Inhibitors of complement factors and uses thereof

Abstract

This invention discloses compounds of formula I and their pharmaceutically acceptable salts. This invention also discloses methods for treating neurodegenerative diseases, inflammatory diseases, autoimmune diseases, or metabolic diseases using the compounds disclosed herein.

Description

Prior technology

[0001] The complement system refers to a group of proteins involved in the innate immune system. This aids or complements the ability of antibodies and phagocytes to clear pathogens from an organism. There are three cascades involved in this system, namely the classical pathway, the lectin pathway and the alternative pathway. The cascades are triggered by different recognition events and lead to the recruitment and activation of a series of proteins capable of tagging the cell surface and amplifying processes that can lead to cell lysis, damage or engulfment.

[0002] The classical pathway is activated by binding of the complement protein C1q either directly to the cell surface or to proteins that bind to the cell surface. In one of the main functions of the classical pathway, CIq can be recruited by antibodies specific for cell surface antigens. CIq is a large polyprotein of 460 kDa consisting of 18 polypeptide chains (6 CIq A chains, 6 CIq B chains and 6 CIq C chains). These chains form a larger symmetrical protein composed of three segments: a tail region, an arm region and a globular head region. The single tail segment is divided into six symmetrical arms, each of which terminates in a bulbous head. The majority of CIq circulating in the blood carries a heterotetrameric complex of the complement proteins CIr and CIs, two serine proteases that initially bind to CIq as inactive zymogens. This larger multi-chain assembly is called the C1-complex. Binding of the C1-complex to the cell surface or to the appropriate complement-fixing epitope of the recruited protein, such as that found in the Fc region of an antibody, induces a conformational change in a series of activation and amplification events. In response to binding, C1r is first activated, followed by cleavage and activation of C1s. Subsequently, complement C4 is recruited into the complex where it is incorporated and cleaved by C1s to C4b. This cleavage results in the exposure of a moiety that allows C4b to be covalently attached to the cell surface. Subsequently, this new complex recruits complement C2, which, in association with C4b, is cleaved from C1s to C2a. The surface-bound complex of C4b and C2a forms the C3-convertase that drives the subsequent cleavage of complement C3 and the surface-bound and activated downstream steps of the complement cascade. A single C1-complex is capable of constituting multiple C3-convertase modules on the surface, leading to a strong amplification of the original targeting event.

[0003] These events can cause tissue damage and cellular clearance / destruction in normal function as well as in disease pathology. It has also been found to play a key role in the pruning of synapses in normal neuronal development and in CNS disease pathology. These outcomes can be driven in various cases by the accumulation of C4 and C3 cleavage products on the surface, the progression of the cascade to the final step of membrane attack complex formation and / or pore-mediated lysis, and the presence of early complement stages. Accumulation of immune complexes of the combined components. In some cases, C1r and / or C1s expression can also be increased by local induction as part of a biological response, and the action of these proteases can further contribute to the development of disease pathology (see, e.g., Xavier et al. Am. J. Renal Physiol, 2019).

[0004] The complement system is a central component of innate immunity and serves as a bridge between innate and adaptive immune responses. However, it can also turn its destructive capabilities against the host cell. Aberrant activation or inadequate regulation of the complement cascade is involved in many diseases and pathological conditions. Accordingly, many neurodegenerative, inflammatory, and autoimmune diseases are believed to result from, or at least substantially be driven by, bursting complement factor activity.

[0005] For example, the cognitive abilities of humans, and especially patients with neurodegenerative diseases, are highly dependent on synapse formation. The formation of precise neuronal circuits during development is a highly regulated and dynamic process. Excessive numbers of synapses are first generated to establish the initial wiring pattern of the brain, but the formation of mature and precise neuronal circuits requires the selective elimination and pruning of specific synapses. Neuronal activity plays an important role in this optimization phase, which exploits the targeting of early components of the classical complement cascade to achieve this elimination.

[0006] However, premature synapse loss in neurodegenerative pathologies results in loss of neuronal activity and aberrant activation of synaptic pruning, thereby leading to cognitive decline. In neurodegenerative diseases such as Alzheimer's disease and glaucoma, complement factors such as complement factor C1 and their subunits such as C1q are expressed in neurons where they act as Signaling in synaptic elimination. See, eg, US Patent Publication Nos. US 2012 / 0195880 and US 2012 / 0328601. In the adult brain, synapse loss often precedes pathology and clinical symptoms in many neurodegenerative diseases long before. Prompt therapeutic intervention to prevent or reduce synapse loss can slow or prevent the development of clinical symptoms of neurodegenerative diseases.

[0007] Accordingly, inhibition or modulation of classical complement activity has been identified as a promising therapeutic strategy. Therefore, there is a need to explore and develop methods for inhibiting or modulating the aberrant activities of these complement factors.

Content of invention

[0008] In certain aspects, the present invention provides compounds represented by formula I or II:, and pharmaceutically acceptable salts thereof, wherein: R1 is hydrogen, halogen, amino, hydroxyl, alkoxy or Alkylthio; V and W are each independently CR or N; each R is independently hydrogen, halogen, nitro, cyano, amino, hydroxyl, alkoxy, alkylthio or alkyl; X is CR or N; Rb is hydrogen, halogen, nitro, cyano, amino, hydroxyl, alkoxy, alkylthio, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclyl, hetero Cyclic group, aryl or heteroaryl; Each U is independently N or CRc; Each Rc is independently hydrogen, halogen, alkoxyl or alkyl; Ring Z1 is five-membered or six-membered aryl or heteroaryl; Ring Z2 is a five-membered or six-membered heterocyclic ring; each R2 is independently halogen, nitro, cyano, amine, acylamino / amido, hydroxyl, alkoxy, alkylthio, acyl, methyl Amino, azido, carbamoyl, carboxyl, carboxylate, guanidine, haloalkyl, haloalkoxy, heteroalkyl, imino, oxime, phosphonate, dialkylphosphine oxide, sulfonate Acyl, sulfonamide, sulfonylurea, sulfinyl, sulfinic acid, sulfonic acid, thiocyanate, thiocarbonyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl , carbocyclyl, heterocyclyl, aryl or heteroaryl; or two adjacent R2 are combined with the intervening carbon atoms to which they are attached to form a 5-membered or 6-membered carbocycle, 5-membered or 6-membered heterocycle, 5-membered Or a 6-membered aryl group, or a 5-membered or 6-membered heteroaryl group; when the valence permits, n is 0 or an integer selected from 1-4; each R6 is independently halogen, nitro, cyano, amino, Acylamino / amido, hydroxyl, side oxygen, carboxyl, alkoxy, alkylthio, acyl, formamidino, azido, carbamido, carboxyl, carboxyl ester, guanidine, haloalkane Haloalkoxy, heteroalkyl, imino, oxime, phosphonate, dialkylphosphine oxide, sulfonyl, sulfonamide, sulfonylurea, sulfinyl, sulfinic acid , sulfonic acid, thiocyanate, thiocarbonyl, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or any two of R6 Independently, the intervening carbon atom(s) to which it is attached is combined to form a carbocyclic or heterocyclic ring; when the valence permits, q is 0 or an integer selected from 1-4; R3 is; M is N(R8 )3, N(R8)2, OR8 or SR8; each R8 is independently hydrogen, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or hetero Aryl; and R3a and R3b are independently hydrogen, alkyl, acyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; or R3a and R3b are combined with a boron atom and two intervening oxygen atoms separating them to form a monocyclic or polycyclic heterocyclyl; or R3a, R3b and M are combined with the boron atom and the intervening atoms to form a polycyclic ring heterocycle.

[0009] In certain aspects, the invention provides pharmaceutical compositions comprising a compound provided herein and a pharmaceutically acceptable excipient.

[0010] In certain aspects, the invention provides methods of making the compounds provided herein.

[0011] In certain aspects, the invention provides methods of treating a disease associated with complement activation in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound provided herein.

[0012] In certain aspects, the invention provides methods of inhibiting C1s, the methods comprising contacting C1s with a compound disclosed herein. In certain aspects, the invention provides methods of inhibiting activated C1s comprising contacting C1s with a compound disclosed herein.

Implementation

[0013] related applications

[0014] This patent application claims priority to U.S. Provisional Patent Application No. 63 / 054,064 filed on July 20, 2020, which is hereby incorporated by reference in its entirety.

[0015] In one aspect, the present invention provides a compound of formula I or II:, or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, halogen, amino, hydroxyl, alkoxy or alkylthio; V and W are each independently CRa or N; each Ra is independently hydrogen, halogen, nitro, cyano, amino, hydroxyl, alkoxy, alkylthio or alkyl; X is CRb or N; Rb is Hydrogen, halogen, nitro, cyano, amino, hydroxy, alkoxy, alkylthio, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclyl, heterocyclyl, aryl Each U is independently N or CRc; Each Rc is independently hydrogen, halogen, alkyl or alkoxy; Ring Z1 is five-membered or six-membered aryl or heteroaryl; Ring Z2 is five member or six-membered heterocycle; each R2 is independently halogen, nitro, cyano, amine, amido (acylamino / amido), hydroxyl, alkoxy, alkylthio, acyl, formamido, azide Nitrogen, carbamoyl, carboxyl, carboxyl ester, guanidine, haloalkyl, haloalkoxy, heteroalkyl, imino, oxime, phosphonate, dialkylphosphine oxide, sulfonyl, sulfo Amide, sulfonylurea, sulfinyl, sulfinic acid, sulfonic acid, thiocyanate, thiocarbonyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl , heterocyclyl, aryl or heteroaryl; or two adjacent R2 are combined with the intervening carbon atoms to which they are attached to form a 5-membered or 6-membered carbocycle, 5-membered or 6-membered heterocycle, 5-membered or 6-membered aromatic or 5-membered or 6-membered heteroaryl; when the valence permits, n is 0 or an integer selected from 1-4; each R6 is independently halogen, nitro, cyano, amino, amido ( acylamino / amido), hydroxyl, pendant oxygen, carboxyl, alkoxy, alkylthio, acyl, formamimidino, azido, carboxyl, carboxyl ester, guanidine, haloalkyl, haloalkane Oxygen, heteroalkyl, imino, oxime, phosphonate, dialkylphosphine oxide, sulfonyl, sulfonamide, sulfonylurea, sulfinyl, sulfinic acid, sulfonic acid, Thiocyanate, thiocarbonyl, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; or any two R6 independently, with The (these) intervening carbon atoms that are connected are combined to form a carbocyclic or heterocyclic ring; when the valence permits, q is 0 or an integer selected from 1-4; R3 is; M is N(R8)3, N (R8)2, OR8 or SR8; each R8 is independently hydrogen, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; and R3a and R3b are independently hydrogen, alkyl, acyl, alkenyl, alkynyl, aralkyl, heteroarylalkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; or R3a and R3b and boron atom and two intervening oxygen atoms separating them to form a monocyclic or polycyclic heterocyclyl; or R3a, R3b and M combine with the boron atom and the intervening oxygen atoms to form a polycyclic heterocycle. It will be appreciated that because in Formula II, Z1 is an aromatic moiety, the bond shared between Ring Z1 and Ring Z2 is of aromatic character.

[0016] In certain embodiments, the compound is represented by formula I-a or II-a:.

[0017] In some preferred embodiments, R1 is hydrogen, amino, hydroxyl, alkoxy or alkylthio. In some preferred embodiments, R1 is hydroxyl or C1-3 alkoxy. In certain preferred embodiments, R1 is amine, preferably -NH2 or -NHCH3, such as NH2.

[0018] In certain embodiments, each R2 is independently halogen, nitro, cyano, amine, acylamino / amido, hydroxyl, alkoxy, alkylthio, phosphonate, di Alkylphosphine oxide, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; or two adjacent R2 and the intervening carbon to which it is attached The atoms are combined to form a 5- or 6-membered carbocycle, a 5- or 6-membered heterocycle, a 5- or 6-membered aryl, or a 5- or 6-membered heteroaryl.

[0019] In some preferred embodiments, each R2 is independently halogen, cyano, amino, amido (acylamino / amido), hydroxyl, alkoxy, dialkylphosphine oxide, haloalkyl , sulfonyl, alkyl, carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaralkyl, or heteroaryl.

[0020] In certain embodiments, each R2 is independently halogen, cyano, amine, acylamino / amido, hydroxyl, alkoxy, dialkylphosphine oxide, alkyl, carbocyclic radical, heterocyclyl, aryl, aralkyl, heteroaralkyl or heteroaryl, for example -F, cyano, -N(H)C(O)R4, -OCF3, -OCH2C(O)NR4, -O(CH2CH2O)rR4, -CF3, -CHF2, -OCH3, -P(=O)(CH3)2, -CH3, -C2H5, cyclopropyl, tetrahydropyranyl or pyridyl; where R4 is an alkane and r is an integer selected from 1-6.

[0021] In certain embodiments, each R2 is independently -F, cyano, -N(H)C(O)R4, -OCF3, -OCH2C(O)N(R4)2, -O(CH2CH2O )rR4, -CF3, -CHF2, -OCH3, -P(=O)(CH3)2, -CH3, -C2H5, cyclopropyl, tetrahydropyranyl, 1,1-two side oxy-1, 2,5-thiadiazolidinyl or pyridyl; wherein R4 is alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; and r is an integer selected from 1-6.

[0022] In certain embodiments, two adjacent R2 are combined with the intervening carbon atoms to which they are attached to form a 5- or 6-membered carbocycle, a 5- or 6-membered heterocycle, a 5- or 6-membered aryl, or 5- or 6-membered heteroaryl. In certain preferred embodiments, two adjacent R2 are combined with the intervening carbon atom to which they are attached to form a 5- or 6-membered heteroaryl.

[0023] In certain embodiments, two adjacent R2 are combined with the intervening carbon atoms to which they are attached to form a 5- or 6-membered heteroaryl ring. In some embodiments, the 5- or 6-membered heteroaryl ring is furan, pyrazole, indazole, or oxazole.

[0024] In certain embodiments, two adjacent R2 are combined with the intervening carbon atoms to which they are attached to form a 5- or 6-membered heterocyclic ring. In some embodiments, the 5- or 6-membered heterocycle is tetrahydrofuran or tetrahydropyran.

[0025] In certain embodiments, each Ra is independently hydrogen, halogen, amine, hydroxyl, alkoxy or alkyl, preferably hydrogen.

[0026] In certain embodiments, Rb is hydrogen, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, preferably hydrogen, C1-C3 alkyl or cyclopropyl. In a preferred embodiment, Rb is methyl.

[0027] In certain embodiments, Rc is hydrogen, halo or alkyl.

[0028] In certain embodiments, one of V, W, and X is N. In certain embodiments, two of V, W and X are N. In certain embodiments, W and X are N, and V is CRa. In certain of these embodiments, Ra is hydrogen. In certain embodiments, V and W are N, and X is CRb. In certain of these embodiments, Rb is hydrogen or methyl. In certain preferred embodiments, Rb is methyl.

[0029] In certain embodiments, U is CRc. In certain embodiments, Rc is hydrogen, F, methyl, methoxy, or Cl. In some preferred embodiments, U is CH.

[0030] In certain embodiments, Ring Z1 is phenyl or a five- or six-membered heteroaryl. In certain preferred embodiments, ring Z1 is phenyl. In such embodiments, for example, the compound may be represented by formula I-b or II-b: .

[0031] In certain embodiments, Ring Z1 is a five- or six-membered heteroaryl. In certain embodiments, Ring Z1 is pyrazolyl. In certain embodiments, Ring Z1 is pyridyl. In these embodiments, for example, the compound can be represented by formula I-c or II-c:.

[0032] In certain embodiments, the compound is represented by Formula I, for example represented by Formula I-a, I-b or I-c. In certain embodiments, the compound is represented by formula I-c-1: wherein n is 0, 1 or 2, and R2a is alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, Heterocyclyl, aryl or heteroaryl.

[0033] In certain embodiments, the compound is represented by formula I-c-2: wherein n is 0, 1 or 2, and R2a is alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbon Cyclic, heterocyclyl, aryl or heteroaryl. In certain embodiments of formula (I-c-1) or (I-c-2), wherein R2a is methyl, difluoromethyl, -CF2CHF2, -CHFCF3, -CH2CF3, -(CH2CH2O)2CH3,.

[0034] In certain embodiments of formula (I-c-1) or (I-c-2), R2a is methyl, difluoromethyl, .

[0035] In certain embodiments of formula (I-c-1) or (I-c-2), R2a is wherein m is an integer from 2 to 6.

[0036] In certain embodiments, R3 is. In other embodiments, R3 is.

[0037] In certain embodiments, R3a and R3b are independently hydrogen, alkyl, acyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclyl, heterocyclyl, aryl or heteroaryl. In certain preferred embodiments, R3a and R3b are hydrogen.

[0038] In certain embodiments, R3a and R3b are combined with a boron atom and two intervening oxygen atoms separating them such that R3 is a heterocyclyl such as a five or six membered heterocyclyl. In certain such embodiments, R3 can be represented as, wherein: each R5 is independently halogen, nitro, cyano, amine, acylamino / amido, hydroxyl, pendant oxy, carboxy, alkane Oxy, alkylthio, alkyl (such as carboxymethyl), aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl or heteroaryl; or any two R5 is independently combined with the intervening carbon atom(s) to which it is attached to form a carbocyclic or heterocyclic ring; and when the valence permits, p is 0 or an integer selected from 1-6. In certain such embodiments, wherein R3 is.

[0039] In some of these embodiments, R3 is.

[0040] In certain embodiments, R3 is and R3a, R3b, and M are combined with a boron atom and intervening atoms such that R3 is a polycyclic heterocycle. For example, R3 can be wherein Rd is H or C1-C4 alkyl, preferably H or methyl, and more preferably H.

[0041] It is understood that coordinate bonds can be formed in compounds comprising atoms with lone electron pairs, such as nitrogen atoms, and boron atoms. That is, lone electron pairs can coordinate with empty boron orbitals. This can be indicated by an arrow from the donor atom to boron, as shown below: . The compounds may or may not exhibit coordinate bonds; both diagrams refer to the same compound.

[0042] In certain embodiments, the compound is represented by Formula II, eg, represented by Formula II-a, II-b, or II-c. In certain embodiments, the compound is represented by Formula II-b-1, II-b-2 or II-b-3: .

[0043] In certain embodiments, each R6 is independently halo, alkyl, or pendant oxy.

[0044] In certain embodiments, ring Z2 is.

[0045] In certain embodiments, ring Z2 is.

[0046] In certain preferred embodiments, R3a is hydrogen. In certain embodiments, R3a is methyl.

[0047] In certain embodiments, the compound is selected from: , or a pharmaceutically acceptable salt thereof.

[0048] In certain embodiments, the pharmaceutically acceptable salt of any one of the above-described compounds is formate, methanesulfonate, ethanesulfonate or maleate .

[0049] In certain aspects, the present invention provides a pharmaceutical composition comprising a compound according to any one of the foregoing technical schemes and a pharmaceutically acceptable excipient.

[0050] Definitions Unless otherwise defined herein, scientific and technical terms used in this application shall have the meaning commonly understood by those of ordinary skill in the art. Generally, in combination with chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and The nomenclature used in nucleic acid chemistry and its techniques is that of the well known and commonly used in the art.

[0051] The methods and techniques of the present invention are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. See, e.g., "Principles of Neural Science", McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, "Intuitive Biostatistics", Oxford University Press, Inc. (1995); Lodish et al., "Molecular Cell Biology, 4th ed." , W. H. Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co., N.Y. (1999); and Gilbert et al., “Developmental Biology, 6th ed. .”, Sinauer Associates, Sunderland, MA (2000).

[0052] Unless otherwise defined herein, chemical terms used herein are used according to conventional usage in the art, such as by "The McGraw-Hill Dictionary of Chemical Terms", Parker, S. Ed., McGraw-Hill , as exemplified by San Francisco, C.A. (1985).

[0053] All of the above and any other publications, patents and published patent applications mentioned in this application are specifically incorporated herein by reference. In case of conflict, the present specification, including its specific definitions, will control.

[0054] The term "agent" is used herein to denote chemical compounds (such as organic or inorganic compounds, mixtures of compounds), biological macromolecules (such as nucleic acids, antibodies including antibody parts and humanized antibodies, chimeric antibodies and human antibodies, and Monoclonal antibodies, proteins or parts thereof such as peptides, lipids, carbohydrates) or extracts made from biological substances such as bacterial, plant, fungal or animal (particularly mammalian) cells or tissues. Agents include, for example, agents whose structures are known and agents whose structures are not known. The ability of such agents to inhibit complement factors may make them suitable for use as "therapeutic agents" in the methods and compositions of the invention.

[0055] "Patient," "subject," or "individual" are used interchangeably and refer to a human or non-human animal. These terms include mammals such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.), and rodents (e.g., mice and rats).

[0056] "Treating" a condition or patient means taking steps to obtain a beneficial or desired result, including clinical results. As used herein and as fully understood in the art, "treatment" is a method used to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical outcomes may include, but are not limited to, amelioration or improvement of one or more symptoms or conditions, detectable or non-detectable, reduction in extent of disease, stabilization of disease state (i.e. not worsening), prevention of disease spread, disease progression Delay or slowing, disease state improvement or palliation, and remission (partial or complete). "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0057] The term "prevention" is recognized in the art and when used in relation to a condition such as local recurrence (e.g. pain), a disease such as cancer, a complex syndrome such as heart failure, or any other medical condition, refers to this term It is well understood in the art and includes administering a composition that reduces the frequency of symptoms of a medical condition or delays the onset of symptoms of a medical condition in a subject relative to a subject not receiving the composition. Thus, preventing cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving prophylactic treatment relative to an untreated control population; and / or delaying growth in a treated population relative to an untreated control population. The presence of cancerous growths can be detected, for example, in a statistically and / or clinically significant amount.

[0058] "Administering / administrating of" a substance, compound or agent to a subject can be performed using one of a variety of methods known to those skilled in the art. For example, a compound or agent can be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ophthalmically, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinal, cranial Intradermal and transdermal (by absorption, for example, through a channel in the skin) administration. The compound or agent may also be suitably introduced by refillable or biodegradable polymeric devices or other devices such as patches and pumps or formulations providing prolonged, slow or controlled release of the compound or agent. Administration can also be performed, eg, once, multiple times, and / or over one or more extended periods of time.

[0059] The appropriate method of administering a substance, compound, or agent to a subject will also depend, for example, on the age and / or physical condition of the subject and the chemical and biological properties (e.g., solubility, digestibility, bioavailability, etc.) of the compound or agent. , stability and toxicity). In some embodiments, the compound or agent is administered to the subject orally, eg, by ingestion. In some embodiments, the orally administered compound or agent is in an extended or sustained release formulation, or is administered using a device for such slow or extended release.

[0060] The phrase "combined administration" as used herein refers to the administration of two or more different therapeutic agents in any form such that a second agent (e.g., two The simultaneous effect of two agents in the body of the patient may include the synergistic effect of the two agents). For example, different therapeutic compounds can be administered concomitantly or sequentially in the same formulation or in separate formulations. Individuals receiving such treatment may thus benefit from the combined effects of different therapeutic agents.

[0061] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or agent is the amount of the drug or agent that will have the intended therapeutic effect when administered to a subject. Full therapeutic effect does not necessarily occur prior to the administration of a single dose, and may only occur after a series of doses are administered. Thus, a therapeutically effective amount can be administered in one or more administrations. The precise effective amount required by a subject will depend, for example, on the size, health and age of the subject and the nature and extent of the condition being treated, such as cancer or MDS. The effective amount for a given situation can be readily determined by one skilled in the art by routine experimentation.

[0062] As used herein, the term "optional" or "depending on the circumstances" means that the subsequently described event or circumstance may or may not occur, and that the description includes the circumstances in which the event or circumstance occurred and the circumstances in which the event or circumstance occurred. Circumstances in which an event or circumstance does not occur. For example, "optionally substituted alkyl" refers to an alkyl group that may be substituted as well as the case where the alkyl group is unsubstituted.

[0063] It will be appreciated that substituents and substitution patterns on the compounds of the present invention may be selected by one of ordinary skill in the art to produce starting materials readily available by techniques known in the art and those methods set forth below. A chemically stable compound synthesized from matter. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.

[0064] The term "optionally substituted" as used herein refers to the free radical replacement of one to six hydrogen radicals in a given structure by radical replacement of the specified substituents including, but not limited to: hydroxyl, hydroxyalkyl, alkane Oxygen, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, Haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2 or -CH2-OP(O)(O-alkyl)2. Preferably, "optionally substituted" means that one to four hydrogen radicals in a given structure are replaced by the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by substituents as mentioned above. It is understood that substituents may be further substituted.

[0065] The term "alkyl" as used herein refers to a saturated aliphatic group including but not limited to C1-C10 straight chain alkyl or C1-C10 branched chain alkyl. Preferably, "alkyl" refers to C1-C6 straight chain alkyl or C1-C6 branched chain alkyl. Most preferably, "alkyl" refers to C1-C4 straight chain alkyl or C1-C4 branched chain alkyl. Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, secondary butyl, tertiary butyl, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl , 3-octyl or 4-octyl and the like. In addition, the term "alkyl" as used throughout the specification, examples, and claims is intended to include unsubstituted alkyl groups as well as substituted alkyl groups, the latter referring to groups having one or more carbons in the hydrocarbon backbone replaced. Alkyl moieties of substituents for hydrogen above, such alkyl moieties include haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, and the like.

[0066] The term "acyl" is recognized in the art and refers to a group represented by the general formula hydrocarbyl C(O)-, preferably alkyl C(O)-.

[0067] The term "amido" is recognized in the art and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbyl C(O)NH-.

[0068] The term "acyloxy" is recognized in the art and refers to a group represented by the general formula hydrocarbyl C(O)O-, preferably alkyl C(O)O-.

[0069] The term "alkoxy" refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0070] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0071] The term "Cx-y" or "Cx-Cy" when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy is intended to include chains containing x A group of up to y carbons. C0 Alkyl indicates hydrogen where the group is in a terminal position, or a bond if internal. A C1-6 alkyl group contains, for example, one to six carbon atoms in the chain.

[0072] The term "alkylamino" as used herein refers to an amino group substituted with at least one alkyl group.

[0073] The term "alkylthio" as used herein refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0074] As used herein, the term "amide" refers to a group, wherein R9, R10 and R11 each independently represent hydrogen or a hydrocarbon group, or R9 and R10 together with the N atom to which they are attached form a ring structure with 4 A heterocyclic ring having up to 8 atoms, or R10 and R11 together with the N atoms to which they are attached form a heterocyclic ring having 4 to 8 atoms in the ring structure.

[0075] As used herein, the term "formamidinyl" refers to a group, wherein R9, R10 and R11 each independently represent hydrogen or a hydrocarbon group, or R9 and R10 form a ring structure together with the N atom to which they are connected. A heterocyclic ring of 4 to 8 atoms, or R10 and R11 together with the N atoms to which they are attached form a heterocyclic ring having 4 to 8 atoms in the ring structure.

[0076] The term "amido" as used herein refers to a group wherein R10 represents hydrogen or a hydrocarbyl group.

[0077] The terms "amine" and "amino group" are recognized in the art and refer to unsubstituted amines and substituted amines and salts thereof, such as moieties which may be represented by: wherein R9, R10 and R10' each independently represents hydrogen or a hydrocarbon group, or R9 and R10 together with the N atom to which they are connected constitute a heterocyclic ring having 4 to 8 atoms in the ring structure.

[0078] The term "aminoalkyl" as used herein refers to an alkyl group substituted with an amino group.

[0079] The term "aralkyl" as used herein refers to an alkyl group substituted with an aryl group.

[0080] The term "aryl" as used herein includes substituted or unsubstituted monocyclic aromatic groups wherein each atom of the ring is carbon. Preferably, the ring is a 5 to 7 member ring, more preferably a 6 member ring. The term "aryl" also includes polycyclic ring systems having two or more rings, wherein two or more carbons are shared by two connecting rings, wherein at least one of the rings is aromatic For example, other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0081] The term "azido" is art recognized and refers to the group -N3.

[0082] The term "urethane" is art recognized and refers to a group wherein R9 and R10 independently represent hydrogen or a hydrocarbyl group.

[0083] The term "carbocyclylalkyl" as used herein refers to an alkyl group substituted with a carbocyclyl group.

[0084] The term "carbocycle" includes 5-7 membered monocycles and 8-12 membered bicycles. Each ring of a bicyclic carbocycle may be selected from saturated rings, unsaturated rings and aromatic rings. Carbocycles include bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring in the fused carbocycle may be selected from saturated rings, unsaturated rings and aromatic rings. In an exemplary embodiment, an aromatic ring such as phenyl may be fused with a saturated or unsaturated ring such as cyclohexane, cyclopentane or cyclohexene. Where valence permits, any combination of saturated bicyclic, unsaturated bicyclic and aromatic bicyclic is included in the definition of carbocyclic. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetralin, bicyclo[4.2.0 ] Oct-3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decahydronaphthalene, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo [4.1.0] Hept-3-ene. A "carbocycle" may be substituted at any one or more positions capable of carrying a hydrogen atom.

[0085] The term "carbocyclylalkyl" as used herein refers to an alkyl group substituted with a carbocyclyl group.

[0086] The term "carbonate" is art recognized and refers to the group -OCO2-.

[0087] The term "carboxy" as used herein refers to a group represented by the formula -CO2H.

[0088] The term "ester" as used herein refers to the group -C(O)OR9, wherein R9 represents a hydrocarbyl group.

[0089] The term "ether" as used herein refers to a hydrocarbyl group attached to another hydrocarbyl group through an oxygen. Thus, the ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers can be symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycles and aryl-O-heterocycles. Ether includes "alkoxyalkyl" which can be represented by the general formula alkyl-O-alkyl.

[0090] The terms "halo" and "halogen" as used herein mean halogen and include chlorine, fluorine, bromine and iodine.

[0091] The term "haloalkyl" as used herein refers to an alkyl group in which one or more hydrogens have been replaced by a halogen.

[0092] The term "haloalkoxy" as used herein refers to an alkoxy group in which one or more hydrogen atoms are replaced by halogen atoms.

[0093] The term "hetaralkyl / heteroaralkyl" as used herein refers to an alkyl group substituted with a heteroaryl group.

[0094] The term "heteroaryl / hetaryl" includes substituted or unsubstituted aromatic monocyclic ring structures, preferably 5-7 membered rings, more preferably 5-6 membered rings, the rings of which The structure includes at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The term "heteroaryl / hetaryl" also includes polycyclic ring systems having two or more rings, wherein two or more carbons are shared by two linking rings, wherein at least one of the rings Being heteroaromatic, for example, the other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyridine, pyridine, and pyrimidine, and the like.

[0095] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen and sulfur.

[0096] The term "heterocyclylalkyl" as used herein refers to an alkyl group substituted with a heterocyclyl group.

[0097] The term "heterocyclic group" and "heterocycle (heterocycle / heterocyclic)" refer to a substituted or unsubstituted non-aromatic ring structure, preferably a 3- to 10-membered ring, more preferably a 3- to 10-membered ring A 7-membered ring whose ring structure includes at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more rings, wherein two or more carbons are shared by two linking rings, wherein one of the rings is At least one is a heterocycle, for example, the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperidine, pyrrolidinium, pyridinium, lactone, lactam and the like.

[0098] The term "hydrocarbyl" as used herein refers to a group bonded through carbon atoms, which group has no =O or =S substituents and generally has at least one carbon-hydrogen bond and is predominantly carbon. chain, but may optionally include heteroatoms. Thus, for the purposes of this application, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered hydrocarbyl, but groups such as acetyl (which is Substituents with =O substituents on ) and ethoxy (attachment via oxygen rather than carbon) are considered hydrocarbyl. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, alkynyl, and combinations thereof.

[0099] The term "hydroxyalkyl" as used herein refers to an alkyl group substituted with a hydroxyl group.

[0100] The term "imine" is recognized in the art and refers to a group in which R9 is hydrogen or a hydrocarbyl group, and R10 represents a hydrocarbyl group, or R9 and R10 form a ring structure together with the N atom to which R9 is attached Heterocyclic rings having 4 to 8 atoms.

[0101] The term "lower" when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy is intended to include the presence of ten or fewer, less Preferably groups of six or fewer atoms. By way of example, "lower alkyl" refers to an alkyl group containing ten or fewer, preferably six or fewer, carbon atoms. In certain embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy substituents defined herein are lower acyl, lower acyloxy, lower alkane, respectively lower alkenyl, lower alkynyl or lower alkoxy, whether alone or in combination with other substituents, such as in the recited hydroxyalkyl and aralkyl groups (in this case, for example, Atoms within an aryl group are not counted when counting carbon atoms in an alkyl substituent).

[0102] The term "oxime" is art recognized and refers to a group wherein R9 represents hydrogen or a hydrocarbyl group.

[0103] The terms "polycyclyl", "polycycle / polycyclic" refer to two or more rings (for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and and / or heterocyclyl) in which two or more atoms are shared by two linking rings, for example, such rings are "fused rings". Each of the polycyclic rings may be substituted or unsubstituted. In certain embodiments, each ring of the polycyclic ring contains 3 to 10, preferably 5 to 7 atoms in the ring.

[0104] The term "sulfate" is art recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

[0105] The term "sulfonamide" is recognized in the art and refers to a group represented by the following general formula: wherein R9 and R10 independently represent hydrogen or a hydrocarbon group.

[0106] The term "argon" is art recognized and refers to the group -S(O)-.

[0107] The term "sulfonate" is art recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

[0108] The term "碸" is art recognized and refers to the group -S(O)2-.

[0109] The term "substituted" refers to a moiety having a substituent that replaces a hydrogen on one or more carbons of the backbone. It is to be understood that "substituted" or "substituted by" includes the implied proviso that the substitution is consistent with the permissible valences of the atoms and substituents being substituted and that the substitution results in a stable compound, e.g. A compound undergoing spontaneous transformation by rearrangement, cyclization, elimination, etc. The term "substituted" as used herein is contemplated to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and / or any permissible substituent of an organic compound described herein satisfying the valence of the heteroatom. Substituents may include any substituent described herein, for example, halogen, hydroxy, carbonyl (such as carboxy, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as thioester, thioacetate or thioformate) ), alkoxy, phosphonyl, phosphate, phosphonate, phosphonite, amine, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio group, sulfate ester, sulfonate ester, sulfamoyl group, sulfonamide group, sulfonyl group, heterocyclyl group, aralkyl group or aromatic or heteroaromatic moiety. Those skilled in the art will understand that moieties substituted on the hydrocarbon chain may themselves be substituted where appropriate.

[0110] The term "sulfanyl" as used herein refers to an alkyl group substituted with a thiol group.

[0111] The term "thioester" as used herein refers to the group -C(O)SR9 or -SC(O)R9, wherein R9 represents a hydrocarbyl group.

[0112] The term "thioether" as used herein is equivalent to an ether in which the oxygen is replaced by sulfur.

[0113] The term "urea" is recognized in the art and can be represented by the following general formula: wherein R9 and R10 independently represent hydrogen or a hydrocarbon group.

[0114] The term "modulate" as used herein includes inhibiting or suppressing a function or activity, such as cell proliferation, as well as enhancing a function or activity.

[0115] The term "inhibit" as used herein includes suppression of a function or activity. In certain embodiments, compounds disclosed herein inhibit complement factors. Complement factor inhibition can be measured according to techniques known to those skilled in the art, such as enzyme assays. For example, C1s inhibition can be determined according to the enzyme assay disclosed herein in Example 174. In some embodiments, the compound inhibits C1s when the PIC50 determined according to the procedure described in Example 174 is at least 5, at least 6, at least 7, at least 8, or at least 9.

[0116] The phrase "pharmaceutically acceptable" is recognized in the art. In certain embodiments, the term includes, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio Compositions, excipients, adjuvants, polymers and other materials and / or dosage forms.

[0117] "Pharmaceutically acceptable salt" or "salt" is used herein to refer to an acid addition salt or a base addition salt that is suitable or compatible with the treatment of a patient.

[0118] The term "pharmaceutically acceptable acid addition salt" as used herein means any non-toxic organic or inorganic salt of any base compound represented by formula I. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as do metal salts such as sodium monohydrogen orthophosphate and potassium hydrogensulfate. Illustrative organic acids which form suitable salts include mono-, di-, and tricarboxylic acids, such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malonic, acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid and salicylic acid; and sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. Mono- or di-acid salts may be formed and such salts may exist in hydrated, solvated or substantially anhydrous form. In general, acid addition salts of compounds of formula I are more soluble in water and various hydrophilic organic solvents, and generally exhibit higher melting points than their free base forms. Selection of appropriate salts is known to those skilled in the art. Other non-pharmaceutically acceptable salts such as oxalate are useful, for example, in isolating compounds of formula I for laboratory use, or for subsequent conversion into pharmaceutically acceptable acid addition salts.

[0119] The term "pharmaceutically acceptable base addition salt" as used herein means any non-toxic organic or inorganic base of any acid compound represented by formula I or any of its intermediates Add salt. Illustrative inorganic bases which form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or barium hydroxide. Illustrative organic bases which form suitable salts include aliphatic, cycloaliphatic or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. Selection of appropriate salts is known to those skilled in the art.

[0120] Many compounds suitable for use in the methods and compositions of the invention have at least one stereogenic center in their structure. This stereogenic center can exist in the R or S configuration, and the R and S notations are used in accordance with the rules described in Pure Appl. Chem. (1976), 45, 11-30. The present invention covers all stereoisomeric forms (including all possible mixtures of stereoisomers) such as enantiomeric and diastereomeric forms of the compounds, salts, prodrugs or mixtures thereof. See eg WO 01 / 062726.

[0121] In addition, certain compounds containing alkenyl groups may exist as Z (same side) or E (different side) isomers. In each case, the invention includes mixtures as well as individual individual isomers.

[0122] Some of the compounds may also exist in tautomeric forms. Although not explicitly indicated in the formulas described herein, such forms are intended to be included within the scope of the invention.

[0123] "Prodrug" or "pharmaceutically acceptable prodrug" refers to a compound that is metabolized, eg, hydrolyzed or oxidized, in the host after administration to form a compound of the invention (eg, a compound of formula I). Typical examples of prodrugs include compounds with biologically labile or cleavable (protecting) groups on functional parts of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated Compounds to produce active compounds. Examples of prodrugs using esters or phosphoramidates as biologically labile or cleavable (protecting) groups are disclosed in U.S. Pat. into this article. The prodrugs of the present invention are metabolized to produce compounds of formula I. The present invention includes within its scope prodrugs of the compounds described herein. Known procedures for selecting and preparing suitable prodrugs are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

[0124] The phrase "pharmaceutically acceptable carrier" as used herein means a liquid or solid filler, diluent, excipient, solvent or carrier such as a liquid or solid suitable for formulating a drug for medical or therapeutic use. A pharmaceutically acceptable material, composition or vehicle for an encapsulating material.

[0125] The terms "Log solubility", "LogS" or "logS" as used herein are used in the art to quantify the water solubility of a compound. The aqueous solubility of a compound significantly affects its absorption and distribution characteristics. Low solubility is often associated with poor absorption. The LogS value is the unit exfoliation logarithm (base 10) of the solubility measured in moles / liter.

[0126] Pharmaceutical Compositions The compositions and methods of the present invention may be used to treat a subject in need thereof. In certain embodiments, the individual is a mammal such as a human or a non-human mammal. When administered to an animal such as a human, the composition or compound is preferably administered in the form of a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example: aqueous solutions, such as water or physiological buffered saline; or other solvents or vehicles, such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In preferred embodiments, when the pharmaceutical compositions are for human administration, in particular, for invasive routes of administration (that is, routes that avoid transport or diffusion through epithelial barriers, such as injection or implantation), , the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to achieve delayed release of the agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in unit dosage forms such as tablets, capsules (including dispersible capsules and gelatin capsules), granules, lyophilizates for reconstitution, powders, solutions, syrups, suppositories, injections or the like. The composition may also be presented in a transdermal delivery system such as a skin patch. The compositions may also be presented in solutions suitable for topical administration such as emulsions, creams or ointments. A pharmaceutically acceptable carrier may contain a physiologically acceptable agent for, for example, stabilizing, increasing the solubility, or increasing the absorption of a compound such as a compound of the present invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose, or polydextrose; antioxidants, such as ascorbic acid or glutathione; chelating agents, low molecular weight proteins; or other stabilizers or excipients. The choice of pharmaceutically acceptable carriers including physiologically acceptable agents depends, for example, on the route of administration of the composition. The formulation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. Pharmaceutical compositions (formulations) may also be liposomes or other polymeric matrices in which, for example, a compound of the invention may be incorporated. For example, liposomes comprising phospholipids or other lipids are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to manufacture and administer.

[0127] In some instances, the pharmaceutical composition can be a solid dispersion. The term "solid dispersion" refers to a solid state system comprising at least two components, one of which is dispersed throughout one or more other components. For example, the solid dispersion can be an amorphous solid dispersion. The term "amorphous solid dispersion" as used herein refers to a stable solid dispersion comprising an amorphous drug substance and a polymer. "Amorphous drug substance" means an amorphous solid dispersion containing the drug substance in substantially amorphous solid state form.

[0128] The phrase "pharmaceutically acceptable" is used herein to mean, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction or other problems or complications , those compounds, materials, compositions and / or dosage forms commensurate with a reasonable benefit / risk ratio.

[0129] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, composition or vehicle. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives , such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyhydric alcohols, such as glycerin, sorbitol Sugar alcohols, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) ) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffered saline; Other non-toxic compatible substances in pharmaceutical formulations.

[0130] The pharmaceutical composition (formulation) may be administered to a subject by any of a variety of routes of administration including, for example: Orally (eg, as a bolus in the form of an aqueous or non-aqueous solution or suspension) liquids, tablets, capsules (including dispersible capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); oral mucosal (e.g., sublingual) absorption; subcutaneous; transdermal ( eg, in the form of a patch applied to the skin); and topical (eg, in the form of a cream, ointment, or spray applied to the skin). The compounds may also be formulated for inhalation. In certain embodiments, compounds can simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable for such suitable routes of administration can be found, for example, in U.S. Pat. in the cited patent.

