Complement factor inhibitors and uses thereof

Abstract

Disclosed are compounds of Formula I and II, as well as pharma- ceutically acceptable salts thereof. Also disclosed are methods of treating a neurodegenerative disorder, an inflammatory disease, an autoimmune disease, an ophthalmic disease, or a metabolic disease using the compounds disclosed herein.

Description

[Technical Field]

[0001] Related Applications This patent application claims priority to U.S. Provisional Patent Application No. 63 / 299,712, filed January 14, 2022, which is incorporated by reference herein in its entirety. [Background technology]

[0002] The complement system refers to a group of proteins involved in the innate immune system. It assists or complements the ability of antibodies and phagocytes to remove pathogens from an organism. There are three cascades involved in this system: the classical pathway, the lectin pathway, and the alternative pathway. Each is triggered by a different recognition event, and each leads to the recruitment and activation of a series of proteins that can tag the cell surface and enhance processes that can cause cell lysis, damage, or phagocytosis.

[0003] The classical pathway is activated by the binding of the complement protein C1q to proteins directly or bound to cell surfaces. In one of its primary functions, C1q can be recruited by antibodies specific for cell surface antigens. C1q is a large 460 kDa multimeric protein composed of 18 polypeptide chains (six C1q A chains, six C1q B chains, and six C1q C chains). These chains form a large symmetric protein composed of three segments: a tail region, an arm region, and a globular head region. The single tail region is divided into six symmetric arms, each of which terminates in a globular head region. Most circulating C1q harbors a heterotetrameric complex of the complement proteins C1r and C1s, two serine proteases that initially bind to C1q as an inactive zymogen. This large multi-chain assembly is known as the C1 complex. Binding of the C1 complex to the appropriate complement-binding epitope on a cell surface or on a recruitment protein, such as that found in the Fc region of an antibody, induces a conformational change that leads to a series of activation and amplification events. In response to binding, C1r is activated first, followed by cleavage and activation of C1s. Complement C4 is then recruited to the complex, where it is internalized by C1 and cleaved to C4b. This cleavage exposes a moiety that can covalently bind C4b to the cell surface. This new complex then recruits complement C2, which binds to C4b and is cleaved to C2a by C1s. The surface-bound complex of C4b and C2a forms the C3-convertase, which drives the subsequent cleavage and surface ligation of complement C3, activating downstream steps in the complement cascade. A single C1 complex can assemble multiple C3-convertase modules on its surface, resulting in a potent amplification of the original targeting event.

[0004] These events can lead to tissue damage and cell clearance / destruction during normal function and disease pathology. They have also been found to play important roles in normal neuronal development and synaptic pruning during CNS disease pathology. In various contexts, such outcomes can be caused by the accumulation of C4 and C3 cleavage products on surfaces, progression of the cascade to the final stage of membrane attack complex formation and / or pore-mediated lysis, and accumulation of immune complexes containing early complement cascade components. In some cases, expression of C1r and / or C1s may be elevated via local induction as part of a biological response, and the actions of these proteases may further contribute to the progression of disease pathology (e.g., Xavier et al., Am. J. Renal Physiol, 2019).

[0005] The complement system is a central component of innate immunity, bridging the gap from innate to adaptive immune responses. However, it can also direct its destructive capabilities against host cells. Abnormal activation or insufficient regulation of the complement cascade is involved in many diseases and pathologies. As a result, many neurodegenerative, inflammatory, and autoimmune diseases are thought to be caused by, or at least substantially caused by, the activity of unleashed complement factors.

[0006] For example, human cognition, and particularly that of patients suffering from neurodegenerative diseases, is highly dependent on synapse formation. The formation of precise neural circuits during development is a highly regulated and dynamic process. While a plethora of synapses is initially generated to establish the brain's initial wiring pattern, the formation of mature, precise neural circuits requires the selective elimination and pruning of specific synapses. Neuronal activity plays a key role in this refinement step, achieving this elimination by targeting early components of the classical complement cascade.

