), and BnONH2·HCl (7.87 g, 49.28 mmol) were added successively, and the mixture was stirred at 0 °C for another 5–6 h. B8 crystal seeds (0.025 g, seeds could be obtained from the same production batch) were added, and the resulting suspension was stirred at 0 °C for 1 h, then warmed to 25 °C. After stirring at the same temperature for 1 h, water (164.12 g) was added dropwise in 3 h, and the resulting suspension was stirred at 25 °C for 16 h, then filtered under vacuum. The wet cake was washed with MeOH / water = 2 / 1 (76.19 g), water (89.20 g × 3), and dried under vacuum to give the title compound as a white powder (24.03 g, yield: 78%, >99.5% ee). The procedure was scaled up to 200 Kg. 1H NMR(400MHz,DMSO-d6)δ 7.95(s,1H),7.68(s,1H),7.57(s,1H),7.50(d,J=8.8Hz,1H),7.44(d,J=11.0Hz,1H) ,7.32(dd,J1=8.8Hz,J2=1.4Hz,1H),7.24(dt,J1=6.0Hz,J2=3.0Hz,3H),7.16(dd,J1 =6.7Hz,J2=2.8Hz,2H),4.96-4.87(m,2H),4.82(p,J=7.9Hz,1H),3.99(s,5H),3.91( s,2H),2.87-2.74(m,2H),2.74-2.64(m,2H),2.40(s,3H),1.93(s,3H),1.38(s,9H); 13 C NMR(100MHz,DMSO-d6)δ 159.10,156.57,155.36,147.13,143.56(d,J=3.0Hz),139.64(d,J=10.1Hz),138.89 ,137.86,137.20,134.78(d,J=4.0Hz),132.69,130.95(d,J=3.0Hz),128.06(d,J=14 .1Hz),127.71,125.94,124.81,123.46,118.94(d,J=12.1Hz),118.40,118.17,117. 74,112.16,109.53,78.39,75.43,47.03,39.62,35.27,31.29,28.02,20.65,9.26;MS m / z[M+H]+ 683.3.

[0174] Step 5. Test Procedure 1: tert-Butyl 6-(4M-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate-propan-1-ol (1 / x) (Intermediate B10) To a 500 mL Radley reactor equipped with an impeller stirrer, tert-butyl 6-[(4M)-4-(2-{(E)-[(benzyloxy)imino]methyl}-6-chloro-3-fluoro-5-methylphenyl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate (B8, 150 g, 219.56 mmol), sodium acetate (27.0 g, 329.34 mmol), NMP (291.3 g), and hydrazine monohydrate (purity: 98-100% 87.9 g, 1756.48 mmol) were added sequentially under N2. The resulting suspension was heated to 80 °C for 1 h and stirred for 48 h. After complete conversion, the mixture was cooled to 20°C and then diluted with ethyl acetate (750 ml) and 10% NaCl aqueous solution (750 g). The mixture was cooled to 10°C and stirred for 30 min. The organic layer was separated and washed three times (750 g x 3) with citric acid / NaCl solution (prepared by adding 31.2 g citric acid to 1 L 10% NaCl aqueous solution) and once with 2% NaHCO3 aqueous solution (750 g). Pre-treated resin (30.0 g Amberchrom 50WX4, made of 4% cross-linked styrene-divinylbenzene based cation exchange resin with sulfonic acid functional groups) was added and the resulting suspension was stirred at 25°C for 8 h, followed by filtration through a pad of cellflock (powdered cellulose). The cake was washed with ethyl acetate (300 mL x 3) and the combined filtrates were concentrated to about 835 mL. The distillation residue was heated to 50°C. 1-propanol (193 g) and B10 crystal seeds (seeds could be obtained from the same manufacturing batch) were added sequentially and the resulting suspension was stirred at 50° C. for 1 h. Extra 1-propanol (64 g) was added and the suspension was stirred at 50° C. for 3 h, followed by the gradual addition of n-heptane (2.31 Kg) in 6 h. The suspension was then cooled to 5° C. in 6 h and held for an extra hour, then filtered under vacuum. The wet cake was washed twice with ethyl acetate:n-heptane=1:3 (228 g) and dried under vacuum to give the title compound as a white powder (115.50 g, yield: 83%, >99.0% ee). The procedure was scaled up to 200 Kg.1 H NMR(400MHz,DMSO-d6)δ 13.07(s,1H),7.87(s,1H),7.57(s,1H),7.54(s,1H),7.44-7.36(m,2H),7.31-7.26(m,1H),4.86(p ,J=8.0Hz,1H),4.02(s,2H),3.94(s,5H),2.93-2.70(m,4H),2.48(s,3H),2.02(s,3H),1.40(s,9H); 13 C NMR(100MHz,DMSO-d6)δ 155.4,147.4,138.8,138.2,137.6,134.1,133.0,132.5,126.8,126.5,125.1,124.9, 123.4,123.3,117.7,112.8,110.9,109.2,78.4,47.0,35.2,31.3,28.0,21.5,9.7;MS m / z[M+H]+ 572.3.