[0131] The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, as a percentage, this amount will range from about 1% to about 99%, preferably from about 5% to about 70%, most preferably from about 10% to about 30% active ingredient.

[0132] Methods of preparing such formulations or compositions include the step of bringing into association the active compound, such as a compound of this invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the invention with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0133] Formulations of the present invention suitable for oral administration may be in the form of capsules (including dispersible capsules and gelatin capsules), cachets, pills, lozenges, lozenges (with a flavoring usually sucrose and acacia or tragacanth). main drug), lyophilizates, powders, granules, or in the form of solutions or suspensions in aqueous or non-aqueous liquids, or in the form of oil-in-water or water-in-oil liquid emulsions, or in the form of elixirs or in the form of a syrup, or in the form of a tablet (using an inert base such as gelatin and glycerin or sucrose and acacia) and / or in the form of a mouthwash and the like, each form containing a predetermined amount of a compound of the invention as active Element. Compositions or compounds can also be administered in the form of boluses, elixirs or pastes.

[0134] For the preparation of solid dosage forms for oral administration (capsules (including dispersible capsules and gelatin capsules), troches, pills, dragees, powders, granules and the like), the active ingredient is mixed with, for example, citric acid One or more pharmaceutically acceptable carriers of sodium or dicalcium phosphate and / or any of the following: (1) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannose Alcohol and / or silicic acid; (2) binder, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; (3) humectant, such as glycerin; (4 ) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retarders, such as paraffin; (6) absorption accelerators, such as four (7) Wetting agents, such as cetyl alcohol and glycerol monostearate; (8) Absorbents, such as kaolin and bentonite; (9) Lubricants, such as talc, calcium stearate, stearin magnesium sulfate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as modified and unmodified cyclodextrins; (11) biocompatible polymers, such as those used in the manufacture of A biocompatible polymer in an amorphous solid dispersion; and (12) a colorant. In the case of capsules (including dispersible capsules and gelatin capsules), troches and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (milk sugar) and high molecular weight polyethylene glycols and the like.

[0135] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may use binders (such as gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (such as sodium starch glycolate or croscarmellose sodium) , surfactant or dispersant to prepare. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0136] Tablets of pharmaceutical compositions and other solid dosage forms such as sugar-coated tablets, capsules (including dispersible capsules and gelatin capsules), pills and granules may be scored or prepared with technologies such as enteric coating and pharmaceutical compounding. Coatings and shells of other coatings known in the art. It can also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethylcellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. It can be sterilized by, for example, filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile water or some other sterile injectable medium just before use. Bacteria solid composition form. These compositions may also optionally contain devitrification agents and may be of such a composition that they release the active ingredient(s) only, or preferentially, optionally in a certain part of the gastrointestinal tract, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, where appropriate, with one or more of the above-described excipients.

[0137] Liquid dosage forms suitable for oral administration include pharmaceutically acceptable emulsions, lyophilizates for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrin and its derivatives; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate Esters, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil) , fatty acid esters of glycerol, tetrahydrofuran alcohol, polyethylene glycol and sorbitan, and mixtures thereof.

[0138] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0139] In addition to the active compounds, suspensions may also contain, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, Agar - suspension of agar and tragacanth and mixtures thereof.

[0140] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants which may be required.

[0141] Ointments, pastes, creams and gels may contain, in addition to the active compounds, substances such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicon Excipients of ketone, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0142] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0143] Transdermal patches have the added advantage of providing controlled delivery of the compounds of the invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of this flux can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0144] The phrase "parenteral administration / administered parenterally" as used herein means modes of administration, other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, Intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion Note. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds and may contain antioxidants, buffers, bacteriostats, solutes to render the formulation isotonic to the blood of the intended recipient, or suspending agents or thickeners. One or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders which can be reconstituted into sterile injectable solutions or dispersions immediately before use.

[0145] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, Vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions and by using surfactants.

[0146] These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents including, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like in the compositions. Additionally, prolonged absorption of the injectable pharmaceutical form is brought about by the inclusion of absorption delaying agents such as aluminum monostearate and gelatin.

[0147] In some instances, slowing the absorption of drugs injected subcutaneously or intramuscularly may be desirable in order to prolong the effect of the drug. This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0148] Injectable depot forms are made by forming microencapsule matrices of the compounds of the invention in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled by the ratio of drug to polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

[0149] For use in the method of the present invention, the active compound may be used by itself or in a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient and a pharmaceutically acceptable carrier form given.

[0150] Introduction methods may also be provided by refillable or biodegradable devices. In recent years, various slow release polymeric devices have been developed and tested in vivo for the controlled delivery of drugs including protein biopharmaceuticals. A variety of biocompatible polymers, including biodegradable and non-biodegradable polymers, including hydrogels, can be used to form implants for sustained release of compounds at specific target sites.

[0151] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration without being toxic to the patient.

[0152] The selected dosage level will depend on various factors including the activity of the particular compound or combination of compounds employed, or its ester, salt or amide; the route of administration; the time of administration; Excretion rate of multiple specific compounds; duration of treatment; other drugs, compounds and / or materials used in combination with one or more specific compounds employed; age, sex, weight, condition, general health of patients treated and prior medical history; and similar factors well known in the medical arts.

[0153] A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can start dosages of the pharmaceutical composition or compound at levels lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. "Therapeutically effective amount" means a concentration of a compound sufficient to elicit the desired therapeutic effect. It is generally understood that an effective amount of a compound will vary according to the subject's weight, sex, age and medical history. Other factors affecting the effective amount can include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent administered with the compound of the invention. Larger total doses can be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13th Ed., 1814-1882, which is incorporated herein by reference).

[0154] In general, a suitable daily dose of the active compound employed in the compositions and methods of this invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such effective dosage will generally depend on the factors described above.

[0155] If desired, the effective daily dose of active compound may be administered in unit dosage form as one, two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day, as appropriate. and. In certain embodiments of the invention, active compounds may be administered two or three times daily. In preferred embodiments, the active compounds will be administered once daily.

[0156] The patient receiving this treatment is any animal in need, including primates, in particular, humans; and other mammals, such as horses, cows, pigs, sheep, cats and dogs; poultry; and In general, pets.

[0157] In certain embodiments, compounds of the invention may be administered alone or in combination with another type of therapeutic agent.

[0158] The present invention includes pharmaceutically acceptable salts of the compounds of the present invention (see Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19.) in the compositions of the present invention and used in the method. In certain embodiments, contemplated salts of the invention include, but are not limited to, alkylammonium, dialkylammonium, trialkylammonium, or tetraalkylammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, salts of L-arginine, benzylphenethylamine, benzylethylenediamine, betaine, calcium hydroxide, choline, tannol , diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-ionamine Acid, Magnesium, 4-(2-Hydroxyethyl)Pyrroline, Piperidine, Potassium, 1-(2-Hydroxyethyl)Pyrrolidine, Sodium, Triethanolamine, Tromethamine and Zinc. In certain embodiments, contemplated salts of the invention include, but are not limited to, salts of Na, Ca, K, Mg, Zn, or other metals. In certain embodiments, contemplated salts of the invention include, but are not limited to, salts of the following: 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxo Glutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, L-ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphor acid, (+)-camphor-10-sulfonic acid, capric acid / decanoic acid, caproic acid / hexanoic acid, caprylic acid / octanoic acid, carbonic acid, cinnamic acid, citric acid, Cyclohexanesulfonic acid, laurylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucoheptanoic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, butyric acid Dienoic acid, L-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid , pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoro Acetic acid and undecylenic acid.

[0159] Pharmaceutically acceptable acid addition salts may also exist in the form of various solvates such as with water, methanol, ethanol, dimethylformamide and the like. Mixtures of such solvates may also be prepared. The source of the solvate may be from the solvent of crystallization, be inherent in the solvent of preparation or crystallization, or be foreign to the solvent. Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavoring and fragrance agents, preservatives and antioxidants It can also be present in the composition.

[0161] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) Oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxymethoxybenzene (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like and (3) metal chelating agents such as citric acid and ethylenediamine.

[0162] Methods of Treatment In certain aspects, the invention provides methods of treating a disease or condition associated with complement activation in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound provided herein. While not being bound by theory, it is believed that the compounds disclosed herein act as C1s inhibitors and can thus prevent complement activation, thereby treating diseases associated with complement activation.

[0163] In certain embodiments, the disease or condition is selected from neurodegenerative disorders, inflammatory diseases, autoimmune diseases, eye diseases, and metabolic disorders. Those skilled in the art will readily appreciate that many diseases or conditions may fall into more than one of the aforementioned categories of diseases. For example, the conditions can be neurological and autoimmune conditions, autoimmune and inflammatory conditions, ophthalmic and neurological conditions, and the like.

[0164] Diseases or conditions associated with complement activation that may be treated according to the methods of the present invention include, but are not limited to: Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, progressive multiple sclerosis glaucoma, myotonic dystrophy, Guillain-Barre´syndrome, myasthenia gravis, spinal muscular atrophy, Down syndrome, Parkinson's disease, Huntington's disease, traumatic brain injury, epilepsy, frontotemporal dementia, diabetes, obesity, atherosclerosis, rheumatoid arthritis, acute respiratory distress syndrome, pemphigus, Pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, immune-mediated necrotizing myopathy, leukoplakia, paraneoplastic syndrome, vasculitic diseases, hypocomplement urticarial vasculitis, chronic spontaneous Urticaria, distal tissue injury after ischemia and reperfusion, complement activation during cardiopulmonary bypass surgery, dermatomyositis, lupus nephritis and resulting glomerulonephritis and vasculitis, renal fibrosis, systemic Lupus erythematosus, Hashimoto's thyroiditis, Addison's disease, celiac disease, Crohn's disease, pernicious anemia, chronic idiopathic demyelinating polyneuropathy, Multifocal motor neuropathy, heparin-induced thrombocytopenia, idiopathic thrombocytopenic purpura, coronary artery endothelial dysfunction induced by cardioplegia, type II membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure, condensation Globulinemia, antiphospholipid syndrome, chronic open corner glaucoma, acute corner locking glaucoma, macular degenerative disease, wet age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, choroidal neovascularization, eye Uveitis, diabetic retinopathy, ischemia-related retinopathy, endophthalmitis, intraocular neovascular disease, diabetic macular edema, pathological myopia, von Hippel-Lindau disease, ocular Histoplasmosis, neuromyelitis optica, central retinal vein occlusion, corneal neovascularization, retinal neovascularization, Leber's hereditary optic neuropathy, optic neuritis, Behcet's retinopathy, ischemia optic neuropathy, retinal vasculitis, ANCA vasculitis, Wegener's granulomatosis, Purtscher retinopathy, Sjogren's dry eye disease, sarcoidosis, Temporal arteritis, polyarteritis nodosa, allograft, hyperacute rejection, hemodialysis, chronic obstructive pulmonary distress syndrome, asthma, aspiration pneumonia, immune thrombocytopenia, autoimmune hemolytic anemia, cold agglutinin disease, febrile autoimmune hemolytic anemia, and coronary artery disease.

[0165] In certain embodiments, diseases or conditions associated with complement activation that may be treated in accordance with the methods of the present invention include Gubarr's syndrome, amyotrophic lateral sclerosis (ALS), Huntington's disease (HD ), geographic atrophy, cold agglutinin disease, febrile autoimmune hemolytic anemia, lupus nephritis, and multifocal motor neuropathy.

[0166] In certain embodiments, the disease or condition associated with complement activation that may be treated in accordance with the methods of the present invention is Gebard syndrome. In certain embodiments, the disease or condition associated with complement activation that can be treated according to the methods of the invention is ALS. In certain embodiments, the disease or condition associated with complement activation that can be treated according to the methods of the invention is HD. In certain embodiments, a disease or condition associated with complement activation that may be treated in accordance with the methods of the invention is geographic atrophy. In certain embodiments, a disease or condition associated with complement activation that may be treated according to the methods of the invention is a cold agglutinin disease. In certain embodiments, the disease or condition associated with complement activation that can be treated according to the methods of the invention is febrile autoimmune hemolytic anemia. In certain embodiments, the disease or condition associated with complement activation that can be treated according to the methods of the invention is lupus nephritis. In certain embodiments, the disease or condition associated with complement activation that can be treated according to the methods of the invention is multifocal motor neuropathy.

[0167] In certain embodiments, the disease or condition is a neurodegenerative disorder, such as a neurodegenerative disorder associated with: loss of synapses or loss of neural connections, wherein the loss of synapses depends on C1q, C1 complex, CR1, C3, CR3, C4, or CR4; pathological activity-dependent synaptic loss; or synaptic phagocytosis by microglia. In certain embodiments, the neurodegenerative disorder is associated with dysregulation of C1s. In certain embodiments, the neurodegenerative disorder is associated with dysregulation or activation of C1s. In certain embodiments, the neurodegenerative disorder is associated with activation of C1s.

[0168] In certain embodiments, the neurodegenerative disorder is selected from Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, progressive multiple sclerosis, glaucoma, myotonia Malnutrition, Gerbar syndrome (GBS), myasthenia gravis, spinal muscular atrophy, Down syndrome, Parkinson's disease, Huntington's disease (HD), traumatic brain injury, epilepsy, age-related Macular degeneration, immune-mediated necrotizing myopathy (IMNM), and frontotemporal dementia.

[0169] In certain embodiments, the neurodegenerative disorder is selected from the group consisting of Gerbar syndrome, Huntington's disease, amyotrophic lateral sclerosis, and geographic atrophy. Age-related macular degeneration (AMD) diseases include wet AMD and dry AMD. In addition, dry AMD involves early, middle and late stages, and the late stage is called geographic atrophy, which refers to the progressive loss of cells in the retina.

[0170] In certain embodiments, the disease or condition is an inflammatory disease, an autoimmune disease, a metabolic disorder, or an eye disease. In certain embodiments, the inflammatory disease, autoimmune disease, metabolic disorder, or eye disease is associated with activation or dysregulation of C1s.

[0171] In certain embodiments, the inflammatory disease, autoimmune disease, metabolic disorder or eye disease is selected from diabetes, obesity, atherosclerosis, rheumatoid arthritis, acute respiratory distress syndrome, pemphigus vulgaris , pemphigus foliaceus, bullous pemphigoid, distal tissue injury after ischemia and reperfusion, complement activation during cardiopulmonary bypass surgery, dermatomyositis, pemphigus, lupus nephritis and the resulting Glomerulonephritis and vasculitis, renal fibrosis, systemic lupus erythematosus, Hashimoto's thyroiditis, Addison's disease, celiac disease, Crohn's disease, pernicious anemia, immune-mediated necrotizing myopathy , leukoplakia, paraneoplastic syndrome, vasculitic diseases, hypocomplement urticarial vasculitis, chronic spontaneous urticaria, chronic idiopathic demyelinating polyneuropathy, polymyalgia rheumatica, multifocal motor neuropathy, Immune thrombocytopenia, heparin-induced thrombocytopenia, idiopathic thrombocytopenic purpura, coronary artery endothelial dysfunction induced by cardioplegia, type II membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure, condensation Globulinemia, antiphospholipid syndrome, chronic open corner glaucoma, acute corner locking glaucoma, macular degenerative disease, wet age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, choroidal neovascularization, eye Uveitis, diabetic retinopathy, ischemia-related retinopathy, endophthalmitis, intraocular neovascular disease, diabetic macular edema, pathological myopia, Heber-Lindau disease, ocular histoplasmosis, optic neurospinal cord Inflammation, central retinal vein occlusion, corneal neovascularization, retinal neovascularization, Leber hereditary optic neuropathy, optic neuritis, Behcet's retinopathy, ischemic optic neuropathy, retinal vasculitis, ANCA vasculitis, Wegener's granulation Tumor disease, Purchas' retinopathy, Sugarlen's dry eye, sarcoidosis, temporal arteritis, polyarteritis nodosa, multiple sclerosis, progressive multiple sclerosis, allograft, hyperacute rejection, blood Dialysis, chronic obstructive pulmonary distress syndrome, asthma, aspiration pneumonia, immune thrombocytopenia, autoimmune hemolytic anemia, cold agglutinin disease, febrile autoimmune hemolytic anemia, and coronary artery disease.

[0172] In some embodiments, the disease is cold agglutinin disease, febrile autoimmune hemolytic anemia, geographic atrophy, lupus nephritis, or multifocal motor neuropathy.

[0173] In certain embodiments, the disease is autoimmune hemolytic anemia such as cold agglutinin disease or febrile autoimmune hemolytic anemia.

[0174] In certain aspects, the invention provides methods of inhibiting C1s comprising contacting C1s with a compound disclosed herein. In certain aspects, the invention provides methods of inhibiting activated C1s comprising contacting C1s with a compound disclosed herein.

[0175] In certain embodiments, contacting the C1s with the compound comprises administering the compound to the individual.

[0176] EXAMPLES The present invention now being generally described, it will be better understood by reference to the following examples, which are included for the purpose of illustrating certain aspects and embodiments of the invention only and are not intended to be limiting this invention.

[0177] General Procedures Liquid Chromatography-Mass Spectrometry Method A (LC-MS Method A) Total Ion Current (TIC) and DAD UV Chromatograms along with MS and UV Spectra associated with peaks were performed on a detector equipped with a PDA and acquired on a UPLC / MS AcquityTM system coupled to a Waters single quadrupole mass spectrometer operating in alternating positive and negative electrospray ionization modes. [LC / MS-ES (+ / -): Analysis performed with Acquity UPLCTMCSSH, C18 column (50 × 2.1 mm, 1.7 µm particle size), column temperature: 40°C, mobile phase: A-water + 0.1% HCOOH / B- CH3CN + 0.1% HCOOH, flow rate: 1.0 mL / min, run time = 2.0 min, gradient: t=0 min 3% B, t= 1.5 min 99.9% B, t = 1.9 min 99.9% B, t = 2.0 min 3% B, end time: 2.0 min]. Positive ES 100-1000, negative ES 100-1000, 210-350 nm UV detection DAD.

[0178] Liquid Chromatography-Mass Spectrometry Method B (LC-MS Method B) Total Ion Current (TIC) and DAD UV Chromatograms along with MS and UV spectra associated with peaks were performed on a detector equipped with a PDA and coupled to Acquisition was performed on a UPLC / MS Acquity™ system of a Waters single quadrupole mass spectrometer operating in alternating positive and negative electrospray ionization modes. [LC / MS-ES (+ / -): Analysis performed using Acquity UPLCTMBEH, C18 column (50 × 2.1 mm, 1.7 µm particle size), column temperature: 40°C, mobile phase: A- 0.1% v / v Ammonia solution pH 10 / B-CH3CN, flow rate: 1.0 mL / min, run time = 2.0 min, gradient: t=0 min 3% B, t= 1.5 min 99.9% B, t = 1.9 min 99.9% B, t = 2.0 min 3% B, end time: 2.0 min]. Positive ES 100-1000, negative ES 100-1000, 210-350 nm UV detection DAD.

[0179] Analytical methods 1H nuclear magnetic resonance (NMR) spectroscopy was carried out using one of the following instruments: Bruker Avance 400 instrument equipped with probe DUAL 400MHz S1, Bruker Avance equipped with probe 6 S1 400 MHz 5mm 1H-13C ID 400 instrument, Bruker Avance III 400 instrument equipped with 5 mm direct probe Broadband BBFO with nanobay, 400 MHz Agilent Direct Drive instrument with ID AUTO-X PFG probe all operating at 400 MHz or operating at 500 MHz Agilent VNMRS500 Direct Drive instrument equipped with a 5 mm triple resonance 1H{13C / 15N} cryogenic probe. Spectra were obtained in the stated solvents at about room temperature unless otherwise stated. In all cases, NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts per million using conventional abbreviations for major peak names: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet Doublet; dt, doublet triplet; br, broad peak.

[0180] Where thin layer chromatography (TLC) has been used, TLC refers to a silica gel TLC (Merck) plate using silica gel F254, Rf is the distance traveled by the compound on the TLC plate divided by the distance traveled by the solvent distance. Perform column chromatography on Biotage silica gel cartridges (KP-Sil, KP-NH, Sfar D, or Sfar Amino D) using an automated flash chromatography (Biotage SP1 or Isolera) system, or reverse-phase column chromatography In the case of the method, it was performed on a Biotage C18 cartridge (KP-C18-HS or Sfar C18 D).

[0181] Compound Preparation Where the preparation of starting materials is not described, such starting materials are either commercially available, known in the literature or can be readily obtained by those skilled in the art using standard procedures. Where it is stated that compounds were prepared analogously to earlier examples or intermediates, the skilled artisan understands that reaction times, reagent equivalent values ​​and temperatures may be modified for each particular reaction and that different work-up or purification techniques may be necessary or desirable. In the case of carrying out the reaction using microwave irradiation, the microwave used is a Biotage Initiator. The actual power supplied was varied during the course of the reaction in order to maintain a constant temperature.

[0182] Example 1-171: Preparation of Exemplary Compound Example 1: [3-(1-aminophthal-6-yl)phenyl]acid ([3-(1-AMINOPHTHALAZIN-6-YL)PHENYL]BORONIC ACID) (1) to 6-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]phthalein-1-amine trifluoro To a solution of acetate (89.0 mg, 0.190 mmol) in THF (2 mL) was added 1 M hydrochloric acid solution (1.0 mL, 1 mmol) and sodium periodate (20.64 mg, 0.100 mmol). The mixture was stirred at room temperature for 16 h and the volatiles were removed by evaporation. The residue was purified by column chromatography (KP-C18-HS, ​​SNAP 12 g) with a gradient elution from 2% to 80% CH3CN in water (+0.1% HCOOH) to give [3-(1-amino Phthalo-6-yl)phenyl] acid (20 mg, 0.075 mmol, 39.1% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.22 (br. s, 2H), 7.52 (t,J= 7.53 Hz, 1H), 7.84 - 7.88 (m, 1H), 7.88 - 7.93 (m, 1H), 8.12 - 8.25 (m, 4H), 8.28 (t,J= 1.55 Hz, 1H), 8.38 (d,J= 8.35 Hz, 1H), 8.97 (d,J= 0.79 Hz, 1H). LC-MS (Method A): r.t. 0.42 min, MS (ESI) m / z = 266.2 [M+H]+.

[0183] Example 2: [3-(1-aminophthalein-6-yl)-4-methoxyphenyl] acid formate (2) converts 6-[2-methoxy-5-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]phthalein-1-amine trifluoroacetate (360.0 mg, 0.730 mmol) was dissolved in THF (21.6 mL) and added 1 M hydrochloric acid solution (10.26 mL, 10.26 mmol). The mixture was stirred vigorously for 3 hours, then evaporated. The residue was purified by column chromatography (KP-C18-HS, ​​30 g) eluting with a gradient of 1% to 40% CH3CN in water (+0.1% HCOOH). Fractions containing the desired compound were pooled and lyophilized to give [3-(1-amino-4-methylphthalo-6-yl)-4-methoxyphenyl] formic acid as a white solid Salt (46 mg, 0.149 mmol, 57.84% yield). 1H NMR (400 MHz, DMSO-d6) δ 3.83 (s, 3H), 7.05 (br. s, 2H), 7.16 (d,J= 8.17 Hz, 1H), 7.84 - 7.90 (m, 2H), 7.96 - 8.01 (m, 2H), 8.16 (s, HCOOH), 8.27 (d, J= 8.40 Hz, 1H), 8.93 (s, 1H). LC-MS (Method A): r.t. 0.43 min, MS (ESI) m / z = 296.2 [M+H]+.

[0184] Example 3: 6-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]phthalein 𠯤 -1-amine trifluoroacetate (3) N-[(2,4-dimethoxyphenyl)methyl]-6-[2-methoxy-5-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]phthalo-1-amine (350.0 mg, 0.660 mmol) in DCM (4.71 mL) and trifluoroacetic acid (4.71 mL ) was stirred at room temperature for 2.5 hours, then it was concentrated under reduced pressure. The residue was suspended in Et2O, stirred for 1 h, filtered on a Hirsch funnel and dried to give 6-[2-methoxy-5-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]phthalein-1-amine trifluoroacetate (350 mg, 0.712 mmol, 100% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.31 (s, 12H), 3.87 (s, 3H), 7.26 (d,J= 8.42 Hz, 1H), 7.71 (d,J= 1.65 Hz, 1H), 7.81 (dd,J= 8.29, 1.69 Hz, 1H), 8.26 (dd,J= 8.53, 1.79 Hz, 1H), 8.31 (d,J= 1.74 Hz, 1H), 8.65 (d,J= 8.56 Hz, 1H) , 9.01 (s, 1H), 9.16 (br. s, 2H), 14.42 (br. s, TFA). LC-MS (Method A): r.t. 0.75 min, MS (ESI) m / z = 378.3 [M+H]+.

[0185] Example 4: [3-(1-amino-4-methylphthalein-6-yl)phenyl]acid (4) converts [3-[1-[(2,4-dimethoxy A solution of phenyl)methylamino]-4-methylphthalo-6-yl]phenyl]acid (20 mg, 0.047 mmol) in DCM (0.250 mL) and trifluoroacetic acid (0.250 mL) was incubated at room temperature After stirring at warm temperature for 2 hours, it was concentrated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​12 g) eluting with a gradient of 1% to 40% CH3CN in water (+0.1% HCOOH). Fractions containing the desired compound were pooled and lyophilized to give [3-(1-amino-4-methylphthalo-6-yl)phenyl]acid (12 mg, 0.043 mmol, Yield 92.29%). 1H NMR (400 MHz, DMSO-d6) δ 2.79 (s, 3H), 7.54 (t,J= 7.6 Hz, 1H), 7.62 (br. s, 2H), 7.89 (d,J= 7.4 Hz, 1H) , 7.97 (d,J= 7.8 Hz, 1H), 8.22 - 8.34 (m, 5H), 8.45 - 8.52 (m, 1H). LC-MS (Method A): r.t. 0.46 min, MS (ESI) m / z = 280.1 [M+H]+.

[0186] Example 5: [3-(4-aminophenoline-7-yl)-4-methoxyphenyl]acid (5) converts 7-[2-methoxyl-5-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]phenolin-4-amine trifluoroacetic acid (450.0 mg, 0.920 mmol) was dissolved in Et2O (12 mL) and added 2 M hydrochloric acid solution (13.34 mL, 26.69 mmol). The mixture was stirred vigorously for 1.5 hours. CH3CN (10 mL) was added and the two phases were separated (Et2O / water+CH3CN). The water+CHCN phase was concentrated under reduced pressure and the residue was purified by column chromatography (KP-C18-HS, ​​60 g) with a gradient elution from 2% to 25% CHCN in water (+0.1% HCOOH) . Fractions containing compound were pooled and lyophilized. The recovered solid was subjected to semi-preparative HPLC purification (Chiralcel OJ-H (25 x 0.46 cm), 5 µm, 85 / 15% v / v n-hexane / (EtOH + 0.1% isopropylamine)). Fractions containing the desired compound were collected and evaporated under reduced pressure to give [3-(4-aminophenolin-7-yl)-4-methoxyphenyl]acid (65 mg, 0.220 mmol, yield 24.05%). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 3.86 (s, 3H), 7.21 (d,J= 8.78 Hz, 1H), 7.91 - 7.95 (m, 2H), 7.97 (dd,J= 8.88, 1.63 Hz, 1H), 8.02 (d,J= 1.55 Hz, 1H), 8.45 - 8.49 (m, 2H), 9.70 (s, 1H), 9.84 (s, 1H). LC-MS (Method A): r.t. 0.43 min, MS (ESI) m / z = 296.2 [M+H]+.

[0187] Example 6: 6-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]-4 -Methylphthalein-1-amine trifluoroacetate (6) converts N-[(2,4-dimethoxyphenyl)methyl]-6-[2-methoxy-5-(4 , 4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]-4-methylphthalein-1-amine (79.0 mg, 0.150 mmol) was dissolved in tris In a mixture of fluoroacetic acid (1 mL) and DCM (1 mL). The mixture was stirred at room temperature for 4 h and the volatiles were evaporated. The residue was dissolved in MeOH and filtered through a short pad of celite. The filtrate was evaporated and the solid residue obtained was triturated twice with Et2O. The solid was dried under vacuum to afford 6-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl as a white solid )phenyl]-4-methylphthalein-1-amine trifluoroacetate (35 mg, 0.069 mmol, 47.47% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.30 (s,12H), 2.74 (s, 3H), 3.84 (s, 3H), 7.24 (d,J= 8.39 Hz, 1H), 7.69 (d,J= 1.72 Hz, 1H), 7.80 (dd,J= 8.39, 1.72 Hz, 1H), 8.19 (dd,J= 8.52, 1.68 Hz, 1H), 8.23 ​​(d,J= 1.68 Hz, 1H), 8.62 (d, J= 8.51 Hz, 1H), 8.85 (s, 2H). LC-MS (Method A): r.t. 0.78 min, MS (ESI) m / z = 392.4 [M+H]+.

[0188] Example 7: [3-(1-amino-4-methylphthalein-6-yl)-4-methoxyphenyl] acid formate (7) converts 6-[2-methoxy yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]-4-methylphthalein-1-amine trifluoroacetic acid The salt (28.0 mg, 0.060 mmol) was suspended in Et2O (2 mL) and 2 M hydrochloric acid solution (0.83 mL, 0.830 mmol) was added. The mixture was stirred vigorously for 45 min and water (5 mL) and Et2O (5 mL) were added. The layers were separated and the aqueous layer was washed with Et2O (3 x 20 mL). The aqueous layer was evaporated and the residue was purified by column chromatography (KP-C18-HS, ​​SNAP 12 g) eluting with a gradient of 1% to 40% CH3CN in water (+0.1% HCOOH). Fractions containing the desired compound were collected and evaporated under reduced pressure to give [3-(1-amino-4-methylphthalein-6-yl)-4-methoxyphenyl as a white solid ] acid formate (12 mg, 0.034 mmol, yield 60.98%). 1H NMR (400 MHz, DMSO-d6+ 2 drops of TFA) δ 2.74 (s, 3 H) 3.85 (s, 3 H) 7.20 (d, J=8.36 Hz, 1 H) 7.86 - 7.97 (m, 2 H) 8.13 (s, 1 H from HCOOH) 8.23 ​​- 8.32 (m, 2 H) 8.69 (d, J=8.58 Hz, 1 H) 9.14 (br. s, 2 H). LC-MS (Method A): r.t. 0.47 min, MS (ESI) m / z = 310.2 [M+H]+.

[0189] Example 8: [3-(4-aminophenoline-7-yl)-4-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethyl Oxygen] ethoxy] ethoxy] ethoxy] ethoxy] phenyl] acid (8) N-[(2,4-dimethoxyphenyl) methyl]-7-[2 -[2-[2-[2-[2-[2-(2-Methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-5-( 4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]phenolin-4-amine (28.0 mg, 0.040 mmol) in DCM (2 mL) and A solution in trifluoroacetic acid (1 mL) was stirred at room temperature for 5 hours, then concentrated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​12 g) with a gradient elution of 2% to 95% CH3CN in water. Fractions containing the desired compound were collected and evaporated under reduced pressure to give [3-(4-aminophenolin-7-yl)-4-[2-[2-[2-[ 2-[2-(2-Methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]phenyl]acid (4.7 mg, 0.008 mmol, 23.76% yield ), the yellow powder turns into a yellow gel in air. 1H NMR (400 MHz, DMSO-d6) δ 3.22 (s, 3H), 3.38 - 3.50 (m, 18H), 3.51 - 3.55 (m, 2H), 3.75 (t,J= 4.68 Hz, 2H), 4.24 ( t,J= 5.77, 3.63 Hz, 2H), 7.21 (d,J= 8.36 Hz, 1H), 7.90 (dd,J= 8.24, 1.69 Hz, 1H), 7.95 (d,J= 1.73 Hz, 1H), 8.01 - 8.08 (m, 4H), 8.41 (d, J= 8.87 Hz, 1H), 8.51 (s, 1H). LC-MS (Method A): r.t. 0.51 min, MS (ESI) m / z = 560.5 [M+H]+.

[0190] Example 9: [3-(1-amino-4-prop-2-ylphthal-6-yl)phenyl] hydrochloride (9) converts 4-prop-2-yl-6- [3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]phthalein-1-amine (23.0 mg, 0.060 mmol) suspended in hydrogen chloride in 2 M solution in Et2O (2.0 mL, 4 mmol) and added water (50 µL). The mixture was stirred for 30 min and additional water (1 mL) was added. The mixture was stirred for another 10 min and the layers were separated. The aqueous layer was washed with Et2O (2 x 1 mL) and then evaporated under reduced pressure to give [3-(1-amino-4-propan-2-ylphthal-6-yl)phenyl]hydrochloride ( 11 mg, 0.032 mmol, yield 54.18%). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 1.36 (d,J= 6.69 Hz, 6H), 3.97 (quintet, J= 6.69 Hz, 1H), 7.55 (t,J= 7.57 Hz, 1H ), 7.92 (d,J= 7.36 Hz, 1H), 7.99 (d,J= 7.68 Hz, 1H), 8.32 (s, 1H), 8.45 (d,J= 8.72 Hz, 1H), 8.49 (s, 1H ), 8.77 (d,J= 8.58 Hz, 1H), 9.24 (br. s, 2H). LC-MS (Method A): r.t. 0.57 min, MS (ESI) m / z = 308.3 [M+H]+.

[0191] Example 10: [3-(1-Amino-4-methylphthalein-6-yl)-4-methylphenyl] acid formate (10) Trifluoroacetic acid (0.600 mL) was added To N-[(2,4-dimethoxyphenyl)methyl]-4-methyl-6-[2-methyl-5-(4,4,5,5-tetramethyl-1, A solution of 3,2-dioxabororol-2-yl)phenyl]phthalo-l-amine (42.0 mg, 0.080 mmol) in DCM (0.600 mL). The reaction mixture was stirred at room temperature for 30 min, then the volatiles were removed. Et2O (1 mL) was added and the mixture was stirred at room temperature for 1 h before it was filtered. The filter cake was dissolved in DMSO and purified by column chromatography (KP-C18-HS, ​​SNAP12) with gradient elution from 2% to 50% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH) . Appropriate fractions were collected and partially concentrated, followed by lyophilization to give [3-(1-amino-4-methylphthalo-6-yl)-4-methylphenyl] formic acid as a white solid Salt (9.12 mg, 0.026 mmol, 33.6% yield). NMR analysis showed partial salt formation (-60%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 2.29 (s, 3 H), 2.72 (s, 3 H), 7.26 (br. s, 2 H), 7.34 (d,J= 8.36 Hz, 1 H), 7.74 - 7.80 (m, 2 H), 7.90 - 7.95 (m, 2 H), 8.06 (br. s, 2 H), 8.15 (s, 0.6 H from HCOOH), 8.39 (d,J= 8.14 Hz, 1 H). LC-MS (Method A): r.t. 0.49 min, MS (ESI) m / z = 294.26 [M+H]+.

[0192] Example 11: [3-(1-amino-4-cyclopropylphthal-6-yl)phenyl] acid formate (11) converts [3-[4-cyclopropyl-1- [(2,4-Dimethoxyphenyl)methylamino]phthalo-6-yl]phenyl]acid (50.0 mg, 0.110 mmol) in DCM (0.200 mL) and trifluoroacetic acid (0.200 mL) The solution in was stirred at room temperature for 1 hour, then it was concentrated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS 30 g) with gradient elution from 1% to 50% CH3CN in water (+0.1% HCOOH). Fractions containing the desired compound were pooled and lyophilized to give [3-(1-amino-4-cyclopropylphthalo-6-yl)phenyl] acid formate (49 mg , 0.140 mmol, yield 127.07%). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 1.02 - 1.19 (m, 4H), 2.88 (ddd, J = 13.20, 8.25, 5.06 Hz, 1H), 7.58 (t, J = 7.58 Hz, 1H) , 7.94 (d, J = 7.40 Hz, 1H), 8.03 (dd, J = 7.88, 1.99 Hz, 1H), 8.13 (s, 1H, HCOOH), 8.35 (s, 1H), 8.48 (dd, J = 8.54 , 1.73 Hz, 1H), 8.72 - 8.80 (m, 2H), 9.19 (s, 2H). LC-MS (Method A): r.t. 0.54 min, MS (ESI) m / z = 352.1 [M+H]+.

[0193] Example 12: [3-(1-amino-4-methylphthalein-6-yl)-4-ethylphenyl] acid formate (12) converts [3-[1-[( 2,4-Dimethoxyphenyl)methylamino]-4-methylphthalein-6-yl]-4-ethylphenyl]acid (36.0 mg, 0.080 mmol) in DCM (1.64 mL) and trifluoroacetic acid (1.64 mL) was stirred at room temperature for 2 hours, then it was concentrated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​12 g) eluting with a gradient of 1% to 40% CH3CN in water (+0.1% HCOOH). Fractions containing the desired compound were collected and lyophilized to give [3-(1-amino-4-methylphthalo-6-yl)-4-ethylphenyl] formic acid as a white powder Salt (22 mg, 0.062 mmol, 79.13% yield). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 1.07 (t,J= 7.52 Hz, 3H), 2.60 (q,J= 7.53 Hz, 2H), 2.74 (s, 3H), 7.41 (d,J = 7.72 Hz, 1H), 7.72 (d,J= 1.36 Hz, 1H), 7.86 (dd,J= 7.70, 1.39 Hz, 1H), 8.12 - 8.17 (m, 2H), 8.14 (s, HCOOH), 8.73 (d,J= 8.36 Hz, 1H), 9.15 (s, 2H). LC-MS (Method A): r.t. 0.54 min, MS (ESI) m / z = 308.3 [M+H]+.

[0194] Example 13: [3-(1-amino-3-methylisoquinolin-6-yl)phenyl] acid; trifluoroacetate (13) will N-[(2,4-di Methoxyphenyl)methyl]-3-methyl-6-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl ] A mixture of isoquinolin-1-amine (150.0 mg, 0.290 mmol) in trifluoroacetic acid (2 mL) and DCM (2 mL) was stirred at room temperature for 30 min, then it was concentrated. The residue was purified by column chromatography (KP-C18-HS, ​​SNAP 30) with gradient elution from 2% to 40% MeCN in water. Fractions containing product were concentrated to give a solid, which was stripped with water and dried in an oven overnight to give [3-(1-amino-3-methylisoquinolin-6-yl) as a white solid ) phenyl] acid trifluoroacetate (53 mg, 0.135 mmol, 45.99% yield). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 2.48 (s, 3 H), 7.10 (s, 1 H), 7.54 (t,J= 7.59 Hz, 1 H), 7.87 - 7.94 (m, 2 H), 8.06 (dd,J= 8.80, 1.76 Hz, 1 H), 8.14 (d,J= 1.76 Hz, 1 H), 8.28 (s, 1 H), 8.62 (d,J= 8.80 Hz, 1 H ), 8.86 (br. s, 2 H), 13.29 (1 H, br. s). LC-MS (Method A): r.t. 0.51 min, MS (ESI) m / z = 279.26 [M+H]+.

[0195] Example 14: 6-(1-hydroxyl-3H-2,1-benzoxaborolan-6-yl)-4-methylphthalein-1-amine formate (14) to N -[(2,4-Dimethoxyphenyl)methyl]-4-methyl-6-[4-(Oxane-2-yloxymethyl)-3-(4,4,5,5 - To a solution of tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]phthalo-1-amine (78.0 mg, 0.120 mmol) in DCM (2 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 1.5 h and then the volatiles were removed. The resulting solid was triturated with Et2O and subsequently dissolved by column chromatography (KP-C18-HS, ​​SNAP 12 g) with a gradient of 1% to 40% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). After isolation and purification, 6-(1-hydroxyl-3H-2,1-benzoxaborolan-6-yl)-4-methylphthalein-1-amine formate ( 18 mg, 0.053 mmol, yield 42.82%). 1H NMR (400 MHz, DMSO-d6) δ 2.77 (s, 3H), 5.08 (s, 2H), 7.02 (s, 2H), 7.60 (d,J= 7.94 Hz, 1H), 8.00 (dd,J= 7.94, 1.85 Hz, 1H), 8.15 (s, 1H, from HCOOH), 8.17 - 8.23 ​​(m, 3H), 8.36 - 8.43 (m, 1H), 9.29 (s, 1H). LC-MS (Method A): r.t. 0.50 min, MS (ESI) m / z = 292.2 [M+H]+.

[0196] Example 15: [3-(1-amino-4-methylphthalein-6-yl)-4-(trifluoromethoxy)phenyl]acid (15) converts [3-[1- [(2,4-Dimethoxyphenyl)methylamino]-4-methylphthalein-6-yl]-4-(trifluoromethoxy)phenyl]acid (22.0 mg, 0.040 mmol ) in DCM (1 mL) and trifluoroacetic acid (1 mL) was stirred at room temperature for 1 h, then it was concentrated under reduced pressure. The crude was subjected to semi-preparative HPLC purification (Chiralcel OJ-H (25 x 0.46 cm), 5 µm, 85 / 15% v / v n-hexane / (EtOH + 0.1% isopropylamine)). Fractions containing the desired compound were collected and evaporated under reduced pressure to give [3-(1-amino-4-methylphthalein-6-yl)-4-(trifluoromethoxy yl)phenyl]acid (6 mg, 0.017 mmol, 38.55% yield). 1H NMR (400 MHz, DMSO-d6+ 1 drop TFA) δ 2.75 (s, 3H), 7.57 (dd,J= 8.24, 1.66 Hz, 1H), 8.03 (dd,J= 8.24, 1.66 Hz, 1H), 8.10 (d,J= 1.69 Hz, 1H), 8.27 (dd,J= 8.52, 1.67 Hz, 1H), 8.33 (d,J= 1.69 Hz, 1H), 8.77 (d,J= 8.58 Hz, 1H), 9.19 (br. s, 2H). LC-MS (Method A): r.t. 0.59 min, MS (ESI) m / z = 364.2 [M+H]+.