[0007] However, premature synapse loss in neurodegenerative conditions leads to a loss of neuronal activity, abnormally activating synaptic pruning, and thereby cognitive decline. In neurodegenerative diseases such as Alzheimer's disease and glaucoma, complement factors such as complement factor C1 and its subunits, C1q, are expressed in neurons and act as signals for synaptic elimination. See, for example, U.S. Patent Publication Nos. 2012 / 0195880 and 2012 / 0328601. In the adult brain, synapse loss often occurs long before the pathology and clinical symptoms of many neurodegenerative diseases. Timely therapeutic intervention to prevent or reduce synapse loss may slow or prevent the progression of clinical symptoms of neurodegenerative diseases.

[0008] Therefore, inhibition or modulation of classical complement activity is recognized as a promising therapeutic strategy. Therefore, there is a need to discover and develop methods to inhibit or modulate the abnormal activity of these complement factors. Summary of the Invention

[0009] In certain embodiments, the present disclosure provides compounds of formula I or II: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, halogen, amino, hydroxyl, alkoxy, or alkylthio; V and W are each independently a or N; Each R a are independently hydrogen, halogen, nitro, cyano, amino, hydroxyl, alkoxy, alkylthio, or alkyl; X is CR b or N, R bis hydrogen, halogen, nitro, cyano, amino, hydroxyl, alkoxy, alkylthio, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; Each U is independently N or CR c and; Each R c are independently hydrogen, halogen, or alkyl; Ring Z 1 is a 5- or 6-membered aryl or heteroaryl; Ring Z 2 is a 5-, 6-, or 7-membered heterocycle; Each R 2 are independently halogen, nitro, cyano, amino, acylamino, amido, hydroxyl, alkoxy, alkylthio, phosphonate, dialkylphosphine oxide, sulfonyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or two adjacent R 2 are joined together 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 a 5- or 6-membered heteroaryl; or R 2 and Ar, together with the intervening atoms to which they are attached, combine to form a 5- to 7-membered carbocyclic ring or a 5- to 7-membered heterocyclic ring; n is 0 or an integer selected from 1 to 3, as long as the valence allows; Each R 6are independently halogen, nitro, cyano, amino, acylamino, amido, hydroxyl, oxo, carboxyl, alkoxy, alkylthio, acyl, amidino, azide, carbamoyl, carboxyl, carboxyester, guanidine, haloalkyl, 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 R 6 are joined together with the intervening carbon atom(s) to which they are attached to form a carbocyclic or heterocyclic ring; q is 0 or an integer selected from 1 to 6, as long as the valence allows; R 3 teeth [ka] and; M is N(R 8 )3, N(R 8 )2, OR 8 or SR 8 and; Each R 8 are independently hydrogen, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R 3a and R 3b are independently hydrogen, alkyl, acyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R 3a and R 3b is joined together with the boron atom and the two intervening oxygen atoms separating them to form a monocyclic or polycyclic heterocyclyl; or R 3a , R 3b and M, together with the boron atom and the intervening oxygen atoms, join to form a polycyclic heterocycle; Ar is aryl or heteroaryl.

[0010] In certain aspects, the present disclosure provides pharmaceutical compositions comprising a compound provided herein and a pharmaceutically acceptable excipient.

[0011] In certain aspects, the present disclosure provides methods of making the compounds provided herein.

[0012] In certain aspects, the present disclosure provides methods of treating a disease associated with complement activation in an individual in need thereof, comprising administering a therapeutically effective amount of a compound provided herein.

[0013] In certain embodiments, the present disclosure provides methods for inhibiting C1s, comprising contacting C1s with a compound disclosed herein. In certain embodiments, the present disclosure provides methods for inhibiting activated C1s, comprising contacting C1s with a compound disclosed herein. DETAILED DESCRIPTION OF THE INVENTION