[0175] Pretreatment of impurity scavenger Amberchrom 50WX4 (200-400 mesh): Amberchrom 50WX4 (30 g) was suspended in methanol (80 g) and the resulting mixture was stirred at room temperature for 10 min and then filtered. The wet cake was rinsed with ethyl acetate (75 g x 2) and dried under reduced pressure.

[0176] Test Procedure 2: tert-Butyl 6-[(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl 3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate (amorphous) (Intermediate B10): To a 100 mL three-neck flask equipped with a magnetic stir bar, tert-butyl 6-[(4M)-4-(2-{(E)-[(benzyloxy)imino]methyl}-6-chloro-3-fluoro-5-methylphenyl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate (B8, 15 g, 21.52 mmol), sodium acetate (0.88 g, 10.76 mmol), NMP (77.3 g), hydrazine monohydrate (85 wt.%, 10.3 g, 172.12 mmol), and water (3.1 g) were added sequentially under N2. The resulting mixture was heated to 80 °C for 1 h and stirred for 50 h. After complete conversion, the reaction mixture was cooled to 40 °C and added dropwise to H2O (250 mL) for 1 h. The resulting suspension was stirred at 40 °C for 1 h, cooled to 10 °C, and stirred for an additional 1 h. After filtration, the wet cake was washed with water (45 mL × 2) and redissolved in DCM (120 mL). 2% NaHCO3 aqueous solution (80 g) was added and the mixture was stirred at 25 °C for 15 min. The organic layer was removed and then the aqueous layer was washed with DCM (30 mL). The combined organic layers were treated with Amberchrom 50WX4 (200-400 mesh, 5 g) at 25 °C for 16 h and filtered. The filtrate was concentrated under vacuum to about 60 g. Ethyl acetate (200 g) was added and the resulting solution was concentrated to 90 g. The above procedure was repeated twice to replace DCM with ethyl acetate. The residue (about 85 g) was heated to 50° C., followed by dropwise addition of n-heptane (115 mL) in 30 min. B10 crystal seeds (seeds could be obtained from the same production batch) were added, and then the mixture was stirred at 50° C. for 6 h. The remaining portion of n-heptane (80 mL) was added in 2 h, and the suspension was stirred at 50° C. for 3 h, cooled to 20° C. in 3 h, and stirred for another 3 h. After filtration, the wet cake was washed with ethyl acetate:n-heptane=1:3 (30 g×3) and dried under vacuum to give the title compound as a white powder (12.31 g, yield: 76%, 96.4% ee). The procedure was scaled up to 3.6 Kg.

[0177] Step 6. 6-[(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-ium hydrogen sulfate (IUPAC name) (Intermediate B11) A 45% H2SO4 aqueous solution (264 Kg) was added to a glass-lined reactor equipped with an impeller agitator under N2. tert-Butyl 6-[(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl 3-(1-methyl-1H-indazol-5-yl)-1-H-pyrazol-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate-propan-1-ol (1 / x) (B10, 35 Kg) was dissolved in THF (52 Kg) and water (2.8 Kg) and the resulting solution was added slowly to the reactor at 20°C for 1 h. After the addition was complete, the funnel was rinsed with THF (5 Kg) and the reaction mixture was stirred at 20°C for an additional 60 min. After complete conversion, the mixture was cooled to 10°C. A 25% aqueous ammonium hydroxide solution (97.9 Kg) was added slowly over 30 min, followed by isopropanol (77.2 Kg). A further portion of 25% aqueous ammonium hydroxide solution (74.0 Kg) was added to adjust the pH range to 7-7.5. The aqueous layer was removed and acetonitrile (166 Kg) was added slowly over 1.5 h to the organic layer at 25°C. B11 seeds (from a previous reaction without seeds) were added and the resulting suspension was stirred for 3 h. A further portion of acetonitrile (95 Kg) was added slowly over 6 h. The resulting suspension was cooled to -15°C over 3 h and further aged for 8 h. After filtration at -15°C, the wet cake was washed with acetonitrile (75Kg x 2) and partially dried under vacuum at 10°C for 24h to give the title compound as a white solid, which was stored at -15°C under argon and used directly in the next step without further purification (32Kg, yield: 92%). MSm / z[M+H] + 472.2