[0197] Example 16: [3-(1-amino-4-methylphthalein-6-yl)-4-[2-[2-[2-[2-[2-(2-methoxy Ethoxy) ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] phenyl] acid (16) will 6-[2-[2-[2-[2-[2-[ 2-(2-Methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-5-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborol-2-yl)phenyl]-4-methylphthalo-1-amine trifluoroacetate (45.0 mg, 0.070 mmol) was suspended in EtO (2 mL) and 2 M hydrochloric acid solution (1.0 mL, 2 mmol). To aid dissolution, DCM (0.200 mL) was added and the viscous mixture became more homogeneous. The mixture was stirred vigorously for 1 h, then evaporated and eluted by column chromatography (KP-C18-HS, ​​2 x 12 g consecutively) with a gradient of 2% to 30% CHCN in water (+0.1% HCOOH). The residue was purified. Fractions containing the desired compound were collected and lyophilized to give [3-(1-amino-4-methylphthalein-6-yl)-4-[2-[2- [2-[2-[2-(2-Methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]phenyl]acid (16 mg, 0.028 mmol, Yield 40.65%), the white sticky solid turned into gel over time. NMR analysis showed partial salt formation (-45%) of the title compound. 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 2.75 (s, 3H), 3.21 (s, 3H), 3.36 - 3.50 (m, 18H), 3.54 (dd,J= 5.73, 3.22 Hz, 2H) , 3.71 - 3.79 (m, 2H), 4.17 - 4.29 (m, 2H), 7.20 (d,J= 8.35 Hz, 1H), 7.90 (dd,J= 8.26, 1.69 Hz, 1H), 7.99 (d,J = 1.66 Hz, 1H), 8.12 (s, 0.4 H from HCOOH), 8.35 (dd,J= 8.57, 1.67 Hz, 1H), 8.41 (d,J= 1.64 Hz, 1H), 8.69 (d,J= 8.60 Hz, 1H), 9.11 (s, 2H). LC-MS (Method A): r.t. 0.56 min, MS (ESI) m / z = 574.52 [M+H]+.

[0198] Example 17: [5-(1-amino-4-methylphthalein-6-yl)pyridin-3-yl]acid (17) to [5-[1-[(2,4-di To a solution of methoxyphenyl)methylamino]-4-methylphthalein-6-yl]pyridin-3-yl]acid (160.0 mg, 0.370 mmol) in DCM (4 mL) was added trifluoro Acetic acid (4 mL), and the mixture was stirred at room temperature for 1 h. The volatiles were evaporated and the solid residue was triturated twice with Et2O. The solid residue was purified by column chromatography (KP-C18-HS, ​​SNAP 12 g) with gradient elution from 1% to 30% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH) to give the The partially purified product was dissolved by column chromatography (KP-C18-HS, ​​SNAP 12 g) with a gradient of 1% to 20% CH3CN alkaline aqueous solution (10 mM ammonium bicarbonate aqueous solution adjusted to pH 10 with ammonia). The partially purified product was isolated and further purified to obtain [5-(1-amino-4-methylphthalo-6-yl)pyridin-3-yl]acid (17 mg, 0.061 mmol) as a white solid , yield 16.32%). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 2.82 (s, 3H), 8.62 (dd,J= 8.58, 1.78 Hz, 1H), 8.69 (d,J= 1.78 Hz, 1H), 8.85 (d ,J= 8.58 Hz, 1H), 9.12 (s, 1H), 9.31 (m, 3H), 9.57 (d,J= 2.15 Hz, 1H). LC-MS (Method B): r.t. 0.31 min, MS (ESI) m / z = 279.1 [M-H]-.

[0199] Example 18: [3-(1-Aminophthaloyl)-6-yl)-4-[(2-chlorobenzoyl)amino]phenyl]acid formate (18) converts [4 -Benzamido-3-[1-[(2,4-dimethoxyphenyl)methylamino]phthalo-6-yl]phenyl]acid (46.97 mg, 0.090 mmol) in DCM (0.250 mL) and trifluoroacetic acid (0.250 mL) was stirred at room temperature for 1 hour, then it was concentrated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​12 g) eluting with a gradient of 1% to 50% CH3CN in water (+0.1% HCOOH). Fractions containing the desired compound were pooled and lyophilized to give [3-(1-aminophthal-6-yl)-4-[(2-chlorobenzoyl)amino] as a white solid Phenyl] acid formate. 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 7.32 - 7.51 (m, 4H), 7.61 (d, J = 8.17 Hz, 1H), 7.95 (s, 2H), 8.05 (s, HCOOH), 8.23 (dd, J = 8.50, 1.83 Hz, 1H), 8.30 (d, J = 1.74 Hz, 1H), 8.72 (d, J = 8.59 Hz, 1H), 9.02 (s, 1H), 9.37 (s, 2H) , 10.29 (s, 1H), 14.57 (s, 1H). LC-MS (Method A): r.t. 0.46 min, MS (ESI) m / z = 465.67 [M+H]+.

[0200] Example 19: [3-(1-amino-4-methylphthalein-6-yl)-4-ethylphenyl] acid formate (19) converts [3-[1-[( 2,4-Dimethoxyphenyl)methylamino]-4-methylphthalein-6-yl]-4-fluorophenyl]acid (56.0 mg, 0.110 mmol) in DCM (3 mL) and A solution in trifluoroacetic acid (0.5 mL) was stirred at room temperature for 2 hours, after which it was concentrated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​sequentially 2 x 12 g) with gradient elution from 2% to 95% CH3CN in water (+0.1% HCOOH). Fractions containing the desired compound were collected and lyophilized to give [3-(1-amino-4-methylphthalo-6-yl)-4-fluorophenyl] acid formate as a white powder (16 mg, 0.047 mmol, yield 41.38%). 1H NMR (400 MHz, DMSO-d6+ 1 drop TFA) δ 2.77 (s, 3H), 7.40 (dd,J= 11.20, 8.29 Hz, 1H), 7.94 - 7.99 (m, 1H), 8.13 (s, 1 H , from HCOOH), 8.14 (dd,J= 8.55, 1.83 Hz, 1H), 8.34 (td,J= 8.55, 1.71 Hz, 1H), 8.37 (s, 1H), 8.77 (d,J= 8.54 Hz, 1H ), 9.19 (br. s, 2H). LC-MS (Method A): r.t. 0.49 min, MS (ESI) m / z = 298.2 [M+H]+.

[0201] Example 20: 6-(1-hydroxyl-5-methoxy-3H-2,1-benzoxaborolan-6-yl)-4-methylphthalein-1-amine (20 ) trifluoroacetic acid (2 mL) was added to N-[(2,4-dimethoxyphenyl)methyl]-6-[2-methoxy-4-(oxalk-2-yloxymeth Base)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]-4-methylphthalein-1-amine (133.0 mg , 0.200 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 1 h and the volatiles were evaporated. The residue was purified by column chromatography (KP-C18-HS, ​​SNAP 12 g) with gradient elution from 1% to 30% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH) to give 6-(1-Hydroxy-5-methoxy-3H-2,1-benzoxaborolan-6-yl)-4-methylphthalein-1-amine (28 mg, 0.087 mmol, yield 42.98%). NMR analysis showed partial salt formation of the title compound (-22%). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 2.72 (s, 3H), 3.84 (s, 3H), 5.03 (s, 2H), 7.24 (s, 1H), 7.80 (s, 1H), 8.10 (s, 0.2 H from HCOOH), 8.23 ​​(dd,J= 8.48, 1.63 Hz, 1H), 8.26 (d,J= 1.63 Hz, 1H), 8.67 (d,J= 8.48 Hz, 1H), 9.11 ( br. s, 2H). LC-MS (Method A): r.t. 0.51 min, MS (ESI) m / z = 322.3 [M+H]+.

[0202] Example 21: 6-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]-3 -Methylisoquinolin-1-amine trifluoroacetate (21) N-[(2,4-dimethoxyphenyl)methyl]-6-[2-methoxy-5-( 4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]-3-methylisoquinolin-1-amine (159.0 mg, 0.290 mmol) in A mixture in DCM (2 mL) and trifluoroacetic acid (2 mL) was stirred at room temperature for 30 min. The volatiles were evaporated, Et2O (4 mL) was added and the mixture was stirred for 1 h, then the solid was collected by filtration and washed with Et2O to give 6-[2-methoxy-5-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]-3-methylisoquinolin-1-amine trifluoroacetate (162 mg, 0.321 mmol , yield 109.19%). NMR analysis showed partial salt formation (-65%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 1.30 (s, 12 H), 2.46 (s, 3 H), 3.84 (s, 3 H), 7.10 (s, 1 H), 7.22 (d, J= 8.36 Hz, 1H), 7.65 (d,J= 1.76 Hz, 1H), 7.77 (dd,J= 8.36, 1.76 Hz, 1H), 7.79 - 7.83 (m, 1H), 7.92 (d,J= 1.32 Hz, 1 H), 8.52 (d, J= 8.80 Hz, 1 H), 8.66 (br. s, 2 H), 13.10 (br. s, 0.65 H, from TFA). LC-MS (Method A): r.t. 0.82 min, MS (ESI) m / z = 391.36 [M+H]+.

[0203] Example 22: [3-(1-amino-3-methylisoquinolin-6-yl)-4-methoxyphenyl] acid (22) converts 6-[2-methoxy- 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]-3-methylisoquinolin-1-amine trifluoroacetate (154.0 mg, 0.310 mmol) in 2 M hydrochloric acid solution (3.82 mL, 7.63 mmol) and Et2O (4 mL) was stirred at room temperature for 2.5 h. Et2O was added and the phases were separated. The aqueous phase was concentrated and purified by column chromatography (KP-C18-HS, ​​sequentially 2 x SNAP 12) with a gradient of 2% to 60% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH) The residue, [3-(1-amino-3-methylisoquinolin-6-yl)-4-methoxyphenyl] acid (28 mg, 0.079 mmol, yield 25.89 %). NMR analysis showed partial salt formation (-40%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 2.46 (s, 3 H), 3.82 (s, 3 H), 7.07 (s, 1 H), 7.17 (d,J= 8.14 Hz, 1 H), 7.83 ( dd,J= 8.69, 1.65 Hz, 1 H), 7.86 - 7.91 (m, 2 H), 7.93 (d,J= 1.54 Hz, 1 H), 8.14 (s, 0.4 H, from HCOOH), 8.54 (d ,J= 8.80 Hz, 1 H), 8.82 (br. s, 2 H). LC-MS (Method A): r.t. 0.52 min, MS (ESI) m / z = 309.23 [M+H]+.

[0204] Example 23: [1-(1-amino-4-methylphthalein-6-yl)pyrazol-4-yl]acid (23) converts [1-[1-[(2,4- Dimethoxyphenyl)methylamino]-4-methylphthalo-6-yl]pyrazol-4-yl]acid (56.0 mg, 0.130 mmol) in DCM (3 mL) and trifluoroacetic acid ( 1 mL) was stirred at room temperature for 2 hours, then it was concentrated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​sequentially 2 x 12 g) with a gradient elution from 2% to 95% CH3CN in water (+0.1% HCOOH) to afford partially pure product. The compound was further purified by column chromatography (KP-C18-HS, ​​sequentially 2 x 12 g) with gradient elution from 2% to 95% CH3CN in water (+0.1% NH4OH). Fractions containing the desired compound were collected and lyophilized to give [1-(1-amino-4-methylphthalo-6-yl)pyrazol-4-yl]acid (12 mg , 0.045 mmol, yield 34.78%). 1H NMR (400 MHz, DMSO-d6) δ 2.74 (s, 3H), 6.81 (s, 2H), 8.06 (s, 3H), 8.27 (d,J= 2.08 Hz, 1H), 8.32 - 8.42 (m, 2H), 8.87 (s, 1H). LC-MS (Method A): r.t. 0.36 min, MS (ESI) m / z = 270.3 [M+H]+.

[0205] Example 24: [4-[2-[2-[2-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydro Thieno[3,4-d]imidazol-4-yl]pentylamino]ethoxy]ethoxy]ethoxy]-3-(1-amino-4-methylphthalein-6 -yl) phenyl] acid formate (24) converts 5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3, 4-d]imidazol-4-yl]-N-[2-[2-[2-[2-(1-amino-4-methylphthalein-6-yl)-4-(4,4, 5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenoxy]ethoxy]ethoxy]ethyl]pentanamide (55.0 mg, 0.070 mmol) in 2 A suspension in M ​​hydrochloric acid solution (0.04 mL, 0.070 mmol) and Et2O (3.686 mL) was stirred at room temperature for 2 hours, then it was evaporated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS 30 g) with gradient elution from 1% to 60% CH3CN in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give [4-[2-[2-[2-[5-[(3aS,4S,6aR)-2-oxo-1,3, 3a ,4,6,6a-Hexahydrothieno[3,4-d]imidazol-4-yl]pentylamino]ethoxy]ethoxy]ethoxy]-3-(1-amine yl-4-methylphthalethyl-6-yl)phenyl] acid formate (13 mg, 0.019 mmol, yield 24.86%). 1H NMR (400 MHz, DMSO-d6) δ 1.07 - 1.39 (m, 2H), 1.41 - 1.67 (m, 3H), 2.04 (t,J= 7.49 Hz, 2H), 2.53 - 2.61 (m, 3H), 2.72 (s, 3H), 2.80 (dd,J= 12.19, 5.06 Hz, 1H), 3.05 - 3.09 (m, 1H), 3.10 - 3.17 (m, 2H), 3.43 - 3.49 (m, 2H), 3.49 - 3.56 (m, 2H), 3.71 - 3.75 (m, 2H), 4.09 - 4.14 (m, 1H), 4.18 - 4.24 (m, 2H), 4.25 - 4.31 (m, 1H), 6.34 (s, 1H), 6.46 (s, 1H), 6.83 (s, 2H), 7.17 (d, J= 8.28 Hz, 1H), 7.76 (t, 1H), 7.84 (d, J= 8.30 Hz, 1H), 7.94 (s, 1H ), 8.02 - 8.06 (m, 3H), 8.13 (s, 1H, HCOOH), 8.17 (s, 1H), 8.27 (d,J= 8.57 Hz, 1H). LC-MS (Method A): r.t. 0.51 min, MS (ESI) m / z = 699.59 [M+H]+.

[0206] Example 25: [5-(1-amino-4-methylphthalein-6-yl)-2-fluoro-4-methoxyphenyl]acid (25) trifluoroacetic acid (2.5 mL ) added to [5-[1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalein-6-yl]-2-fluoro-4-methoxybenzene ] acid (140.0 mg, 0.290 mmol) in DCM (2.5 mL), and the mixture was stirred at room temperature for 1 h. The volatiles were evaporated and the residue was triturated with Et2O. The residue was dissolved in MeOH and filtered through a short pad of celite. MeOH was evaporated and the residue was purified by column chromatography (KP-C18-HS, ​​SNAP 12 g) with gradient elution from 1% to 40% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH) , [5-(1-Amino-4-methylphthalein-6-yl)-2-fluoro-4-methoxyphenyl]acid was obtained as a white solid (23 mg, 0.070 mmol, yield 23.97%). NMR analysis showed partial salt formation of the title compound (-21%). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 2.73 (s, 3H), 3.85 (s, 3H), 7.00 (d,J= 11.41 Hz, 1H), 7.75 (d,J= 7.21 Hz, 1H ), 8.11 (s, 0.2H from HCOOH), 8.23 ​​(dd,J= 8.46, 1.63 Hz, 1H), 8.26 (d,J= 1.63 Hz, 1H), 8.66 (d,J= 8.46 Hz, 1H) , 9.11 (br. s, 2H). LC-MS (Method A): r.t. 0.49 min, MS (ESI) m / z = 328.2 [M+H]+.

[0207] Example 26: 6-(1-Hydroxy-3,4-dihydro-2,1-benzoxaborin-7-yl)-4-methylphthalein-1-amine Formate (26) Trifluoroacetic acid (2.5 mL) was added to N-[(2,4-dimethoxyphenyl)methyl]-4-methyl-6-[4-[2-(㗁Alk-2-yloxy)ethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]phthalein-1- The amine (50.0 mg, 0.080 mmol) was in solution in DCM (2.5 mL) and the mixture was stirred at room temperature for 1 h. The volatiles were evaporated and the residue was triturated with Et2O. The residue was dissolved in MeOH and filtered through a short pad of celite. MeOH was evaporated and the residue was purified by column chromatography (KP-C18-HS, ​​SNAP 12 g) with gradient elution from 1% to 40% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH), 6-(1-Hydroxy-3,4-dihydro-2,1-benzoxaborin-7-yl)-4-methylphthalein-1-amine was obtained as a white solid Formate salt (13 mg, 0.037 mmol, 47.36% yield). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 2.80 (s, 3H), 2.96 (t,J= 5.90 Hz, 2H), 4.12 (t,J= 5.90 Hz, 2H), 7.42 (d,J = 7.92 Hz, 1H), 8.00 (dd,J= 7.92, 2.10 Hz, 1H), 8.11 (s, 1H from HCOOH), 8.23 ​​(d,J= 2.10 Hz, 1H), 8.40 (d,J= 1.80 Hz, 1H), 8.45 (dd, J= 8.58, 1.80 Hz, 1H), 8.74 (d, J= 8.58 Hz, 1H), 9.12 (br. s, 2H). LC-MS (Method A): r.t. 0.54 min, MS (ESI) m / z = 306.3 [M+H]+.

[0208] Example 27: [4-[2-[2-[2-[2-[5-[(3AS,4S,6AR)-2-oxo-1,3,3A,4,6, 6A-Hexahydrothieno[3,4-D]imidazol-4-yl]pentylamino]ethoxy]ethoxy]ethoxy]ethoxy]-3-(4-amino Phenyl-7-yl)phenyl] acid formate (27) converts 5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazole- 4-yl]-N-{2-[2-(2-{2-[2-(4-Aminothioline-7-yl)-4-(4,4,5,5-tetramethyl- 1,3,2-dioxoborol-2-yl)phenoxy]ethoxy}ethoxy)ethoxy]ethyl}pentanamide (200.0 mg) and 2 M hydrochloric acid solution (2.5 mL, 5 mmol) in MeCN (2 mL) was stirred at room temperature for 2 h. Then, the mixture was washed with Et2O and the aqueous phase was concentrated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS 30 g) with gradient elution from 1% to 60% CH3CN in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give [4-[2-[2-[2-[2-[5-[(3aS,4S,6aR)-2-oxo-1 as a white solid , 3,3a,4,6,6a-Hexahydrothieno[3,4-d]imidazol-4-yl]pentylamino]ethoxy]ethoxy]ethoxy]ethoxy] - 3-(4-Aminophenolin-7-yl)phenyl] acid formate (37 mg, 0.051 mmol, 12.75% yield over three steps). 1H NMR (400 MHz, DMSO-d6) δ 1.21 - 1.38 (m, 2H), 1.38 - 1.54 (m, 3H), 1.54 - 1.67 (m, 1H), 2.05 (t,J= 7.42 Hz, 2H), 2.52 - 2.61 (m, 1H), 2.81 (dd, J= 12.43, 5.07 Hz, 1H), 3.07 (ddd, J= 8.49, 6.14, 4.38 Hz, 1H), 3.15 (q, J= 5.80 Hz, 2H) , 3.34 (t,J= 5.89 Hz, 2H), 3.38 - 3.48 (m, 4H), 3.44 - 3.52 (m, 2H), 3.49 - 3.56 (m, 2H), 3.70 - 3.76 (m, 2H), 4.07 - 4.15 (m, 1H), 4.18 - 4.25 (m, 2H), 4.29 (dd,J= 7.77, 5.03 Hz, 1H), 6.35 (s, 1H), 6.40 (s, 1H), 7.16 (d,J = 8.35 Hz, 1H), 7.24 (s, 2H), 7.76 - 7.90 (m, 3H), 7.97 (d,J= 1.75 Hz, 1H), 8.08 (s, 2H), 8.14 - 8.23 ​​(m, 3H) , 8.61 (s, 1H). LC-MS (Method B): r.t. 0.58 min, MS (ESI) m / z = 729.62 [M+H]+.

[0209] Example 28: [5-(1-amino-4-methylphthalein-6-yl)-4-methoxy-2-methylphenyl] acid formate (28) converts 6- [2-Methoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]-4-methyl Phthalo-1-amine trifluoroacetate (140.0 mg, 0.270 mmol) was suspended in Et2O (8 mL) and 2 M hydrochloric acid solution (3.93 mL, 7.85 mmol) was added. The mixture was vigorously stirred for 1 hour then evaporated. The residue was purified by column chromatography (KP-C18-HS, ​​12 g) eluting with a gradient of 1% to 30% CH3CN in water (+0.1% HCOOH). Fractions containing the desired compound were collected and lyophilized to give [5-(1-amino-4-methylphthalein-6-yl)-4-methoxy-2-methyl as a white powder Phenyl] acid formate (24 mg, 0.065 mmol, 24.11% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.52 (s, 3H), 2.72 (s, 3H), 3.82 (s, 3H), 6.97 (s, 1H), 7.52 (br.s, 1H), 7.64 ( s, 1H), 7.96 (br. s, 2H), 8.05 - 8.11 (m, 2H), 8.15 (s, 1H from HCOOH), 8.38 (d,J= 8.50 Hz, 1H). LC-MS (Method A): r.t. 0.53 min, MS (ESI) m / z = 324.2 [M+H]+.

[0210] Example 29: [3-(1-Amino-4-methylphthalein-6-yl)-4-cyanophenyl]acid (29) Trifluoroacetic acid (1 mL) was added to [4 -cyano-3-[1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalethyl-6-yl]phenyl]acid (35.0 mg, 0.080 mmol) in suspension in DCM (1 mL). The mixture was stirred at room temperature for 2 h, then the volatiles were removed. The residue was purified by column chromatography (KP-C18-HS, ​​sequentially 2×SNAP 12) with gradient elution from 2% to 60% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH), [3-(1-Amino-4-methylphthalein-6-yl)-4-cyanophenyl] acid (7.9 mg, 0.026 mmol, 33.72% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 2.78 (s, 3 H), 8.05 (s, 1 H), 8.13 - 8.19 (m, 2 H), 8.40 (d,J= 8.36 Hz, 1 H), 8.49 (s, 1 H), 8.81 (d, J= 8.58 Hz, 1 H). LC-MS (Method A): r.t. 0.47min, MS (ESI) m / z = 305.17 [M+H]+.

[0211] Example 30: [5-(1-amino-4-methylphthalein-6-yl)-6-methoxypyridin-3-yl] acid (30) converts [5-[1-[ (2,4-dimethoxyphenyl)methylamino]-4-methylphthalein-6-yl]-6-methoxypyridin-3-yl]acid (54.0 mg, 0.120 mmol) in A suspension in DCM (1 mL) and trifluoroacetic acid (1 mL) was stirred at room temperature for 1 h, then it was concentrated. Et2O (1 mL) was added to the residue and the mixture was stirred for 1 h before it was filtered and washed with Et2O. The filter cake was dissolved in DMSO and eluted by column chromatography (KP-C18-HS, ​​SNAP 12) with a gradient of 2% to 80% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). Purification afforded [5-(1-amino-4-methylphthalein-6-yl)-6-methoxypyridin-3-yl] acid as a white solid (6.5 mg, 0.021 mmol, yield 17.87%). 1H NMR (400 MHz, methanol-d4) δ 2.82 (s, 3 H), 4.03 (s, 3 H), 8.12 (br. s, 1 H), 8.29 (dd,J= 8.47, 1.65 Hz, 1 H ), 8.36 - 8.40 (m, 1 H), 8.46 (d,J= 8.36 Hz, 1 H), 8.49 (br. s, 1 H). LC-MS (Method A): r.t. 0.44 min, MS (ESI) m / z = 311.15 [M+H]+.

[0212] Example 31: [3-(4-Amino-5-fluorophenolin-7-yl)-4-methoxyphenyl]acid (31) converts N-[(2,4-dimethoxy phenyl)methyl]-5-fluoro-7-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl )Phenyl]phenolin-4-amine (90.0 mg, 0.130 mmol) in DCM (2 mL) and trifluoroacetic acid (2 mL) was stirred at room temperature for 2 days, then it was concentrated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​30 g) eluting with a gradient of 1% to 50% CH3CN in water (+0.1% HCOOH). Fractions containing the desired compound were pooled and lyophilized to afford [3-(4-amino-5-fluorophenolin-7-yl)-4-methoxyphenyl]acid (17 mg , 0.054 mmol, yield 41.13%). NMR analysis showed partial salt formation (-45%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 3.86 (s, 3H), 7.17 (d,J= 8.34 Hz, 1H), 7.28 (s, 2H), 7.52 (d,J= 13.74 Hz, 1H), 7.87 (dd,J= 8.26, 1.72 Hz, 1H), 7.94 - 8.00 (m, 2H), 8.03 (s, 2H), 8.14 (s, 0.45H, HCOOH), 8.63 (s, 1H). LC-MS (Method A): r.t. 0.44 min, MS (ESI) m / z = 314.09 [M+H]+.

[0213] Example 32: 6-(1-Hydroxy-6-methoxy-3,4-dihydro-2,1-benzoxaborin-7-yl)-4-methyl Phthalo-1-amine formate (32) Trifluoroacetic acid (1 mL) was added to N-[(2,4-dimethoxyphenyl)methyl]-6-[2-methoxy- 4-[2-(Olkane-2-yloxy)ethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzene ]-4-Methylphthalein-1-amine (11.0 mg, 0.020 mmol) in suspension in DCM (1 mL). The mixture was stirred at room temperature for 2 h and the volatiles were evaporated. The residue was purified by column chromatography (KP-C18-HS, ​​SNAP 12 g) with gradient elution from 1% to 30% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH) to give 6-(1-Hydroxy-6-methoxy-3,4-dihydro-2,1-benzoxaborin-7-yl)-4-methylphthalein- 1-Amine formate (4 mg, 0.010 mmol, 63.88% yield). NMR and LC-MS analysis showed the presence of ~15% 2-[4-(1-amino-4-methylphthalethyl-6-yl)-3-methoxyphenyl]ethan-1-ol. 1H NMR (400 MHz, DMSO-d6) δ 2.70 (s, 3H), 2.94 (t,J= 5.88 Hz, 2H), 3.84 (s, 3H), 4.11 (t,J= 5.88 Hz, 2H), 6.84 (s, 2H), 7.05 (s, 1H), 7.76 (s, 1H), 7.95 (dd,J= 8.46, 1.70 Hz, 1H), 7.98 (d,J= 1.70 Hz, 1H), 8.16 (s, 1H, from HCOOH), 8.25 (d,J= 8.46 Hz, 1H), 8.38 (s, 1H). LC-MS (Method A): r.t. 0.56 min, MS (ESI) m / z = 336.3 [M+H]+.

[0214] Example 33: [4-[2-[2-[2-[2-[2-[2-[5-[(3AS,4S,6AR)-2-oxo-1,3,3A ,4,6,6A-Hexahydrothieno[3,4-D]imidazol-4-yl]pentylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] Ethoxy]-3-(4-aminophenoline-7-yl)phenyl]acid (33) converts 5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thiophene And[3,4-d]imidazol-4-yl]-N-{17-[2-(4-aminophenolin-7-yl)-4-(4,4,5,5-tetramethyl -1,3,2-dioxabororol-2-yl)phenoxy]-3,6,9,12,15-pentaoxahadecan-1-yl}pentanamide (60.0 mg, 0.070 mmol ) was suspended in CH3CN (1 mL) and 2 M hydrochloric acid solution (960.75 µL, 1.92 mmol) was added. The mixture was vigorously stirred for 1 hour then evaporated. The residue was purified by column chromatography (KP-C18-HS, ​​12 g) eluting with a gradient of 1% to 30% CH3CN in water (+0.1% HCOOH). Fractions containing the desired compound were pooled and lyophilized to give [4-[2-[2-[2-[2-[2-[2-[5-[(3aS,4S, 6aR )-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentylamino]ethoxy]ethoxy yl]ethoxy]ethoxy]ethoxy]ethoxy]-3-(4-aminophenolin-7-yl)phenyl]acid (12.7 mg, 0.016 mmol, yield 23.42%). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 1.21 - 1.36 (m, 2H), 1.40 - 1.57 (m, 4H), 1.56 - 1.71 (m, 1H), 2.07 (t,J= 7.39 Hz, 2H), 2.57 - 2.64 (m, 1H), 2.78 - 2.85 (m, 1H), 3.06 - 3.13 (m, 1H), 3.18 (q,J= 5.71 Hz, 2H), 3.37 (t,J= 5.89 Hz , 2H), 3.40 - 3.49 (m, 13H), 3.50 - 3.55 (m, 2H), 3.69 - 3.78 (m, 2H), 4.17 (dd,J= 7.83, 4.45 Hz, 1H), 4.20 - 4.25 (m , 2H), 4.33 - 4.38 (m, 1H), 7.19 (d,J= 8.36 Hz, 1H), 7.84 (t,J= 5.61 Hz, 1H), 7.93 - 7.98 (m, 1H), 8.01 - 8.06 ( m, 1H), 8.08 (s, 1H), 8.10 (s, 1H), 8.43 - 8.49 (m, 2H), 9.68 (s, 1H), 9.82 (s, 1H). LC-MS (Method A): r.t. 0.53 min, MS (ESI) m / z = 771.8 [M+H]+.

[0215] Example 34: [3-(1-amino-4-methylphthalein-6-yl)-2-fluoro-4-methoxyphenyl] acid formate (34) step 1: Palladium(II) diacetate (5.59 mg, 0.020 mmol), 6-(3-chloro-2-fluoro-6-methoxyphenyl)-N-[(2,4-dimethoxyphenyl)methanol base]-4-methylphthalein-1-amine (233.0 mg, 0.500 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (18.99 mg, 0.040 mmol), potassium acetate (146.61 mg, 1.49 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2 -Boroxane-2-yl)-1,3,2-Boroxane (379.35 mg, 1.49 mmol) was dissolved in 1,4-dioxane (12.66 mL). The mixture was degassed with Ar for 10 min, then stirred at 90 °C for 18 h. The mixture was filtered through a pad of Celite, washed with EtOAc and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (KP-C18-HS, ​​SNAP 30 g) using a gradient elution from 1% to 95% CHCN in water to give [3-(1-{[(2,4-di Methoxyphenyl)methyl]amino}-4-methylphthalein-6-yl)-2-fluoro-4-methoxyphenyl]acid {LC-MS (Method A): r.t. 0.68 min , MS (ESI) m / z = 478.4 [M+H]+} and N-[(2,4-dimethoxyphenyl)methyl]-6-[2-fluoro-6-methoxy- 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]-4-methylphthalein-1-amine {LC-MS (Method A): r.t. 0.94 min, MS (ESI) m / z = 560.4 [M+H]+} of 140 mg mixture which was used in the next step without further purification.

[0216] Step 2: The material obtained in Step 1 was dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 1 h and the volatiles were evaporated. The residue was dissolved in MeOH (20 mL) and filtered through a short pad of celite. The filtrate was evaporated and the obtained solid was triturated with Et2O. The solid residue was purified by column chromatography (KP-C18-HS, ​​SNAP 12 g) with gradient elution from 1% to 40% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH) to give [3-(1-Amino-4-methylphthalein-6-yl)-2-fluoro-4-methoxyphenyl] acid formate (29 mg, 0.078 mmol, yield 15.6 % over two steps). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 2.67 (s, 3H), 3.77 (s, 3H), 7.00 (d,J= 8.49 Hz, 1H), 7.63 - 7.83 (m, 1H), 8.08 (s, 1H), 8.10 (s, 0.5H from HCOOH), 8.18 (s, 1H), 8.69 (d, J= 8.48 Hz, 1H), 9.11 (s, 2H). LC-MS (Method A): r.t. 0.47 min, MS (ESI) m / z = 328.3 [M+H]+.

[0217] Example 35: [5-(1-amino-4-methylphthalein-6-yl)-2-(difluoromethyl)-4-methoxyphenyl]acid (35) Palladium(II) acetate (1.347 mg, 0.006 mmol), 6-[5-chloro-4-(difluoromethyl)-2-methoxyphenyl]-N-[(2,4-dimethoxy Phenyl)methyl]-4-methylphthalein-1-amine (60 mg, 0.120 mmol), potassium acetate (35.33 mg, 0.360 mmol), dicyclohexyl-[2-[2,4,6-tri (Propan-2-yl)phenyl]phenyl]phosphine (5.721 mg, 0.012 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaboroxane-2-yl)-1,3,2-dioxaboroxane (91.43 mg, 0.360 mmol) dissolved in 1,4-dioxane (0.880 mL) in a microwave vial . The resulting mixture was degassed with N2 for 10 min and then stirred at 75 °C for 2 h. Then, it was cooled to room temperature and filtered through celite, washing with EtOAc. The filtrate was evaporated, and the residue was dissolved in DCM (0.500 mL) and trifluoroacetic acid (0.500 mL). The resulting mixture was stirred at room temperature for 2 hours, then it was concentrated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​12 g) with a gradient of 1% to 40% CH3CN in water. Fractions containing the desired compound were pooled and lyophilized to afford [5-(1-amino-4-methylphthalein-6-yl)-2-(difluoromethyl)-4 as a white solid -methoxyphenyl] acid (2.5 mg, 0.007 mmol, 5.8% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.74 (s, 3H), 3.90 (s, 3H), 7.37 (s, 1H), 7.53 (t,J= 56.3 Hz, 1H), 7.88 (s, 1H) , 8.21 - 8.39 (m, 2H), 8.49 (s, 2H), 8.68 (d, J= 8.52 Hz, 1H), 9.06 (br. s, 2H). LC-MS (Method A): r.t. 0.58 min, MS (ESI) m / z = 360.1 [M+H]+.

[0218] Example 36: [3-(1-amino-4-methylphthalein-6-yl)-4-cyano-5-fluorophenyl] acid formate (36) converts [4-cyano Base-3-[1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalein-6-yl]-5-fluorophenyl]acid (45.0 mg, 0.100 mmol) in DCM (0.500 mL) and trifluoroacetic acid (0.500 mL) was stirred at room temperature for 3 h, then it was concentrated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​11 g) eluting with a gradient of 1% to 50% CH3CN in water (+0.1% HCOOH). Fractions containing the desired compound were pooled and lyophilized to give [3-(1-amino-4-methylphthalein-6-yl)-4-cyano-5-fluorophenyl as a white solid ] acid formate (16 mg, 0.043 mmol, yield 45.61%). NMR analysis showed partial formation of a salt of the title compound. 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 2.76 (s, 3H), 7.88 (d,J= 9.6 Hz, 1H), 7.99 (s, 1H), 8.13 (s, 1H, HCOOH), 8.41 (d,J= 8.4 Hz, 1H), 8.53 (s, 1H), 8.81 (d,J= 8.5 Hz, 1H), 9.31 (s, 2H). LC-MS (Method A): r.t. 0.52 min, MS (ESI) m / z = 369.13 [M+H]+.

[0219] Example 37: [5-(1-Amino-4-methylphthalein-6-yl)-4-methoxy-2-(trifluoromethyl)phenyl]acid formate (37 ) Step 1: Palladium(II) diacetate (5.14 mg, 0.020 mmol), 6-[5-chloro-2-methoxy-4-(trifluoromethyl)phenyl]-N-[(2, 4-dimethoxyphenyl)methyl]-4-methylphthalein-1-amine (237.0 mg, 0.460 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2 -yl)phenyl]phenyl]phosphine (17.45 mg, 0.040 mmol), potassium acetate (134.72 mg, 1.37 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5 -Tetramethyl-1,3,2-dioxaboroxane-2-yl)-1,3,2-dioxaboroxane (348.6 mg, 1.37 mmol) was dissolved in 1,4-dioxane (8 mL )middle. The mixture was degassed with Ar for 10 min, then stirred at 90 °C for 18 h. The mixture was filtered through a pad of Celite, washing with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (KP-C18-HS, ​​SNAP 30 g) with gradient elution from 1% to 95% CHCN in water to give [5-(1-{[ (2,4-dimethoxyphenyl)methyl]amino}-4-methylphthalein-6-yl)-4-methoxy-2-(trifluoromethyl)phenyl]acid with N -[(2,4-dimethoxyphenyl)methyl]-6-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-di 15 mg of the mixture of oxaborox-2-yl)-4-(trifluoromethyl)phenyl]-4-methylphthalein-l-amine was used in the next step without further purification.

[0220] Step 2: The mixture obtained in Step 1 was dissolved in DCM (1 mL) and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 h and the volatiles were evaporated to give crude 6-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboronium- 2-yl)-4-(trifluoromethyl)phenyl]-4-methylphthalein-1-amine trifluoroacetate.

[0221] Step 3: The crude material obtained in Step 2 was suspended in 2 M hydrochloric acid solution (1.0 mL, 2 mmol) and Et2O (2 mL), and the mixture was stirred at room temperature for 20 min. Water (20 mL) was added and the layers were separated. The aqueous layer was washed with Et2O (3 x 20 mL) and evaporated. The residue was purified by column chromatography (KP-C18-HS, ​​SNAP 12 g) with gradient elution from 1% to 40% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH) to give Solid [5-(1-amino-4-methylphthalein-6-yl)-4-methoxy-2-(trifluoromethyl)phenyl] acid formate (3.5 mg, 0.008 mmol, yield 1.74%, after three steps). 1H NMR (400 MHz, DMSO-d6+ TFA) δ 2.74 (s, 3H), 3.89 (s, 3H), 7.39 (s, 1H), 7.69 (s, 1H), 8.11 (s, 1H, from HCOOH), 8.25 - 8.36 (m, 2H), 8.69 (d, J= 9.08 Hz, 1H), 9.16 (s, 2H). LC-MS (Method A): r.t. 0.55 min, MS (ESI) m / z = 378.1 [M+H]+.

[0222] Example 38: 3-(1-Amino-4-methylphthalein-6-yl)-5-(trifluoromethyl)phenyl]acid (38) Trifluoroacetic acid (2 mL) was added To [3-[1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalein-6-yl]-5-(trifluoromethyl)phenyl]acid (90.0 mg, 0.180 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 1 h and the volatiles were evaporated. The residue was dissolved in MeOH and the precipitate was filtered through a short pad of celite. The filtrate was evaporated and the obtained solid was triturated with Et2O. The solid residue was purified by column chromatography (KP-C18-HS, ​​SNAP 12 g) with gradient elution from 1% to 50% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH) to give [3-(1-Amino-4-methylphthalein-6-yl)-5-(trifluoromethyl)phenyl] acid (20.5 mg, 0.059 mmol, 32.63% yield) as a white solid. NMR analysis showed partial salt formation (-20%) of the title compound. 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 2.81 (s, 3H), 8.09 (s, 0.2H from HCOOH), 8.21 (s, 1H), 8.30 (s, 1H), 8.50 (d, J= 1.44 Hz, 1H), 8.52 (dd, J= 8.50, 1.81 Hz, 1H), 8.57 (s, 1H), 8.78 (d, J= 8.51 Hz, 1H), 9.17 (s, 2H). LC-MS (Method A): r.t. 0.60 min, MS (ESI) m / z = 348.2 [M+H]+.

[0223] Example 39: [3-(1-Amino-4-methylphthalein-6-yl)-4-(trifluoromethyl)phenyl] acid formate (39) converts [3-[ 1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalein-6-yl]-4-(trifluoromethyl)phenyl]acid (93.0 mg, 0.190 mmol) in DCM (0.500 mL) and trifluoroacetic acid (0.500 mL) was stirred at room temperature for 2 hours, then it was concentrated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​30 g) eluting with a gradient of 1% to 50% CH3CN in water (+0.1% HCOOH). Fractions containing the desired compound were pooled and lyophilized to afford [3-(1-amino-4-methylphthalein-6-yl)-4-(trifluoromethyl)phenyl as a white solid ] acid formate (50 mg, 0.127 mmol, yield 68.01%). 1H NMR (400 MHz, DMSO-d6) δ 2.67 (s, 3H), 7.01 (br. s, 2H), 7.80 - 7.92 (m, 4H), 8.04 (d,J= 7.85 Hz, 1H), 8.15 ( s, 1H, HCOOH), 8.33 (d, J= 8.42 Hz, 1H), 8.51 (br. s, 2H). LC-MS (Method A): r.t. 0.59 min, MS (ESI) m / z = 394.4 [M+H]+.

[0224] Example 40: [3-(1-Amino-4-methylphthalein-6-yl)-5-dimethylphosphorylphenyl] acid formate (40) converts [3-[ 1-[(2,4-Dimethoxyphenyl)methylamino]-4-methylphthalein-6-yl]-5-dimethylphosphorylphenyl]acid (94.0 mg, 0.190 mmol) in DCM (0.500 mL) and trifluoroacetic acid (0.500 mL) was stirred at room temperature for 2 hours, then it was concentrated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​30 g) eluting with a gradient of 1% to 50% CH3CN in water (+0.1% HCOOH). Fractions containing the desired compound were pooled and lyophilized to give [3-(1-amino-4-methylphthalein-6-yl)-5-dimethylphosphorylphenyl as a white solid ] Acid formate (37 mg, 0.092 mmol, 49.58% yield). 1H NMR (400 MHz, DMSO-d6+ TFA) δ 1.81 (s, 3H), 1.84 (s, 3H), 2.81 (s, 3H), 8.11 (s, 1H, HCOOH), 8.27 - 8.35 (m, 2H) , 8.43 - 8.55 (m, 3H), 8.78 (d, J= 8.60 Hz, 1H), 9.18 (s, 2H). LC-MS (Method A): r.t. 0.38 min, MS (ESI) m / z = 402.4 [M+H]+.

[0225] Example 41: [5-(1-amino-4-methylphthalein-6-yl)-4-cyano-2-methylphenyl] acid (41) step 1: trifluoroacetic acid (2 mL) was added to 2-[1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalein-6-yl]-5-methyl-4-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)benzonitrile (123.42 mg, 0.220 mmol) in DCM (2 mL) and the mixture Stir at room temperature for 1 h. The volatiles were evaporated and the residue was dissolved in MeOH (15 mL). The solution was filtered through a short pad of celite and the volatiles were evaporated. The solid residue was triturated with Et2O (3 x 5 mL) and dried under vacuum.