[0014] In certain aspects, the present disclosure provides compounds of Formula I or II: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, halogen, amino, hydroxyl, alkoxy, or alkylthio; V and W are each independently a or N; Each R a are independently hydrogen, halogen, nitro, cyano, amino, hydroxyl, alkoxy, alkylthio, or alkyl; X is CR b or N; R bis hydrogen, halogen, nitro, cyano, amino, hydroxyl, alkoxy, alkylthio, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; Each U is independently N or CR c and; Each R c are independently hydrogen, halogen, or alkyl; Ring Z 1 is a 5- or 6-membered aryl or heteroaryl; Ring Z 2 is a 5-, 6-, or 7-membered heterocycle; Each R 2 are independently halogen, nitro, cyano, amino, acylamino, amido, hydroxyl, alkoxy, alkylthio, phosphonate, dialkylphosphine oxide, sulfonyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or two adjacent R 2 are joined together 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; or R 2 and Ar, together with the intervening atoms to which they are attached, combine to form a 5- to 7-membered carbocyclic ring or a 5- to 7-membered heterocyclic ring; n is 0 or an integer selected from 1 to 3, as long as the valence allows; Each R 6are independently halogen, nitro, cyano, amino, acylamino, amido, hydroxyl, oxo, carboxyl, alkoxy, alkylthio, acyl, amidino, azide, carbamoyl, carboxyl, carboxy 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, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R 6 any two of, together with the intervening carbon atom(s) to which they are attached, are joined to form a carbocyclic or heterocyclic ring; q is 0 or an integer selected from 1 to 6, as long as the valence allows; R 3 teeth [ka] and; M is N(R 8 )3, N(R 8 )2, OR 8 or SR 8 and; Each R 8 are independently hydrogen, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R 3a and R 3b are independently hydrogen, alkyl, acyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R 3a and R 3b is joined together with the boron atom and the two intervening oxygen atoms separating them to form a monocyclic or polycyclic heterocyclyl; or R 3a , R 3b and M together with the boron atom and the intervening oxygen atoms bond to form a polycyclic heterocycle; Ar is aryl or heteroaryl.

[0015] In certain embodiments, the compound has formula Ia or II-a: [ka] or a pharmaceutically acceptable salt thereof.

[0016] In certain embodiments, the compound has formula III-a or III-b: [ka] or a pharmaceutically acceptable salt thereof.

[0017] In certain embodiments, one or two of V, W, and X are N. In some embodiments, V and W are N and X is CR b In some preferred embodiments, W and X are N and V is CR a is.

[0018] In certain embodiments, R a is hydrogen, halogen, amino, hydroxyl, alkoxy, or alkyl. In certain preferred embodiments, R a is hydrogen.

[0019] In certain embodiments, R b is hydrogen, halogen, alkyl (e.g., C1-C3 alkyl, preferably methyl), alkenyl, alkynyl, carbocyclyl (e.g., cyclopropyl), or heterocyclyl, preferably hydrogen, C1-C3 alkyl. In certain preferred embodiments, R b is methyl or cyclopropyl.

[0020] In certain embodiments, U is CR c In certain embodiments, R c is hydrogen, fluoro, chloro, or methyl, preferably hydrogen.

[0021] In certain embodiments, the compound has formula IV-a or IV-b: [ka] or a pharmaceutically acceptable salt thereof.

[0022] In certain embodiments, the compound has formula V: [ka] or a pharmaceutically acceptable salt thereof.

[0023] In certain embodiments, the compound has formula VI: [ka] or a pharmaceutically acceptable salt thereof, wherein Y is O, NH, or CH2, and when Y is NH or CH2, it is optionally R 6 (e.g., when so substituted, Y is NR 6 or C(H)R 6 or C(R 6 )2).

[0024] In certain embodiments, the compound has formula VI-a: [ka] or a pharmaceutically acceptable salt thereof.

[0025] In certain embodiments, the compound has one of the following formulas: [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, R 6is halogen, alkyl, carbocyclyl, or oxo, preferably halogen, alkyl, or oxo. In certain preferred embodiments, n is 0, q is 0, and, if present, t is 1. In other preferred embodiments, n is 0, q is 0, and, if present, t is 2. In certain embodiments, R 6 is methyl and q is 1 or 2.