[0178] Step 7. 1-{6-[(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one-propan-2-ol (1 / 1) In a glass-lined reactor equipped with an impeller agitator, 6-[(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-ium hydrogen sulfate (B11 wet cake, 3.83 Kg), IPA (9.06 Kg), and water (6.01 Kg) were added under N2. The resulting clear solution was stirred at 15 °C for 20 min and then cooled to 0-5 °C. 5% NaHCO3 aqueous solution (8.21 Kg) was added over 0.5-1 h to maintain the internal temperature below 10 °C. Additional NaHCO3 powder (0.61 Kg) was added in one portion followed by dropwise addition of acrylic anhydride (0.25 Kg) over 15 min. The dropping funnel was rinsed with DCM (1.0 Kg) and the mixture was stirred at 0-5 °C for 1.5 h. After complete conversion, the mixture was warmed to 20-30 °C and stirred for 30 min. DCM (18.10 Kg) was added and the organic layer was separated and washed with 2% NaCl aqueous solution (11.73 Kg). The organic layer was concentrated and extra IPA (7.5 Kg) was added in several portions to sufficiently replace DCM with IPA to control the water content to <0.5%. After distillation, the residue was cooled to 30 °C. IPA (14 Kg) was added and the mixture was cooled to 20 °C and stirred for 24 h. The resulting suspension was filtered under vacuum and the wet cake was washed with IPA (1.8 Kg) and then dissolved in DCM (15 Kg). Silica gel (0.6 Kg) was added and the suspension was stirred at 25° C. for an additional 2.5 h. After filtration, the DCM in the filtrate was again thoroughly replaced with IPA under vacuum and the resulting IPA suspension was cooled to 20° C. in 2 h and aged for an additional 18 h. After filtration, the wet cake was rinsed with IPA (2.2 Kg) and dried under vacuum to give the title compound as a white powder (0.69 Kg, yield: 60%, 99.6% ee). The procedure was scaled up to 77 Kg.1 H NMR(400MHz,DMSO-d6)δ 13.10(s,1H),7.88(s,1H),7.58(s,1H),7.54(s,1H),7.43-7.36(m,2H),7.30(d,J=8.0 Hz,1H),6.38-6.25(m,1H),6.11(dt,J1=16.0Hz,J2=4.0Hz,1H),5.72-5.63(m,1H),4.96 -4.84(m,1H),4.39(s,1H),4.35-4.27(m,2H),4.11(s,1H),4.04(s,1H),3.94(s,3H),3. 83-3.72(m,1H),2.97-2.73(m,4H),2.48(s,3H),2.03(s,3H),1.05(s,3H),1.03(s,3H); 13 C NMR(100MHz,DMSO-d6)δ 164.4,147.4,138.8,138.3,137.8,137.7,134.1,133.0,132.5,127.0,126.8,126.5,126.3,125.1,124.9,123.4, MS m / z[M+H]+ 526.2.

[0179] This isopropyl solvate form of Compound A can be converted to another solvate or hydrate as described in WO 2021 / 1224222 A1 or below.

[0180] Example 2 The compound of formula (Ia) in 2-propanol form obtained according to step 7 of Example 1 was dried overnight at ambient conditions to provide a crystalline hydrate (modified HA) form of Compound A, which exhibited the XRPD characteristics shown above or in WO 2021 / 124222 A1.