[0226] Step 2: The material obtained in Step 1 was suspended in Et20 (2 mL) and 2 M hydrochloric acid solution (2.0 mL, 0.300 mmol) and the mixture was stirred at room temperature for 30 min. The mixture was diluted with water (10 mL) and washed with Et20 (3 x 10 mL). The aqueous layer was evaporated and the residue was purified by column chromatography (KP-C18-HS, ​​SNAP 30 g) with gradient elution from 1% to 30% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH) things. Fractions containing the desired compound were evaporated to give a white solid, which was triturated with MeOH (3 x 0.5 mL) and dried under vacuum to give [5-(1-amino-4) as a white solid -Methylphthalein(6-yl)-4-cyano-2-methylphenyl]acid (4.5 mg, 0.014 mmol, 6.4% yield over two steps). 1H NMR (400 MHz, DMSO-d6+ 2 drops of TFA) δ 2.52 (s, 3 H peak partially overlapping with DMSO-d6 signal), 2.69 - 2.84 (m, 3H), 7.73 - 7.81 (m, 1H), 7.86 (s, 1H), 8.31 - 8.38 (m, 1H), 8.41 (br. s, 1H), 8.78 (d, J= 8.51 Hz, 1H), 9.21 (br. s, 2H). LC-MS (Method A): r.t.: 0.51 min, MS (ESI) m / z = 319.5 [M+H]+.

[0227] Example 42: [3-(1-Amino-4-methylphthalein-6-yl)-4-methoxy-5-methylphenyl] acid formate (42) converts 6- [2-Methoxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]-4-methyl Phthalo-1-amine trifluoroacetate (94.0 mg, 0.230 mmol) was suspended in Et2O (5 mL) and 2 M hydrochloric acid solution (3.0 mL, 6 mmol) was added. To aid dissolution, DCM (50 μL) was added. The mixture was vigorously stirred for 2 hours then evaporated. The residue was purified by column chromatography (KP-C18-HS, ​​30 g) eluting with a gradient of 2% to 95% CH3CN in water (+0.1% HCOOH). Fractions containing the desired compound were collected and lyophilized to give [3-(1-amino-4-methylphthalein-6-yl)-4-methoxy-5-methyl as a white powder Phenyl] acid formate (50.42 mg, 0.137 mmol, 58.89% yield). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 2.33 (s, 3H), 2.75 (s, 3H), 3.38 (s, 3H), 7.78 (dd, J = 16.2, 1.7 Hz, 2H), 8.12 (s, 0.58H from HCOOH), 8.30 (dd, J = 8.5, 1.7 Hz, 1H), 8.34 (d, J = 1.6 Hz, 1H), 8.72 (d, J = 8.6 Hz, 1H), 9.14 ( br. s, 2H). LC-MS (Method A): r.t. 0.52 min, MS (ESI) m / z = 324.3 [M+H]+.

[0228] Example 43: [5-(1-Amino-4-methylphthalein-6-yl)-2-cyclopropyl-4-methoxyphenyl]acid (43) palladium diacetate ( II) (3.21 mg, 0.010 mmol), 6-(5-chloro-4-cyclopropyl-2-methoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl] -4-Methylphthalein-1-amine (140.0 mg, 0.290 mmol), dicyclohexyl-[2-[2,4,6-tri(prop-2-yl)phenyl]phenyl]phosphine (13.62 mg, 0.030 mmol), potassium acetate (84.12 mg, 0.860 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-di Boroxane-2-yl)-1,3,2-dioxaboroxane (217.67 mg, 0.860 mmol) was dissolved in 1,4-dioxane (2.857 mL) in a microwave vial. The resulting mixture was degassed with N2 for 10 min and stirred at 75 °C for 2 h. Then, it was cooled to room temperature and filtered through celite, washing with EtOAc. The filtrate was evaporated, and the residue was dissolved in DCM (0.500 mL) and trifluoroacetic acid (0.500 mL). The resulting mixture was stirred at room temperature for 2 hours, then it was concentrated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​12 g) eluting with a gradient of 1% to 50% CH3CN in water (+0.1% HCOOH). Fractions containing the desired compound were pooled and lyophilized to give [5-(1-amino-4-methylphthalein-6-yl)-2-cyclopropyl-4-methoxy as a white solid phenyl] acid (1.6 mg, 0.005 mmol, 9.869% yield). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 0.71 - 0.80 (m, 2H), 0.90 - 0.99 (m, 2H), 1.70 (s, 1H), 2.69 (s, 3H), 3.78 (s, 3H), 6.50 (s, 1H), 6.70 (m, 2H), 7.52 (s, 1H), 7.94 (dd,J= 8.48, 1.70 Hz, 1H), 7.97 (d,J= 1.74 Hz, 1H), 8.21 (d, J= 8.52 Hz, 1H), 8.28 (br. s, 2H). LC-MS (Method A): r.t. 0.58 min, MS (ESI) m / z = 350.3 [M+H]+.

[0229] Example 44: [5-(1-Amino-4-methylphthalein-6-yl)-4-methoxy-2-(trifluoromethoxy)phenyl]acid (44) 6-[2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-4-(trifluoromethoxy)benzene ]-4-Methylphthalein-1-amine trifluoroacetate (180.0 mg, 0.180 mmol) was suspended in Et2O (10.64 mL) and 2 M hydrochloric acid solution (2.35 mL, 4.7 mmol) was added. To aid dissolution, DCM (0.05 mL) was added and the viscous mixture became more homogeneous. The mixture was stirred vigorously for 5 h, then evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​12 g) eluting with a gradient of 2% to 80% CH3CN in water. Fractions containing the desired compound were collected and lyophilized to give [5-(1-amino-4-methylphthalein-6-yl)-4-methoxy-2-(tri Fluoromethoxy)phenyl] acid (2.13 mg, 0.005 mmol, 2.98% yield). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 2.74 (s, 3H), 3.87 (s, 3H), 7.10 (s, 1H), 7.78 (s, 1H), 8.28 (dd, J = 8.5, 1.6 Hz, 1H), 8.31 (d, J = 1.6 Hz, 1H), 8.69 (d, J = 8.5 Hz, 1H), 9.14 (br. s, 2H). LC-MS (Method A): r.t. 0.60 min, MS (ESI) m / z = 394.3 [M+H]+.

[0230] Example 45: [5-(1-amino-4-methylphthalein-6-yl)-2-methoxy-3-methylphenyl]acid (45) trifluoroacetic acid (2 mL) was added to [5-[1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalein-6-yl]-2-methoxy-3-methanol phenyl] acid (41.0 mg, 0.090 mmol) in DCM (2 mL), and the mixture was stirred at room temperature for 1 h. The volatiles were evaporated and the residue was dissolved in MeOH. The solution was filtered through a short pad of celite and the filtrate was evaporated. The residue was purified by column chromatography (KP-C18-HS, ​​SNAP 30 g) with gradient elution from 1% to 40% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH). The obtained partially purified product was subjected to semi-preparative HPLC purification (column: Chiralcel OJ-H (25 × 2.0 cm), 5 µm. Mobile phase: 80 / 20% v / v n-hexane / (ethanol + 0.1 % isopropylamine). Flow rate: 17 ml / min), [5-(1-amino-4-methylphthalein-6-yl)-2-methoxy-3-methanol was obtained as white solid phenyl] acid (4.5 mg, 0.014 mmol, 16.08% yield). 1H NMR (400 MHz, methanol-d4) δ 2.37 (s, 3H), 2.82 (s, 3H), 3.84 (s, 3H), 7.62 (br. s, 1H), 7.71 (d,J= 2.45 Hz, 1H), 8.30 - 8.37 (m, 2H), 8.52 - 8.58 (m, 1H). LC-MS (Method A): r.t. 0.54 min, MS (ESI) m / z = 324.23 [M+H]+.

[0231] Example 46: 7-(1-hydroxyl-6-methoxy-3,4-dihydro-2,1-benzoxaborin-7-yl)phenoline-4- Amine trifluoroacetate (46) Step 1: Palladium(II) diacetate (3.36 mg, 0.010 mmol), 7-[5-chloro-2-methoxy-4-[2-(oxane-2 -yloxy)ethyl]phenyl]-N-[(2,4-dimethoxyphenyl)methyl]phenolin-4-amine (169.0 mg, 0.300 mmol), dicyclohexyl-[2 - [2,4,6-tris(prop-2-yl)phenyl]phenyl]phosphine (11.43 mg, 0.020 mmol), potassium acetate (88.21 mg, 0.900 mmol) and 4,4,5,5-tetra Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolidine (228.25 mg, 0.900 mmol ) was dissolved in 1,4-dioxane (4 mL). The mixture was degassed with Ar for 10 min, then stirred at 90 °C for 5 h. The mixture was filtered through a pad of Celite, washed with EtOAc and the filtrate was concentrated in vacuo.

[0232] Step 2: The crude product obtained in Step 1 was suspended in DCM (4 mL) and trifluoroacetic acid (4 mL) was added. The mixture was stirred at room temperature for 4 h and the volatiles were evaporated. The residue was purified by column chromatography (KP-C18-HS, ​​SNAP 30 g) with gradient elution from 1% to 15% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH). The obtained partially purified product was subjected to semi-preparative HPLC purification (column: Chiralcel OD-H (25 × 2.0 cm), 5 µm. Mobile phase: 80 / 20% v / v n-hexane / (ethanol + 0.1 % isopropylamine). Flow rate: 17 ml / min). Fractions containing the desired compound were collected and evaporated. The residue was dissolved in MeOH (+ 5% TFA) (5 mL) and water (5 mL) was added. Evaporation of the mixture afforded 7-(1-hydroxy-6-methoxy-3,4-dihydro-2,1-benzoxaborin-7-yl)phenidate as a light yellow solid Phenyl-4-amine trifluoroacetate (5.7 mg, 0.013 mmol, 4.3% yield over two steps). 1H NMR (400 MHz, methanol-d4+ 2 drops TFA) δ 3.01 (t,J= 5.99 Hz, 2H), 3.90 (s, 3H), 4.25 (t,J= 5.99 Hz, 2H), 7.02 (s, 1H ), 7.73 (s, 1H), 7.96 (dd,J= 8.86, 1.61 Hz, 1H), 8.00 (dd,J= 1.61, 0.65 Hz, 1H), 8.31 (d,J= 8.86 Hz, 1H), 8.43 (s, 1H). LC-MS (Method A): r.t. 0.51 min, MS (ESI) m / z = 322.2 [M+H]+.

[0233] Example 47: [3-(1-Amino-4-methylphthalein-6-yl)-5-dimethylphosphoryl-2-fluorophenyl] acid formate (47) 6-(3-Chloro-5-dimethylphosphoryl-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl)methyl]-4-methylphthalein-1 -amine (75.0 mg, 0.150 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2- base)-1,3,2-dioxaboroxane (111.18 mg, 0.440 mmol) and potassium acetate (42.97 mg, 0.440 mmol) were dissolved in 1,4-dioxane (1.558 mL). The resulting solution was degassed with N2 for 10 minutes, followed by the addition of palladium(II) diacetate (1.64 mg, 0.010 mmol) and dicyclohexyl-[2-[2,4,6-tris(propan-2-yl)phenyl ]phenyl]phosphine (6.96 mg, 0.010 mmol). The resulting reaction mixture was stirred at 75 °C for 2 h, then it was cooled to room temperature and filtered through celite, washing with EtOAc. The filtrate was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.8 mL). The resulting mixture was stirred at room temperature for 2 hours, then it was concentrated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS 30 g) with gradient elution from 1% to 50% CH3CN in water (+0.1% HCOOH). Fractions containing the desired compound were collected and evaporated under reduced pressure to give [3-(1-amino-4-methylphthalein-6-yl)-5-dimethylphosphonium as a white solid phenyl-2-fluorophenyl] acid formate (8.5 mg, 0.020 mmol, yield 13.9%). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 1.74 (s, 3H), 1.78 (s, 3H), 2.77 (s, 3H), 8.08 (m, 2H), 8.13 (s, 1H, HCOOH) , 8.30 - 8.43 (m, 2H), 8.78 (d, J= 8.5 Hz, 1H), 9.23 (br. s, 2H). LC-MS (Method A): r.t. 0.36 min, MS (ESI) m / z = 374.2 [M+H]+.

[0234] Example 48: [3-(4-Aminothioline-7-yl)-2-fluoro-4-methoxyphenyl]acid (48) Step 1: Palladium(II) diacetate (4.48 mg, 0.020 mmol), 7-(3-chloro-2-fluoro-6-methoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]phenolin-4-amine (181.0 mg, 0.400 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (15.21 mg, 0.030 mmol), potassium acetate (117.41 mg , 1.2 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1, 3,2-Dioxane (303.79 mg, 1.2 mmol) was dissolved in 1,4-dioxane (10 mL). The mixture was degassed with Ar for 10 min, then stirred at 50 °C for 9 h. The mixture was filtered through a pad of celite, washed with EtOAc and concentrated in vacuo.

[0235] Step 2: The crude material from Step 1 was dissolved in a mixture of DCM (2 mL) and trifluoroacetic acid (4 mL). The mixture was stirred at room temperature for 3 h and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge (5 g). The cartridge was washed with 4CV MeOH, 2CV MeOH / H2O (8:2), and 1CV MeOH. The product was eluted from an SCX cartridge with 3 CV of a 2 M solution of NH3 in MeOH. Volatiles were evaporated and the residue was purified by column chromatography (KP-C18-HS, ​​SNAP 30 g) with gradient elution from 1% to 15% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH) to obtain [3-(4-aminophenolin-7-yl)-2-fluoro-4-methoxyphenyl]acid (46 mg, 0.147 mmol, 56.75% yield, through two steps). NMR analysis showed partial salt formation (-51%) of the title compound. 1H NMR (400 MHz, DMSO-d6+ TFA) δ 3.79 (s, 3H), 7.03 (d,J= 8.53 Hz, 1H), 7.68 - 7.75 (m, 1H), 7.78 (d,J= 8.78 Hz, 1H ), 7.85 (s, 1H), 8.10 (s, 0.5H, from HCOOH) 8.45 - 8.51 (m, 2H), 9.74 (s, 1H), 9.87 (s, 1H). LC-MS (Method A): r.t. 0.41 min, MS (ESI) m / z = 314.7 [M+H]+.

[0236] Example 49: [3-(1-Amino-4-methylphthalein-6-yl)-4-methoxy-5-(trifluoromethyl)phenyl]acid (49) converts [ 3-[1-[(2,4-Dimethoxyphenyl)methylamino]-4-methylphthalein-6-yl]-4-methoxy-5-(trifluoromethyl) A solution of phenyl]acid (135.0 mg, 0.260 mmol) in DCM (3 mL) and trifluoroacetic acid (3 mL) was stirred at room temperature for 2 hours before it was concentrated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​30 g) eluting with a gradient of 2% to 95% CH3CN in water (+0.1% HCOOH). Fractions containing the desired compound were collected and evaporated under reduced pressure to give [3-(1-amino-4-methylphthalein-6-yl)-4-methoxy-5 as a white powder -(trifluoromethyl)phenyl] acid (40 mg, 0.106 mmol, 41.43% yield). 1H NMR (400 MHz, methanol-d4) δ 2.82 (s, 3H), 3.41 (s, 3H), 7.98 (br. s, 2H), 8.30 - 8.36 (m, 1H), 8.43 (d, J = 1.7 Hz, 1H), 8.53 (dd,J= 8.5, 0.6 Hz, 1H). LC-MS (Method A): r.t. 0.61 min, MS (ESI) m / z = 378.2 [M+H]+.

[0237] Example 50: [5-(1-Amino-4-methylphthalein-6-yl)-2-chloro-4-methoxyphenyl] acid (50) Step 1: 6-( 5-Bromo-4-chloro-2-methoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]-4-methylphthalein-1-amine (139.0 mg, 0.260 mmol), potassium acetate (77.39 mg, 0.790 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9.64 mg, 0.010 mmol) and 4,4,5 ,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborol (200.24 mg, 0.790 mmol) was dissolved in 1,4-dioxane (3.475 mL). The mixture was degassed with Ar for 10 min, then stirred at 100 °C for 40 h. The mixture was cooled to room temperature, diluted with EtOAc and filtered through a short pad of celite. The volatiles were evaporated to give a black oil which was used in the next step without further purification.

[0238] Step 2: The crude material from Step 1 was combined with similar crude material by the same procedure described in Step 1 but with 41 mg 6-(5-bromo-4-chloro-2 -Methoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]-4-methylphthalein-1-amine as starting material. The combined crude materials were dissolved in a mixture of DCM (4 mL) and trifluoroacetic acid (4 mL). The mixture was stirred at room temperature for 3 h and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge (5 g). The cartridge was washed with 4CV MeOH, 2CV MeOH / H2O (8:2), and 1CV MeOH. The product was eluted from an SCX cartridge with 3 CV of a 2 M solution of NH3 in MeOH. The volatiles were evaporated and the residue was purified by column chromatography (KP-C18-HS, ​​SNAP 30 g) with gradient elution from 1% to 25% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH) [5-(1-Amino-4-methylphthalein-6-yl)-2-chloro-4-methoxyphenyl]acid (38 mg, 0.111 mmol, yield rate of 32%, after two steps). 1H NMR (400 MHz, DMSO-d6+ TFA) δ 2.71 (s, 3H), 3.83 (s, 3H), 7.17 (s, 1H), 7.63 (s, 1H), 8.20 - 8.26 (m, 2H), 8.66 (d, J= 8.44 Hz, 1H), 9.10 (br. s, 2H). LC-MS (Method A): r.t. 0.53 min, MS (ESI) m / z = 344.2 [M+H]+.

[0239] Example 51: [3-(4-Aminophenoline-7-yl)-4-(Olkane-4-yloxy)phenyl] acid formate (51) Step 1: diacetic acid Palladium(II) (3.08 mg, 0.010 mmol), 7-[5-chloro-2-(oxalk-4-yloxy)phenyl]-N-[(2,4-dimethoxyphenyl) Methyl]phenolin-4-amine (134.0 mg, 0.270 mmol), dicyclohexyl-[2-[2,4,6-tri(prop-2-yl)phenyl]phenyl]phosphine (10.48 mg, 0.020 mmol), potassium acetate (80.88 mg, 0.820 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboron (209.28 mg, 0.820 mmol) was dissolved in 1,4-dioxane (3.29 mL). The mixture was degassed with Ar for 10 min, then stirred at 85 °C for 4 h. The mixture was filtered through a pad of Celite, washed with EtOAc and the filtrate was concentrated in vacuo.

[0240] Step 2: The crude material from Step 1 was dissolved in a mixture of DCM (2 mL) and trifluoroacetic acid (4 mL). The mixture was stirred at room temperature for 3 h and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge (5 g). The cartridge was washed with 4CV MeOH, 2CV MeOH / H2O (8:2), and 1CV MeOH. The product was eluted from an SCX cartridge with 3 CV of 2 M NH3 in MeOH. The volatiles were evaporated and the residue was purified by column chromatography (KP-C18-HS, ​​SNAP 30 g) with gradient elution from 1% to 20% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH) to obtain [3-(4-aminophenolin-7-yl)-4-(azan-4-yloxy)phenyl]acid formate (38 mg, 0.092 mmol, Yield 34% over two steps). 1H NMR (400 MHz, DMSO-d6+2D TFA) δ 1.51 - 1.66 (m, 2H), 1.92 - 2.03 (m, 2H), 3.42 - 3.54 (m, 2H), 3.67 - 3.77 (m, 2H) , 4.71 - 4.79 (m, 1H), 7.24 (d,J= 8.44 Hz, 1H), 7.88 (dd,J= 8.40, 1.51 Hz, 1H), 7.96 (d,J= 1.51 Hz, 1H), 7.99 ( dd,J= 8.87, 1.34 Hz, 1H), 8.08 (d,J= 1.20 Hz, 1H), 8.10 (s, 1H, from HCOOH), 8.44 - 8.52 (m, 2H), 9.67 (s, 1H), 9.80 (s, 1H). LC-MS (Method A): r.t. 0.46 min, MS (ESI) m / z = 366.2 [M+H]+.

[0241] Example 52: [3-(1-amino-4-methylphthalein-6-yl)-5-pyridin-3-ylphenyl] acid formate (52) converts [3-[1 -[(2,4-Dimethoxyphenyl)methylamino]-4-methylphthalein-6-yl]-5-pyridin-3-ylphenyl]acid (55.0 mg, 0.110 mmol) A solution in DCM (1 mL) and trifluoroacetic acid (1 mL) was stirred at room temperature for 2 h before it was concentrated under reduced pressure. The resulting crude was purified by column chromatography (KP-C18-HS, ​​30 g) with a gradient elution from 2% to 95% CH3CN in water (+0.1% HCOOH). Fractions containing the desired compound were collected and evaporated under reduced pressure to give [3-(1-amino-4-methylphthalein-6-yl)-5-pyridin-3-yl as a yellow powder Phenyl] acid formate (6 mg, 0.015 mmol, 13.73% yield). 1H NMR (400 MHz, methanol-d4) δ 2.87 (s, 3H), 7.55 - 7.63 (m, 1H), 8.00 - 8.16 (m, 3H), 8.25 (dt,J= 8.0, 2.0 Hz, 1H), 8.39 - 8.54 (m, 5H), 8.58 (dd, J= 4.9, 1.6 Hz, 1H), 8.95 (d, J= 2.3, 0.9 Hz, 1H). LC-MS (Method A): r.t. 0.39 min, MS (ESI) m / z = 357.3 [M+H]+.

[0242] Example 53: 7-[2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]phenoline -4-Amino trifluoroacetate (53) [3-(4-aminophenolin-7-yl)-4-methoxyphenyl] acid (100.0 mg, 0.240 mmol) and 2,3- A solution of dimethylbutane-2,3-diol (31.27 mg, 0.260 mmol) in dichloromethane (2 mL) and trifluoroacetic acid (0.500 mL) was stirred at room temperature for 2 hours, then it was stirred under reduced pressure Concentration under reduced pressure afforded an orange oil. This material was triturated with diethyl ether. The solvent was decanted and the resulting solid was dissolved with dichloromethane. The volatiles were removed in vacuo to give 7-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2 as a yellow solid -yl)phenyl]phenolin-4-amine trifluoroacetate (111 mg, 0.226 mmol, 93.91% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.31 (s, 12H), 3.88 (s, 3H), 7.27 (d,J= 8.42 Hz, 1H), 7.72 (d,J= 1.65 Hz, 1H), 7.81 (dd,J= 8.27, 1.67 Hz, 1H), 7.94 - 7.99 (m, 2H), 8.45 (d,J= 8.73 Hz, 1H), 8.49 (s, 1H), 9.64 (s, 2H). LC-MS (Method A): r.t. 0.73 min, MS (ESI) m / z = 378.13 [M+H]+.

[0243] Example 54: 7-{2-methoxy-5-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora Tricyclo[6.1.1.02,6]dec-4-yl]phenyl}phenoline-4-amine (54)[3-(4-aminophenoline-7-yl)-4-methoxybenzene base] acid (100.0 mg, 0.340 mmol) and (1S,3R,4S,5S)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol (57.69 mg, 0.340 mmol) in THF (4 mL) was stirred at room temperature for three hours (after 1 hour, the suspension became a clear solution), then the mixture was concentrated in vacuo. The residue was triturated with diethyl ether, the solvent was decanted, and the solid residue was collected and dried to give 7-{2-methoxy-5-[(1S,2S,6R,8S)-2, as an off-white solid. 9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl]phenyl}phenolin-4-amine (97 mg, 0.226 mmol , yield 66.67%). 1H NMR (400 MHz, methanol-d4) δ 0.94 (s, 3H), 1.24 (d,J= 10.88 Hz, 1H), 1.35 (s, 3H), 1.51 (s, 3H), 1.93 - 2.02 (m, 2H), 2.15 (t,J= 5.43 Hz, 1H), 2.26 - 2.34 (m, 1H), 2.48 (dd,J= 13.17, 9.68 Hz, 1H), 3.91 (s, 3H), 4.52 (dd,J = 8.79, 1.79 Hz, 1H), 7.19 (d,J= 8.20 Hz, 1H), 7.80 (dd,J= 8.79, 1.71 Hz, 1H), 7.82 - 7.88 (m, 2H), 8.14 (d,J= 8.76 Hz, 1H), 8.18 (d,J= 1.68 Hz, 1H), 8.60 (s, 1H). LC-MS (Method A): r.t. 0.90 min, MS (ESI) m / z = 430.18 [M+H]+.

[0244] Example 55: 3-(1-Amino-8-fluoro-4-methylphthalein-6-yl)-4-methoxyphenyl]acid (55) palladium(II) diacetate ( 3.12 mg, 0.010 mmol), 6-(5-chloro-2-methoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]-8-fluoro-4-methyl Phthalo-1-amine (144.44 mg, 0.280 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (13.24 mg, 0.030 mmol) , potassium acetate (81.8 mg, 0.830 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2 -yl)-1,3,2-dioxaboroxane (211.65 mg, 0.830 mmol) was dissolved in 1,4-dioxane (2.653 mL) in a microwave vial. The resulting reaction mixture was stirred at 75 °C for 2 h, then it was cooled to room temperature and filtered through celite, washing with EtOAc. The filtrate was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for 2 hours, then it was concentrated under reduced pressure. The residue was dissolved with MeOH and this solution was loaded onto an SCX cartridge (5 g), the cartridge was washed with MeOH / H2O (9:1) and then eluted with 7 M ammonia in MeOH. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by flash chromatography (KP-C18-HS 30 g) eluting with a gradient of 1% to 70% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and then lyophilized to give [3-(1-amino-8-fluoro-4-methylphthalein-6-yl)-4-methoxyphenyl] as a white solid Acid (25 mg, 0.076 mmol, 27.1% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.72 (s, 3H), 3.85 (s, 3H), 6.59 (s, 2H), 7.18 (d,J= 8.34 Hz, 1H), 7.82 (dd,J= 13.51, 1.50 Hz, 1H), 7.83 - 7.91 (m, 2H), 7.93 (d, J= 1.73 Hz, 1H), 8.04 (s, 2H). LC-MS (Method B): r.t. 0.64 min, MS (ESI) m / z = 328.1 [M+H]+.

[0245] Example 56: 7-(1-amino-4-methylphthalein-6-yl)-1-hydroxyl-4H-2,1-benzoxaborin-3-one Trifluoroacetate (56) 1 M aqueous LiOH (1.34 mL, 1.34 mmol) was added to 2-[4-(1-amino-4-methylphthalein-6-yl)-2-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]ethyl acetate (150.0 mg, 0.340 mmol) in methanol (2 mL), and The mixture was stirred at room temperature for 3 h. The mixture was quenched with 1 M hydrochloric acid solution until the pH reached 6-7, and the volatiles were evaporated. The residue was purified by column chromatography (KP-C18-HS, ​​SNAP 30 g) with gradient elution from 1% to 30% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH). Fractions containing the desired compound were evaporated to give a solid which was triturated with MeOH (4 x 0.5 mL), dried under vacuum, dissolved in water (+ 10% TFA) and dried under vacuum to give 7-(1-Amino-4-methylphthalein-6-yl)-1-hydroxy-4H-2,1-benzoxaborin-3-one trifluoro as white solid Acetate (15.8 mg, 0.036 mmol, 10.88% yield). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA + 2 drops D2O) δ 2.76 (s, 3H), 3.85 (s, 2H), 7.34 (d,J= 8.00 Hz, 1H), 7.84 (dd,J= 8.00, 2.18 Hz, 1H), 8.07 (d,J= 2.18 Hz, 1H), 8.37 (d,J= 1.24 Hz, 1H), 8.40 (dd,J= 8.63, 1.64 Hz, 1H), 8.66 (d, J= 8.56 Hz, 1H). LC-MS (Method A): r.t. 0.46 min, MS (ESI) m / z = 320.1 [M+H]+.

[0246] Example 57: [3-(1-Amino-4-methylphthalein-6-yl)-5-fluoro-4-methoxyphenyl] acid trifluoroacetate (57) [ 3-[1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalein-6-yl]-5-fluoro-4-methoxyphenyl]acid ( 9 mg, 0.019 mmol) in DCM (0.50 mL) and trifluoroacetic acid (0.25 mL) was stirred at room temperature for 2 h, then the volatiles were removed. MeOH (1 mL) was added and the mixture was filtered through a pad of Celite, washing with MeOH. Removal of volatiles afforded [3-[1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalein-6-yl]-5- as a white solid Fluoro-4-methoxyphenyl] acid trifluoroacetate (9.0 mg, 0.020 mmol). 1H NMR (400 MHz, DMSO-d6) δ 2.76 (s, 3 H), 3.81 - 3.84 (m, 3 H), 7.72 (dd,J= 12.43, 1.43 Hz, 1H), 7.78 (s, 1 H) , 8.20 (d,J= 8.36 Hz, 1H), 8.25 (s, 1 H), 8.30 (s, 2 H), 8.63 (d,J= 8.58 Hz, 1H), 14.23 (br.s, 1 H) . LC-MS (Method A): r.t. 0.53 min, MS (ESI) m / z = 328.12 [M+H]+.

[0247] Example 58: [3-(4-Aminothioline-7-yl)-4-methoxy-5-(Olkane-4-yl)phenyl]acid (58) palladium diacetate ( II) (1.62 mg, 0.010 mmol), 7-[5-chloro-2-methoxy-3-(oxalk-4-yl)phenyl]-N-[(2,4-dimethoxybenzene Base) methyl] phenolin-4-amine (75.0 mg, 0.140 mmol), dicyclohexyl-[2-[2,4,6-tri(prop-2-yl)phenyl]phenyl]phosphine (6.88 mg, 0.010 mmol), potassium acetate (42.46 mg, 0.430 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-di Boroxane-2-yl)-1,3,2-dioxaboroxane (109.87 mg, 0.430 mmol) was dissolved in 1,4-dioxane (1.531 mL) in a microwave vial. The resulting reaction mixture was stirred at 80 °C for 2 h, then it was cooled to room temperature and filtered through celite, washing with EtOAc. The filtrate was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for 2 hours, then it was concentrated under reduced pressure. The residue was dissolved with MeOH and this solution was loaded onto an SCX cartridge (5 g), the cartridge was washed with MeOH / H2O (9:1) and then eluted with 7 M ammonia in MeOH. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​30 g) with gradient elution from 1% to 70% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and then lyophilized to give [3-(4-aminophenolin-7-yl)-4-methoxy-5-(oxalan-4-yl)benzene as a white solid base] acid (19 mg, 0.050 mmol, yield 34.74%). 1H NMR (400 MHz, methanol-d4) δ 1.75 - 1.84 (m, 2H), 1.83 - 1.99 (m, 3H), 3.45 (s, 3H), 3.60 - 3.69 (m, 2H), 4.07 - 4.14 (m , 2H), 7.60 - 7.75 (m, 2H), 8.06 (dd,J= 8.86, 1.59 Hz, 1H), 8.08 - 8.11 (m, 2H), 8.41 (d,J= 8.80 Hz, 1H), 8.49 ( s, 1H). LC-MS (Method B): r.t. 0.61 min, MS (ESI) m / z = 380.1 [M+H]+.

[0248] Example 59: [3-(1-Amino-4-methylphthalein-6-yl)-4-(3-methylbutyrylamino)phenyl] acid formate (59) with N -[2-[1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalein-6-yl]-4-(4,4,5,5-tetra Methyl-1,3,2-dioxaborol-2-yl)phenyl]-3-methylbutanamide (47.0 mg, 0.080 mmol) in DCM (0.600 mL) and trifluoroacetic acid (0.600 mL) The mixture was stirred at room temperature for 1 h, then the volatiles were removed. The residue was dissolved in MeOH and loaded onto an SCX cartridge (2 g), the cartridge was washed slowly with MeOH / water (9:1 ) and then with MeOH, and then eluted with 2 M ammonia in MeOH . The volatiles were removed and the residue was purified by column chromatography (KP-C18-HS, ​​SNAP 18) with a gradient elution from 2% to 30% MeCN in water to afford [3-( 1-Amino-4-methylphthalein-6-yl)-4-(3-methylbutyrylamino)phenyl] acid formate (10.2 mg, 0.024 mmol, 31.23% yield). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 0.75 (d,J= 6.60 Hz, 6H), 1.86 - 1.91 (1 H, m), 2.00 (d,J= 7.04 Hz, 2H), 2.73 ( s, 3 H), 7.50 (d,J= 7.92 Hz, 1H), 7.85 - 7.90 (m, 2 H), 8.10 - 8.13 (m, 1 H), 8.10 - 8.16 (m, 2 H), 8.19 ( d,J= 1.54 Hz, 1H), 8.70 (d,J= 8.58 Hz, 1H), 9.52 (s, 1H). LC-MS (Method A): r.t. 0.46 min, MS (ESI) m / z = 379.18 [M+H]+.

[0249] Example 60: 7-[5-(1,3,6,2-dioxadioxazaborolin-2-yl)-2-methoxyphenyl]phenoline-4-amine ( 60) Add 2-(2-hydroxyethylamino)ethanol (16.24 µL, 0.170 mmol) to [3-(4-aminophenolin-7-yl)-4-methoxyphenyl]acid ( 50.0 mg, 0.170 mmol) in suspension in THF (1 mL). The resulting mixture was stirred at 40 °C for three hours, then it was evaporated in vacuo. The residue was triturated with acetonitrile and the resulting solid was filtered, washed with acetonitrile and dried to give 7-[5-(1,3,6,2-dioxadioxazaborin-2) as a white solid -yl)-2-methoxyphenyl]phenolin-4-amine (37 mg, 0.102 mmol, 59.96% yield). 1H NMR (400 MHz, methanol-d4) δ 3.15 - 3.20 (m, 4H), 3.80 - 3.86 (m, 4H), 3.92 (s, 3H), 7.21 (d,J= 8.37 Hz, 1H), 7.77 ( s, 1H), 7.81 (d,J= 8.42 Hz, 1H), 7.95 (dd,J= 8.85, 1.66 Hz, 1H), 8.08 (d,J= 1.59 Hz, 1H), 8.28 (d,J= 8.83 Hz, 1H), 8.51 (s, 1H).

[0250] Example 61: [3-(1-Amino-4-methylphthalein-6-yl)-4-(4-methylpentylamino)phenyl] acid formate (61) N-[2-[1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalein-6-yl]-4-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]-4-methylpentanamide (42.0 mg, 0.070 mmol) in DCM (0.80 mL) and trifluoroacetic acid (0.50 mL) was stirred at room temperature for 1.5 h, after which time the volatiles were removed. The residue was dissolved in MeOH and loaded onto an SCX cartridge (2 g), the cartridge was washed with MeOH / water (9:1 ) and then MeOH, and then eluted with 2 M ammonia in MeOH. The volatiles were removed and the residue was purified by column chromatography (Sfär C18) with a gradient elution from 2% to 30% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH) to give a white solid [3-(1-amino-4-methylphthalein-6-yl)-4-(4-methylpentylamino)phenyl] acid formate (10 mg, 0.023 mmol, Yield 33.93%). 1H NMR (400 MHz, DMSO-d6) δ 0.71 - 0.76 (m, 6H), 1.28 (br. s, 3 H), 2.09 - 2.14 (m, 2H), 2.69 (s, 3 H), 6.77 (br . s, 2H), 7.50 (d,J= 7.92 Hz, 1H), 7.79 - 7.83 (m, 2H), 7.86 (s, 1H), 7.90 (d,J= 1.32 Hz, 1H), 8.22 (br . s, 3 H), 8.28 (d,J= 8.58 Hz, 1H), 9.36 (s, 1 H). LC-MS (Method A): r.t. 0.52 min, MS (ESI) m / z = 393.2 [M+H]+.

[0251] Example 62: [3-(1-amino-4-methylphthalein-6-yl)-4-dimethylphosphorylphenyl] acid formate (62) palladium diacetate ( II) (4.28 mg, 0.020 mmol), 6-(5-chloro-2-dimethylphosphorylphenyl)-N-[(2,4-dimethoxyphenyl)methyl]-4- Methylphthalein-1-amine (210.0 mg, 0.380 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (14.53 mg, 0.030 mmol), potassium acetate (112.2 mg, 1.14 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)-1,3,2-dioxaboroxane (290.33 mg, 1.14 mmol) was dissolved in 1,4-dioxane (4 mL) in a microwave vial, and the mixture was deoxygenated under N2 for 10 minute. Subsequently, the mixture was stirred at 75°C for 1.5 hours. The mixture was filtered through a pad of celite, washed with methanol and the filtrate was concentrated in vacuo. The residue was dissolved in DCM (3 mL) and trifluoroacetic acid (3 mL) and stirred at room temperature for 2 hours. Then, the mixture was evaporated in vacuo, and the residue was dissolved in MeOH / H20 (9:1), loaded onto an SCX cartridge and kept on the SCX cartridge for 20 min for absorption. Subsequently, the cartridge was washed with MeOH / H2O (9:1) and eluted with 2 M methanolic ammonia solution. The basic fraction was evaporated and purified by column chromatography (KP-C18-HS, ​​SNAP10) with a gradient elution from 5% to 95% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH) remnants. Fractions containing product were combined and lyophilized to give [3-(1-amino-4-methylphthalein-6-yl)-4-dimethylphosphorylphenyl] as a white solid Acid formate (33.82 mg, 0.084 mmol, 22.12% yield). 1H NMR (400 MHz, DMSO-d6+ TFA drops) δ 1.52 (s, 3H), 1.56 (s, 3H), 2.71 (s, 3H), 7.84 (d,J= 3.94 Hz, 1H), 7.87 - 7.95 ( m, 1H), 7.99 - 8.04 (m, 1H), 8.12 (s, HCOOH, 1H), 8.21 (dd,J= 8.40, 1.69 Hz, 1H), 8.37 (d,J= 1.65 Hz, 1H), 8.69 (d, J= 8.44 Hz, 1H), 9.17 (br. s, 2H). LC-MS (Method A): r.t. 0.33 min, MS (ESI) m / z = 356.1 [M+H]+.

[0252] Example 63: [5-(1-amino-4-methylphthalein-6-yl)-2-methoxy-4-(trifluoromethyl)phenyl]acid (63) Palladium(II) acetate (3.68 mg, 0.020 mmol), 6-[5-chloro-4-methoxy-2-(trifluoromethyl)phenyl]-N-[(2,4-dimethoxy Phenyl)methyl]-4-methylphthalein-1-amine (170.0 mg, 0.330 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl] Phenyl]phosphine (15.65 mg, 0.030 mmol), potassium acetate (96.64 mg, 0.980 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaboroxane-2-yl)-1,3,2-dioxaboroxane (250.05 mg, 0.980 mmol) dissolved in 1,4-dioxane (3.469 mL) in a microwave vial . The resulting reaction mixture was stirred at 80 °C for 2 h, then it was cooled to room temperature and filtered through celite, washing with EtOAc. The filtrate was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature for 2 hours, then it was concentrated under reduced pressure. The residue was dissolved with MeOH and this solution was loaded onto an SCX cartridge (5 g), the cartridge was washed with MeOH / H2O (9:1) and then eluted with 7 M ammonia in MeOH. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​30 g) with gradient elution from 1% to 70% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and subsequently lyophilized to give [5-(1-amino-4-methylphthalein-6-yl)-2-methoxy-4-(trifluoromethane) as a white solid yl)phenyl]acid (52 mg, 0.138 mmol, 41% yield). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 2.70 (s, 3H), 3.95 (s, 3H), 7.37 (s, 1H), 7.56 (s, 1H), 8.00 - 8.11 (m, 1H) , 8.11 (s, 1H), 8.70 (d, J= 8.47 Hz, 1H), 9.19 (s, 2H). LC-MS (Method A): r.t. 0.59 min, MS (ESI) m / z = 378.1 [M+H]+.

[0253] Example 64: [3-(4-aminophenoline-7-yl)-4-(3-methylbutyrylamino)phenyl]acid formate (64) converts N-[2- [4-[(2,4-Dimethoxyphenyl)methylamino]phenolin-7-yl]-4-(4,4,5,5-tetramethyl-1,3,2- A mixture of dioxaborol-2-yl)phenyl]-3-methylbutanamide (54.0 mg, 0.090 mmol) in DCM (1.5 mL) and trifluoroacetic acid (1 mL) was stirred at room temperature overnight, Volatiles were then removed. The residue was dissolved in MeOH / water (9:1 ) and loaded onto an SCX cartridge (2 g), which was washed with MeOH / water (9:1 ) and then eluted with 2 M ammonia in MeOH. The volatiles were removed and the residue was purified by column chromatography (Sfär C18, 12 g) with a gradient elution from 2% to 20% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH) to give [3-(4-Aminophenoline-7-yl)-4-(3-methylbutyrylamino)phenyl] acid formate (22.1 mg, 0.054 mmol, 59.51% yield) as a white solid ). 1H NMR (400 MHz, DMSO-d6+ 1 drop TFA) δ 0.74 - 0.82 (m, 6 H), 1.85 - 1.96 (1 H, m), 2.03 (d,J= 7.04 Hz, 2H), 7.49 (d, J= 7.92 Hz, 1H), 7.78 - 7.84 (m, 2H), 7.85 - 7.91 (m, 2H), 8.46 - 8.52 (m, 2H), 9.55 (1H, s), 9.76 (br.s , 1H), 9.88 (br. s, 1H). LC-MS (Method A): r.t. 0.41 min, MS (ESI) m / z = 365.16 [M+H]+.

[0254] Example 65: [3-(4-aminophenoline-7-yl)-4-(4-methylpentamido)phenyl]acid formate (65) converts N-[2- [4-[(2,4-Dimethoxyphenyl)methylamino]phenolin-7-yl]-4-(4,4,5,5-tetramethyl-1,3,2- A mixture of dioxaborol-2-yl)phenyl]-4-methylpentanamide (61.0 mg, 0.100 mmol) and trifluoroacetic acid (1 mL) in DCM (1.5 mL) was stirred at room temperature overnight, Volatiles were then removed. The residue was dissolved in MeOH / water (9:1 ) and loaded onto an SCX cartridge (2 g), the cartridge was washed with MeOH / water (9:1 ) and eluted with 2 M ammonia in MeOH. The volatiles were removed and the residue was purified by column chromatography (Sfär C18, 12 g) with a gradient elution from 2% to 20% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH) to give [3-(4-Aminophenolin-7-yl)-4-(4-methylpentylamino)phenyl] acid formate (14.3 mg, 0.034 mmol, yield 33.74%). 1H NMR (400 MHz, DMSO-d6+ 1 drop TFA) δ 0.76 (d,J= 6.16 Hz, 6H), 1.25 -1.32 (m, 3 H), 2.13 (t,J= 7.15 Hz, 2H), 7.47 ( d,J= 7.92 Hz, 1H), 7.77 - 7.82 (m, 2H), 7.85 - 7.90 (m, 2H), 8.46 - 8.53 (m, 2H), 9.58 (s, 1H), 9.75 (br. s, 1H), 9.89 (br. s, 1H). LC-MS (Method A): r.t. 0.47 min, MS (ESI) m / z = 379.18 [M+H]+.