[0026] In certain embodiments, Ar is unsubstituted. In other embodiments, Ar is substituted with at least one substituent. In certain embodiments, at least one substituent is alkyl (e.g., methyl), halogen (e.g., fluoro), haloalkyl (e.g., difluoromethyl or trifluoromethyl), alkoxy (e.g., methoxy or haloalkoxy (e.g., trifluoromethoxy or difluoromethoxy)), cyano, heterocyclyl (e.g., N-morpholinyl), amide (e.g., —NHC(O)CH or —C(O)N(H)CH), ester (e.g., —C(O)OCH), or sulfonamide (e.g., —NH—S(O)CH). In certain embodiments, at least one substituent is alkyl (e.g., methyl), halogen (e.g., fluoro), haloalkyl (e.g., difluoromethyl or trifluoromethyl), alkoxy (e.g., methoxy), cyano, heterocyclyl (e.g., N-morpholinyl), amide (e.g., —NHC(O)CH3 or —C(O)N(H)CH3), ester (e.g., —C(O)OCH3), or sulfonamide (e.g., —NH—S(O)2CH3).

[0027] In certain embodiments, Ar is an optionally substituted 5- or 6-membered heteroaryl, such as furanyl, thienyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrrolyl, imidazolyl, diazolyl, tetrazolyl, thiazolyl, isothiazolyl, triazolyl, thiadiazolyl, isoxazolyl, oxazolyl, and pyrimidinyl. In certain embodiments, Ar is pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, imidazolyl, 1,2,4-thiadiazolyl, tetrazolyl, thiazolyl, oxazolyl, and pyrimidinyl. In certain preferred embodiments, Ar is pyrazolyl. In certain embodiments, Ar is a 5- or 6-membered heteroaryl (e.g., pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, imidazolyl, 1,2,4-thiadiazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrimidinyl) substituted with at least one alkyl, halogen, haloalkyl, alkoxy (e.g., haloalkoxy), cyano, heterocyclyl, amide, ester, or sulfonamide. In certain embodiments, Ar is a 5- or 6-membered heteroaryl (e.g., pyrazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, imidazolyl, 1,2,4-thiadiazolyl, tetrazolyl, thiazolyl, oxazolyl, and pyrimidinyl) substituted with at least one alkyl, halogen, haloalkyl, alkoxy, cyano, heterocyclyl, amide, ester, or sulfonamide group.

[0028] In certain embodiments, Ar is an optionally substituted aryl, such as phenyl. In certain preferred embodiments, Ar is an aryl (e.g., phenyl) substituted with at least one alkyl, halogen, haloalkyl, alkoxy, cyano, heterocyclyl, amide, ester, or sulfonamide group.

[0029] In certain embodiments, R 1 is amino, for example, —NH 2 or —NHCH 3 , preferably —NH 2 .

[0030] In certain embodiments, each R 2 is independently halogen, cyano, amino, acylamino, amido, hydroxyl, alkoxy, dialkylphosphine oxide, haloalkyl, sulfonyl, alkyl (e.g., methyl), carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaralkyl, or heteroaryl. In certain embodiments, R 2 is OR 2a and then R 2a is alkyl (e.g., methyl or isopropyl, optionally substituted with heterocyclyl or heteroaryl, respectively), aryl (e.g., phenyl), haloalkyl, or cycloalkyl. In further embodiments, R 2a is methyl, difluoromethyl, -CF2CHF2, -CHFCF3, -CH2CF3, -(CH2CH2O)2CH3, [ka] or cyclopropyl. In certain embodiments, R 2a is methyl, difluoromethyl, -CF2CHF2, -CHFCF3, -CH2CF3, -(CH2CH2O)2CH3, [ka] Preferably, R 2 OR 2a If R 2a is methyl.

[0031] In certain embodiments, R 2 and Ar, together with the intervening atoms to which they are attached, combine to form a 5- to 7-membered carbocyclic ring or a 5- to 7-membered heterocyclic ring. For example, R 2 and Ar bond together with the intervening atoms to which they are bonded, [ka] may be formed.

[0032] In certain embodiments, R 3 teeth [ka] In other embodiments, R 3 teeth [ka] is.

[0033] In certain embodiments, R 3a and R 3b are each independently hydrogen, alkyl, acyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain preferred embodiments, R 3a and R 3b are hydrogen atoms.