[0181] Example 3: Alternative preparation of crystalline hydrate (modified HA) preparation 25 mg of compound of formula (Ia) (Example 1, Step 7) was added to 0.1 mL of methanol. The resulting clear solution was stirred at 25° C. for 3 days. The resulting solution was seeded with the crystalline hydrate (modified HA) obtained in Example 1A. The resulting suspension was equilibrated for another day, after which the solids were allowed to settle. The solids were collected by centrifugal filtration and dried overnight at ambient conditions. After drying overnight at ambient conditions, the wet cake had formed the crystalline hydrate (modified HA).

Claims

1. A process for preparing a compound of formula (I) or a salt, hydrate or solvate thereof, comprising the steps of: 【Chemistry 1】 Compound B11b* or a salt thereof 【Chemistry 2】 with acrylic acid or a reactive derivative of acrylic acid to form a compound of formula (Ia) and, optionally, subsequently forming a salt or hydrate or solvate of the compound of formula (Ia).

2. A process for preparing a compound of formula (Ia) or a salt, hydrate or solvate thereof, comprising the steps of: 【Chemistry 3】 Compound Intermediate B11* 【Chemistry 4】 wherein r is 1, 2, 3, 4, or 5, especially 1 to 3, e.g., 1 or 2; q is 1, 2, 3, 4, or 5, especially 1 to 3, e.g., 1 or 2; and A is an acid anion of an organic or inorganic acid, or its deprotonated free form without said acid anion. with acrylic acid or a reactive derivative thereof; Optionally, by forming a salt of the compound of formula (Ia) or by converting a hydrate or solvate of the compound of formula (Ia) into the free form or into a different hydrate or solvate, or by converting the free form of the compound of formula (Ia) into its hydrate or solvate. A method comprising:

3. 2. The method according to claim 1 or the method for preparing intermediate B11*, comprising the steps of: 【Chemistry 5】 (Wherein, Pr1 is a protecting group.) to form compound B11*.

4. A process for the preparation of the method or intermediate B10* according to any one of claims 1 to 3, comprising the steps of: 【Chemistry 6】 (wherein Pr1 is a nitrogen protecting group, Pr2 is a protected hydroxyl group or an unsubstituted or substituted amino group, and Xc is halogeno or pseudohalogeno.) and reacting said compound with said compound.

5. The method according to any one of claims 1 to 4 or the method for preparing intermediate B8*, comprising the steps of: 【Chemistry 7】 wherein Pr1 is a nitrogen protecting group and Xc is halogeno or pseudohalogeno, and a compound of the formula Pr2-NH ２ wherein Pr2 is a protected hydroxyl group or an unsubstituted or substituted amino group, or a hydroxyolamine derivative of the formula Pr2-NH ２ wherein Pr2 is a protected hydroxyl group or an unsubstituted or substituted amino group.

6. The method or the method for preparing intermediate B7* according to any one of claims 1 to 5, comprising the steps of: 【Chemistry 8】 (wherein Q is a formyl group in the acetal or Schiff base form, Pr1 is a nitrogen protecting group, and Xc is halogeno or pseudohalogeno.) to form intermediate B7*, optionally in the presence of an acid.

7. A process for the preparation of intermediate B8* according to any one of claims 1 to 6, wherein the process steps are carried out in a one-pot synthesis.