[0255] Example 66: 6-(4,4-difluoro-1-hydroxyl-3H-2,1-benzoxaborin-7-yl)-4-methylphthalein-1 -Amine (66) 6-[4-[2-[tertiary butyl(dimethyl)silyl]oxyl-1,1-difluoroethyl]-3-chlorophenyl]-N-[ (2,4-dimethoxyphenyl)methyl]-4-methylphthalein-1-amine (66.0 mg, 0.110 mmol), 4,4,5,5-tetramethyl-2-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaboroxene (54.58 mg, 0.210 mmol), cesium fluoride (32.65 mg, 0.210 mmol), a mixture of trimethyl(2,2,2-trifluoroethoxy)silane (38.86 mg, 0.230 mmol) and dichlorobis(trimethylphosphine)nickel (0.61 mg, 0.002 mmol) Dissolve in THF (0.7 mL) in a microwave vial and degas with N2 for 10 min. The mixture was heated to 100 °C for 3 h under microwave irradiation in a microwave reactor. Then, the mixture was cooled to room temperature and filtered through a pad of celite, washing with MeOH. The filtrate was evaporated, and the residue was dissolved in DCM (4 mL) and trifluoroacetic acid (4 mL) and stirred at room temperature for 2 h, then concentrated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​30 g) eluting with a gradient of 2% to 95% CH3CN in water (+0.1% HCOOH). Fractions containing partially purified product were collected and evaporated. The recovered solid was subjected to semi-preparative HPLC purification (Chiralcel OJ-H (25 x 2.0 cm), 5 µm, 60 / 40% v / v n-hexane / (EtOH + 0.1% isopropylamine)). Fractions containing the desired compound were collected and evaporated under reduced pressure to give 6-(4,4-difluoro-1-hydroxy-3H-2,1-benzoxaborinane as an off-white powder Dien-7-yl)-4-methylphthalein-1-amine (2 mg, 0.006 mmol, 3.5% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.78 (s, 3H), 4.45 (t,J= 12.37 Hz, 2H), 6.81 (s, 2H), 7.85 (d,J= 8.03 Hz, 1H), 8.18 - 8.23 ​​(m, 3H), 8.31 (s, 1H), 8.39 (d, J= 8.42 Hz, 1H). LC-MS (Method A): r.t. 0.61 min, MS (ESI) m / z = 342.1 [M+H]+.

[0256] Example 67: [3-(4-Amino-5-methylphenolin-7-yl)-4-methoxyphenyl] acid (67) converts 7-(5-chloro-2-methyl Oxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]-5-methylphenolin-4-amine (205.0 mg, 0.460 mmol), 4,4,5,5 -Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaboroxine (347.11 mg, 1.37 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (17.38 mg, 0.040 mmol), potassium acetate (134.15 mg, 1.37 mmol) and palladium(II) diacetate (5.11 mg, 0.020 mmol) were dissolved in 1,4-dioxane (4 mL) in a microwave vial and degassed with N2 for 15 min. The mixture was stirred at 75 °C for 1.5 h, then it was cooled to room temperature and filtered through celite, washing with MeOH. The filtrate was evaporated, and the residue was dissolved in DCM (4 mL) and trifluoroacetic acid (4 mL) and stirred at room temperature for 2 h, then concentrated under reduced pressure. The residue was dissolved in MeOH / H20 (9:1), loaded onto an SCX cartridge and kept on the SCX cartridge for 20 min for absorption. Subsequently, the cartridge was washed with MeOH / H2O (9:1) and eluted with 2 M methanolic ammonia solution. The basic fraction was evaporated and the residue was purified by column chromatography (KP-C18-HS, ​​12 g) with a gradient elution from 2% to 95% CH3CN in water (+0.1% HCOOH). Fractions containing the desired compound were pooled and lyophilized. The recovered solid was subjected to semi-preparative HPLC purification (Chiralcel OJ-H (25 x 2.0 cm), 5 µm, 80 / 20% v / v n-hexane / (EtOH + 0.1% isopropylamine)). Fractions containing the desired compound were collected and lyophilized to give [3-(4-amino-5-methylphenolin-7-yl)-4-methoxyphenyl]acid as a white powder ( 41 mg, 0.133 mmol, yield 34.2%). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 2.93 (s, 3H), 3.85 (s, 3H), 7.19 (d,J= 8.27 Hz, 1H), 7.67 (s, 1H), 7.84 (d ,J= 1.65 Hz, 1H), 7.87 - 7.95 (m, 2H), 8.42 (s, 1H), 8.59 (s, 1H), 9.75 (s, 1H). LC-MS (Method A): r.t. 0.46 min, MS (ESI) m / z = 310.1 [M+H]+.

[0257] Example 68: [3-(1-Amino-4-methylphthalein-6-yl)-2-fluoro-4-(trifluoromethyl)phenyl] acid formate (68) Palladium(II) diacetate (2.66 mg, 0.010 mmol), 6-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-N-[(2,4-dimethoxybenzene Base) methyl]-4-methylphthalein-1-amine (171.43 mg, 0.240 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]benzene phosphine (11.31 mg, 0.020 mmol), potassium acetate (69.84 mg, 0.710 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1, 3,2-dioxaboroxane-2-yl)-1,3,2-dioxaboroxane (180.71 mg, 0.710 mmol) was dissolved in 1,4-dioxane (2.449 mL) in a microwave vial, And the mixture was deoxygenated under N2 for 10 min. The resulting reaction mixture was stirred at 80 °C for 2 h, then it was cooled to room temperature and filtered through celite, washing with EtOAc. The filtrate was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (1.5 mL). The resulting mixture was stirred at room temperature for 2 hours, then it was concentrated under reduced pressure. The residue was purified by column chromatography (Sfär C18, 30 g) with a gradient elution from 1% to 70% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and then lyophilized to give [3-(1-amino-4-methylphthalein-6-yl)-2-fluoro-4-(trifluoromethyl) as a white solid Phenyl] acid formate (7 mg, 0.017 mmol, 7% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.65 (s, 3H), 6.86 (s, 2H), 7.71 (d,J= 7.92 Hz, 1H), 7.74 - 7.89 (m, 2H), 7.89 (s, 1H), 8.17 (s, 1H, HCOOH), 8.32 (d, J= 8.44 Hz, 1H), 8.63 (s, 2H). LC-MS (Method A): r.t. 0.56 min, MS (ESI) m / z = 366.05 [M+H]+.

[0258] Example 69: 7-[5-(11,13-dioxa-12-boradispiro[4.0.46.35]tridec-12-yl)-2-methoxyphenyl]phenoline- 4-Amine (69) 1-(1-Hydroxycyclopentyl)cyclopent-1-ol (11.54 mg, 0.070 mmol) was added to [3-(4-aminophenolin-7-yl)-4- Methoxyphenyl] acid (20.0 mg, 0.070 mmol) in suspension in THF (1 mL). The resulting mixture was stirred at 40 °C for 3 h, then it was evaporated in vacuo. The residue was triturated with diethyl ether, and the resulting solid was filtered, washed with diethyl ether and dried to afford 7-[5-(11,13-dioxa-12-borabispiro[4.0. 46.35] Tridec-12-yl)-2-methoxyphenyl]phenolin-4-amine (17 mg, 0.040 mmol, 58.43% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.67 - 1.84 (m, 16H), 3.84 (s, 3H), 7.16 - 7.25 (m, 3H), 7.62 - 7.69 (m, 2H), 7.74 (dd,J = 8.25, 1.68 Hz, 1H), 8.04 (d,J= 1.72 Hz, 1H), 8.20 (d,J= 8.75 Hz, 1H), 8.61 (s, 1H).

[0259] Example 70: [5-(1-amino-4-methylphthalein-6-yl)-2-benzamidophenyl]acid (70) converts N-[2-chloro-4 -[1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalein-6-yl]phenyl]benzamide (640.0 mg, 1.15 mmol), 4 ,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxo Boron (643.43 mg, 2.53 mmol), cesium fluoride (349.89 mg, 2.3 mmol), trimethyl(2,2,2-trifluoroethoxy) silane (416.53 mg, 2.42 mmol) and dichlorobis( A mixture of trimethylphosphine)nickel (6.49 mg, 0.020 mmol) was dissolved in THF (11 mL) in a microwave vial and degassed with N2 for 10 min. The mixture was heated in a microwave reactor at 100 °C for 4.5 h under microwave irradiation. It was then cooled to room temperature, filtered through a pad of celite, washed with MeOH and evaporated. The residue was purified by column chromatography (KP-C18-HS, ​​30 g) eluting with a gradient of 2% to 95% CH3CN in water (+0.1% HCOOH). Collect partially pure N-[4-(1-{[(2,4-dimethoxyphenyl)methyl]amino}-4-methylphthalein-6-yl)-2-(4 , 4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]benzamide and evaporated. The residue was dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (KP-C18-HS, ​​12 g) eluting with a gradient of 1% to 50% aqueous CH3CN (+0.1% HCOOH). Fractions containing the desired compound were collected and lyophilized to give [5-(1-amino-4-methylphthalein-6-yl)-2-benzamidophenyl] as a yellow powder Acid (18 mg, 0.045 mmol, 30.34% yield). 1H NMR (400 MHz, methanol-d4) δ 2.87 (s, 3H), 7.57 (d,J= 8.36 Hz, 1H), 7.67 - 7.75 (m, 2H), 7.78 - 7.85 (m, 1H), 7.92 ( dd,J= 8.40, 2.27 Hz, 1H), 8.02 (d,J= 2.21 Hz, 1H), 8.22 - 8.27 (m, 2H), 8.39 (dd,J= 8.56, 1.81 Hz, 1H), 8.43 (d ,J= 1.52 Hz, 1H), 8.53 (d,J= 8.56 Hz, 1H). LC-MS (Method A): r.t. 0.48 min, MS (ESI) m / z = 399.1 [M+H]+.

[0260] Example 71: [5-(1-Amino-4-methylphthalein-6-yl)-2-(trifluoromethyl)pyridin-3-yl]acid formate (71) Fluoroacetic acid (3.5 mL) was added to N-[(2,4-dimethoxyphenyl)methyl]-4-methyl-6-[5-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborol-2-yl)-6-(trifluoromethyl)pyridin-3-yl]phthalo-l-amine (214.0 mg, 0.370 mmol) in DCM (3.5 mL) solution and the mixture was stirred at room temperature for 1 h before volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge (2 g), which was washed with MeOH / water (9:1 ) and then eluted with 1 M ammonia in MeOH. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 30 g) with a gradient elution from 1% to 30% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH) to afford HC1 as a white solid. [5-(1-Amino-4-methylphthalein-6-yl)-2-(trifluoromethyl)pyridin-3-yl] acid formate (9.7 mg, 0.025 mmol, yield 6.675% ). 1H NMR (400 MHz, DMSO-d6+ 3 drops TFA) δ 2.83 (s, 3H), 8.13 (s, 1H, HCOOH), 8.50 - 8.71 (m, 3H), 8.80 (d,J= 9.30 Hz, 1H) , 9.22 (s, 2H), 9.28 (d, J= 2.32 Hz, 1H). LC-MS (Method A): r.t. 0.42 min, MS (ESI) m / z = 349.10 [M+H]+.

[0261] Examples 72 and 73: 6-(1-hydroxyl-3-methyl-3,4-dihydro-2,1-benzoxaborin-7-yl)-4-methan Phthalate-1-amine enantiomer 1 (72) and enantiomer 2 (73) will 6-[4-[2-[tertiary butyl(dimethyl)silyl]oxy Propyl]-3-chlorophenyl]-N-[(2,4-dimethoxyphenyl)methyl]-4-methylphthalein-1-amine (168.0 mg, 0.280 mmol), 4, 4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaboron Dicyclohexyl-[2-[2,4,6-tri(prop-2-yl)phenyl]phenyl]phosphine (10.82 mg, 0.020 mmol), potassium acetate (83.52 mg, 0.850 mmol) and palladium(II) diacetate (3.18 mg, 0.010 mmol) were dissolved in 1,4-dioxane (3.47 mL) in a microwave vial and degassed with N2 for 10 min. The mixture was stirred at 75 °C for 1.5 h, then it was cooled to room temperature and filtered through celite, washing with MeOH. The filtrate was evaporated, and the residue was dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL) and stirred at room temperature for 2 h, then concentrated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​12 g) eluting with a gradient of 1% to 60% CH3CN in water (+0.1% HCOOH). Appropriate fractions were collected and evaporated. The recovered solid was subjected to semi-preparative chiral HPLC purification (Chiralpak AD-H (25 x 2.0 cm), 5 µm, 88 / 12% v / v n-hexane / (EtOH + 0.1% isopropylamine)). Fractions containing the two separated enantiomers were collected independently and lyophilized to afford enantiomer 1 6-(1-hydroxy-3-methyl-3,4- Dihydro-2,1-benzoxaborin-7-yl)-4-methylphthalein-1-amine (1.46 mg, 0.005 mmol, 1.613% yield) and as a white solid Enantiomer 2 6-(1-Hydroxy-3-methyl-3,4-dihydro-2,1-benzoxaborin-7-yl)-4-methyl Phthalo-1-amine (1.4 mg, 0.004 mmol, 1.546% yield).

[0262] Characterization of enantiomer 1: 1H NMR (400 MHz, methanol-d4) δ 1.43 (d, J= 6.27 Hz, 3H), 2.78 - 2.88 (m, 4H), 2.97 (dd, J= 16.03 , 3.42 Hz, 1H), 4.37 - 4.47 (m, 1H), 7.35 (d,J= 7.89 Hz, 1H), 7.81 (dd,J= 7.83, 2.17 Hz, 1H), 8.05 (d,J= 2.13 Hz , 1H), 8.19 (dd,J= 8.54, 1.80 Hz, 1H), 8.23 ​​- 8.30 (m, 2H). LC-MS (Method A): r.t. 0.61 min, MS (ESI) m / z = 320.1 [M+H]+. Analytical chiral HPLC: column Chiralpak AD-H (25 × 0.46 cm), 5 μm, mobile phase: 88 / 12% v / v n-hexane / (ethanol + 0.1% isopropylamine), flow rate: 1.0 mL / min, DAD 220 nm ring 20 µL, >99% a / a enantiomer 1, trace enantiomer 2 by UV (8.5 min).

[0263] Characterization of enantiomer 2: 1H NMR (400 MHz, methanol-d4) δ 1.43 (d, J= 6.27 Hz, 3H), 2.78 - 2.88 (m, 4H), 2.97 (dd, J= 16.03 , 3.42 Hz, 1H), 4.37 - 4.47 (m, 1H), 7.35 (d,J= 7.89 Hz, 1H), 7.81 (dd,J= 7.83, 2.17 Hz, 1H), 8.05 (d,J= 2.13 Hz , 1H), 8.19 (dd,J= 8.54, 1.80 Hz, 1H), 8.23 ​​- 8.30 (m, 2H). LC-MS (Method A): r.t. 0.61 min, MS (ESI) m / z = 320.1 [M+H]+. Analytical chiral HPLC: column Chiralpak AD-H (25 × 0.46 cm), 5 μm, mobile phase: 88 / 12% v / v n-hexane / (ethanol + 0.1% isopropylamine), flow rate: 1.0 mL / min, DAD 220 nm loop 20 µL, 3.8% a / a enantiomer 1 by UV (8.7 min), 96.2% a / a enantiomer 2 by UV (10.0 min).

[0264] Example 74: [5-(1-Amino-4-methylphthalein-6-yl)-2-(trifluoromethyl)phenyl] acid formate (74) converts N-[( 2,4-Dimethoxyphenyl)methyl]-4-methyl-6-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2 -yl)-4-(trifluoromethyl)phenyl]phthalein-1-amine (250.0 mg, 0.430 mmol) in DCM (1.5 mL) and trifluoroacetic acid (0.700 mL) was stirred overnight at room temperature , followed by removal of volatiles. The residue was dissolved in MeOH and loaded onto an SCX cartridge (2 g), the cartridge was washed with MeOH / water (9:1 ) and then eluted with 2 M ammonia in MeOH. The volatiles were removed and the residue was purified by column chromatography (Sfar C18 D, 12 g) with a gradient elution from 2% to 40% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH), [5-(1-Amino-4-methylphthalein-6-yl)-2-(trifluoromethyl)phenyl] acid formate (19.6 mg, 0.050 mmol, yield ) was obtained as a white solid. rate of 11.56%). 1H NMR (400 MHz, DMSO-d6+ 1 drop TFA) δ 2.83 (s, 3 H), 7.86 (d,J= 8.36 Hz, 1H), 8.08 - 8.18 (m, 3 H), 8.50 (d,J= 1.32 Hz, 1H), 8.54 (dd, J= 8.69, 1.65 Hz, 1H), 8.78 (d, J= 8.58 Hz, 1H), 9.21 (br. s, 2H). LC-MS (Method A): r.t. 0.52 min, MS (ESI) m / z = 348.08 [M+H]+.

[0265] Example 75: [4-methoxy-3-[4-(methylamino) phenolin-7-yl] phenyl] acid formate (75) converts 7-(5-chloro-2 -Methoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]-N-methylphenolin-4-amine (200.0 mg, 0.440 mmol), 4,4,5 ,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborol (338.64 mg, 1.33 mmol), dicyclohexyl-[2-[2,4,6-tri(prop-2-yl)phenyl]phenyl]phosphine (16.95 mg, 0.040 mmol), potassium acetate (130.87 mg, 1.33 mmol) and palladium(II) diacetate (4.99 mg, 0.020 mmol) were dissolved in 1,4-dioxane (4 mL) in a microwave vial and degassed with N2 for 15 min. The mixture was stirred at 75 °C for 1.5 h, then it was cooled to room temperature and filtered through celite, washing with MeOH. The filtrate was evaporated and the residue was dissolved in DCM (3 mL) and trifluoroacetic acid (3 mL) and stirred at room temperature for 1 h before it was concentrated under reduced pressure. The residue was dissolved in MeOH / H2O (9:1) and loaded onto an SCX cartridge and kept on the SCX cartridge for 20 min for absorption. Subsequently, the cartridge was washed with MeOH / H2O (9:1) and eluted with 2 M methanolic ammonia solution. The basic fraction was evaporated and the residue was purified by column chromatography (KP-C18-HS, ​​30 g) with a gradient elution from 5% to 95% CH3CN in water (+0.1% HCOOH). Fractions containing the desired compound were collected and lyophilized to give [4-methoxy-3-[4-(methylamino)phenolin-7-yl]phenyl]carboxylic acid formic acid as a light yellow solid Salt (42 mg, 0.118 mmol, 26.6% yield). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 3.30 (d,J= 4.96 Hz, 3H), 3.86 (s, 3H), 7.21 (d,J= 8.74 Hz, 1H), 7.89 - 7.96 (m , 2H), 8.00 (dd,J= 8.83, 1.65 Hz, 1H), 8.05 (d,J= 1.62 Hz, 1H), 8.13 (s, 1 H, from HCOOH), 8.47 (d,J= 8.96 Hz, 1H), 8.71 (s, 1H), 10.14 (d, J= 5.39 Hz, 1H). LC-MS (Method A): r.t. 0.45 min, MS (ESI) m / z = 310.05 [M+H]+.

[0266] Example 76: [3-(4-Aminothioline-7-yl)-4-[2-oxo-2-(propan-2-ylamino)ethoxy]phenyl]acid Formate (76) palladium(II) diacetate (3.46 mg, 0.020 mmol), 2-[4-chloro-2-[4-[(2,4-dimethoxyphenyl)methylamino ]phenolin-7-yl]phenoxy]-N-propan-2-ylacetamide (160.68 mg, 0.310 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2 -yl)phenyl]phenyl]phosphine (14.7 mg, 0.030 mmol), potassium acetate (90.8 mg, 0.930 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5 -Tetramethyl-1,3,2-dioxaboron-2-yl)-1,3,2-dioxaborol (234.94 mg, 0.930 mmol) 1,4-dioxaborol dissolved in a microwave vial Alkanes (3.084 mL) and the mixture was deoxygenated under N2 for 10 min. The resulting reaction mixture was stirred at 80 °C for 2 h, then it was cooled to room temperature and filtered through celite, washing with EtOAc. The filtrate was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (1.5 mL). The resulting mixture was stirred at room temperature for 2 hours, then it was concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 30 g) eluting with a gradient of 1% to 70% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and then lyophilized to give [3-(4-aminophenolin-7-yl)-4-[2-oxo-2-(propan-2-yl) as a white solid Amino)ethoxy]phenyl] acid formate (35 mg, 0.082 mmol, 26.45% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.00 (d,J= 6.60 Hz, 6H), 3.78 - 3.96 (m, 1H), 4.55 (s, 2H), 7.05 (d,J= 8.36 Hz, 1H) , 7.21 (s, 2H), 7.44 (d,J= 7.81 Hz, 1H), 7.82 (dd,J= 8.29, 1.71 Hz, 1H), 7.89 (dd,J= 8.75, 1.82 Hz, 1H), 7.97 ( d,J= 1.71 Hz, 1H), 8.07 (s, 2H), 8.17 (s, from HCOOH, 1H), 8.19 - 8.28 (m, 2H), 8.62 (s, 1H). LC-MS (Method A): r.t. 0.52 min, MS (ESI) m / z = 381.1 [M+H]+.

[0267] Example 77: 7-[2-methoxy-4-(trifluoromethyl)-5-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5 -Dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl]phenyl]phenoline-4-amine (77) bis[(-)-pinanediol radical]di Boron (1.31 g, 3.67 mmol), 7-[5-bromo-2-methoxy-4-(trifluoromethyl)phenyl]-N-[(2,4-dimethoxyphenyl)methanol Dioxin-4-amine (0.67 g, 1.22 mmol) and potassium acetate (0.36 g, 3.67 mmol) were dissolved in 1,4-dioxane (12.22 mL) in a microwave vial and the mixture was deoxygenated under N2 10 min. Subsequently, palladium(II) diacetate (13.72 mg, 0.060 mmol) and dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (46.6 mg, 0.100 mmol) and the mixture was deoxygenated for another 10 min under N2. The mixture was stirred at 110°C for 10 hours. The mixture was filtered through a pad of celite, washing with DCM, and the filtrate was concentrated in vacuo. The red solid residue was dissolved in DCM (2.5 mL) and trifluoroacetic acid (2.5 mL) and stirred at room temperature for 3 h before it was evaporated in vacuo. The residue was dissolved with MeOH, and this solution was loaded onto an SCX cartridge (5 g), which was washed with MeOH and then eluted with 7 M ammonia in MeOH. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 30 g) eluting with a gradient of 1% to 70% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give 7-[2-methoxy-4-(trifluoromethyl)-5-[(1S,2S,6R,8S)-2,9 as a white solid , 9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl]phenyl]phenolin-4-amine (33 mg, 0.066 mmol, Yield 5.4%). 1H NMR (400 MHz, DMSO-d6) δ 0.87 (s, 3H), 1.19 (d,J= 10.75 Hz, 1H), 1.28 (s, 3H), 1.44 (s, 3H), 1.81 - 1.89 (m, 1H), 1.89 - 1.95 (m, 1H), 2.08 (t,J= 5.50 Hz, 1H), 2.19 - 2.31 (m, 1H), 2.35 - 2.47 (m, 1H), 3.94 (s, 3H), 4.57 (dd,J= 8.81, 2.02 Hz, 1H), 7.25 (s, 2H), 7.49 (s, 1H), 7.72 (dd,J= 8.74, 1.79 Hz, 1H), 7.82 (s, 1H), 8.13 ( d,J= 1.74 Hz, 1H), 8.24 (d,J= 8.77 Hz, 1H), 8.64 (s, 1H). LC-MS (Method A): r.t. 0.96 min, MS (ESI) m / z = 396.33 [M+H]+.

[0268] Example 78: 7-{2-fluoro-6-methoxy-3-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa- 4-Boratricyclo[6.1.1.02,6]dec-4-yl]phenyl}phenoline-4-amine (78) [3-(4-aminophenoline-7-yl)-2- Fluoro-4-methoxyphenyl] acid (82.0 mg, 0.260 mmol) and (1S,3R,4S,5S)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4 - A suspension of diol (43.7 mg, 0.260 mmol) in THF (3.214 mL) was stirred at room temperature for 1 h, then at 60 °C for 30 min and then evaporated in vacuo. The residue was triturated with Et2O, filtered and washed with Et2O. The resulting yellow powder was purified by column chromatography (KP-sil silica gel, sequentially 2 x SNAP10) eluting with a gradient of 0% to 20% EtOAc containing EtOH. The appropriate fractions were concentrated and the residue was suspended in water and evaporated using a V10 evaporator to give 7-{2-fluoro-6-methoxy-3-[(1S,2S,6R) as a yellowish solid , 8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl]phenyl}phenoline-4-amine (49.6 mg, 0.111 mmol, yield 43.2%). 1H NMR (400 MHz, DMSO-d6) δ 0.88 (s, 3 H), 1.10 (d,J= 10.78 Hz, 1H), 1.29 (s, 3 H), 1.44 (s, 3 H), 1.78 - 1.95 (m, 2H), 2.07 - 2.12 (m, 1H), 2.21 - 2.28 (m, 1H), 2.35 - 2.45 (m, 1H), 3.82 (s, 3H), 4.53 (d,J= 6.82 Hz, 1H), 7.08 (d,J= 8.58 Hz, 1H), 7.21 (s, 2H), 7.53 (d,J= 8.58 Hz, 1H), 7.73 (dd,J= 8.25, 7.15 Hz, 1H ), 7.97 (s, 1 H), 8.22 (d,J= 8.80 Hz, 1H), 8.64 (s, 1 H). LC-MS (Method A): r.t. 0.89 min, MS (ESI) m / z = 448.24 [M+H]+.

[0269] Example 79: [3-(4-aminophenoline-7-yl)-4-[[(2S)-4,4-difluoropyrrolidin-2-yl]methoxyl]phenyl] Acid (79) Palladium(II) diacetate (3.5 mg, 0.020 mmol), (2S)-2-[[4-chloro-2-[4-[(2,4-dimethoxyphenyl)methyl Amino]phenolin-7-yl]phenoxy]methyl]-4,4-difluoropyrrolidine-1-carboxylic acid tertiary butyl ester (200.0 mg, 0.310 mmol), dicyclohexyl-[2- [2,4,6-tris(propan-2-yl)phenyl]phenyl]phosphine (14.87 mg, 0.030 mmol), potassium acetate (91.85 mg, 0.940 mmol) and 4,4,5,5-tetramethyl Dioxyboron-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborolidine (237.66 mg, 0.940 mmol) Dissolve in 1,4-dioxane (3.839 mL) in a microwave vial and deoxygenate the mixture under N2 for 10 min. The mixture was stirred at 80 °C for 2 hours, then it was filtered through a pad of celite, washed with MeOH and the filtrate was concentrated in vacuo. The residue was dissolved in DCM (2.5 mL) and trifluoroacetic acid (2.5 mL). The resulting mixture was stirred at room temperature for 4 hours, then it was concentrated under reduced pressure. The residue was dissolved with MeOH and this solution was loaded onto an SCX cartridge (5 g), the cartridge was washed with MeOH / H2O (9:1) and then eluted with 7 M ammonia in MeOH. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 30 g) eluting with a gradient of 1% to 70% MeCN (+0.1% ammonium hydroxide) in water (+0.1% ammonium hydroxide). Appropriate fractions were collected and lyophilized to give [3-(4-aminophenolin-7-yl)-4-[[(2S)-4,4-difluoropyrrolidine-2 as a white solid -yl]methoxy]phenyl]acid (30 mg, 0.075 mmol, 13.73% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.96 - 2.15 (m, 1H), 2.23 - 2.36 (m, 1H), 2.89 (br. s, 1H), 3.00 - 3.20 (m, 2H), 3.53 - 3.63 (m, 1H), 3.97 - 4.13 (m, 2H), 7.12 - 7.19 (m, 3H), 7.79 - 7.87 (m, 2H), 7.97 (d,J= 1.75 Hz, 1H), 8.00 (s, 2H ), 8.16 (d,J= 1.70 Hz, 1H), 8.19 (d,J= 8.80 Hz, 1H), 8.61 (s, 1H). LC-MS (Method A): r.t. 0.58 min, MS (ESI) m / z = 401.14 [M+H]+.

[0270] Example 80: [3-(phenolin-7-yl)-4-methoxyphenyl]acid (80) palladium(II) diacetate (8.92 mg, 0.040 mmol), 7-(5- Chloro-2-methoxyphenyl) phenoline (215.0 mg, 0.790 mmol), dicyclohexyl-[2-[2,4,6-tri(prop-2-yl)phenyl]phenyl]phosphine ( 30.29 mg, 0.060 mmol), potassium acetate (233.83 mg, 2.38 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- Dioxaboroxane-2-yl)-1,3,2-dioxaboroxane (605.04 mg, 2.38 mmol) was dissolved in 1,4-dioxane (8 mL) in a microwave vial and the mixture was heated under N2 Deoxygenate for 10 min. The mixture was stirred at 75 °C for 1.5 h, then filtered through a pad of Celite, washed with MeOH and the filtrate concentrated in vacuo. The residue was dissolved in MeOH / H20 (9:1) and loaded onto an SCX cartridge. The mixture was left on an SCX cartridge for 20 min, and the cartridge was then eluted with MeOH / H20 (9:1 ) followed by 2 M methanolic ammonia. The basic fraction was evaporated and dissolved by column chromatography (Sfar C18 D, 2 x 6 g consecutively) with a gradient of 5% to 95% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). The residue was isolated and purified. Appropriate fractions were combined and lyophilized to afford [3-(phenolin-7-yl)-4-methoxyphenyl]acid (19 mg, 0.068 mmol, 7.3% yield) as a light yellow solid ). 1H NMR (400 MHz, DMSO-d6) δ 3.86 (s, 3H), 7.19 (d,J= 8.32 Hz, 1H), 7.88 (dd,J= 8.26, 1.72 Hz, 1H), 7.95 - 8.15 (m, 5H), 8.23 ​​(d, J= 5.79 Hz, 1H), 8.53 (s, 1H), 9.38 (d, J= 5.78 Hz, 1H). LC-MS (Method A): r.t. 0.70 min, MS (ESI) m / z = 281.05 [M+H]+.

[0271] Example 81: [3-(1-amino-4-methylphthalein-6-yl)-4-[[(2S)-4,4-difluoropyrrolidine-2-carbonyl]amino ] phenyl] acid (81) 6-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl) phenyl] -N-[(2,4-dimethoxyphenyl)methyl]-4-methylphthalein-1-amine (50.0 mg, 0.090 mmol), (2S)-4,4-difluoro-1 -[(2-Methylprop-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid (26.25 mg, 0.100 mmol), [dimethylamino(3-triazolo[4,5-b] A solution of pyridyloxy)methylene]-dimethylammonium hexafluorophosphate (39.73 mg, 0.100 mmol) and triethylamine (0.02 mL, 0.140 mmol) in DMF (1.5 mL) was stirred overnight at 40°C , which was then diluted with EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue was dissolved in dichloromethane (0.500 mL) and trifluoroacetic acid (0.500 mL). The resulting mixture was stirred at room temperature for three hours before it was evaporated in vacuo. The residue was dissolved with MeOH and this solution was loaded onto an SCX cartridge (1 g), which was washed with MeOH / H20 (9:1) and then eluted with 7 M ammonia in MeOH. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 12 g) eluting with 1% to 70% MeCN (+0.1% ammonium hydroxide) in water (+0.1% ammonium hydroxide). Appropriate fractions were collected and lyophilized. The recovered solid was subjected to semi-preparative HPLC purification (Chiralcel OJ-H (25 x 0.46 cm), 5 µm, 60 / 40% v / v n-hexane / (EtOH + 0.1% isopropylamine)). Fractions containing the desired compound were collected and evaporated under reduced pressure to give [3-(1-amino-4-methylphthalein-6-yl)-4-[[(2S) as a white solid - 4,4-Difluoropyrrolidine-2-carbonyl]amino]phenyl] acid (4 mg, 0.009 mmol, 9.9% yield). 1H NMR (400 MHz, methanol-d4) δ 2.16 - 2.31 (m, 1H), 2.43 - 2.60 (m, 1H), 2.77 - 2.82 (m, 4H), 3.02 - 3.14 (m, 1H), 3.86 - 3.95 (m, 1H), 7.68 (s, 1H), 7.75 (d,J= 8.10 Hz, 1H), 7.89 - 8.02 (m, 2H), 8.13 (d,J= 1.69 Hz, 1H), 8.33 (d, J= 8.47 Hz, 1H). LC-MS (Method B): r.t. 0.43 min, MS (ESI) m / z = 428.08 [M+H]+.

[0272] Example 82: [3-(4-Aminothioline-7-yl)-4-(oxolan-2-ylmethoxy)phenyl] acid formate (82) diacetic acid Palladium(II) (4.44 mg, 0.020 mmol), 7-[5-chloro-2-(oxolan-2-ylmethoxy)phenyl]-N-[(2,4-dimethoxy Phenyl)methyl]phenolin-4-amine (200.0 mg, 0.400 mmol), dicyclohexyl-[2-[2,4,6-tri(prop-2-yl)phenyl]phenyl]phosphine ( 18.84 mg, 0.040 mmol), potassium acetate (116.37 mg, 1.19 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- Dioxaboroxane-2-yl)-1,3,2-dioxaboroxane (301.12 mg, 1.19 mmol) was dissolved in 1,4-dioxane (3.839 mL) in a microwave vial and the mixture was heated under N2 Deoxygenate for 10 min. The mixture was stirred at 75 °C for 2 h, then it was filtered through a pad of celite, washing with MeOH. The filtrate was concentrated in vacuo, and the residue was dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL) and stirred at room temperature overnight before it was evaporated in vacuo. The residue was dissolved with MeOH, and this solution was loaded onto an SCX cartridge (5 g). The mixture was left standing on an SCX cartridge for 20 min, then it was eluted with MeOH / H2O (9:1) followed by 7M methanolic ammonia solution. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 30 g) eluting with a gradient of 1% to 30% MeCN (+0.1% HCOOH) in degassed aqueous solution (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give [3-(4-aminophenolin-7-yl)-4-(oxolan-2-ylmethoxy)phenyl] as a white solid Acid formate (33 mg, 0.080 mmol, 20% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.59 - 1.82 (m, 3H), 1.85 - 2.00 (m, 1H), 3.52 - 3.75 (m, 2H), 4.00 - 4.17 (m, 3H), 7.14 (d ,J= 8.35 Hz, 1H), 7.19 (s, 2H), 7.78 - 7.86 (m, 2H), 7.96 (d,J= 1.73 Hz, 1H), 8.00 (s, 2H), 8.12 - 8.24 (m, 2H + HCOOH, 1H), 8.60 (s, 1H). LC-MS (Method B): r.t. 0.49 min, MS (ESI) m / z = 366.1 [M+H]+.

[0273] Example 83: [5-(4-Aminothioline-7-yl)-4-methoxy-2-(trifluoromethyl)phenyl] acid formate (83) to 7-[ 2-Methoxy-4-(trifluoromethyl)-5-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora To a suspension of tricyclo[6.1.1.02,6]dec-4-yl]phenyl]phenolin-4-amine (20.0 mg, 0.040 mmol) in DCM (500 μL) was added methyl acid (9.63 mg, 0.160 mmol) and trifluoroacetic acid (25 μL). The resulting mixture was stirred overnight at room temperature. 3 M hydrochloric acid solution (500.0 µL, 0.040 mmol) was added and the resulting mixture was stirred at 40°C for 4 days. The mixture was diluted with MeOH and the resulting solution was loaded onto an SCX cartridge (1 g), which was washed with MeOH and then eluted with 7 M ammonia in MeOH. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 6 g) eluting with a gradient of 1% to 70% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give [5-(4-aminophenolin-7-yl)-4-methoxy-2-(trifluoromethyl)phenyl]acid as a white solid Formate salt (8 mg, 0.020 mmol, 48.62% yield). 1H NMR (400 MHz, DMSO-d6) δ 3.89 (s, 3H), 7.23 (s, 2H), 7.37 (s, 1H), 7.60 (s, 1H), 7.72 (dd,J= 8.70, 1.79 Hz, 1H), 8.12 - 8.18 (m, 1H and HCOOH 1H), 8.23 ​​(d,J= 8.78 Hz, 1H), 8.33 (s, 2H), 8.62 (s, 1H). LC-MS (Method A): r.t. 0.50 min, MS (ESI) m / z = 364.1 [M+H]+.

[0274] Example 84: [5-(1-amino-4-methylphthalein-6-yl)-6-(trifluoromethyl)pyridin-3-yl]acid (84) makes 6-[5 -Chloro-2-(trifluoromethyl)pyridin-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]-4-methylphthalein-1-amine formate (182.66 mg, 0.340 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl) -1,3,2-dioxaboronium (260.15 mg, 1.02 mmol), potassium acetate (100.54 mg, 1.02 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl ) A mixture of phenyl]phenyl]phosphine (13.02 mg, 0.030 mmol) and palladium(II) diacetate (3.83 mg, 0.020 mmol) in 1,4-dioxane (5 mL) was degassed under Ar for 10 min, followed by heating at 85 °C for 6 h 30 min. The mixture was filtered through a pad of Celite, washed with MeOH and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (7 mL) and trifluoroacetic acid (7 mL) was added. The mixture was stirred at room temperature for 1 h. The volatiles were evaporated to give a brown solid residue, which was dissolved in MeOH and loaded onto an SCX cartridge (5 g), the cartridge was washed three times with a 9:1 mixture of MeOH / HO and then washed with 7 parts of ammonia in MeOH. M solution dissolves. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 12 g) with a gradient elution of 1% to 40% MeCN in 10 mM aqueous ammonium bicarbonate adjusted to pH 10 with ammonia. The obtained partially purified product was subjected to semi-preparative HPLC purification (MDAP Waters with mass spectrometry detection (MS: ZQ2000). Column: xBridge C18 (30 × 100 mm, 3 µm). Conditions: [A2: After ammonia 10 mM ammonium bicarbonate aqueous solution adjusted to pH 10]; [B2: MeCN]. Gradient: 10.0% B2 to 50.0% B2 in 10 min (flow rate: 40.00 mL / min). Detection: UV / Vis + MS ( ES+)) to give [5-(1-amino-4-methylphthalein-6-yl)-6-(trifluoromethyl)pyridin-3-yl]acid (11.5 mg, 0.033 mmol, yield 9.7%). 1H NMR (400 MHz, DMSO-d6+ TFA) δ 2.67 (s, 3H), 8.10 (dd,J= 8.40, 1.24 Hz, 1H), 8.23 ​​(d,J= 1.38 Hz, 1H), 8.26 (s, 1H ), 8.75 (d, J= 8.47 Hz, 1H), 9.09 (s, 1H), 9.21 (br. s, 1H). LC-MS (Method A): r.t. 0.48 min, MS (ESI) m / z = 349.10 [M+H]+.

[0275] Example 85: [3-(4-Aminothioline-7-yl)-4-(difluoromethoxy)phenyl]acid (85) Palladium(II) diacetate (5.0 mg, 0.020 mmol), 7-[5-chloro-2-(difluoromethoxy)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]phenolin-4-amine (210.0 mg , 0.450 mmol), dicyclohexyl-[2-[2,4,6-tri(prop-2-yl)phenyl]phenyl]phosphine (16.97 mg, 0.040 mmol) and potassium acetate (131.03 mg, 1.34 mmol ) was dissolved in 1,4-dioxane (3.5 mL) in a microwave vial and the mixture was deoxygenated under N2 for 10 min. Add 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2- Boron dioxide (339.03 mg, 1.34 mmol) was added and the mixture was deoxygenated under N2 for another 10 min. Subsequently, the mixture was stirred at 70 °C for 90 min. The mixture was filtered through a pad of Celite, washed with EtOAc and the filtrate was concentrated in vacuo. The residue was dissolved in DCM (3 mL) and trifluoroacetic acid (1.8 mL) and the mixture was stirred at room temperature overnight. The volatiles were removed, and the residue was dissolved in a 9:1 mixture of MeOH and H20, then loaded onto an SCX cartridge (10 g), the cartridge was washed with a 9:1 mixture of MeOH and H20 and then ammonium on A 2 M solution in MeOH eluted. The basic fraction was concentrated and the residue was purified by column chromatography (Sfar C18 D, 30 g) with a gradient elution from 2% to 50% MeOH (+0.1% HCOOH) in water (+0.1% HCOOH) [3-(4-Aminophenolin-7-yl)-4-(difluoromethoxy)phenyl]acid (25.7 mg, 0.078 mmol, 17.3% yield) was obtained as a white solid . 1H NMR (400 MHz, DMSO-d6+ 1 drop TFA) δ 7.32 (t,J= 73.51 Hz, 1 H), 7.38 (d,J= 8.14 Hz, 1H), 7.93 - 8.03 (m, 4 H), 8.51 (s, 1H), 8.53 (d, J= 8.80 Hz, 1H), 9.72 - 9.97 (m, 2H). LC-MS (Method A): r.t. 0.48 min, MS (ESI) m / z = 332.04 [M+H]+.