[0034] In certain embodiments, R 3a and R 3b together with the boron atom and the two intervening oxygen atoms separating them form R 3 is linked to form a heterocyclyl, such as a 5- or 6-membered heterocyclyl. In certain such embodiments, R 3 teeth, [ka] It may be expressed as During the ceremony, Each R 5 are independently halogen, nitro, cyano, amino, acylamino, amido, hydroxyl, oxo, carboxy, alkoxy, alkylthio, alkyl (e.g., carboxymethyl), aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or any two R 5 independently, together with the intervening carbon atom(s) to which they are attached, combine to form a carbocyclic or heterocyclic ring; q is 0 or an integer selected from 1 to 6, as valence permits. 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] is.

[0035] In certain embodiments, R 3 teeth [ka] and R 3a , R 3b and M together with the boron atom and any intervening atoms form R 3 are bonded to form a polycyclic heterocycle. For example, R 3 teeth, [ka] wherein R d is H or C1-C4 alkyl, preferably H or methyl, more preferably H.

[0036] It will be understood that a coordinate bond may be formed in a compound containing an atom with a lone pair of electrons (e.g., a nitrogen atom) and a boron atom. That is, the lone pair of electrons may coordinate with an empty orbital of the boron. This is sometimes indicated by an arrow from the donor atom to the boron, as shown below. [ka] Such compounds may be represented with or without coordinate bonds; both refer to the same compound.

[0037] In certain embodiments, ring Z 2 teeth, [ka] In some embodiments, ring Z 2 teeth, [ka] is.

[0038] In certain embodiments, R 3a is methyl. In certain preferred embodiments, R 3a is hydrogen.

[0039] In certain embodiments, the compound is [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0040] In certain embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0041] In certain embodiments, the pharmaceutically acceptable salt of any of the above compounds is a formate, hydrochloride, methanesulfonate, ethanesulfonate, or maleate salt.

[0042] In certain aspects, the present disclosure provides a pharmaceutical composition comprising a compound according to any one of the preceding claims and a pharmaceutically acceptable excipient.

[0043] definition Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. Generally, the nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein are those well known and commonly used in the art.

[0044] The methods and techniques of the present disclosure are generally performed according to conventional methods known in the art and as described in various general and more specific references cited and discussed throughout this specification, unless otherwise indicated. See, for example, "Principles of Neural Science," McGraw-Hill Medical, New York, NY (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., NY (1999); and Gilbert et al., "Developmental Biology, 6th ed.", Sinauer Associates, Inc., Sunderland, MA, (2000).

[0045] Chemical terms used herein are used in accordance with conventional usage in the art as exemplified by "The McGraw-Hill Dictionary of Chemical Terms," ​​Parker S., Ed., McGraw-Hill, San Francisco, CA (1985).

[0046] 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.

[0047] The term "agent" is used herein to mean a compound (e.g., an organic or inorganic compound, a mixture of compounds), a biological macromolecule (e.g., nucleic acids, antibodies containing portions thereof, as well as humanized, chimeric, and human antibodies and monoclonal antibodies, proteins or portions thereof, e.g., peptides, lipids, carbohydrates), or an extract made from biological material such as bacterial, plant, fungal, or animal (e.g., mammalian) cells or tissues. Agents include, for example, agents of known structure and agents of unknown structure. The ability of such agents to inhibit complement factors may make them suitable as "therapeutic agents" in the methods and compositions of the present disclosure.

[0048] The terms "patient," "subject," or "individual" are used interchangeably and refer to either a human or non-human animal. These terms include mammals, such as humans, primates, livestock animals (including cows, pigs, etc.), pets (e.g., dogs, cats, etc.), and rodents (e.g., mice and rats).

[0049] "Treating" a condition or patient refers to taking measures to obtain beneficial or desired results, including clinical results. As used herein, and as well understood in the art, "treatment" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, diminishment of the extent of the disease, stabilization of the disease state (i.e., not worsening), prevention of disease spread, delay or slowing of disease progression, improvement or palliation of the disease state, and remission (whether partial or total). "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0050] The term "prevention," when used in reference to a condition (e.g., local recurrence (e.g., pain), a disease such as cancer, a complex syndrome such as heart failure, or any other medical condition), is art-recognized and well understood in the art, and includes administration of a composition that reduces the frequency of or delays the onset of symptoms of a medical condition in a subject compared to subjects who do not receive the composition. Thus, preventing cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving prophylactic treatment compared to an untreated control population, and / or delaying the occurrence of detectable cancerous growths in a treated population compared to an untreated control population, e.g., by a statistically and / or clinically significant amount.