8. The method according to any one of claims 1 to 7 or the method for preparing intermediate B6*, comprising the steps of: 【Chemistry 9】 (Wherein, Pr1 is a nitrogen protecting group; (a) Lb is borono (-B(OH) ２ ), a boronic acid diester moiety, BF ３ In the case of K, MgX (wherein X is Cl, Br, or I), Zn(RZ) (wherein RZ is halogen or alkyl), Sn(RD)(RE)(RF) (wherein each of RD, RE, and RF is methyl or n-butyl), or Si(RG)(RH)(RI) (wherein each of RG, RH, and RI is hydrogen, fluoro, hydroxy, alkyl, alkoxy, or Li), Xb is hydrogen, halogeno, -OSO ２ RA (wherein RA is C １ ~C ４ -alkyl, fluoro-C １ ~ ６ -alkyl, or substituted phenyl), or ORB, where R is C １ ~C ４ -alkyl), or (b) Lb is hydrogen, halogeno, -OSO ２ RA (wherein RA is C １ ~C ４ -alkyl, fluoro-C １ ~C ６ -alkyl, or substituted phenyl), or ORB, where R is C １ ~C ４ -alkyl), Xb is borono (-B(OH) ２ ), a boronic acid diester moiety, BF ３ K, MgX, where X is Cl, Br, or I, Zn(RZ), where RZ is halogen or alkyl, Sn(RD)(RE)(RF), where each of RD, RE, and RF is methyl, n-butyl, and Si(RG)(RH)(RI), where each of RG, RH, and RI is hydrogen, fluoro, hydroxy, alkyl, alkoxy, or Li. and, In the presence of a chiral (enantiomerically pure) mono- or (especially) bisphosphine ligand catalyst and a palladium source reagent, intermediate B5* 【Chemistry 10】 wherein Q is formyl or, in particular, the acetal or Schiff base form of the formyl group; Lb is (a') (especially) a borono (-B(OH)) when Xb is exactly as defined above for Xb under (a). ２ ), a boronic acid diester moiety, BF ３ K, MgX, where X is Cl, Br, or I, Zn(RZ), where RZ is halogen or alkyl, Sn(RD)(RE)(RF), where each of RD, RE, and RF is methyl, n-butyl, Si(RG)(RH)(RI), where each of RG, RH, and RI is hydrogen, fluoro, hydroxy, alkyl, alkoxy, or Li; or (b') when Xb is exactly as defined above under (b) for Xb, Lb is hydrogen, halogeno, -OSO ２ RA (wherein RA is C １ ~C ４ -alkyl, fluoro-C １ ~C ６ -alkyl, or substituted phenyl), or ORB, where R is C １ ~C ４ -alkyl), Xc is halogen or pseudohalogen. to form intermediate B6*.

9. The method or method for preparing intermediate B4* according to any one of claims 1 to 8, comprising the steps of: (a) Lb is borono(-B(OH) ２ ), a boronic acid diester moiety, BF ３ In the case of K, MgX (wherein X is Cl, Br, or I), Zn(RZ) (wherein RZ is halogen or alkyl), Sn(RD)(RE)(RF) (wherein each of RD, RE, and RF is methyl or n-butyl), or Si(RG)(RH)(RI) (wherein each of RG, RH, and RI is hydrogen, fluoro, hydroxy, alkyl, alkoxy, or Li), Xb is halogeno, -OSO ２ RA (wherein RA is C １ ~C ４ -alkyl, fluoro-C １ ~C ６ -alkyl, or substituted phenyl), or ORB, where R is C １ ~C ４ -alkyl), or (b) Lb is hydrogen, halogeno, -OSO ２ RA (wherein RA is C １ ~C ４ -alkyl, fluoro-C １ ~C ６ -alkyl, or substituted phenyl), or ORB, where R is C １ ~C ４ -alkyl), Xb is borono (-B(OH) ２ ), a boronic acid diester moiety, BF ３ K, MgX, where X is Cl, Br, or I, Zn(RZ), where RZ is halogen or alkyl, Sn(RD)(RE)(RF), where each of RD, RE, and RF is methyl, n-butyl, Si(RG)(RH)(RI), where each of RG, RH, and RI is hydrogen, fluoro, hydroxy, alkyl, alkoxy, or Li; Intermediate B3* 【Chemistry 11】 (wherein Pr1 is a nitrogen protecting group) and a reagent capable of inserting a group Xb (wherein Lb is borono (-B(OH) ２ ), a boronic acid diester moiety, BF ３ In the case of K, MgX (wherein X is Cl, Br, or I), Zn(RZ) (wherein RZ is halogen or alkyl), Sn(RD)(RE)(RF) (wherein each of RD, RE, and RF is methyl or n-butyl), or Si(RG)(RH)(RI) (wherein each of RG, RH, and RI is hydrogen, fluoro, hydroxy, alkyl, alkoxy, or Li), Xb is halogeno, -OSO ２ RA (wherein RA is C １ ~C ４ -alkyl, fluoro-C １ ~C ６ -alkyl, or substituted phenyl), or ORB, where R is C １ ~C ４ -alkyl), or (b) Lb is hydrogen, halogeno, -OSO ２ RA (wherein RA is C １ ~C ４ -alkyl, fluoro-C １ ~C ６ -alkyl, or substituted phenyl), or ORB, where R is C １ ~C ４ -alkyl), Xb is borono (-B(OH) ２ ), a boronic acid diester moiety, BF ３ K, MgX, where X is Cl, Br, or I, Zn(RZ), where RZ is halogen or alkyl, Sn(RD)(RE)(RF), where each of RD, RE, and RF is methyl, n-butyl, Si(RG)(RH)(RI), where each of RG, RH, and RI is hydrogen, fluoro, hydroxy, alkyl, alkoxy, or Li. and reacting said compound with said compound.