[0276] Example 86: 7-[4-(trifluoromethyl)-3-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4 -Boratricyclo[6.1.1.02,6]dec-4-yl]phenyl]phenolin-4-amine (86) bis[(+)-pinanediolyl]diboron (259.35 mg, 0.720 mmol), 7-[3-chloro-4-(trifluoromethyl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]phenoline-4-amine (130.0 mg, 0.240 mmol) and potassium acetate (71.08 mg, 0.720 mmol) were dissolved in 1,4-dioxane (2.5 mL) in a microwave vial and the mixture was deoxygenated under N2 for 10 min. Add palladium(II) diacetate (2.71 mg, 0.010 mmol) and dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (9.21 mg, 0.020 mmol ) and the mixture was deoxygenated for another 10 min under N2. Subsequently, the mixture was stirred at 80° C. for 4.5 hours. The mixture was filtered through a pad of Celite, washed with MeOH and the filtrate was concentrated. The residue was dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL) was added. The mixture was stirred for 8 hours then evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge, which was eluted first with MeOH and then with 2 M methanolic ammonia. The basic fraction was evaporated and dissolved by column chromatography (Sfar C18 D, consecutively 2 x 6 g) with a gradient of 2% to 95% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). The residue was isolated and purified. The obtained partially purified product was subjected to semi-preparative HPLC purification (column: Chiralpak IC (25 × 2.0 cm), 5 µm. Mobile phase: 80 / 20% v / v n-hexane / (ethanol + 0.1% iso Propylamine). Flow rate: 17 ml / min). Fractions containing the desired compound were collected and evaporated. The residue was dissolved in MeCN / water and lyophilized to give 7-[4-(trifluoromethyl)-3-[(1S,2S,6R,8S)-2,9,9-tris as a white powder Methyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl]phenyl]phenolin-4-amine (3.2 mg, 0.007 mmol, 2.9% yield ). 1H NMR (400 MHz, DMSO-d6) δ 0.90 (s, 3H), 1.28 (d,J= 10.80 Hz, 1H), 1.31 (s, 3H), 1.49 (s, 3H), 1.87 - 2.01 (m, 2H), 2.12 (t,J= 5.46 Hz, 1H), 2.24 - 2.33 (m, 1H), 2.40 - 2.47 (m, 1H), 4.62 (dd,J= 8.83, 2.08 Hz, 1H), 7.31 (s , 2H), 7.93 (d,J= 8.23 ​​Hz, 1H), 7.98 (dd,J= 8.80, 1.91 Hz, 1H), 8.16 (d,J= 8.57 Hz, 1H), 8.19 (s, 1H), 8.31 - 8.39 (m, 2H), 8.65 (s, 1H). LC-MS (Method A): r.t. 0.97 min, MS (ESI) m / z = 468.23 [M+H]+.

[0277] Example 87: [3-(1-amino-4-methylphthalein-6-yl)-4-(1,2-thiazol-4-amido)phenyl]acid (87) 1,2-Thiazole-4-carboxylic acid (26.98 mg, 0.210 mmol), triethylamine (0.04 mL, 0.300 mmol) and [dimethylamino(3-triazolo[4,5-b]pyridyloxy A solution of )methylene]-dimethylammonium hexafluorophosphate (93.9 mg, 0.250 mmol) in DMF (1.5 mL) was stirred at room temperature for 1 hour, followed by addition of 6-[2-amino-5-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl] - 4-Methylphthalein-1-amine (100.0 mg, 0.190 mmol) and the reaction mixture was stirred at 40 °C overnight. The reaction mixture was evaporated and the residue was purified by column chromatography (Sfar C18 D, 12 g) eluting with a gradient of 5% to 70% MeCN in water. Appropriate fractions were evaporated. The residue was dissolved in DCM (1 mL) and trifluoroacetic acid (1 mL) and the resulting mixture was stirred at room temperature for 3 h before it was evaporated in vacuo. The residue was dissolved with MeOH / H2O (9:1) and this solution was loaded onto an SCX cartridge (2 g), the cartridge was washed with MeOH / H2O (9:1) and then washed with 7 M ammonia in MeOH The solution dissolves. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 6 g) with gradient elution from 5% to 60% MeCN in water to afford [3-(1-amino-4-methanol) as a yellow solid Phthalophthal-6-yl)-4-(1,2-thiazole-4-carbonylamino)phenyl] acid (2.5 mg, 0.006 mmol, 3.248% yield). 1H NMR (400 MHz, DMSO-d6+ 2 drops of TFA) δ 3.08 (s, 3 H) 6.99 - 7.06 (m, 1 H) 7.76 (s, 2 H) 8.26 - 8.34 (m, 1 H) 8.48 - 8.55 ( m, 1 H) 8.61 - 8.68 (m, 1 H) 9.15 (s, 1 H) 9.92 (s, 1 H). LC-MS (Method A): r.t. 0.73 min, MS (ESI) m / z = 406.1 [M+H]+.

[0278] Example 88: [5-(4-aminophenolin-7-yl)-2-(trifluoromethyl)phenyl] acid formate (88) converts 7-[4-(trifluoroform Base)-3-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decane-4 -yl]phenyl]phenolin-4-amine (56.0 mg, 0.020 mmol) was dissolved in water (1 mL), MeCN (1 mL) and MeOH (1 mL) and formic acid (0.05 µL, 0.001 mmol) was added. The mixture was stirred at 40 °C for 3 days. Low conversion to acid product was observed. 6 M hydrochloric acid solution (2.0 mL, 12 mmol) was added and the mixture was stirred at 45°C for 24 hours. The mixture was partially evaporated, then diluted with MeOH and loaded onto an SCX cartridge. The cartridge was eluted first with MeOH and then with 2 M methanolic ammonia. The basic fraction was concentrated in vacuo and washed with 2% to 95% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH) by column chromatography (Sfar C18 D, sequentially 2 x SNAP 6). The residue was purified by gradient elution. Partial concentration of the appropriate fractions in vacuo and subsequent lyophilization afforded [5-(4-aminophenolin-7-yl)-2-(trifluoromethyl)phenyl]acid as a pale pink powder Formate salt (3 mg, 0.008 mmol, 36.69% yield). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 7.88 (d,J= 8.13 Hz, 1H), 7.96 - 8.06 (m, 2H), 8.12 - 8.16 (m, 1 H plus 1 H, from HCOOH) , 8.23 ​​(d,J= 8.88 Hz, 1H), 8.51 (s, 1H), 8.60 (d,J= 8.88 Hz, 1H), 9.82 (s, 1H), 9.97 (s, 1H). LC-MS (Method A): r.t. 0.46 min, MS (ESI) m / z = 334.07 [M+H]+.

[0279] Example 89: [5-(1-amino-4-methylphthalein-6-yl)-2-(2-methylpropionylamino)phenyl]acid (89) converts [5- [1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalein-6-yl]-2-(2-methylpropionylamino)phenyl] The acid (56.0 mg, 0.110 mmol) was dissolved in DCM (1.371 mL) and trifluoroacetic acid (1.371 mL) was added. The mixture was stirred for 2 hours. The mixture was evaporated in vacuo and eluted by column chromatography (Sfar C18 D, sequentially 2×SNAP6) with a gradient of 1% to 50% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). The residue was purified. Appropriate fractions were collected and lyophilized to afford partially pure product. This material was subjected to semi-preparative HPLC purification (column: Chiralpak IC (25 x 2.0 cm), 5 µm, mobile phase: 50 / 50% v / v n-hexane / (ethanol / methanol 1 / 1 + 0.1% isopropylamine ), flow rate: 17 ml / min). Fractions containing the product were collected and lyophilized to give [5-(1-amino-4-methylphthalein-6-yl)-2-(2-methylpropionylamino) as a white powder ) phenyl] acid (4 mg, 0.011 mmol, 10.1% yield). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 1.27 (d, J= 6.79 Hz, 6H), 2.81 (s, 3H), 3.01 (quintet, J= 6.91 Hz, 1H), 7.36 (d ,J= 8.27 Hz, 1H), 7.95 - 8.05 (m, 2H), 8.37 (s, 1H), 8.44 (d,J= 8.60 Hz, 1H), 8.75 (d,J= 8.57 Hz, 1H), 9.17 (br. s, 2H). LC-MS (Method A): r.t. 0.38 min, MS (ESI) m / z = 365.16 [M+H]+.

[0280] Example 90: 7-{2-fluoro-6-methoxy-3-[(1R,2R,6S,8R)-2,6,9,9-tetramethyl-3,5-diox Hetero-4-boratricyclo[6.1.1.02,6]dec-4-yl]phenyl}phenoline-4-amine (90)[3-(4-aminophenoline-7-yl)- 2-Fluoro-4-methoxyphenyl] acid (26.0 mg, 0.080 mmol) and (1R,3S,4R,5R)-3,4,6,6-tetramethylbicyclo[3.1.1]heptane A suspension of -3,4-diol (15.3 mg, 0.080 mmol) in THF (0.830 mL) was stirred at 45 °C for three hours, then it was evaporated in vacuo. The residue was purified by column chromatography (KP-sil silica gel, SNAP 10) with a gradient elution from 10% to 100% EtOAc containing EtOH to afford 7-{2-fluoro-6 as an off-white solid -Methoxy-3-[(1R,2R,6S,8R)-2,6,9,9-tetramethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6 ]dec-4-yl]phenyl}phenolin-4-amine (23 mg, 0.050 mmol, 60.03% yield). 1H NMR (400 MHz, DMSO-d6) δ 0.87 (s, 3H), 1.27 (s, 3H), 1.40 (s, 3H), 1.43 (s, 3H), 1.80 - 2.10 (m, 4H), 2.13 - 2.30 (m, 2H), 3.80 (s, 3H), 7.05 (d, J= 8.50 Hz, 1H), 7.21 (s, 2H), 7.44 - 7.55 (m, 1H), 7.60 - 7.72 (m, 1H) , 7.86 - 8.01 (m, 1H), 8.21 (d, J= 8.74 Hz, 1H), 8.63 (s, 1H). LC-MS (Method A): r.t. 0.92 min, MS (ESI) m / z = 462.3 [M+H]+.

[0281] Example 91: [3-(4-Aminothioline-7-yl)-4-{[1-(trifluoromethyl)cyclopropyl]methoxy}phenyl]acid formate ( 91) Palladium(II) diacetate (2.373 mg, 0.011 mmol), 7-[5-chloro-2-[[1-(trifluoromethyl)cyclopropyl]methoxy]phenyl]-N- [(2,4-Dimethoxyphenyl)methyl]phenoline-4-amine (115 mg, 0.211 mmol), dicyclohexyl-[2-[2,4,6-tri(propane-2- yl)phenyl]phenyl]phosphine (10 mg, 0.021 mmol), potassium acetate (62.24 mg, 0.634 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5- Tetramethyl-1,3,2-dioxaboroxane-2-yl)-1,3,2-dioxaboroxane (161.06 mg, 0.634 mmol) dissolved in 1,4-dioxane in a microwave vial (2.207 mL). The resulting reaction mixture was stirred at 75 °C for 2 h, then it was cooled to room temperature and filtered through celite, washing with EtOAc. The filtrate was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature overnight, then it was concentrated under reduced pressure. The residue was dissolved with MeOH, and this solution was loaded onto an SCX cartridge (5 g). The mixture was left standing on an SCX cartridge for 20 min, then it was eluted sequentially with MeOH / H2O (9:1) and 7 M ammonia in MeOH. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 30 g) eluting with a gradient of 1% to 30% MeCN (+0.1% HCOOH) in degassed aqueous solution (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give [3-(4-aminophenolin-7-yl)-4-[[1-(trifluoromethyl)cyclopropyl]methoxyl as a white solid phenyl] acid formate (26 mg, 0.058 mmol, 27.4% yield). 1H NMR (400 MHz, DMSO-d6) δ 0.92 - 1.04 (m, 4H), 4.22 (s, 2H), 7.15 (d, J = 8.39 Hz, 1H), 7.19 (s, 2H), 7.77 - 7.84 ( m, 2H), 7.97 (d, J = 1.71 Hz, 1H), 8.04 (s, 2H), 8.13 - 8.21 (m, 3H), 8.60 (s, 1H). LC-MS (Method A): r.t. 0.61 min, MS (ESI) m / z = 404.1 [M+H]+.

[0282] Example 92: [3-(4-amino-6-fluorophenolin-7-yl)-4-methoxyphenyl] acid formate (92) palladium (II) diacetate (5.44 mg, 0.020 mmol), 7-(5-chloro-2-methoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]-6-fluorosphenoline-4-amine (220.0 mg, 0.480 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (23.11 mg, 0.050 mmol), potassium acetate (142.71 mg , 1.45 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1, 3,2-Dioxaboroxane (0.37 g, 1.45 mmol) was dissolved in 1,4-dioxane (4.85 mL) in a microwave vial. The resulting reaction mixture was stirred at 75 °C for 2 h, then it was cooled to room temperature and filtered through celite, washing with EtOAc. The filtrate was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (1.5 mL). The resulting mixture was stirred at room temperature overnight, then it was concentrated under reduced pressure. The residue was dissolved with MeOH, and this solution was loaded onto an SCX cartridge (5 g). The mixture was left standing on an SCX cartridge for 20 min, then it was eluted with MeOH / H2O (9:1) followed by 7M methanolic ammonia solution. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 30 g) with gradient elution from 1% to 30% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give [3-(4-amino-6-fluorophenolin-7-yl)-4-methoxyphenyl] acid formate (45 mg, 0.125 mmol, yield 26%). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 3.80 (s, 3H), 7.18 (d,J= 8.47 Hz, 1H), 7.78 (d,J= 1.64 Hz, 1H), 7.87 (d,J = 6.31 Hz, 1H), 7.97 (dd,J= 8.30, 1.72 Hz, 1H), 8.11 (s, from HCOOH), 8.35 (d,J= 10.26 Hz, 1H), 8.48 (s, 1H), 9.70 - 9.80 (m, 2H). LC-MS (Method A): r.t. 0.45 min, MS (ESI) m / z = 314.1 [M+H]+.

[0283] Example 93: [5-(1-amino-4-methylphthalein-6-yl)-2-[(2-chlorobenzoyl)amino]phenyl]acid (93) [2-Amino-5-[1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalein-6-yl]phenyl]acid (150.0 mg, 0.340 mmol) in anhydrous THF (3.376 mL) was added 2-chlorobenzoyl chloride (43.16 µL, 0.340 mmol) dropwise. Then, triethylamine (94.11 µL, 0.680 mmol) was added and the mixture was stirred at room temperature under N2 atmosphere overnight. Water was added and the resulting mixture was extracted three times with DCM. The combined organic phases were filtered through a hydrophobic frit (phase separator) and evaporated. The residue was dissolved in DCM (3 mL) and trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 4 hours, then evaporated in vacuo. The residue was purified by column chromatography (Sfar C18 D, sequentially 2 x SNAP 6) with a gradient elution of 1% to 50% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). The obtained partially purified product was subjected to semi-preparative HPLC purification (MDAP Waters with mass spectrometry detection (MS: ZQ2000). Column: CSH C18 (30 × 100 mm, 3 µm). Conditions: [A1: water + 0.1% HCOOH]; [B1:MeCN]. Gradient: 10.0% B1 to 60.0% B1 in 10 min (flow rate: 40.00 mL / min)). Fractions containing the product were collected and lyophilized to give [5-(1-amino-4-methylphthalein-6-yl)-2-[(2-chlorobenzoyl) as a pale yellow powder )amino]phenyl]acid (6 mg, 0.014 mmol, 8.082% yield). 1H NMR (400 MHz, methanol-d4+ 2 drops TFA) δ 2.87 (s, 3H), 7.41 (d,J= 8.34 Hz, 1H), 7.55 - 7.63 (m, 1H), 7.65 - 7.72 (m, 2H) , 7.82 (d,J= 7.67 Hz, 1H), 7.93 (dd,J= 8.34, 2.25 Hz, 1H), 8.05 (d,J= 2.22 Hz, 1H), 8.43 (dd,J= 8.58, 1.78 Hz, 1H), 8.47 (d,J= 1.73 Hz, 1H), 8.63 (d,J= 8.56 Hz, 1H). LC-MS (Method A): r.t. 0.52 min, MS (ESI) m / z = 433.18 [M+H]+.

[0284] Examples 94 and 95: 7-(4-Aminothioline-7-yl)-3-methyl-3,4-dihydro-1H-2,1-benzoxaborinidine En-1-ol Enantiomer 1 (94) and Enantiomer 2 (95) Palladium(II) diacetate (4.47 mg, 0.020 mmol), 7-[4-[2-[tertiary Butyl(dimethyl)silyl]oxypropyl]-3-chlorophenyl]-N-[(2,4-dimethoxyphenyl)methyl]phenolin-4-amine (230.0 mg , 0.400 mmol), dicyclohexyl-[2-[2,4,6-tri(prop-2-yl)phenyl]phenyl]phosphine (15.17 mg, 0.030 mmol), potassium acetate (117.11 mg, 1.19 mmol ) and bis[(+)-pinanediolyl]diboron (427.32 mg, 1.19 mmol) were dissolved in 1,4-dioxane (5 mL) in a microwave vial and the mixture was deoxygenated under N for 10 min . Subsequently, the mixture was stirred at 80° C. for 20 hours. The mixture was filtered through Celite, washing with MeOH three times. The filtrate was concentrated in vacuo, then the residue was dissolved in DCM (30.95 mL) and trifluoroacetic acid (30.95 mL) was added. The mixture was stirred at room temperature for 6 hours, then evaporated and the residue loaded onto an SCX cartridge. The cartridge was eluted first with MeOH and then with 2 M methanolic ammonia. The basic fraction was evaporated and the residue was purified by column chromatography (Sfar C18 D, SNAP 30) with a gradient elution from 2% to 45% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH) things. Appropriate fractions were collected and lyophilized to give racemic 7-(1-hydroxy-3-methyl-3,4-dihydro-2,1-benzoxaborine as a light yellow powder Hexadien-7-yl) phenolin-4-amine (18 mg). This material was subjected to semi-preparative chiral HPLC purification (column Chiralcel OD-H (25 x 2.0 cm), 5 µm, 85 / 15% v / v n-hexane / (ethanol + 0.1% isopropylamine), flow rate: 17 ml / min). Fractions containing the two separated enantiomers were collected independently and evaporated, and the two residues were individually dissolved in MeCN / water and lyophilized to give enantiomer 17 as a white powder -(1-Hydroxy-3-methyl-3,4-dihydro-2,1-benzoxaborin-7-yl)phenolin-4-amine (5.2 mg, 0.017 mmol, Yield 4.25%) and enantiomer 2 7-(1-hydroxy-3-methyl-3,4-dihydro-2,1-benzoxaborinine as white powder -7-yl)phenolin-4-amine (5.7 mg, 0.019 mmol, 4.75% yield).

[0285] Characterization of Enantiomer 1: 1H NMR (400 MHz, DMSO-d6) δ 1.33 (d, J= 6.16 Hz, 3 H), 2.78 (dd, J= 16.07, 10.12 Hz, 1 H), 2.95 (dd,J= 16.18, 3.19 Hz, 1H), 4.27 - 4.39 (m, 1H), 7.22 (s, 2H), 7.36 (d,J= 7.92 Hz, 1H), 7.87 - 7.97 ( m, 2H), 8.21 (d, J= 1.98 Hz, 1H), 8.27 - 8.32 (m, 2H), 8.61 (s, 2H). LC-MS (Method A): r.t. 0.56 min, MS (ESI) m / z = 306.25 [M+H]+. Analytical chiral HPLC: column Chiralcel OD-H (25 × 0.46 cm), 5 μm mobile phase: 85 / 15% v / v n-hexane / (ethanol + 0.1% isopropylamine), flow rate: 1.0 ml / min ), DAD 220 nm ring 20 µL, 100% a / a enantiomer 1 by UV (14.8 min), enantiomer 2 not detected.

[0286] Characterization of enantiomer 2: 1H NMR (400 MHz, DMSO-d6) δ 1.33 (d, J= 6.16 Hz, 3 H), 2.78 (dd, J= 17.17, 10.10 Hz, 1 H), 2.95 (dd,J= 16.07, 3.30 Hz, 1H), 4.27 - 4.39 (m, 1H), 7.22 (s, 2H), 7.36 (d,J= 7.92 Hz, 1H), 7.88 - 7.96 ( m, 2H), 8.21 (d, J= 1.98 Hz, 1H), 8.27 - 8.32 (m, 2H), 8.61 (s, 2H). LC-MS (Method A): r.t. 0.56 min, MS (ESI) m / z = 306.29 [M+H]+. Analytical chiral HPLC: column Chiralcel OD-H (25 × 0.46 cm), 5 μm mobile phase: 85 / 15% v / v n-hexane / (ethanol + 0.1% isopropylamine), flow rate: 1.0 ml / min , DAD 220 nm loop 20 µL, 1% a / a enantiomer 1 by UV (15.1 min), 99% a / a enantiomer 2 by UV (19.5 min).

[0287] Example 96: 7-{2-methoxy-5-[(1S,2R,6S,8S)-2,6-dimethyl-3,5-dioxa-4-boratricyclic [6.1.1.02,6]dec-4-yl]phenyl}phenolin-4-amine (96)[3-(4-aminophenolin-7-yl)-4-methoxyphenyl] acid (50.0 mg, 0.160 mmol) and (1R,3S,4R,5R)-3,4,6,6-tetramethylbicyclo[3.1.1]heptane-3,4-diol (29.35 mg, 0.160 mmol) in THF (1.5 mL) was stirred overnight at 50 °C, then it was evaporated in vacuo. The residue was triturated with diethyl ether and the resulting solid was filtered, washed with diethyl ether and dried to give 7-{2-methoxy-5-[(1S,2R,6S,8S)-2 as an off-white solid ,6-Dimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl]phenyl}phenolin-4-amine (50 mg, 0.113 mmol, Yield 70.81%). 1H NMR (400 MHz, DMSO-d6) δ 0.88 (s, 3H), 1.27 (s, 3H), 1.28 - 1.33 (m, 1H), 1.41 (s, 3H), 1.44 (s, 3H), 1.89 - 2.01 (m, 2H), 2.04 (t, J= 5.60 Hz, 1H), 2.09 - 2.20 (m, 1H), 2.27 (dd, J= 14.85, 4.27 Hz, 1H), 3.84 (s, 3H), 7.17 - 7.27 (m, 3H), 7.64 - 7.70 (m, 2H), 7.72 (dd,J= 8.23, 1.69 Hz, 1H), 8.05 (d,J= 1.76 Hz, 1H), 8.20 (d,J= 8.71 Hz, 1H), 8.60 (s, 1H). LC-MS (Method A): r.t. 0.92 min, MS (ESI) m / z = 444.3 [M+H]+.

[0288] Example 97: [3-(4-Aminothioline-7-yl)-4-(difluoromethoxy)-2-fluorophenyl] acid formate (97) step 1: Di Palladium(II) acetate (2.68 mg, 0.010 mmol), 7-[3-chloro-6-(difluoromethoxy)-2-fluorophenyl]-N-[(2,4-dimethoxybenzene Base) methyl] phenolin-4-amine (117.0 mg, 0.240 mmol), dicyclohexyl-[2-[2,4,6-tri(prop-2-yl)phenyl]phenyl]phosphine (9.11 mg, 0.020 mmol), potassium acetate (70.32 mg, 0.720 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-di Boroxane-2-yl)-1,3,2-dioxaboroxane (181.95 mg, 0.720 mmol) was dissolved in 1,4-dioxane (1.95 mL) in a microwave vial and the mixture was desorbed with Ar. Air for 10 min. Subsequently, the mixture was stirred at 90° C. for 4 hours. The mixture was filtered, washed with MeOH and the filtrate was concentrated in vacuo. LC-MS (Method A): r.t. 0.92 min, MS (ESI) m / z = 582.3 [M+H]+.

[0289] Step 2: The crude material from Step 1 was dissolved in DCM (1.76 mL) and trifluoroacetic acid (1.06 mL) and the mixture was stirred at room temperature overnight before it was concentrated under reduced pressure. The residue was dissolved in MeOH / H2O (9:1) and loaded onto an SCX cartridge (5 g). The cartridge was washed with MeOH / H2O (9:1) and the product was eluted from the SCX cartridge with 2 M NH3 in MeOH. The basic fraction was evaporated and eluted by column chromatography (KP-C18-HS, ​​30 g) with a gradient of 2% to 20% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). The residue was purified. Fractions containing the desired compound were pooled and lyophilized to afford [3-(4-aminophenolin-7-yl)-4-(difluoromethoxy)-2-fluorophenyl as a white solid ] Acid formate (15.9 mg, 0.040 mmol, 7.3% yield). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 7.24 (d,J= 8.36 Hz, 1H), 7.30 (t,J= 73.07 Hz, 1H), 7.74 - 7.87 (m, 2H), 7.89 (s , 1H), 8.13 (s, 1H, from HCOOH), 8.84 - 8.57 (m, 2H), 9.83 (br s, 1H), 9.95 (br s, 1H). LC-MS (Method A): r.t. 0.41 min, MS (ESI) m / z = 350.02 [M+H]+.

[0290] Example 98: [3-(4-aminophenolin-7-yl)-4-[(1,2-thiazol-4-yl)methoxy]phenyl]acid (98) Step 1: Palladium(II) diacetate (4.74 mg, 0.020 mmol), 7-[5-chloro-2-(1,2-thiazol-4-ylmethoxy)phenyl]-N-[(2,4- Dimethoxyphenyl)methyl]phenolin-4-amine (219.0 mg, 0.420 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]benzene phosphine (16.09 mg, 0.030 mmol), potassium acetate (124.23 mg, 1.27 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1, 3,2-Dioxaboroxane-2-yl)-1,3,2-dioxaboroxane (321.46 mg, 1.27 mmol) was dissolved in 1,4-dioxane (4.635 mL). The mixture was degassed with Ar for 10 min, then stirred at 75 °C for 6 h. The mixture was filtered through a pad of Celite, washed with EtOAc and the filtrate was concentrated in vacuo.

[0291] Step 2: The crude material from Step 1 was dissolved in a mixture of DCM (3 mL) and trifluoroacetic acid (3 mL). The mixture was stirred overnight at room temperature and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge (5 g). The cartridge was washed with MeOH / H2O (9:1) and the product was then eluted from the SCX cartridge with a 2 M solution of NH3 in MeOH. The volatiles were evaporated and the residue was purified by column chromatography (KP-C18-HS, ​​SNAP 30 g) with gradient elution from 2% to 30% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH) things. Fractions containing partially purified product were collected and evaporated. The recovered solid was subjected to semi-preparative HPLC purification (Chiralcel OJ-H (25 x 2.0 cm), 5 µm, 70 / 30% v / v n-hexane / (EtOH + 0.1% isopropylamine)). Fractions containing the desired compound were collected and evaporated under reduced pressure. The residue was dissolved in CHCN and water and lyophilized to give 3-(4-aminophenolin-7-yl)-4-(1,2-thiazol-4-ylmethoxy)benzene as a white powder base] acid (18 mg, 0.048 mmol, yield 11.3%). 1H NMR (400 MHz, DMSO-d6+2D TFA) δ 5.36 (s, 2H), 7.34 (d,J= 8.76 Hz, 1H), 7.89 - 7.98 (m, 2H), 8.00 - 8.06 (m, 2H ), 8.39 - 8.53 (m, 2H), 8.66 (s, 1H), 9.03 (s, 1H), 9.70 (s, 1H), 9.82 (s, 1H). LC-MS (Method A): r.t. 0.47 min, MS (ESI) m / z = 379.12 [M+H]+.

[0292] Example 99: 7-(4-Aminothioline-7-yl)-5-fluoro-3,4-dihydro-1H-2,1-benzoxaborin-1 -Alcohol formate (99) Step 1: Palladium(II) diacetate (6.23 mg, 0.028 mmol), 7-[4-[2-[tertiary butyl(dimethyl)silyl]oxyethyl Base]-3-chloro-5-fluorophenyl]-N-[(2,4-dimethoxyphenyl)methyl]phenolin-4-amine (323.0 mg, 0.555 mmol), dicyclohexyl- [2-[2,4,6-Tri(propan-2-yl)phenyl]phenyl]phosphine (21.16 mg, 0.045 mmol), potassium acetate (163.35 mg, 1.66 mmol) and bis[(+)-pinene Alkanediolyl]diboron (596.02 mg, 1.66 mmol) was dissolved in 1,4-dioxane (6.46 mL). The mixture was degassed with Ar for 10 min, then stirred at 80 °C for 24 h. The mixture was filtered through a pad of celite, washing with MeOH and the filtrate was concentrated in vacuo.

[0293] Step 2: The crude material from Step 1 was dissolved in a mixture of DCM (6 mL) and trifluoroacetic acid (6 mL). The mixture was stirred at room temperature for 6 hours and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge (10 g). The cartridge was washed with MeOH, then the product was eluted from the SCX cartridge with 2 M NH3 in MeOH. Volatiles were evaporated and the residue was purified by column chromatography (KP-C18-HS, ​​SNAP 30 g) with gradient elution from 2% to 45% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH) thing. Fractions containing product were collected and lyophilized to give 7-(5-fluoro-1-hydroxy-3,4-dihydro-2,1-benzoxaborin- 7-yl)phenoline-4-amine formate (19 mg, 0.054 mmol, 9.7%). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 2.94 (t,J= 5.96 Hz, 2H), 4.15 (t,J= 5.97 Hz, 2H), 7.26 (s, 2H), 7.84 (dd,J = 10.92, 1.82 Hz, 1H), 7.97 (dd,J= 8.82, 1.96 Hz, 1H), 8.09 (d,J= 1.80 Hz, 1H), 8.14 (s, 1 H from HCOOH), 8.30 (d, J= 8.82 Hz, 1H), 8.35 (d, J= 1.88 Hz, 1H), 8.61 (s, 1H), 8.80 (br. s, 1H). LC-MS (Method A): r.t. 0.52 min, MS (ESI) m / z = 310.15 [M+H]+.

[0294] Example 100: [7-(4-Aminothioline-7-yl)-1-benzofuran-5-yl] acid formate (100) Step 1: Palladium(II) diacetate ( 3.47 mg, 0.020 mmol), 7-(5-chloro-1-benzofuran-7-yl)-N-[(2,4-dimethoxyphenyl)methyl]phenoline-4-amine ( 138.0 mg, 0.310 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (11.8 mg, 0.020 mmol), potassium acetate (91.12 mg, 0.930 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3 , 2-Dioxaboroxane (235.77 mg, 0.930 mmol) was dissolved in 1,4-dioxane (2.3 mL) in a microwave vial and the mixture was degassed with Ar for 10 min. Subsequently, the mixture was stirred at 70° C. for 1.5 hours. The mixture was filtered, washed with MeOH and the filtrate was concentrated in vacuo. LC-MS (Method A): r.t. 0.96 min, MS (ESI) m / z = 538.3 [M+H]+.

[0295] Step 2: The crude material from Step 1 was dissolved in DCM (2.5 mL) and trifluoroacetic acid (1.5 mL) and the mixture was stirred at room temperature overnight before it was concentrated under reduced pressure. The residue was dissolved in MeOH / H2O (9:1) and loaded onto an SCX cartridge (5 g). The cartridge was washed with MeOH / H2O (9:1) and the product was eluted from the SCX cartridge with 2 M NH3 in MeOH. The basic fraction was evaporated and eluted by column chromatography (KP-C18-HS, ​​30 g) with a gradient of 2% to 20% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH). The residue was purified. Fractions containing the desired compound were collected and concentrated to give [7-(4-aminophenolin-7-yl)-1-benzofuran-5-yl]acid formate (22.7 mg , 0.065 mmol, yield 7.569%). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 7.15 (d,J= 2.20 Hz, 1H), 8.12 (s, 1H, from HCOOH), 8.15 (d,J= 2.20 Hz, 1H), 8.24 ( s, 1H), 8.27 (s, 1H), 8.35 (dd,J= 9.02, 1.54 Hz, 1H), 8.48 - 8.51 (m, 2H), 8.61 (d,J= 9.02 Hz, 1H), 9.76 (s , 1H), 9.93 (s, 1H). LC-MS (Method A): r.t. 0.48 min, MS (ESI) m / z = 306.2 [M+H]+.

[0296] Example 101: 7-[2-(difluoromethoxy)-5-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa- 4-boratricyclo[6.1.1.02,6]dec-4-yl]phenyl]phenoline-4-amine (101)[3-(4-aminophenoline-7-yl)-4- (Difluoromethoxy)phenyl] acid (700.0 mg, 2.11 mmol) and (1S,3R,4S,5S)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4 - A suspension of diol (359.96 mg, 2.11 mmol) in THF (28 mL) was stirred at 45 °C overnight, then the mixture was concentrated in vacuo. The residue was triturated with diethyl ether. The solid was collected by filtration and dried in an oven at 45 °C for 48 h to give 7-{2-difluoromethoxy-5-[(1S,2S,6R,8S)-2,9 as a white solid ,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl]phenyl}phenolin-4-amine (658 mg, 1.414 mmol, Yield 66.88%). 1H NMR (400 MHz, DMSO-d6) δ 0.88 (s, 3H), 1.07 - 1.13 (m, 1 H), 1.29 (3 H, s), 1.46 (3 H, s), 1.87 (d,J= 14.75 Hz, 1H) 1.92 (br. s, 1H), 2.11 (t,J= 5.50 Hz, 1H), 2.20 - 2.28 (m, 1H), 2.41 (dd,J= 14.31, 8.80 Hz, 1H) , 4.57 (dd,J= 8.69, 1.65 Hz, 1H), 7.25 (s, 2 H), 7.31 (t,J= 72.8 Hz 1 H) 7.41 (d,J= 8.58 Hz, 1H), 7.69 (dd, J= 8.80, 1.76 Hz, 1H), 7.81 - 7.86 (m, 2H), 8.10 (d,J= 1.54 Hz, 1H), 8.26 (d,J= 8.80 Hz, 1H), 8.65 (s, 1H ). LC-MS (Method A): r.t. 0.92 min, MS (ESI) m / z= 466.25 [M+H]+.

[0297] Example 102: 7-[2-(difluoromethoxy)-5-[(1R,2R,6S,8R)-2,6,9,9-tetramethyl-3,5-diox Hetero-4-boratricyclo[6.1.1.02,6]dec-4-yl]phenyl]phenoline-4-amine (102)[3-(4-aminophenoline-7-yl)- 4-(Difluoromethoxy)phenyl]acid (50.0 mg, 0.150 mmol) and (1R,3S,4R,5R)-3,4,6,6-tetramethylbicyclo[3.1.1]heptane - A suspension of 3,4-diol (27.27 mg, 0.150 mmol) in THF (1.5 mL) was stirred at 50 °C overnight and then it was evaporated in vacuo. The residue was triturated with diethyl ether, the solvent was decanted and the solid residue was collected and dried to give 7-[2-(difluoromethoxy)-5-[(1R,2R,6S,8R) as an off-white solid -2,6,9,9-tetramethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl]phenyl]phenoline-4-amine ( 45 mg, 0.094 mmol, yield 63.43%). 1H NMR (400 MHz, DMSO-d6) δ 0.89 (s, 3H), 1.28 (s, 3H), 1.30 (d,J= 10.68 Hz, 1H), 1.43 (s, 3H), 1.47 (s, 3H) , 1.91 - 2.03 (m, 2H), 2.06 (t,J= 5.59 Hz, 1H), 2.11 - 2.22 (m, 1H), 2.29 (dd,J= 14.88, 4.23 Hz, 1H), 7.25 (br.s , 2H), 7.30 (t,J= 73.55 Hz, 1H), 7.39 (d,J= 8.55 Hz, 1H), 7.68 (dd,J= 8.73, 1.81 Hz, 1H), 7.80 (m, 2H), 8.09 (d,J= 1.78 Hz, 1H), 8.26 (d,J= 8.78 Hz, 1H), 8.65 (s, 1H). LC-MS (Method A): r.t. 0.96 min, MS (ESI) m / z = 480.3 [M+H]+.

[0298] Example 103: 7-{2-methoxy-5-[(1S,2S,6R,8S)-2,6,9,9-tetramethyl-3,5-dioxa-4- Boratricyclo[6.1.1.02,6]dec-4-yl]phenyl}phenoline-4-amine (103)[3-(4-aminophenoline-7-yl)-4-methoxy phenyl] acid (50.0 mg, 0.170 mmol) and (1S,3R,4S,5S)-3,4,6,6-tetramethylbicyclo[3.1.1]heptane-3,4-diol ( 31.22 mg, 0.170 mmol) in THF (1.597 mL) was stirred at 50°C for 24 hours. No product formation was observed. MeOH (0.1 mL) was added and the mixture became a clear solution. The reaction was stirred for 24 hours before it was evaporated in vacuo. The residue was loaded onto an SCX cartridge, which was eluted first with MeOH and then with 2 M methanolic NH3 solution. The basic fraction was evaporated and the residue was dissolved in MeCN / HO and lyophilized to give 7-{2-methoxy-5-[(1S,2S,6R,8S)-2, as a white solid. 6,9,9-Tetramethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl]phenyl}phenoline-4-amine (60 mg, 0.135 mmol, yield 79.87%). 1H NMR (400 MHz, DMSO-d6) δ 0.89 (s, 3H), 1.28 (s, 3H), 1.32 (d,J= 10.59 Hz, 1H), 1.42 (s, 3H), 1.46 (s, 3H) , 1.90 - 2.02 (m, 2H), 2.03 - 2.09 (m, 1H), 2.10 - 2.21 (m, 1H), 2.28 (dd,J= 14.76, 4.16 Hz, 1H), 3.85 (s, 3H), 7.13 - 7.23 (m, 3H), 7.65 - 7.75 (m, 3H), 8.06 (d,J= 1.72 Hz, 1H), 8.20 (d,J= 8.77 Hz, 1H), 8.62 (s, 1H). LC-MS (Method A): r.t. 0.94 min, MS (ESI) m / z = 444.27 [M+H]+.

[0299] Example 104: [7-(1-Amino-4-methylphthalein-6-yl)-1-benzofuran-5-yl]acid (104) Step 1: Palladium(II) diacetate ) (1.81 mg, 0.010 mmol), 6-(5-chloro-1-benzofuran-7-yl)-N-[(2,4-dimethoxyphenyl)methyl]-4-methyl Phthalo-1-amine (74.0 mg, 0.160 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (6.14 mg, 0.010 mmol) and potassium acetate (47.37 mg, 0.480 mmol) were dissolved in 1,4-dioxane (1.5 mL) in a microwave vial and the mixture was degassed with Ar for 10 min. Add 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2- Boron dioxide (122.57 mg, 0.480 mmol) and the mixture was degassed under Ar for another 10 minutes. Subsequently, the mixture was stirred at 75°C for 3 hours. The mixture was filtered, washed with methanol and the filtrate was concentrated in vacuo. LC-MS (Method A): r.t. 0.99 min, MS (ESI) m / z = 552.3 [M+H]+.

[0300] Step 2: The crude material from Step 1 was dissolved in DCM (1.25 mL) and trifluoroacetic acid (0.75 mL) and the mixture was stirred at room temperature overnight before it was concentrated under reduced pressure. The residue was dissolved in MeOH / H2O (9:1) and loaded onto an SCX cartridge (2 g). The cartridge was washed with MeOH / H2O (9:1) and the product was eluted from the SCX cartridge with 2 M NH3 in MeOH. The basic fraction was evaporated and the residue was purified by column chromatography (KP-C18-HS, ​​12 g) with a gradient elution from 2% to 20% MeCN in water (+0.1% HCOOH). Fractions containing the desired compound were pooled and lyophilized to give [7-(1-amino-4-methylphthalein-6-yl)-1-benzofuran-5-yl] as a white solid Acid (15 mg, 0.047 mmol, 29.4% yield). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 2.81 (s, 3H), 7.15 (d,J= 2.2 Hz, 1H), 8.11 - 8.17 (m, 1H), 8.23 ​​(s, 1H), 8.26 (s, 1H), 8.65 (dd,J= 8.58, 1.54 Hz, 1H), 8.68 (d,J= 1.32 Hz, 1H), 8.81 (d,J= 8.58 Hz, 1H), 9.22 (br.s, 2H). LC-MS (Method A): r.t. 0.53 min, MS (ESI) m / z = 320.2 [M+H]+.

[0301] Example 105: [3-(4-aminophenolin-7-yl)-4-(1,1,2,2-tetrafluoroethoxy)phenyl] acid formate (105) Palladium(II) diacetate (5.38 mg, 0.020 mmol), 7-[5-chloro-2-(1,1,2,2-tetrafluoroethoxy)phenyl]-N-[(2,4- Dimethoxyphenyl)methyl]phenolin-4-amine (250.0 mg, 0.480 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]benzene phosphine (22.84 mg, 0.050 mmol), potassium acetate (141.04 mg, 1.44 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1, 3,2-dioxaboroxane-2-yl)-1,3,2-dioxaboroxane (360 mg, 1.44 mmol) was dissolved in 1,4-dioxane (4.79 mL) in a microwave vial and Degas with N2 for 10 min. The resulting reaction mixture was stirred at 75 °C for 2 h, then it was cooled to room temperature and filtered through celite, washing with EtOAc. The filtrate was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL). The resulting mixture was stirred at room temperature for 4 hours, then it was concentrated under reduced pressure. The residue was dissolved with MeOH and this solution was loaded onto an SCX cartridge (5 g), which was washed with MeOH / H20 (9:1) and then eluted with 7 M ammonia in MeOH. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​30 g) with gradient elution from 1% to 70% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give [3-(4-aminophenolin-7-yl)-4-(1,1,2,2-tetrafluoroethoxy)benzene as a white solid ] acid formate salt (21 mg, 0.049 mmol, yield 10.1%). 1H NMR (400 MHz, DMSO-d6) δ 6.51 (t,J= 51.90 Hz, 1H), 7.24 (s, 2H), 7.44 - 7.52 (m, 1H), 7.67 (dd,J= 8.75, 1.81 Hz, 1H), 7.93 (dd,J= 8.20, 1.71 Hz, 1H), 8.10 (d,J= 1.71 Hz, 1H), 8.12 (d,J= 1.77 Hz, 1H), 8.17 (s, from HCOOH), 8.25 (d,J= 8.75 Hz, 1H), 8.33 (s, 2H), 8.64 (s, 1H). LC-MS (Method A): r.t. 0.54 min, MS (ESI) m / z = 382.4 [M+H]+.