[0051] "Administering" or "administration" of a substance, compound, or agent to a subject can be accomplished using one of a variety of methods known to those of skill in the art. For example, a compound or agent can be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (e.g., by absorption through cutaneous channels). A compound or agent can also be suitably delivered via a rechargeable or biodegradable polymeric or other device (e.g., patch and pump) or formulation that provides sustained, slow, or controlled release of the compound or agent. Administration can also be carried out, for example, once, multiple times, and / or over one or more extended periods of time.

[0052] Suitable methods of administering a substance, compound, or agent to a subject also depend, for example, on the age and / or health of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments, the compound or agent is administered to the subject orally, e.g., by ingestion. In some embodiments, the orally administered compound or agent is in a sustained- or slow-release formulation or is administered using such a slow- or sustained-release device.

[0053] As used herein, the term "co-administration" refers to any administration form of two or more different therapeutic agents in which a second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are effective in a patient simultaneously, which may include a synergistic effect of the two agents). For example, the different therapeutic compounds may be administered in the same formulation or in separate formulations, and may be administered simultaneously or sequentially. Thus, an individual receiving such treatment can benefit from the combined effects of the different therapeutic agents.

[0054] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or agent refers to the amount of the drug or agent that, when administered to a subject, has the intended therapeutic effect. The full therapeutic effect does not necessarily occur with the administration of a single dose, but may occur only after the administration of a series of doses. Thus, a therapeutically effective amount can be administered in one or more doses. The exact effective amount required for a subject depends, for example, on the subject's size, health, and age, as well as the nature and extent of the condition being treated, such as cancer or MDS. Those skilled in the art can easily determine the effective amount for a given situation through routine experimentation.

[0055] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes occurrences when the event or circumstance occurs and occurrences when it does not occur. For example, "optionally substituted alkyl" refers to alkyl being substituted as well as alkyl being unsubstituted.

[0056] It is understood that the substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skill in the art to result in chemically stable compounds that can be readily synthesized from readily available starting materials by techniques known in the art, as well as those methods set forth below. When a substituent is itself substituted with more than one group, it is understood that these multiple groups can be on the same carbon or on different carbons, so long as a stable structure results.

[0057] As used herein, the term "optionally substituted" refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a specified substituent, including, but not limited to, hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH-O-alkyl, -OP(O)(O-alkyl), or -CH-OP(O)(O-alkyl). Preferably, "optionally substituted" refers to the replacement of one to four hydrogen radicals in a given structure with the above substituents. More preferably, one to three hydrogen radicals are replaced by such substituents. It is understood that the substituents may be further substituted.

[0058] As used herein, the term "alkyl" refers to a C1-C 10 Straight chain alkyl group or C1-C 10"Alkyl" refers to saturated aliphatic groups, including, but not limited to, branched chain alkyl groups. Preferably, the "alkyl" group refers to a C1-C6 straight chain alkyl group or a C1-C6 branched chain alkyl group. Most preferably, the "alkyl" group refers to a C1-C4 straight chain alkyl group or a C1-C4 branched chain alkyl group. Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, or 4-octyl. Furthermore, the term "alkyl," as used throughout the specification, examples, and claims, is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl.

[0059] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0060] The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

[0061] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0062] 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.

[0063] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0064] "C x~y " or "C x ~C y The term "C alkyl" when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups containing x to y carbons in the chain. C alkyl indicates a hydrogen when the group is terminal and a bond when the group is internal. 1-6 Alkyl groups, for example, contain 1 to 6 carbon atoms in the chain.

[0065] The term "alkylamino," as used herein, refers to an amino group substituted with at least one alkyl group.

[0066] 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-.

[0067] The term "amide" as used herein refers to the group: [ka] In the formula, R 9 , R 10、 and R 11 each independently represents hydrogen or a hydrocarbyl group, or R 9 and R 10 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure, or R 10 and R 11 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0068] The term "amidino" as used herein refers to the group: [ka] In the formula, R 9 , R 10、 and R 11 each independently represents hydrogen or a hydrocarbyl group, or R 9 and R 10 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure, or R 10 and R 11 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0069] The term "amide" as used herein refers to the group: [ka] In the formula, R 10 represents hydrogen or a hydrocarbyl group.