10. A process for the preparation of the method or intermediate B3* according to any one of claims 1 to 9, comprising the steps of: 【Chemistry 12】 (Wherein, La is a borono, boronic acid diester moiety, BF ３ K, MgX, where X is Cl, Br, or I, Zn(RZ), where RZ is halogen or alkyl, Sn(RD)(RE)(RF), where each of RD, RE, and RF is methyl, n-butyl, and Si(RG)(RX)(RY), where each of RG, RX, and RY is hydrogen, fluoro, hydroxy, alkyl, alkoxy, or Li. and intermediate B1* in the presence of a cross-coupling catalyst. 【Chemistry 13】 (Wherein, Pr1 is a nitrogen protecting group, and Xa is hydrogen, halogeno, -OSO ２ RA (wherein RA is C １ ~C ４ -alkyl, fluoro-C １ ~C ６ -alkyl, or substituted phenyl), or ORB, where R is C １ ~C ４ 4-alkyl) and reacting with to form intermediate B3*.

11. In intermediate B4*, Pr1 is a nitrogen protecting group selected from the group consisting of tert-butyoxycarbonyl, carbobenzoxycarbonyl (Cbz), benzyl (Bn), methoxybenzyl (MPM), trifluoroacetyl, acetyl, fluoren-9-yl-methoxycarbonyl (Fmoc), and trityl (Tr); Xb is hydrogen, halogeno, a mesylate moiety, a triflate moiety, or a tosylate moiety; In intermediate B5*, Q is 【Chemistry 14】 (In the formula, R １ and R ２ are independently selected from alkyl or arylalkyl, or together form an alkenyl bridge which may be unsubstituted or substituted with one or more moieties selected from alkyl, aryl, and arylalkyl, some preferred moieties being: 【Chemistry 15】 (In the formula, R １ and R ２ are independently selected from hydrogen and alkyl and further aryl; 【Chemistry 16】 (In the formula, R １ and R ２ are independently selected from hydrogen, alkyl, and further aryl. and The following group: 【Chemistry 17】 is a special case) moreover -CH=N-R', where R' is selected from alkyl, aryl, alkoxy, and S(=O)-R" where R" is selected from alkyl, aryl, and alkoxy, e.g., -S(=O)-alkyl (e.g., tert-butyl) or -S(=O)phenyl. is selected from the group consisting of Chiral (enantiomerically pure) mono- or (especially) bisphosphine ligand catalysts include 【Chemistry 18】 and especially - Group 1 consisting of: 【Chemistry 19】 - Group 2 consisting of: 【Chemistry 20】 and - Group 3 consisting of: 【Chemistry 21】 is selected from the group consisting of The palladium source reagent is selected from the group consisting of palladium sources, Pd(OAc), ２ , Pd(OPiv) ２ , Pd(OCOEt) ２ , PdCl ２ , PdBr ２ , PdI ２ , Pd(OH) ２ , PdSO ４ , Pd(TFA) ２ , Pd(dba) ２ , Pd ２ (dba) ３ , Pd(acac) ２ , Pd ２ (dba) ３ CHCl ３ , Pd(PPh ３ ) ４ , Pd(PPh ３ ) ２ C ２ , Pd(CH ３ C.N. ２ C ２ , Pd(PhCN) ２ C ２ , [Pd(π-allyl)Cl] ２ [Pd(π-cinnamyl)Cl] ２ , Pd[P(o-Tol) ３ ] ２ , Pd / C, Pd(OH) ２ / C, [PdG1] ２ , [PdG2] ２ , [PdG3] ２ , [PdG4] ２ .. Pd(BINAP)Cl ２ , Pd(dppe)Cl ２ , Pd(dppp)Cl ２ , Pd(dppb)Cl ２ , and Pd(dppf)Cl ２ Any Pd salt or complex can be used, for example, the Pd(II) salt or complex selected for the bisphosphonic ligand, e.g., Pd(OAc) ２ , Pd(TFA) ２ , and Pd(PhCN) ２ C ２ or Pd(0) for bisphosphine monoxides, e.g., Pd ２ (dba) ３ Or Pd(dba) ２ can be used, The reaction is preferably carried out in the presence of a base, e.g., Cs ２ CO ３ , CsOH·H ２ O, CsHCO ３ , CsOPiv, CsF, CsOAc, K ３ P.O. ４ , K ２ CO ３ , KHCO ３ , KF, TMSOK, NaOH, NaHCO ３ , KOH, NaOMe, KOMe, NaOEt, KOEt, KO ｔ Bu, NaO ｔ Bu, NaOAc, KOAc, DABCO, DBU, TEA, DIPEA, Cy ２ NMe, pyridine, 2,6-lutidine, etc. (Cs ２ CO ３ In particular, the micronized form is a preferred example) in the presence of DMF, DMSO, NMP, water, MeOH, EtOH, i-PrOH, tert-amyl alcohol, toluene, o-xylene, m-xylene, p-xylene, 1,3,5-trimethylbenzene, 1,3,5-trifluorobenzene, chlorobenzene, trifluoromethylbenzene, 1,2-difluorobenzene, n-heptane, n-hexane, c-hexane, n-pentane, THF, 2-MeTHF, 1,4-dioxane, MTBE, CPME, i-Pr ２ O, n-Bu ２ O, Ph ２ O, DME (1,2-dimethoxyethane), MeO(CH ２ CH ２ O) ２ Me, cyclohexane, acetonitrile, DCM, Et ３ N, DIPEA, 2,6-lutidine, ethyl acetate, i-propyl acetate, t-butyl acetate, MIBK, and sulfolane (for example, as examples that can be used), the total amount of water in the reaction mixture is preferably kept at about 1.5 (for example, 1.2-1.8) equivalents per mol of intermediate B4*, and the reaction is preferably carried out at a temperature in the range of 0° C. to the boiling temperature of the reaction mixture, in particular at an elevated temperature in the range of 25-90° C., for example 50-75° C., for example 60-70° C.; The method according to any one of claims 1 to 10.