[0302] Example 106: [3-(4-Aminothioline-7-yl)-4-(1,2,2,2-tetrafluoroethoxy)phenyl]acid (106) Step 1: Make 7-[5-Chloro-2-(1,2,2,2-tetrafluoroethoxy)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]phenoline-4 -amine (100.0 mg, 0.190 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2- A mixture of -1,3,2-dioxaboroxane (145.97 mg, 0.570 mmol) and potassium acetate (56.41 mg, 0.570 mmol) in 1,4-dioxane (2.8 mL) was desorbed under argon After 10 min, dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (7.31 mg, 0.020 mmol) and palladium(II) diacetate ( 2.15 mg, 0.010 mmol) and the mixture was stirred at 70°C for 1 hour. Subsequently, the temperature was raised to 85°C and the mixture was stirred for 26 hours. The reaction mixture was cooled to room temperature and filtered through a pad of Celite, washed with MeOH and EtOAc, and the filtrate was concentrated in vacuo. LC-MS (Method A): r.t. 1.00 min, MS (ESI) m / z = 614.2 [M+H]+.

[0303] Step 2: The crude material from Step 1 was combined with a similar crude from 27 mg 7-[5-chloro-2-(1,2,2,2-tetrafluoroethane oxy)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]phenolin-4-amine. This material was dissolved in trifluoroacetic acid (2 mL) and DCM (2 mL) and the mixture was stirred at room temperature for 6 h before the volatiles were removed under reduced pressure. The residue was dissolved in MeOH / H2O (9:1), then loaded onto an SCX cartridge (5 g), the cartridge was washed with MeOH / H2O (9:1) and then washed with a 2 M solution of ammonia in MeOH Dissolution. The basic fractions were collected and evaporated under reduced pressure. The residue was purified twice by column chromatography (Sfar C18 D, 12 g) eluting with a gradient of 1% to 25% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized. The residue was subjected to semi-preparative HPLC purification (CSH C18 (30 x 100 mm, 3 µm); gradient from 18.0% to 30.0% MeCN in water + 0.1% HCOOH) to afford [3-(4-amine phenolin-7-yl)-4-(1,2,2,2-tetrafluoroethoxy)phenyl] acid (6.5 mg, 0.017 mmol, 8.9% yield). 1H NMR (400 MHz, DMSO-d6+ 3 drops TFA) δ 6.90 (dd,J= 56.91, 3.01 Hz, 1H), 7.41 (d,J= 8.17 Hz, 1H), 7.88 (dd,J= 8.84, 1.51 Hz , 1H), 7.93 (d,J= 1.35 Hz, 1H), 7.98 - 8.02 (m, 2H), 8.06 (s, 0.12 H from HCOOH), 8.47 (s, 1H), 8.50 (d,J= 8.88 Hz, 1H), 9.72 (s, 1H), 9.84 (s, 1H). LC-MS (Method A): r.t. 0.55 min, MS (ESI) m / z = 382.1 [M+H]+.

[0304] Example 107: [3-(4-Aminothioline-7-yl)-4-[2-(2-methoxyethoxy)ethoxy]phenyl] acid formate (107 ) Palladium (II) diacetate (3.0 mg, 0.010 mmol), 7-[5-chloro-2-[2-(2-methoxyethoxy)ethoxy]phenyl]-N-[( 2,4-dimethoxyphenyl)methyl]phenolin-4-amine (140.0 mg, 0.270 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl) Phenyl]phenyl]phosphine (10.19 mg, 0.020 mmol), potassium acetate (78.66 mg, 0.800 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl 1,3,2-dioxaboroxane-2-yl)-1,3,2-dioxaboroxane (203.54 mg, 0.800 mmol) dissolved in 1,4-dioxane (3.5 mL) and degassed with N2 for 10 min. The resulting reaction mixture was stirred at 80 °C for 1 h, then it was cooled to room temperature and filtered through celite, washing with EtOAc. The filtrate was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (3 mL). The resulting mixture was stirred overnight at room temperature before it was evaporated in vacuo. The residue was dissolved in MeOH / H2O (9:1), loaded onto an SCX cartridge and the cartridge was allowed to sit for 20 min. Subsequently, the cartridge was washed with MeOH / HO (9:1) and the product was eluted with 7 M methanolic ammonia solution. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by flash chromatography (Sfar C18 D, 12 g) eluting with a gradient of 1% to 15% MeCN (+0.1% HCOOH) in water (+ 0.1% HCOOH). Appropriate fractions were collected and lyophilized to give [3-(4-aminophenolin-7-yl)-4-[2-(2-methoxyethoxy)ethoxyl as a white powder ]phenyl] acid formate (45 mg, 0.105 mmol, 38.88% yield). 1H NMR (400 MHz, DMSO-d6) δ 3.17 (s, 3H), 3.37 - 3.43 (m, 2H), 3.49 - 3.54 (m, 2H), 3.66 - 3.79 (m, 2H), 4.18 - 4.25 (m , 2H), 7.16 (d,J= 8.36 Hz, 1H), 7.21 (s, 2H), 7.81 - 7.87 (m, 2H), 7.97 (d,J= 1.73 Hz, 1H), 8.01 (s, 2H) , 8.15 (s, 1 H from HCOOH), 8.17 - 8.20 (m, 2H), 8.61 (s, 1H). LC-MS (Method A): r.t. 0.47 min, MS (ESI) m / z = 384.2 [M+H]+.

[0305] Example 108: [5-(4-Aminothioline-7-yl)-4-(difluoromethoxy)-2-methylphenyl]acid (108) Step 1: Make 7-[ 5-Chloro-2-(difluoromethoxy)-4-methylphenyl]-N-[(2,4-dimethoxyphenyl)methyl]phenolin-4-amine (100.0 mg, 0.210 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3 , a mixture of 2-dioxaboroxane (156.78 mg, 0.620 mmol), potassium acetate (60.59 mg, 0.620 mmol) in 1,4-dioxane (3.75 mL) was degassed under Ar for 10 min, followed by addition of dioxane Cyclohexyl-[2-[2,4,6-tri(prop-2-yl)phenyl]phenyl]phosphine (7.85 mg, 0.020 mmol) and palladium(II) diacetate (2.31 mg, 0.010 mmol) and The mixture was stirred at 70°C for 1 hour. Subsequently, the temperature was raised to 95 °C and the mixture was stirred overnight. The mixture was cooled to RT, diluted with MeOH and filtered through celite, washed with MeOH and EtOAc, and the filtrate was concentrated in vacuo. LC-MS (Method A): r.t. 1.01 min, MS (ESI) m / z = 578.2 [M+H]+.

[0306] Step 2: The crude material from Step 1 was dissolved in trifluoroacetic acid (2 mL) and DCM (2 mL) and the mixture was stirred at room temperature for 6 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in MeOH / H2O (9:1), then loaded onto an SCX cartridge (5 g), which was washed with MeOH / H2O (9:1) and It was then eluted with 2 M ammonia in MeOH. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 12 g) eluting with a gradient of 1% to 30% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give a pale yellow solid which was subjected to semi-preparative HPLC purification (Chiralpak AS-H (25 × 2.0 cm), 5 µm, 80 / 20% v / v n-hexane / (EtOH + 0.1% isopropylamine)) to give [5-(4-aminophenolin-7-yl)-4-(difluoromethoxy)-2-methylphenyl]acid (7.4 mg, 0.021 mmol, yield 10.0%). 1H NMR (400 MHz, DMSO-d6+ 6 drops of TFA) δ 2.49-2.51 (s, 3H peak masked by DMSO-d5 solvent peak), 7.07 (t,J= 74.08 Hz, 1H), 7.10 (s, 1H) , 7.70 (s, 1H), 7.88 (d,J= 9.86 Hz, 1H), 7.94 (s, 1H), 8.02 (s, 0.26 H from HCOOH), 8.43 (d,J= 2.52 Hz, 1H), 8.47 (d,J= 8.70 Hz, 1H), 9.64 (s, 1H), 9.79 (s, 1H). LC-MS (Method A): r.t. 0.51 min, MS (ESI) m / z = 346.1 [M+H]+.

[0307] Example 109: [3-(4-aminoquinolin-7-yl)-4-methoxyphenyl] acid formate (109) palladium(II) diacetate (5.16 mg, 0.020 mmol ), 7-(5-chloro-2-methoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]quinolin-4-amine (200.0 mg, 0.460 mmol), Dicyclohexyl-[2-[2,4,6-tri(prop-2-yl)phenyl]phenyl]phosphine (17.54 mg, 0.040 mmol), potassium acetate (135.39 mg, 1.38 mmol) and 4,4 ,5,5-Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborol (350.33 mg, 1.38 mmol) was dissolved in 1,4-dioxane (5 mL) in a microwave vial and degassed with N2 for 10 min. The resulting reaction mixture was stirred at 80 °C for 2 h, then it was cooled to room temperature and filtered through celite, washing with EtOAc. The filtrate was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (2 mL). The resulting mixture was stirred overnight at room temperature before it was evaporated in vacuo. The residue was dissolved in MeOH / H2O (9:1), loaded onto an SCX cartridge and the cartridge was allowed to sit for 20 min. Subsequently, the cartridge was washed with MeOH / H2O (9:1) and eluted with 7 M methanolic ammonia solution. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 12 g) eluting with a gradient of 1% to 15% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give [3-(4-aminoquinolin-7-yl)-4-methoxyphenyl] acid formate (38 mg, 0.112 mmol) as a white powder , yield 24.34%). 1H NMR (400 MHz, DMSO-d6) δ 3.85 (s, 3H), 6.79 (dd,J= 6.93, 1.03 Hz, 1H), 7.19 (m, 1H), 7.83 (dd,J= 8.78, 1.66 Hz, 1H), 7.88 - 7.93 (m, 2H), 8.01 (d,J= 1.66 Hz, 1H), 8.13 (s, 1 H from HCOOH), 8.39 - 8.47 (m, 2H), 8.89 - 8.98 (m, 2H). LC-MS (Method A): r.t. 0.46 min, MS (ESI) m / z = 295.2 [M+H]+.

[0308] Example 110: [3-(4-Aminothioline-7-yl)-4-[2-(oxol-2-yl)ethoxy]phenyl]acid (110) Palladium(II) acetate (3.89 mg, 0.020 mmol), 7-[5-chloro-2-[2-(oxolan-2-yl)ethoxy]phenyl]-N-[(2,4 -Dimethoxyphenyl)methyl]phenolin-4-amine (180.0 mg, 0.346 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl] Phenyl]phosphine (16.5 mg, 0.030 mmol), potassium acetate (101.91 mg, 1.04 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaboroxane-2-yl)-1,3,2-dioxaboroxane (263.7 mg, 1.04 mmol) dissolved in 1,4-dioxane (3.45 mL) in a microwave vial And degas with N2 for 10 min. The resulting reaction mixture was stirred at 80 °C for 2 h, then it was cooled to room temperature and filtered through celite, washing with EtOAc. The filtrate was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (1.5 mL). The resulting mixture was stirred at room temperature for 4 hours, then it was concentrated under reduced pressure. The residue was dissolved with MeOH and this solution was loaded onto an SCX cartridge (5 g), which was washed with MeOH / H20 (9:1) and then eluted with 7 M ammonia in MeOH. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​30 g) with gradient elution from 1% to 70% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give [3-(4-aminophenolin-7-yl)-4-[2-(oxolan-2-yl)ethoxyl as a pale yellow solid. phenyl]acid (40 mg, 0.105 mmol, 30.3% yield). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 1.28 - 1.49 (m, 1H), 1.64 - 1.79 (m, 2H), 1.79 - 1.94 (m, 3H), 3.54 (q,J= 7.43 Hz, 1H), 3.69 (q,J= 7.16 Hz, 1H), 3.82 (quin,J= 6.77 Hz, 1H), 4.07 - 4.18 (m, 2H), 7.13 (d,J= 8.12 Hz, 1H), 7.83 - 8.06 (m, 4H), 8.36 - 8.51 (m, 2H), 9.62 (br. s, 1H), 9.76 (br. s, 1H). LC-MS (Method A): r.t. 0.53 min, MS (ESI) m / z = 380.3 [M+H]+.

[0309] Example 111: [3-(1-Amino-4-methylisoquinolin-6-yl)-4-methoxyphenyl]acid (111) palladium(II) diacetate (3.5 mg , 0.020 mmol), 6-(5-chloro-2-methoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]-4-methylisoquinoline-1- Amine (140.0 mg, 0.310 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (14.87 mg, 0.030 mmol), potassium acetate (91.81 mg, 0.940 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1 , 3,2-dioxaboroxane (0.24 g, 0.940 mmol) was dissolved in 1,4-dioxane (3.11 mL) in a microwave vial and degassed with N2 for 10 min. The resulting reaction mixture was stirred at 80 °C for 2 h, then it was cooled to room temperature and filtered through celite, washing with EtOAc. The filtrate was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (1.5 mL). The resulting mixture was stirred at room temperature for 4 hours, then it was concentrated under reduced pressure. The residue was dissolved with MeOH and this solution was loaded onto an SCX cartridge (5 g), which was washed with MeOH / H20 (9:1) and then eluted with 7 M ammonia in MeOH. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​30 g) with gradient elution from 1% to 70% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give [3-(1-amino-4-methylisoquinolin-6-yl)-4-methoxyphenyl]acid (28 mg , 0.091 mmol, yield 29.4%). 1H NMR (400 MHz, DMSO-d6) δ 2.36 (s, 3H), 3.81 (s, 3H), 6.64 (s, 2H), 7.13 (d,J= 8.27 Hz, 1H), 7.61 (dd,J= 8.62, 1.67 Hz, 1H), 7.65 (s, 1H), 7.77 - 8.07 (m, 4H), 8.17 (s, 1H), 8.21 (d,J= 8.64 Hz, 1H). LC-MS (Method A): r.t. 0.53 min, MS (ESI) m / z = 309.2 [M+H]+.

[0310] Example 112: [3-(4-Aminothioline-7-yl)-4-[2-(oxol-3-yl)ethoxy]phenyl]acid formate (112 ) Palladium (II) diacetate (3.24 mg, 0.010 mmol), 7-[5-chloro-2-[2-(oxolane-3-yl)ethoxy]phenyl]-N-[( 2,4-dimethoxyphenyl)methyl]phenoline-4-amine (150.0 mg, 0.290 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl) Phenyl]phenyl]phosphine (11.0 mg, 0.020 mmol), potassium acetate (84.93 mg, 0.870 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl 1,3,2-dioxaboroxane-2-yl)-1,3,2-dioxaboroxane (219.75 mg, 0.870 mmol) dissolved in 1,4-dioxane (3 mL) and degassed with N2 for 10 min. The resulting reaction mixture was stirred at 80 °C for 1 h, then it was cooled to room temperature and filtered through celite, washing with EtOAc. The filtrate was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (2.5 mL) and trifluoroacetic acid (2.5 mL). The resulting mixture was stirred overnight at room temperature before it was evaporated in vacuo. The residue was dissolved in MeOH / H2O (9:1), loaded onto an SCX cartridge and the cartridge was allowed to sit for 20 min. Subsequently, the cartridge was washed with MeOH / H2O (9:1) and eluted with 7 M methanolic ammonia solution. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 12 g) eluting with a gradient of 1% to 15% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give [3-(4-aminophenolin-7-yl)-4-[2-(oxolan-3-yl)ethoxyl as a white powder ]phenyl] acid formate (45 mg, 0.106 mmol, 36.55% yield). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 1.38 - 1.55 (m, 1H), 1.72 - 1.85 (m, 2H), 1.89 - 2.01 (m, 1H), 2.16 - 2.27 (m, 1H), 3.16 - 3.25 (m, 1H), 3.52 - 3.61 (m, 1H), 3.61 - 3.74 (m, 2H), 4.08 - 4.16 (m, 2H), 7.21 (d,J= 8.27 Hz, 1H), 7.87 - 7.95 (m, 2H), 7.97 - 8.05 (m, 2H), 8.13 (s, 1H from HCOOH), 8.44 - 8.51 (m, 2H), 9.71 (br. s, 1H), 9.83 (br. s, 1H). LC-MS (Method A): r.t. 0.51 min, MS (ESI) m / z = 380.3 [M+H]+.

[0311] Example 113: 7-{2-methoxy-5-[(1R,2R,6S,8R)-2,9,9-trimethyl-3,5-dioxa-4-bora Tricyclo[6.1.1.02,6]dec-4-yl]phenyl}phenoline-4-amine (113)[3-(4-aminophenoline-7-yl)-4-methoxybenzene base] acid (50.0 mg, 0.170 mmol) and (1R,3S,4R,5R)-3,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol (28.85 mg, 0.170 mmol) in THF (1.5 mL) was stirred overnight at 50 °C and then evaporated in vacuo. The residue was triturated with diethyl ether, the solvent was decanted and the solid residue collected and dried in an oven at 50 °C overnight. 1H NMR showed the presence of residual diethyl ether, so the solid was suspended in cyclohexane, filtered and dried to give 7-{2-methoxy-5-[(1R,2R,6S,8R) as a white solid -2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl]phenyl}phenoline-4-amine (36 mg , 0.084 mmol, yield 49.49%). 1H NMR (400 MHz, DMSO-d6) δ 0.88 (s, 3H), 1.07 - 1.12 (m, 1H), 1.29 (s, 3H), 1.45 (s, 3H), 1.80 - 1.96 (m, 2H), 2.10 (t,J= 5.47 Hz, 1H), 2.16 - 2.29 (m, 1H), 2.35 - 2.46 (m, 1H), 3.86 (s, 3H), 4.53 (dd,J= 8.68, 1.81 Hz, 1H) , 7.19 (br. s, 2H), 7.23 (d,J= 8.36 Hz, 1H), 7.67 - 7.73 (m, 2H), 7.77 (dd,J= 8.25, 1.69 Hz, 1H), 8.08 (d,J = 1.73 Hz, 1H), 8.21 (d,J= 8.79 Hz, 1H), 8.62 (s, 1H). LC-MS (Method A): r.t. 0.91 min, MS (ESI) m / z = 430.3 [M+H]+.

[0312] Example 114: [3-(4-Aminothioline-7-yl)-4-[(4,4-dimethyloxol-2-yl)methoxy]phenyl]acid (114) Step 1: Palladium(II) diacetate (4.77 mg, 0.020 mmol), 7-[5-chloro-2-[(4,4-dimethyloxol-2-yl)methoxy Base]phenyl]-N-[(2,4-dimethoxyphenyl)methyl]phenolin-4-amine (227.0 mg, 0.430 mmol), dicyclohexyl-[2-[2,4, 6-tris(prop-2-yl)phenyl]phenyl]phosphine (16.21 mg, 0.030 mmol), potassium acetate (125.14 mg, 1.28 mmol) and 4,4,5,5-tetramethyl-2-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborol (323.81 mg, 1.28 mmol) was dissolved in 1,4 - in dioxane (5 mL). The mixture was degassed with N2 for 10 min, then stirred at 75 °C for 6 h. The mixture was filtered through a pad of celite, washing with MeOH and the filtrate was concentrated in vacuo.

[0313] Step 2: The crude material from Step 1 was dissolved in a mixture of DCM (3.11 mL) and trifluoroacetic acid (3.11 mL). The mixture was stirred overnight at room temperature and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge (10 g). The cartridge was washed with MeOH / H2O (9:1) and the product was then eluted from the SCX cartridge with a 2 M solution of NH3 in MeOH. The volatiles were evaporated and the residue was purified by column chromatography (KP-C18-HS, ​​SNAP 30 g) with gradient elution from 2% to 30% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH) things. Appropriate fractions were collected and lyophilized to afford partially pure product. This material was subjected to semi-preparative HPLC purification (Chiralpak AD-H (25 x 2.0 cm), 5 µm, 75 / 25% v / v n-hexane / (ethanol / methanol 1 / 1 + 0.1% isopropylamine)). Fractions containing product were collected and evaporated under reduced pressure, then the residue was dissolved in CHCN and water and lyophilized to give [3-(4-aminophenolin-7-yl)-4 as a white powder - [(4,4-Dimethyloxol-2-yl)methoxy]phenyl] acid (45.21 mg, 0.115 mmol, 27.05% yield). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 0.92 (s, 3H), 1.01 (s, 3H), 1.42 - 1.54 (m, 1H), 1.64 - 1.79 (m, 1H), 3.23 - 3.37 ( m, 2H), 4.00 - 4.18 (m, 2H), 4.24 - 4.33 (m, 1H), 7.20 (d,J= 8.37 Hz, 1H), 7.89 - 7.94 (m, 2H), 7.98 (d,J= 1.53 Hz, 1H), 8.03 (dd,J= 8.87, 1.55 Hz, 1H), 8.46 - 8.51 (m, 2H), 9.70 (s, 1H), 9.83 (s, 1H). LC-MS (Method A): r.t. 0.58 min, MS (ESI) m / z = 394.16 [M+H]+.

[0314] Example 115: [3-(4-Aminothioline-7-yl)-4-(2-cyclopropylethoxy)phenyl] acid formate (115) step 1: 7- [5-Chloro-2-(2-cyclopropylethoxy)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]phenolin-4-amine (292.0 mg, 0.600 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3, A mixture of 2-dioxoboroxane (453.99 mg, 1.79 mmol) and potassium acetate (175.45 mg, 1.79 mmol) in 1,4-dioxane (6.5 mL) was degassed under argon for 10 min, followed by the addition of di Cyclohexyl-[2-[2,4,6-tri(prop-2-yl)phenyl]phenyl]phosphine (22.73 mg, 0.050 mmol) and palladium(II) diacetate (6.69 mg, 0.030 mmol) and The mixture was stirred at 80°C for 2 hours. The mixture was cooled to rt, then diluted with MeOH and filtered through celite, washed with MeOH and EtOAc, and the filtrate was evaporated under reduced pressure. LC-MS (Method A): r.t. 1.05 min, MS (ESI) m / z = 582.4 [M+H]+.

[0315] Step 2: The crude material from Step 1 was dissolved in trifluoroacetic acid (4 mL) and DCM (6 mL) and the mixture was stirred at room temperature for 3 hours, then the volatiles were removed under reduced pressure. The residue was dissolved in MeOH / H2O (9:1) and loaded onto an SCX cartridge (10 g), the cartridge was washed with MeOH / H2O (9:1) and then dissolved with a 7 M solution of ammonia in MeOH. leave. The basic fractions were collected and evaporated under reduced pressure, and washed with 1% to 35% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH) by column chromatography (Sfar C18 D, 30 g). The residue was purified by gradient elution. Appropriate fractions were collected and lyophilized to give [3-(4-aminophenolin-7-yl)-4-(2-cyclopropylethoxy)phenyl]carboxylic acid formic acid as an off-white solid Salt (91 mg, 0.230 mmol, 38.3% yield). 1H NMR (400 MHz, DMSO-d6+ 3 drops TFA) δ -0.13 - 0.17 (m, 2H), 0.21 - 0.59 (m, 2H), 0.76 (dtt,J= 12.02, 7.32, 3.71 Hz, 1H), 1.61 (q,J= 6.45 Hz, 2H), 4.14 (t,J= 6.42 Hz, 2H), 7.20 (d,J= 8.32 Hz, 1H), 7.84 - 7.95 (m, 2H), 7.97 - 8.03 (m, 2H), 8.12 (s, 0.56 H, HCOOH), 8.47 (d, J= 8.77 Hz, 1H), 8.47 (s, 1H), 9.69 (s, 1H), 9.81 (s, 1H). LC-MS (Method A): r.t. 0.62 min, MS (ESI) m / z = 350.3 [M+H]+.

[0316] Example 116: [5-(1-Amino-4-methylphthalein-6-yl)-2-cyano-4-methoxyphenyl] acid formate (116) Step 1: 2-chloro-4-[1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalein-6-yl]-5-methoxybenzonitrile ( 169 mg, 0.280 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)- A mixture of 1,3,2-dioxaboroxane (214.15 mg, 0.840 mmol) and potassium acetate (82.76 mg, 0.840 mmol) in 1,4-dioxane (5 mL) was degassed under argon for 10 min , followed by addition of dicyclohexyl-[2-[2,4,6-tri(prop-2-yl)phenyl]phenyl]phosphine (10.72 mg, 0.020 mmol) and palladium(II) diacetate (3.16 mg, 0.010 mmol) and the mixture was stirred at 85°C for 2 hours. The mixture was cooled to room temperature, then diluted with MeOH and filtered through celite, washed with MeOH and EtOAc, and the filtrate was evaporated in vacuo. LC-MS (Method A): r.t. 0.68 min, MS (ESI) m / z = 485.3 [M+H]+.

[0317] Step 2: The crude material from Step 1 was dissolved in trifluoroacetic acid (1.8 mL) and DCM (3 mL) and the mixture was stirred at room temperature for 3 hours, then the volatiles were removed under reduced pressure. The residue was dissolved in MeOH / H2O (9:1), then loaded onto an SCX cartridge (5 g), the cartridge was washed with MeOH / H2O (9:1) and then washed with a 2 M solution of ammonia in MeOH Dissolution. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 30 g) eluting with a gradient of 1% to 25% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give an off-white solid, which was subjected to semi-preparative HPLC purification (CSH C18 (30 x 100 mm, 3 µm), gradient from 1.0% to 40.0 MeCN in water + 0.1% HCOOH) to give [5-(1-Amino-4-methylphthalein-6-yl)-2-cyano-4-methoxyphenyl] acid formate (10 mg, 0.026 mmol, Yield 9.3%). 1H NMR (400 MHz, DMSO-d6+ 5 drops TFA) δ 2.72 (s, 3H), 3.89 (s, 3H), 7.59 (s, 1H), 7.94 (s, 1H), 8.09 (s, 1H, from HCOOH ), 8.27 (dd,J= 8.55, 1.57 Hz, 1H), 8.32 (d,J= 1.42 Hz, 1H), 8.70 (d,J= 8.52 Hz, 1H), 9.15 (s, 2H). LC-MS (Method A): r.t. 0.48 min, MS (ESI) m / z = 335.1 [M+H]+.

[0318] Example 117: [3-(4-Aminothioline-7-yl)-4-cyclobutoxyphenyl]acid (117) Palladium(II) diacetate (3.3 mg, 0.010 mmol), 7-(5-Chloro-2-cyclobutyloxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]phenolin-4-amine (140.0 mg, 0.290 mmol), Dicyclohexyl-[2-[2,4,6-tri(prop-2-yl)phenyl]phenyl]phosphine (14.02 mg, 0.030 mmol), potassium acetate (86.6 mg, 0.880 mmol) and 4,4 ,5,5-Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborol (224.08 mg, 0.880 mmol) was dissolved in 1,4-dioxane (2.7 mL) in a microwave vial and degassed with N2 for 10 min. The resulting reaction mixture was stirred at 80 °C for 2 h, then it was cooled to room temperature and filtered through celite, washing with EtOAc. The filtrate was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL). The resulting mixture was stirred at room temperature for 4 hours, then it was concentrated under reduced pressure. The residue was dissolved with MeOH and this solution was loaded onto an SCX cartridge (5 g), which was washed with MeOH / H20 (9:1) and then eluted with 7 M ammonia in MeOH. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​30 g) with gradient elution from 1% to 70% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give [3-(4-aminophenolin-7-yl)-4-cyclobutyloxyphenyl]acid (34 mg, 0.101 mmol, Yield 34.8%). 1H NMR (400 MHz, DMSO-d6+ 3 drops TFA) δ 1.61 - 1.70 (m, 1H), 1.71 - 1.82 (m, 1H), 1.97 - 2.09 (m, 2H), 2.38 - 2.48 (m, 2H), 4.72 - 4.85 (m, 1H), 6.97 (d,J= 8.38 Hz, 1H), 7.85 (d,J= 8.21 Hz, 1H), 7.95 (s, 1H), 7.99 (d,J= 8.93 Hz, 1H ), 8.09 (d,J= 4.23 Hz, 1H), 8.42 - 8.48 (m, 2H), 9.64 (br. s, 1H), 9.78 (br. s, 1H). LC-MS (Method A): r.t. 0.56 min, MS (ESI) m / z = 336.1 [M+H]+.

[0319] Example 118: [3-(4-aminophenolin-7-yl)-4-(2,2,2-trifluoroethoxy)phenyl] acid formate (118) diacetic acid Palladium(II) (2.63 mg, 0.010 mmol), 7-[5-chloro-2-(2,2,2-trifluoroethoxy)phenyl]-N-[(2,4-dimethoxy Phenyl)methyl]phenolin-4-amine (118.0 mg, 0.230 mmol), dicyclohexyl-[2-[2,4,6-tri(prop-2-yl)phenyl]phenyl]phosphine ( 8.93 mg, 0.020 mmol), potassium acetate (68.95 mg, 0.700 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- Boroxane-2-yl)-1,3,2-boroxane (178.4 mg, 0.700 mmol) was dissolved in 1,4-dioxane (2.5 mL) in a microwave vial and degassed with N2 10 min. The resulting reaction mixture was stirred at 80 °C for 1 h, then it was cooled to room temperature and filtered through celite, washing with EtOAc. The filtrate was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (2 mL). The resulting mixture was stirred overnight at room temperature before it was evaporated in vacuo. The residue was dissolved in MeOH / H2O (9:1), loaded onto an SCX cartridge and the cartridge was allowed to sit for 20 min. Subsequently, the cartridge was washed with MeOH / H2O (9:1) and eluted with 7 M methanolic ammonia solution. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 12 g) eluting with a gradient of 5% to 20% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give [3-(4-aminophenolin-7-yl)-4-(2,2,2-trifluoroethoxy)phenyl] acid formate ( 32 mg, 0.078 mmol, yield 33.91%). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 4.88 (q,J= 8.78 Hz, 2H), 7.32 (d,J= 8.79 Hz, 1H), 7.87 - 8.01 (m, 4H), 8.13 (s , 1H from HCOOH), 8.43 - 8.53 (m, 2H), 9.74 (br. s, 1H), 9.84 (br. s, 1H). LC-MS (Method A): r.t. 0.52 min, MS (ESI) m / z = 364.1 [M+H]+.

[0320] Example 119: [4-(4-Aminozoline-7-yl)-2-methyl-1,3-benzoxazol-6-yl]acid formate (119) step 1: 7-(6-Chloro-2-methyl-1,3-benzoxazol-4-yl)-N-[(2,4-dimethoxyphenyl)methyl]phenoline-4- Amine (136.0 mg, 0.300 mmol), potassium acetate (86.87 mg, 0.890 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3, A mixture of 2-dioxaboroxane-2-yl)-1,3,2-dioxaboroxane (224.79 mg, 0.890 mmol) was dissolved in 1,4-dioxane (8.435 mL) and the mixture was washed with Ar Degas for 10 minutes. Palladium(II) diacetate (3.31 mg, 0.010 mmol) was added and the mixture was degassed for 10 minutes, then stirred at 75°C for 1 hour. The mixture was cooled to room temperature, then diluted with EtOAc and MeOH, filtered and the filtrate concentrated in vacuo. LC-MS (Method A): r.t. 0.93 min, MS (ESI) m / z = 553.3 [M+H]+.

[0321] Step 2: The crude material from Step 1 was dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL) and stirred at room temperature overnight, then the reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeOH / H2O (9:1) and loaded onto an SCX cartridge (5 g). The cartridge was washed with MeOH / H2O (9:1) and the product was eluted from the SCX cartridge with 2 M NH3 in MeOH. The basic fraction was evaporated and washed with 2% to 20% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH) by column chromatography (KP-C18-HS, ​​6 g + 6 g consecutively) The residue was purified by gradient elution. Appropriate fractions were collected and lyophilized to give [4-(4-aminophenolin-7-yl)-2-methyl-1,3-benzoxazol-6-yl as a yellowish solid ] Acid formate (5.4 mg, 0.015 mmol, 5% yield). 1H NMR (400 MHz, DMSO-d6+ 3 drops TFA) δ 2.71 (s, 3H), 8.11 (s, 1H), 8.14 (s, 1H from HCOOH), 8.29 (s, 1H), 8.43 (d,J = 10.56 Hz, 1H), 8.49 (s, 1H), 8.59 (d,J= 9.02 Hz, 1H), 8.71 (d,J= 1.54 Hz, 1H), 9.73 (br. s, 1H), 9.89 (br . s, 1H). LC-MS (Method A): r.t. 0.43 min, MS (ESI) m / z = 321.1 [M+H]+.

[0322] Example 120: [3-(4-Aminophenoline-7-yl)-4-(propan-2-ylaminoformyl)phenyl] acid formate (120) step 1: di Palladium(II) acetate (2.06 mg, 0.010 mmol), 4-chloro-2-[4-[(2,4-dimethoxyphenyl)methylamino]phenolin-7-yl]-N- Propan-2-ylbenzamide formate (90 mg, 0.169 mmol), dicyclohexyl-[2-[2,4,6-tri(prop-2-yl)phenyl]phenyl]phosphine ( 6.99 mg, 0.010 mmol), potassium acetate (53.97 mg, 0.550 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- Dioxaboroxane-2-yl)-1,3,2-dioxaboroxane (139.65 mg, 0.550 mmol) was dissolved in 1,4-dioxane (3 mL). The mixture was degassed with N2 for 10 min, then stirred at 75 °C for 3 h. The mixture was filtered through a pad of celite, washing with MeOH and the filtrate was concentrated in vacuo.

[0323] Step 2: The crude material from Step 1 was dissolved in a mixture of DCM (1 mL) and trifluoroacetic acid (1 mL). The mixture was stirred overnight at room temperature and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge (10 g). The cartridge was washed with MeOH / H2O (9:1) and the product was then eluted from the SCX cartridge with a 2 M solution of NH3 in MeOH. Volatiles were evaporated and dissolved by column chromatography (KP-C18-HS, ​​2 × SNAP 12 g consecutively) with a gradient of 2% to 25% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The residue was isolated and purified. Appropriate fractions were collected and lyophilized to give [3-(4-aminophenolin-7-yl)-4-(propan-2-ylaminoformyl)phenyl]carboxylic acid formic acid as a white powder Salt (12 mg, 0.030 mmol, 17.7% yield). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 0.93 (d,J= 6.60 Hz, 6H), 3.82 - 3.93 (m, 1H), 7.50 (d,J= 7.51 Hz, 1H), 7.77 (dd ,J= 8.75, 1.66 Hz, 1H), 7.83 (d,J= 1.63 Hz, 1H), 7.89 - 7.96 (m, 2H), 8.11 (s, 0.77 H from HCOOH), 8.21 (d,J= 7.81 Hz, 1H), 8.43 - 8.49 (m, 2H), 9.74 (s, 1H), 9.86 (s, 1H). LC-MS (Method A): r.t. 0.36 min, MS (ESI) m / z = 351.26 [M+H]+.

[0324] Example 121: [3-(4-Aminozoline-7-yl)-4-{[(2R,4S,6S)-2,6-dimethyloxoalk-4-yl]oxy}phenyl]acid (121) Step 1: Palladium(II) diacetate (4.41 mg, 0.020 mmol), 7-(5-chloro-2-{[(2R,4s,6S)-2,6-di Methyloxalk-4-yl]oxy}phenyl)-N-[(2,4-dimethoxyphenyl)methyl]phenolin-4-amine (210.0 mg, 0.390 mmol), potassium acetate (115.77 mg, 1.18 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl) - 1,3,2-Dioxaboroxane (299.56 mg, 1.18 mmol) was dissolved in 1,4-dioxane (13 mL) and the mixture was degassed with Ar for 10 min. Subsequently, the mixture was stirred at 75°C for 3 hours. The mixture was filtered, washed with methanol and the filtrate was concentrated in vacuo. LC-MS (Method A): r.t. 0.98 min, MS (ESI) m / z = 426.5 [M+H]+.

[0325] Step 2: The crude material from Step 1 was dissolved in DCM (3 mL) and trifluoroacetic acid (3 mL), stirred at room temperature for 10 h, then it was concentrated under reduced pressure. The residue was dissolved in MeOH / H2O (9:1) and loaded onto an SCX cartridge (5 g). The cartridge was washed with MeOH / H2O (9:1) and the product was eluted from the SCX cartridge with 2 M NH3 in MeOH. The basic fraction was evaporated and washed with 2% to 20% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH) by column chromatography (KP-C18-HS, ​​consecutively 12 g + 12 g) The residue was purified by gradient elution. Fractions containing the desired compound were collected and lyophilized to give [3-(4-aminophenolin-7-yl)-4-{[(2R,4s,6S)-2,6 as a white solid -Dimethyloxan-4-yl]oxy}phenyl]acid (58 mg, 0.147 mmol, 37.7% yield). 1H NMR (400 MHz, DMSO-d6) δ 0.91 - 1.02 (m, 6H), 1.31 - 1.43 (m, 2H), 1.80 (br. d,J= 12.6 Hz, 2H), 3.51 - 3.65 (m, 2H ), 4.89 (quin,J= 2.5 Hz, 1H), 7.15 (d,J= 8.5 Hz, 1H), 7.21 (br. s, 2H), 7.78 - 7.84 (m, 2H), 7.97 (d,J= 1.6 Hz, 1H), 8.02 (br. s, 2H), 8.12 - 8.25 (m, 2H), 8.61 (s, 1H). LC-MS (Method A): r.t. 0.52 min, MS (ESI) m / z = 394.2 [M+H]+.

[0326] Example 122: [7-(4-Aminozoline-7-yl)-2-methyl-1,3-benzoxazol-5-yl]acid formate (122) Step 1: Palladium(II) diacetate (0.66 mg, 0 mmol), 7-(5-chloro-2-methyl-1,3-benzoxazol-7-yl)-N-[(2,4-di Methoxyphenyl)methyl]phenolin-4-amine (27.0 mg, 0.060 mmol), potassium acetate (17.25 mg, 0.180 mmol) and 4,4,5,5-tetramethyl-2-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborol (44.63 mg, 0.180 mmol) was dissolved in 1,4-di Oxane (1.6 mL) and the mixture was degassed with Ar for 10 min. Subsequently, the mixture was stirred at 75° C. for 1 hour. The mixture was filtered, washed with methanol and the filtrate was concentrated in vacuo. LC-MS (Method A): r.t. 0.88 min, MS (ESI) m / z = 553.3 [M+H]+.

[0327] Step 2: The crude material from Step 1 was dissolved in DCM (2 mL) and trifluoroacetic acid (1 mL) and stirred at room temperature overnight before it was concentrated under reduced pressure. The residue was dissolved in MeOH / H2O (9:1) and loaded onto an SCX cartridge (2 g). The cartridge was washed with MeOH / H2O (9:1) and the product was eluted from the SCX cartridge with 2 M NH3 in MeOH. The basic fraction was evaporated and washed with 2% to 20% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH) by column chromatography (KP-C18-HS, ​​6 g + 6 g consecutively) The residue was purified by gradient elution. Appropriate fractions were collected and lyophilized to give [7-(4-aminophenolin-7-yl)-2-methyl-1,3-benzoxazol-5-yl as a brownish solid ] Acid formate (2.5 mg, 0.007 mmol, 11.7% yield). 1H NMR (400 MHz, DMSO-d6+ TFA drops) δ 2.71 (s, 3H), 8.14 (s, 1H from HCOOH), 8.22 (s, 1H), 8.27 (s, 1H), 8.35 (dd,J= 9.02, 1.32 Hz, 1H), 8.45 (d,J= 1.10 Hz, 1H), 8.52 (s, 1H), 8.62 (d,J= 9.02 Hz, 1H), ), 9.80 (br.s, 1H), 9.97 (br. s, 1H). LC-MS (Method A): r.t. 0.42 min, MS (ESI) m / z = 321.1 [M+H]+.

[0328] Example 123: [3-(4-Aminozoline-7-yl)-4-{[(2R,4R,6S)-2,6-dimethyloxane-4-yl]oxy}phenyl] acid formate (123) step 1: Palladium(II) diacetate (2.71 mg, 0.010 mmol), 7-(5-chloro-2-{[(2R,4r,6S)-2, 6-Dimethyloxan-4-yl]oxy}phenyl)-N-[(2,4-dimethoxyphenyl)methyl]phenoline-4-amine formate (140.0 mg, 0.240 mmol), potassium acetate (71.06 mg, 0.720 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboron (2-yl)-1,3,2-dioxaboroxane (183.87 mg, 0.720 mmol) was dissolved in 1,4-dioxane (8.7 mL) and the mixture was degassed with Ar for 10 min. Subsequently, the mixture was stirred at 75° C. for 90 minutes. The mixture was filtered, washed with methanol and the filtrate was concentrated in vacuo. LC-MS (Method A): r.t. 1.00 min, MS (ESI) m / z = 626.4 [M+H]+.

[0329] Step 2: The crude material from Step 1 was dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL) and stirred at room temperature overnight, then concentrated under reduced pressure. The residue was dissolved in MeOH / H2O (9:1) and loaded onto an SCX cartridge (5 g). The cartridge was washed with MeOH / H2O (9:1) and the product was eluted from the SCX cartridge with 2 M NH3 in MeOH. The basic fraction was evaporated and washed with 2% to 20% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH) by column chromatography (KP-C18-HS, ​​consecutively 12 g + 12 g) The residue was purified by gradient elution. Appropriate fractions were collected and lyophilized to give [3-(4-aminophenolin-7-yl)-4-{[(2R,4r,6S)-2,6-dimethyl as a white solid oxalk-4-yl]oxy}phenyl] acid formate salt (10.3 mg, 0.023 mmol, 9.6% yield). ( m, 1H), 7.31 (d,J= 8.58 Hz, 1H), 7.89 (dd,J= 8.36,1.76 Hz, 1H), 7.96 (d,J= 1.54 Hz, 1H), 7.98 (dd,J= 8.80 , 1.54 Hz, 1H), 8.08 (d,J= 1.32 Hz, 1H), 8.13 (s, 1H from HCOOH), 8.45 - 8.50 (m, 2H), 9.69 (s, 1H), 9.81 (s, 1H ). LC-MS (Method A): r.t. 0.54 min, MS (ESI) m / z = 394.2 [M+H]+.

[0330] Example 124: [3-(4-Aminothioline-7-yl)-4-(pyrrolidine-1-carbonyl)phenyl]acid (124) Step 1: Palladium(II) diacetate ( 3.24 mg, 0.010 mmol), [4-chloro-2-[4-[(2,4-dimethoxyphenyl)methylamino]phenolin-7-yl]phenyl]-pyrrolidine-1 Dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (10.99 mg, 0.020 mmol), acetic acid Potassium (84.87 mg, 0.860 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl )-1,3,2-dioxaboroxane (219.61 mg, 0.860 mmol) was dissolved in 1,4-dioxane (3.5 mL). The mixture was degassed with N2 for 10 min, then stirred at 75 °C for 3 h. The mixture was filtered through a pad of celite, washing with MeOH and the filtrate was concentrated in vacuo.

[0331] Step 2: The crude material from Step 1 was dissolved in a mixture of DCM (2 mL) and trifluoroacetic acid (2 mL). The mixture was stirred overnight at room temperature and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge (10 g). The cartridge was washed with MeOH / H2O (9:1) and the product was then eluted from the SCX cartridge with a 2 M solution of NH3 in MeOH. The volatiles were evaporated and the residue was purified by column chromatography (KP-C18-HS, ​​SNAP 30 g) with gradient elution from 2% to 30% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH) things. Appropriate fractions were collected and lyophilized to afford partially pure product. This material was subjected to semi-preparative HPLC purification (column: Chiralpak AD-H (25 × 2.0 cm), 5 µm, mobile phase: 70 / 30% v / v n-hexane / (EtOH + 0.1% isopropylamine), mobile Rate: 17 ml / min). Fractions containing product were collected and evaporated under reduced pressure. The residue was dissolved in CHCN and water and lyophilized to give [3-(4-aminophenolin-7-yl)-4-(pyrrolidine-1-carbonyl)phenyl]acid (22 mg, 0.061 mmol, yield 21.07%). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 1.56 - 1.72 (m, 4H), 2.96 (t,J= 6.55 Hz, 2H), 3.30 (t,J= 6.74 Hz, 2H), 7.47 (dd ,J= 7.61, 1.78 Hz, 1H), 7.80 - 7.87 (m, 2H), 7.97 (dd,J= 7.57, 1.14 Hz, 1H), 8.02 (s, 1H), 8.47 - 8.52 (m, 2H), 9.78 (s, 1H), 9.90 (s, 1H). LC-MS (Method A): r.t. 0.40 min, MS (ESI) m / z = 363.22 [M+H]+.

[0332] Example 125: [4-(1-Amino-4-methylphthalein-6-yl)-2-methyl-1,3-benzoxazol-6-yl]acid formate ( 125) Step 1: Palladium(II) diacetate (2.03 mg, 0.010 mmol), 6-(6-chloro-2-methyl-1,3-benzoxazol-4-yl)-N-[( 2,4-dimethoxyphenyl)methyl]-4-methylphthalein-1-amine (86.0 mg, 0.180 mmol), potassium acetate (53.31 mg, 0.540 mmol) and 4,4,5,5 -Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaboroxine (137.95 mg, 0.540 mmol) was dissolved in 1,4-dioxane (5.3 mL) and the mixture was degassed with Ar for 10 min. Subsequently, the mixture was stirred at 75° C. for 1 hour. The reaction mixture was filtered, washed with methanol and the filtrate was concentrated in vacuo. LC-MS (Method A): r.t. 0.97 min, MS (ESI) m / z = 567.3 [M+H]+.

[0333] Step 2: The crude material from Step 1 was dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL) and stirred at room temperature overnight, then concentrated under reduced pressure. The residue was dissolved in MeOH / H2O (9:1) and loaded onto an SCX cartridge (2 g). The cartridge was washed with MeOH / H2O (9:1) and the product was eluted from the SCX cartridge with 2 M NH3 in MeOH. The basic fraction was evaporated and the crude was subjected to semi-preparative HPLC purification [CSH C18 (2.1 x 50 mm, 1.7 µm), 3% to 99.9% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH) Gradient]. Appropriate fractions were collected and lyophilized to give [4-(1-amino-4-methylphthalethyl-6-yl)-2-methyl-1,3-benzoxazole as a white solid - 6-yl] acid formate (16.1 mg, 0.042 mmol, 23.3% yield). 1H NMR (400 MHz, DMSO-d6+ TFA drops) δ 2.71 (s, 3H), 2.80 (s, 3H), 8.10 - 8.14 (m, 1H and 1H from HCOOH), 8.32 (s, 1H), 8.79 ( s, 2H), 8.88 (s, 1H), 9.18 (br. s, 2H). LC-MS (Method A): r.t. 0.50 min, MS (ESI) m / z = 335.2 [M+H]+.

[0334] Example 126: [3-(4-aminophenoline-7-yl)-4-[(6-oxopiperidin-3-yl)oxy]phenyl]acid (126) converts di Palladium(II) acetate (3.68 mg, 0.020 mmol), 5-[4-chloro-2-[4-[(2,4-dimethoxyphenyl)methylamino]phenolin-7-yl] Phenoxy]piperidin-2-one (170.0 mg, 0.330 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (15.62 mg , 0.030 mmol), potassium acetate (96.44 mg, 0.980 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxo Boroxane-2-yl)-1,3,2-dioxoboroxane (249.54 mg, 0.980 mmol) was dissolved in 1,4-dioxane (3.2 mL) in a microwave vial and degassed with N2 for 10 min . The resulting reaction mixture was stirred at 80 °C for 2 h, then it was cooled to room temperature and filtered through celite, washing with EtOAc. The filtrate was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL). The resulting mixture was stirred at room temperature for 4 hours, then it was concentrated under reduced pressure. The residue was dissolved with MeOH and this solution was loaded onto an SCX cartridge (5 g), which was washed with MeOH / H20 (9:1) and then eluted with 7 M ammonia in MeOH. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (KP-C18-HS, ​​30 g) with gradient elution from 1% to 70% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to afford 10 mg of partially purified product. This material was further purified by column chromatography (KP-C18-HS, ​​12 g) with a gradient elution of 1% to 70% MeCN (+0.1% NH4OH) in water (+0.1% NH4OH). Appropriate fractions were collected and lyophilized to give [3-(4-aminophenolin-7-yl)-4-(6-oxopiperidin-3-yl)oxybenzene as a white solid base] acid (3.5 mg, 0.009 mmol, 2.7% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.92 - 2.08 (m, 2H), 2.09 - 2.20 (m, 2H), 3.25- 3.48 (m, 2H and signal from water), 4.84 - 4.96 (m, 1H ), 7.18 (s, 2H), 7.24 (d,J= 8.42 Hz, 1H), 7.31 - 7.34 (m, 1H), 7.73 (dd,J= 8.75, 1.78 Hz, 1H), 7.84 (dd,J= 8.24, 1.74 Hz, 1H), 7.98 (d,J= 1.73 Hz, 1H), 8.01 - 8.10 (br. s, 2H), 8.12 (d,J= 1.71 Hz, 1H), 8.16 (d,J= 8.82 Hz, 1H), 8.61 (s, 1H). LC-MS (Method B): r.t. 0.41 min, MS (ESI) m / z = 379.2 [M+H]+.

[0335] Example 127: 2-[4-(4-Aminothioline-7-yl)-2-(dihydroxyboryl)phenyl]acetic acid (127) Step 1: Making N-[(2,4 -Dimethoxyphenyl)methyl]-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenoline-4-amine (0.93 g, 2.2 mmol), 2-{4-chloro-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo [6.1.1.02,6]dec-4-yl]phenyl}acetic acid tertiary butyl ester (0.89 g, 2.2 mmol), potassium dihydrogen phosphate (299.4 mg, 2.2 mmol) and tripotassium phosphate (933.99 mg, 4.4 mmol ) in 1,4-dioxane (35 mL) and water (8 mL) was degassed under argon for 10 min, followed by the addition of [1,1'-bis(di-tertiary butylphosphino) Ferrocene]dichloropalladium(II) (143.83 mg, 0.220 mmol) and the mixture was heated at 85 °C for 4 hours. The mixture was cooled to room temperature, diluted with EtOAc and filtered through celite, washing with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (Sfar Amino D, 55 g) eluting with a gradient of 0% to 100% EtOAc in cyclohexane to give a light brown solid Crude 2-[4-(4-{[(2,4-dimethoxyphenyl)methyl]amino}phenolin-7-yl)-2-[(1S,2S,6R,8S )-2,9,9-Trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]dec-4-yl]phenyl]acetic acid tertiary butyl ester (730 mg ). Purity was ~62% according to LC-MS. This material was used in the next step without further purification. LC-MS (Method A): r.t. 1.19 min, MS (ESI) m / z = 664.3 [M+H]+.

[0336] Step 2: The material from Step 1 was dissolved in DCM (6 mL) and trifluoroacetic acid (3 mL) and the mixture was stirred at room temperature for 3 hours. The volatiles were removed under reduced pressure and the residue thus obtained was subjected to semi-preparative HPLC purification [first purification conditions (CSH C18 (2.1 x 50 mm, 1.7 µm), 3% to 99.9% MeCN in water (+0.1 % HCOOH); second purification condition Kinetex 1.7 μm EVO C18 100A (2.1 × 50 mm, 1.7 μm), gradient from 3% to 99.9% MeCN in 10 mM aqueous ammonium bicarbonate adjusted to pH 10 with ammonia) . Lyophilization of appropriate fractions afforded 2-[4-(4-aminophenolin-7-yl)-2-boronphenyl]acetic acid (15.5 mg, 0.048 mmol) as a light yellow solid, some of which Salt for its ammonium salt. 1H NMR (400 MHz, DMSO-d6+ 3 drops TFA) δ 3.79 (s, 2H), 7.31 (d,J= 8.14 Hz, 1H), 7.75 (s, 1H), 7.93 - 8.21 (m, 3H), 8.46 (s, 1H), 8.53 (d, J= 8.95 Hz, 1H), 9.70 (s, 1H), 9.86 (s, 1H). LC-MS (Method A): r.t. 0.47 min, MS (ESI) m / z = 324.1 [M+H]+.

[0337] Example 128: [7-(4-Aminothioline-7-yl)-2,2-difluoro-2H-1,3-benzodioxol-5-yl]acid (128) Step 1: Palladium(II) diacetate (4.62 mg, 0.020 mmol), 7-(6-chloro-2,2-difluoro-1,3-benzodioxole-4 -yl)-N-[(2,4-dimethoxyphenyl)methyl]phenoline-4-amine (200 mg, 0.410 mmol), dicyclohexyl-[2-[2,4,6- Tris(prop-2-yl)phenyl]phenyl]phosphine (15.7 mg, 0.030 mmol), potassium acetate (121.19 mg, 1.23 mmol) and 4,4,5,5-tetramethyl-2-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaboroxine (313.59 mg, 1.23 mmol) was dissolved in 1,4-bis in methane (5 mL). The mixture was degassed with N2 for 10 min, then stirred at 75 °C for 3 h. The mixture was filtered through a pad of celite, washing with MeOH and the filtrate was concentrated in vacuo.

[0338] Step 2: The crude material from Step 1 was dissolved in a mixture of DCM (3 mL) and trifluoroacetic acid (3 mL). The mixture was stirred overnight at room temperature and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge (10 g). The cartridge was washed with MeOH / H2O (9:1) and the product was then eluted from the SCX cartridge with a 2 M solution of NH3 in MeOH. The volatiles were evaporated and the residue was purified by column chromatography (KP-C18-HS, ​​SNAP 30 g) with gradient elution from 2% to 30% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH) A partially pure product was obtained. This material was further purified by column chromatography (KP-C18-HS, ​​SNAP 11 g) with a gradient elution of 5% to 85% CH3CN in water (+0.1% ammonium hydroxide). Appropriate fractions were collected and lyophilized to give [7-(4-aminophenolin-7-yl)-2,2-difluoro-1,3-benzodioxane as a white powder Penten-5-yl] acid (31 mg, 0.090 mmol, 21.82% yield). 1H NMR (400 MHz, DMSO-d6+2 drops of TFA) δ 7.80 (s, 1H), 8.12 (s, 1H), 8.18 (dd,J= 8.92, 1.82 Hz, 1H), 8.25 (d,J= 1.66 Hz, 1H), 8.50 (s, 1H), 8.61 (d,J= 8.96 Hz, 1H), 9.83 (s, 1H), 9.99 (s, 1H). 19F NMR (377 MHz, DMSO-d6) δ -48.74. LC-MS (Method A): r.t. 0.93 min, MS (ESI) m / z = 346.08 [M+H]+.

[0339] Example 129: [3-(4-Aminoquinolin-6-yl)-4-methoxyphenyl] acid formate (129) Step 1: Palladium(II) diacetate (14.16 mg , 0.060 mmol), 6-(5-chloro-2-methoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]quinolin-4-amine (590.0 mg, 1.26 mmol), potassium acetate (371.45 mg, 3.78 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)-1,3,2-dioxaboroxane (961.14 mg, 3.78 mmol) was dissolved in 1,4-dioxane (34 mL) and the mixture was degassed with Ar for 10 min. Subsequently, the mixture was stirred overnight at 75°C. The reaction was not complete so additional palladium(II) diacetate (3.54 mg, 0.015 mmol), potassium acetate (92.94 mg, 0.95 mmol) and 4,4,5,5-tetramethyl-2-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,3,2-dioxaborol (240.28 mg, 0.95 mmol) and the mixture was reheated at 90°C Stir for 4 hours. The reaction mixture was filtered, washed with methanol and the filtrate was concentrated in vacuo. LC-MS (Method A): r.t. 0.94 min, MS (ESI) m / z = 527.3 [M+H]+.

[0340] Step 2: The crude material from Step 1 was dissolved in DCM (3 mL) and trifluoroacetic acid (3 mL) and stirred at room temperature overnight before it was concentrated under reduced pressure. The residue was dissolved in MeOH / H2O (9:1) and loaded onto an SCX cartridge (20 g). The cartridge was washed with MeOH / H2O (9:1) and the product was eluted from the SCX cartridge with 2 M NH3 in MeOH. The basic fraction was evaporated and washed with 2% to 30% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH) by column chromatography (KP-C18-HS, ​​consecutively 12 g + 12 g) The residue was purified by gradient elution. Appropriate fractions were collected and lyophilized to give [3-(4-aminoquinolin-6-yl)-4-methoxyphenyl] acid formate (53.6 mg, 0.158 mmol) as a white solid , yield 12.5%). 1H NMR (400 MHz, DMSO-d6+ TFA drops) δ 3.79 (d,J= 1.54 Hz, 3H), 6.78 (d,J= 6.82 Hz, 1H), 7.08 - 7.16 (m, 1H), 7.82 - 7.91 ( m, 3H), 8.04 - 8.13 (m, 2H), 8.33 - 8.42 (m, 1H), 8.48 (d, J=1.32 Hz, 1H), 8.91 (br. s, 2H). LC-MS (Method A): r.t. 0.44 min, MS (ESI) m / z = 295.1 [M+H]+.

[0341] Example 130: [3-(8-amino-1,7-phenidin-3-yl)-4-methoxyphenyl] acid formate (130) diacetate palladium (II) ( 4.12 mg, 0.020 mmol), 3-(5-chloro-2-methoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]-1,7-phenidine-8 -amine (160.0 mg, 0.370 mmol), dicyclohexyl-[2-[2,4,6-tri(prop-2-yl)phenyl]phenyl]phosphine (14.0 mg, 0.030 mmol), potassium acetate ( 108.07 mg, 1.1 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)- 1,3,2-Dioxaboroxane (279.63 mg, 1.1 mmol) was dissolved in 1,4-dioxane (3.5 mL) in a microwave vial and degassed with N2 for 10 min. The resulting reaction mixture was stirred at 80 °C for 1 h, then it was cooled to room temperature and filtered through celite, washing with MeOH. The filtrate was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (3 mL). The resulting mixture was stirred overnight at room temperature before it was evaporated in vacuo. The residue was dissolved in MeOH / H2O (9:1), loaded onto an SCX cartridge and the cartridge was allowed to sit for 20 min. Subsequently, the cartridge was washed with MeOH / H2O (9:1) and eluted with 7 M methanolic ammonia solution. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 12 g) eluting with a gradient of 5% to 20% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give [3-(8-amino-1,7-phenidin-3-yl)-4-methoxyphenyl] acid formate as a white solid ( 87 mg, 0.255 mmol, yield 68.91%). 1H NMR (400 MHz, DMSO-d6) δ 6.90 (br. s, 2H), 6.97 (d,J= 5.73 Hz, 1H), 7.18 (d,J= 8.21 Hz, 1H), 7.84 - 7.92 (m, 3H), 8.02 (br. s, 2H), 8.15 (s, 1H, from HCOOH), 8.20 (d, J= 2.16 Hz, 1H), 8.90 (d, J= 2.11 Hz, 1H). LC-MS (Method A): r.t. 0.46 min, MS (ESI) m / z = 296.2 [M+H]+.

[0342] Example 131: [3-(1-Amino-4-methylphthalein-6-yl)-4-(difluoromethoxy)phenyl] acid formate (131) palladium diacetate (II) (2.31 mg, 0.010 mmol), 6-[5-chloro-2-(difluoromethoxy)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]- 4-Methylphthalein-1-amine (100.0 mg, 0.210 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (7.85 mg , 0.020 mmol), potassium acetate (60.59 mg, 0.620 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxo Boroxane-2-yl)-1,3,2-dioxoboroxane (156.78 mg, 0.620 mmol) was dissolved in 1,4-dioxane (2.2 mL) in a microwave vial and degassed with N2 for 10 min . The resulting reaction mixture was stirred at 80 °C for 1 h, then it was cooled to room temperature and filtered through celite, washing with MeOH. The filtrate was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (2 mL). The resulting mixture was stirred overnight at room temperature before it was evaporated in vacuo. The residue was dissolved in MeOH / H2O (9:1), loaded onto an SCX cartridge (10 g) and the cartridge was allowed to stand for 20 min. Subsequently, the cartridge was washed with MeOH / H2O (9:1) and eluted with 7 M methanolic ammonia solution. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by flash chromatography (Sfar C18 D, 12 g) eluting with a gradient of 5% to 20% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give [3-(1-amino-4-methylphthalein-6-yl)-4-(difluoromethoxy)phenyl]acid as a white solid Formate salt (31 mg, 0.079 mmol, 37.61% yield). 1H NMR (400 MHz, DMSO-d6+ 2 drops TFA) δ 2.74 (s, 3H), 7.32 (t,J= 73.56 Hz, 1H), 7.37 (d,J= 8.21 Hz, 1H), 7.97 (dd,J = 8.24, 1.71 Hz, 1H), 8.05 (d,J= 1.70 Hz, 1H), 8.13 (s, 1H from HCOOH), 8.26 (dd,J= 8.52, 1.71 Hz, 1H), 8.33 (d,J = 1.68 Hz, 1H), 8.74 (d,J= 8.55 Hz, 1H), 9.16 (br. s, 2H).

[0343] Example 132: 7-[2-(difluoromethoxy)-5-[(1S,2S,6R,8S)-2,6,9,9-tetramethyl-3,5-diox Hetero-4-boratricyclo[6.1.1.02,6]dec-4-yl]phenyl]phenoline-4-amine (132)[3-(4-aminophenoline-7-yl)- 4-(Difluoromethoxy)phenyl]acid (60.0 mg, 0.180 mmol) and (1S,3R,4S,5S)-3,4,6,6-tetramethylbicyclo[3.1.1]heptane A suspension of -3,4-diol (32.73 mg, 0.180 mmol) in THF (1.9 mL) was stirred at 50 °C overnight, then the mixture was concentrated in vacuo. The residue was triturated with diethyl ether (2 mL) for two hours, the solvent was decanted, and the solid residue was collected and dried in an oven at 50 °C to give 7-[2-(difluoromethoxy )-5-[(1S,2S,6R,8S)-2,6,9,9-tetramethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decane- 4-yl]phenyl]phenolin-4-amine (58.2 mg, 0.121 mmol, 67.5% yield). 1H NMR (400 MHz, DMSO-d6) δ 0.89 (s, 3H), 1.28 (s, 3H), 1.30 (d,J= 10.78 Hz, 1H), 1.43 (s, 3H), 1.47 (s, 3H) , 1.92 - 2.03 (m, 2H), 2.06 (t,J= 5.61 Hz, 1H), 2.13 - 2.22 (m, 1H), 2.29 (dd,J= 14.75, 4.18 Hz, 1H), 7.25 (s, 2H ), 7.30 (t,J=73.73 Hz, 1H), 7.39 (d,J=8.58 Hz, 1H), 7.68 (dd,J= 8.58, 1.76, 1H), 7.78 - 7.82 (s, 2H), 8.09 (d,J= 1.54 Hz, 1H), 8.26 (d,J= 8.58 Hz, 1H), 8.65 (s, 1H). LC-MS (Method A): r.t. 0.96 min, MS (ESI) m / z = 480.4 [M+H]+.

[0344] Example 133: 7-{5-[(3AR,6AS)-3A,6A-dimethyl-hexahydrocyclopenta[D][1,3,2]dioxaborolan-2-yl ]-2-methoxyphenyl}phenoline-4-amine (133) [3-(4-aminophenoline-7-yl)-4-methoxyphenyl]acid (50.0 mg, 0.170 mmol) and (1R,2S)-1,2-dimethylcyclopentane-1,2-diol (22.06 mg, 0.170 mmol) in THF (2.4 mL) was stirred overnight at 45°C, The mixture was then concentrated in vacuo. The residue was triturated with diethyl ether (2.5 mL) for one hour, the solvent was decanted, and the solid residue was collected and dried in an oven at 50 °C to give 7-{5-[(3aR,6aS) as a white solid -3a,6a-Dimethyl-hexahydrocyclopenta[d][1,3,2]dioxaborolan-2-yl]-2-methoxyphenyl}phenoline-4-amine ( 54.3 mg, 0.139 mmol, yield 82.33%). 1H NMR (400 MHz, DMSO-d6) δ 1.37 (s, 6H), 1.49 - 1.70 (m, 4H), 1.96 (dd,J= 12.32, 5.06 Hz, 2H), 3.86 (s, 3H), 7.17 - 7.23 (m, 3H), 7.66 - 7.71 (m, 2H), 7.73 (dd,J= 8.14, 1.76 Hz, 1H), 8.07 (d,J= 1.76 Hz, 1H), 8.20 (d,J= 8.80 Hz , 1H), 8.62 (s, 1H). LC-MS (Method A): r.t. 0.76 min, MS (ESI) m / z = 390.3 [M+H]+.

[0345] Example 134: [5-(4-Aminothioline-7-yl)-4-methoxy-2-methylphenyl] acid formate (134) Step 1: Palladium diacetate ( II) (8.36 mg, 0.040 mmol), 7-(5-chloro-2-methoxy-4-methylphenyl)-N-[(2,4-dimethoxyphenyl)methyl] Phenyl-4-amine (335.0 mg, 0.740 mmol), potassium acetate (219.21 mg, 2.23 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaboroxane-2-yl)-1,3,2-dioxaboroxane (567.22 mg, 2.23 mmol) was dissolved in 1,4-dioxane (12.5 mL) and the mixture Degas with Ar for 10 min. Subsequently, the mixture was stirred overnight at 95°C. The mixture was filtered, washed with methanol and the filtrate was concentrated in vacuo. LC-MS (Method A): r.t. 0.99 min, MS (ESI) m / z = 542.4 [M+H]+.

[0346] Step 2: The crude material from Step 1 was dissolved in DCM (8 mL) and trifluoroacetic acid (6.5 mL) and stirred at room temperature for seven hours before it was concentrated under reduced pressure. The residue was dissolved in MeOH / H2O (9:1) and loaded onto an SCX cartridge (20 g). The cartridge w...

Claims

1. A compound represented by Formula I or Formula II, or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, halogen, amino, hydroxyl, alkoxy, or alkylthio; V and W are each independently CRa or N; each Ra is independently hydrogen, halogen, nitro, cyano, amino, hydroxyl, alkoxy, alkylthio, or alkyl; X is CRb or N; Rb is hydrogen, halogen, nitro, cyano, amino, hydroxyl, alkoxy, alkylthio, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclic, heterocyclic, aryl, or heteroaryl; each U is independently N or CRc; each Rc is independently hydrogen, halogen, alkyl, or alkoxy; ring Z1 is a five- or six-membered aryl or heteroaryl; ring Z2 is a five- or six-membered heterocycle; Each R2 is independently a halogen, nitro, cyano, amino, acylamino, hydroxyl, alkoxy, alkylthio, acetyl, formamidinyl, azide, aminomethyl, carboxyl, carboxyl ester, guanidine, haloalkyl, haloalkoxy, heteroalkyl, imino, oxime, phosphonate, dialkylphosphine oxide, sulfonyl, sulfonamide, sulfonylurea, sulfinyl, sulfinic acid, sulfonic acid, thiocyanate, thiocarbonyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl; or two adjacent R2s combined with the intervening carbon atoms to which they are attached to form a 5- or 6-membered carbocyclic ring, a 5- or 6-membered heterocyclic ring, a 5- or 6-membered aryl, or a 5- or 6-membered heteroaryl; where valence permits, n is 0 or an integer selected from 1 to 4; Each R6 is independently a halogen, nitro, cyano, amino, acylamino, hydroxyl, side oxygen, carboxyl, alkoxy, alkylthio, acetylated, formamidinyl, azide, aminomethylacetylated, carboxyl, carboxyl ester, guanidine, haloalkyl, haloalkoxy, heteroalkyl, imino, oxime, phosphonate, dialkylphosphine oxide, sulfonyl, sulfonamide, sulfonylurea, sulfinyl, sulfinic acid, sulfonic acid, thiocyanate, thiocarbonyl, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclic, heterocyclic, aryl, or heteroaryl; or any two R6s combined with the carbon atom(e) to which they are attached to form a carbocyclic or heterocyclic ring; when valence permits, q is 0 or an integer selected from 1 to 4; R3 is; M is N(R8)3, N(R8)2, OR8, or SR8; Each R8 is independently hydrogen, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl; and R3a and R3b are independently hydrogen, alkyl, acetyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclic, heterocyclic, aryl, or heteroaryl; or R3a and R3b are combined with a boron atom and two intervening oxygen atoms separating them to form a monocyclic or polycyclic heterocyclic group; or R3a, R3b, and M are combined with the boron atom and the intervening oxygen atoms to form a polycyclic heterocycle.

2. The compound of claim 1, wherein the compound is represented by formula Ia or II-a:

3. The compound of claim 1 or 2, wherein R1 is a hydroxyl or C1-3 alkoxy group.

4. The compound of claim 1 or 2, wherein R1 is an amino group.

5. The compound as claimed in claim 4, wherein R1 is -NH2 or -NHCH3.

6. A compound of any one of claims 1 to 5, wherein each R2 is independently a halogen, nitro, cyano, amino, acylamino, hydroxyl, alkoxy, alkylthio, phosphonate, dialkylphosphine oxide, alkyl, aralkyl, heteroaryl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl or heteroaryl; or two adjacent R2s combined with the intervening carbon atom to which they are attached to form a 5- or 6-membered carbocyclic ring, a 5- or 6-membered heterocyclic ring, a 5- or 6-membered aryl, or a 5- or 6-membered heteroaryl.

7. A compound of any one of claims 1 to 5, wherein each R2 is independently a halogen, cyano, amino, acylamino, hydroxyl, alkoxy, dialkylphosphine oxide, haloalkyl, sulfonyl, alkyl, carbocyclic, heterocyclic, aryl, aralkyl, heteroaryl, or heteroaryl.

8. A compound of any one of claims 1 to 5, wherein each R2 is independently a halogen, cyano, amino, acylamino, hydroxyl, alkoxy, dialkylphosphine oxide, alkyl, carbocyclic, heterocyclic, aryl, aralkyl, heteroaryl, or heteroaryl.

9. The compound of any one of claims 1 to 5, wherein: Each R2 is independently -F, cyano, -C(O)N(R4)2, -N(H)C(O)R4, -OCF3, -OCH2C(O)N(R4)2, -O(CH2CH2O)rR4, -CF3, -CHF2, -OCH3, -P(=O)(CH3)2, -CH2COOH, -CH3, -C2H5, cyclopropyl, tetrahydropiperanyl, 1,1-di-side-oxy-1,2,5-thiadiazolidinyl or pyridinyl; wherein R4 is alkyl, alkenyl, carbocyclic, heterocyclic, aryl or heteroaryl; or two R4 together with a nitrogen atom form a 5- to 6-membered heterocycle; and r is an integer selected from 1 to 6.

10. The compound of any one of claims 1 to 5, wherein: Each R2 is independently -F, cyano, -N(H)C(O)R4, -OCF3, -OCH2C(O)N(R4)2, -O(CH2CH2O)rR4, -CF3, -CHF2, -OCH3, -P(=O)(CH3)2, -CH3, -C2H5, cyclopropyl, tetrahydropiperanyl, 1,1-di-side-oxy-1,2,5-thiadiazolidinyl or pyridinyl; wherein R4 is alkyl, alkenyl, carbocyclic, heterocyclic, aryl or heteroaryl; and r is an integer selected from 1 to 6.

11. The compound of any one of claims 1 to 10, wherein each R2 is independently deuterated.

12. A compound of any one of claims 1 to 5, wherein two adjacent R2s are combined with the intervening carbon atoms to which they are attached to form a 5- or 6-membered carbon ring, a 5- or 6-membered heterocycle, a 5- or 6-membered aryl ring, or a 5- or 6-membered heteroaryl ring.

13. The compound of claim 12, wherein two adjacent R2 atoms, together with the intervening carbon atoms to which they are attached, combine to form a 5- or 6-membered heteroaryl ring.

14. The compound of claim 13, wherein the 5- or 6-membered heteroaryl ring is furan, pyrazole, indazole or acetazole.

15. The compound of claim 12, wherein two adjacent R2 atoms, together with the intervening carbon atoms to which they are attached, combine to form a 5- or 6-membered heterocycle.

16. The compound of claim 15, wherein the 5- or 6-membered heterocycle is tetrahydrofuran or tetrahydropiperan.

17. The compound of any one of claims 1 to 16, wherein each Ra is independently hydrogen, halogen, amino, hydroxyl, alkoxy or alkyl.

18. The compound of claim 17, wherein Ra is hydrogen.

19. A compound of any one of claims 1 to 18, wherein Rb is hydrogen, halogen, alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic.

20. The compound of claim 19, wherein Rb is hydrogen, C1-C3 alkyl or cyclopropyl, preferably methyl.

21. A compound of any one of claims 1 to 20, wherein each Rc is independently hydrogen, halogen or alkyl.

22. The compound of any one of claims 1 to 21, wherein one of V, W and X is N.

23. The compound of any one of claims 1 to 21, wherein two of V, W and X are N.

24. The compound of claim 21, wherein W and X are N, and V is CRa.

25. The compound of claim 24, wherein Ra is hydrogen.

26. The compound of claim 23, wherein V and W are N, and X is CRb.

27. The compound of claim 26, wherein Rb is a methyl group.

28. The compound of any one of claims 1 to 27, wherein U is CRc.

29. A compound of any one of claims 1 to 28, wherein Rc is hydrogen, F, methyl, methoxy or Cl.

30. The compound of any one of claims 1 to 29, wherein ring Z1 is phenyl or a five- or six-membered heteroaryl group.

31. The compound of claim 30, wherein ring Z1 is phenyl.

32. The compound of claim 31, wherein the compound is represented by formula Ib or II-b:

33. The compound of claim 30, wherein ring Z1 is a five- or six-membered heteroaryl group.

34. The compound of claim 33, wherein ring Z1 is a pyrazolyl group.

35. The compound of claim 33, wherein ring Z1 is pyridyl.

36. The compound of claim 35, wherein the compound is represented by formula Ic or II-c:

37. A compound of any one of claims 1 to 36, wherein the compound is represented by formula I, Ia, Ib or Ic.

38. The compound of claim 36, wherein the compound is represented by formula Ic-1 or Ic-2, wherein R2a is alkyl, aralkyl, heteroaryl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl or heteroaryl.

39. The compound of claim 38, wherein R2a is methyl, difluoromethyl, -CF2CHF2, -CHFCF3, -CH2CF3, -(CH2CH2O)2CH3.

40. The compound of claim 38, wherein R2a is methyl, difluoromethyl, or methyl.

41. The compound of claim 38, wherein R2a is, and m is an integer from 2 to 6.

42. The compound of any one of claims 37 to 41, wherein R3 is...

43. The compound of claim 42, wherein R3a and R3b are independently hydrogen, alkyl, acetylated, alkenyl, heteroaryl, carbocyclic, heterocyclic, aryl or heteroaryl.

44. The compound of claim 42, wherein R3a and R3b are hydrogen.

45. The compound of claim 42, wherein R3a and R3b are combined with the boron atom and the two intervening oxygen atoms that separate them such that R3 is a heterocyclic group.

46. ​​The compound of claim 45, wherein R3 is, wherein: Each R5 is independently halogenated, nitro, cyano, amino, acylamino, hydroxyl, septyloxy, carboxyl, alkoxy, alkylthio, alkyl (e.g., carboxymethyl), aralkyl, heteroaryl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, or heteroaryl; or any two R5s are independently combined with the intervening carbon atom(e) to which they are attached to to form a carbocyclic or heterocyclic ring; and when valence permits, p is 0 or an integer selected from 1 to 6.

47. The compound of claim 46, wherein R3 is...

48. The compound of claim 47, wherein R3 is...

49. A compound of any one of claims 37 to 41, wherein R3 is; and R3a, R3b and M are combined with the boron atom and the intervening atoms such that R3 is a polycyclic heterocycle.

50. The compound of claim 49, wherein R3 is, and wherein Rd is H or C1-C4 alkyl.

51. The compound of claim 50, wherein Rd is H or methyl.

52. The compound of claim 50, wherein Rd is H.

53. A compound of any one of claims 1 to 36, wherein the compound is represented by formula II, II-a, II-b or II-c.

54. The compound of claim 32, wherein the compound is represented by formula II-b-1, II-b-2 or II-b-3.

55. The compound of claim 54, wherein each R6 is independently a halogen, alkyl, carbocyclic, allyl, or lateral oxygen group.

56. The compound of claim 54, wherein each R6 is independently a halogen, alkyl or lateral oxygen group.

57. The compound of claim 54, wherein ring Z2 is [missing information].

58. The compound of claim 54, wherein ring Z2 is [missing information].

59. The compound of any one of claims 53 to 58, wherein R3a is hydrogen.

60. The compound of any one of claims 53 to 58, wherein R3a is a methyl group.

61. A compound of any one of claims 1 to 58, wherein the compound is selected from: , or a pharmaceutically acceptable salt thereof.

62. The compound of any one of claims 1 to 59, wherein the pharmaceutically acceptable salt is a formate, methanesulfonate, ethanesulfonate or maleate.

63. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 62 and a pharmaceutically acceptable excipient.

64. A method of treating a disease or condition related to complement activation in an individual in need, comprising administering a therapeutically effective amount of any one of claims 1 to 62 or a composition of claim 63.

65. The method of claim 64, wherein the disease or condition is selected from neurodegenerative diseases, inflammatory diseases, autoimmune diseases, eye diseases, and metabolic diseases.

66. The method of claim 64 or 65, wherein the disease or condition associated with complement activation is selected from Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, progressive multiple sclerosis, glaucoma, myotonic dystrophy, Guillain-Barré syndrome, myasthenia gravis, spinal muscular atrophy, Down syndrome, Parkinson's disease, Huntington's disease. Diseases, traumatic brain injury, epilepsy, frontotemporal lobe dementia, diabetes, obesity, atherosclerosis, rheumatoid arthritis, acute respiratory distress syndrome, pemphigus, pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, immune-mediated necrotizing myopathy, leukoplakia, paraneoplastic syndrome, vasculitis, hypocomplement-type urticarial vasculitis, chronic spontaneous urticaria, distal tissue injury after ischemia and reperfusion, complement activation during cardiopulmonary bypass surgery, dermatomyositis, lupus nephritis and the resulting glomerulonephritis and vasculitis, renal fibrosis, systemic lupus erythematosus, Hashimoto's thyroiditis, Addison's disease, celiac disease, Crohn's disease Diseases, pernicious anemia, chronic idiopathic demyelinating polyneuropathy, multifocal motor neuropathy, heparin-induced thrombocytopenic purpura, coronary artery endothelial cell dysfunction induced by cardiac paralysis, type II membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure, cryoglobulinemia, antiphospholipid syndrome, chronic open-angle glaucoma, acute closed-angle glaucoma, macular degeneration, wet age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, choroidal neovascularization, uveitis, diabetic retinopathy, ischemia-related retinopathy, endophthalmitis, intraocular neovascularization, diabetic macular edema, pathological myopia, von Hippel-Lindau disease, ocular histoplasmosis, neuromyelitis optica, central retinal vein occlusion, corneal neovascularization, retinal neovascularization, Leber's hereditary optic neuropathy Hereditary optic neuropathy, optic neuritis, Behcet's retinopathy, ischemic optic neuropathy, retinal vasculitis, ANCA vasculitis, Wegener's granulomatosis, Purtscher retinopathyRetinopathy, Sjogren's dry eye disease, sarcoidosis, temporal arteritis, polyarteritis nodosa, allogeneic transplantation, hyperacute rejection, hemodialysis, chronic obstructive pulmonary syndrome, asthma, aspiration pneumonia, immune thrombocytopenic purpura, autoimmune hemolytic anemia, cold agglutinin disease, thermosensitive autoimmune hemolytic anemia, and coronary artery disease.

67. The method of any of claims 64 to 65, wherein the disease or condition is a neurodegenerative disease.

68. The method of claim 67, wherein the neurodegenerative condition is associated with loss of synapse or loss of neural connection.

69. The method of claim 68, wherein the neurodegenerative condition is associated with loss of C1q, C1 complex, CR1, C3, CR3, C4 or CR4-dependent synapses.

70. The method of claim 68, wherein the neurodegenerative condition is associated with abnormal activation or regulation of C1s.

71. The method of claim 68, wherein the neurodegenerative condition is associated with pathological activity-dependent synaptic loss.

72. The method of claim 68, wherein the neurodegenerative condition is associated with synaptic phagocytosis of microglia.

73. The method of any one of claims 67 to 72, wherein the neurodegenerative condition is selected from Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, progressive multiple sclerosis, glaucoma, myotonic dystrophy, Gurbach's syndrome, myasthenia gravis, spinal muscular atrophy, Down syndrome, Parkinson's disease, Huntington's disease, traumatic brain injury, epilepsy, wet age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, and frontotemporal dementia.

74. The method of claim 73, wherein the neurodegenerative condition is selected from Gba syndrome, Huntington's disease, amyotrophic lateral sclerosis and geographic atrophy.

75. The method of any of claims 64 to 66, wherein the disease or condition is an inflammatory disease, an autoimmune disease, a metabolic disorder, or an eye disease.

76. The method of claim 75, wherein the inflammatory disease, autoimmune disease, metabolic disorder or eye disease is associated with abnormal activation or regulation of C1s.

77. The method of claim 75 or 76, wherein the inflammatory disease, autoimmune disease, metabolic disorder, or eye disease is selected from diabetes mellitus, obesity, atherosclerosis, rheumatoid arthritis, acute respiratory distress syndrome, pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, distal tissue injury following ischemia and reperfusion, complement activation during cardiopulmonary bypass surgery, dermatomyositis, pemphigus, lupus nephritis and resulting glomerulonephritis and vasculitis, renal fibrosis, systemic lupus erythematosus, Hashimoto's thyroiditis, Addison's disease, chylous leukemia, etc. Diarrhea, Crohn's disease, pernicious anemia, immune-mediated necrotizing myopathy, leukoplakia, paraneoplastic syndrome, vasculitis, hypocomplement-type urticarial vasculitis, chronic spontaneous urticaria, chronic idiopathic demyelinating polyneuropathy, polymyalgia rheumatica, multifocal motor neuropathy, immune thrombocytopenic purpura, heparin-induced thrombocytopenic purpura, coronary endothelial cell dysfunction induced by cardiac arrest, type II membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure, cryoglobulinemia, antiphospholipids Syndrome, chronic open-angle glaucoma, acute closed-angle glaucoma, macular degeneration, wet age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, choroidal neovascularization, uveitis, diabetic retinopathy, ischemic retinopathy, endophthalmitis, intraocular neovascularization, diabetic macular edema, pathological myopia, Feng Heber-Lindau disease, ocular histoplasmosis, neuromyelitis optica, central retinal vein occlusion, corneal neovascularization, retinal neovascularization, Leber hereditary optic neuropathy, Optic neuritis, Behcet's retinopathy, ischemic optic neuropathy, retinal vasculitis, ANCA vasculitis, Wegener's granulomatosis, Pursha's retinopathy, Hughley's dry eye disease, sarcoidosis, temporal arteritis, polyarteritis nodosa, multiple sclerosis, progressive multiple sclerosis, allogeneic transplantation, hyperacute rejection, hemodialysis, chronic obstructive pulmonary syndrome, asthma, aspiration pneumonia, immune thrombocytopenic purpura, autoimmune hemolytic anemia, cold agglutinin disease, thermosensitive autoimmune hemolytic anemia, and coronary artery disease.

78. The method of claim 77, wherein the disease or condition is selected from myasthenia gravis, type 1 diabetes mellitus, Hashimoto's thyroiditis, Addison's disease, celiac disease, Crohn's disease, pernicious anemia, pemphigus vulgaris, leukoplakia, autoimmune hemolytic anemia, cold agglutinin disease, warm autoimmune hemolytic anemia, paraneoplastic syndrome, vasculitis, hypocomplement-type urticarial vasculitis, chronic spontaneous urticaria, polymyalgia rheumatica, temporal arteritis, Wegener's granulomatosis, immune thrombocytopenic purpura, wet age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, lupus nephritis, systemic lupus erythematosus, and multifocal motor neuropathy.

79. The method of claim 78, wherein the disease or condition is selected from cold agglutinin disease, febrile autoimmune hemolytic anemia, geographic atrophy, lupus nephritis and multifocal motor neuropathy.

80. A method for inhibiting activated C1s, comprising contacting the activated C1s with a compound of any one of claims 1 to 62 or a composition of claim 63.

81. The method of claim 80, wherein contacting the C1s with the compound comprises administering the compound to an individual.