12. A process for preparing a compound of formula (1a) or a salt, hydrate or solvate thereof, comprising the following reaction: 【Chemical 22】 (In the formula, Xa is iodo or chloro or especially bromo, Pr1 is tert-butoxycarbonyl; La is -B(OH) ２ and Xb is chloro, bromo, or iodo; Xc is chloro or, especially, fluoro; Q is the formula 【Chemistry 23】 is a group represented by Lb is represented by the formula 【Chemistry 24】 is a group represented by Lc is benzyloxy; q is 1, 2, or 3; r is 1, 2, or 3; A is Cl － , B － , F － , HSO4 ４ － , or S.O. ４ ２－ (It is) A method comprising:

13. Coupling of intermediate B4* with intermediate B5* using a chiral catalyst 【Chemistry 25】 A process for preparing intermediate B6* comprising:

14. The following scheme 【Chemistry 26】 A process for the preparation of a compound of formula (Ia) according to the following:

15. formula 【Chemical 27】 wherein Q is a formyl group or a formyl group in acetal or (even) Schiff base form, Pr1 is a nitrogen protecting group; Xc is halogen or pseudohalogen. Intermediate B6*.

16. formula 【Chemistry 28】 (Wherein, Pr1 is a nitrogen protecting group; Xc is halogen or pseudohalogen. Intermediate B7*.

17. formula 【Chemical Formula 29】 (Wherein, Pr1 is a nitrogen protecting group; Pr2 is a protected hydroxyl group or an unsubstituted or substituted amino group, and Xc is halogeno or pseudohalogeno. Intermediate B8*.

18. formula 【Chemistry 30】 where Pr1 is a nitrogen protecting group. Intermediate B10*.

19. formula 【Chemistry 31】 wherein r is 1, 2, 3, 4 or 5, especially 1 to 3, e.g. 1 or 2; q is 1, 2, 3, 4 or 5, especially 1 to 3, e.g. 1 or 2; and A is an acid anion of an organic or inorganic acid, with acrylic acid or a reactive derivative thereof. Intermediate B11*.

20. The method according to any one of claims 1 to 14, wherein the method is carried out on an industrial scale, for example above a 10 g scale or 1 kilogram scale.

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