[0070] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and their salts, e.g., [ka] refers to a part that can be represented by In the formula, R 9 , R 10 , and R 10 each independently represents hydrogen or a hydrocarbyl group, or R 9 and R 10 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0071] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0072] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0073] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of the rings being aromatic, and the other cyclic rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0074] The term "azido" is art-recognized and refers to the group --N.sub.3.

[0075] The term "carbamate" is art-recognized and refers to the group: [ka] In the formula, R 9 and R 10 independently represent hydrogen or a hydrocarbyl group.

[0076] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocyclic group.

[0077] The term "carbocycle" includes 5- to 7-membered monocyclic rings and 8- to 12-membered bicyclic rings. Each ring in a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Carbocycles include bicyclic molecules in which one, two, or more atoms are shared between two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each ring shares two adjacent atoms with the other ring. Each ring in a fused carbocycle may be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Valence permitting, any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocycles include decalin, 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 that can have a hydrogen atom.

[0078] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocyclic group.

[0079] The term "carbonate" is art-recognized and refers to an -OCO2- group.

[0080] The term "carboxy," as used herein, refers to a group represented by the formula -CO2H.

[0081] The term "ester" as used herein refers to an ester that is an ester of -C(O)OR 9 refers to a group, wherein R 9 represents a hydrocarbyl group.

[0082] The term "ether," as used herein, refers to a hydrocarbyl group linked to another hydrocarbyl group through an oxygen. Thus, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which may be represented by the general formula: alkyl-O-alkyl.

[0083] The terms "halo" and "halogen" as used herein mean halogen and include chloro, fluoro, bromo, and iodo.

[0084] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogens have been replaced with a halogen.

[0085] The term "haloalkoxy," as used herein, refers to an alkoxy group in which one or more hydrogen atoms are replaced with halogen atoms.

[0086] The terms "hetaryl" and "heteroaryl" as used herein refer to an alkyl group substituted with a hetaryl group.

[0087] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic monocyclic ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, which ring structures contain at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, and at least one of the rings is heteroaromatic; for example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0088] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0089] The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted with a heterocycle group.

[0090] The terms "heterocyclyl," "heterocycle," and "heterocyclic" refer to a substituted or unsubstituted non-aromatic ring structure, preferably 3- to 10-membered, more preferably 3- to 7-membered, which ring structure contains at least one heteroatom, preferably 1-4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, and at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0091] As used herein, the term "hydrocarbyl" refers to a group bonded through a carbon atom that does not have an =O or =S substituent, typically having at least one carbon-hydrogen bond and a primarily carbon backbone, but which may optionally contain heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl for purposes of this application, while substituents such as acetyl (which has an =O substituent on the linking carbon) and ethoxy (which is linked through an oxygen rather than a carbon) are not considered hydrocarbyl. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, alkynyl, and combinations thereof.

[0092] The term "hydroxyalkyl," as used herein, refers to an alkyl group substituted with a hydroxy group.

[0093] The term “imine” is art-recognized and refers to the group: [ka] In the formula, R 9 is hydrogen or a hydrocarbyl group, and R 10 represents a hydrocarbyl group, or R 9 and R 10 is R 9 together with the N atom to which it is attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0094] The term "lower," when used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups having 10 or fewer, preferably 6 or fewer atoms in the substituent. For example, "lower alkyl" refers to an alkyl group containing 10 or fewer, preferably 6 or fewer, carbon atoms. In certain embodiments, an acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituent as defined herein is a lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, respectively, whether appearing alone or in combination with other substituents, such as in descriptions like hydroxyalkyl and aralkyl (in which, for example, atoms in an aryl group are not counted when counting the carbon atoms of the alkyl substituent).

[0095] The term "oxime" is art-recognized and refers to the group: [ka] In the formula, R 9 represents hydrogen or a hydrocarbyl group.

[0096] The term "phosphonate" is art-recognized and refers to the following group: [ka]

[0097] The term “dialkylphosphine oxide” is art-recognized and refers to the group: [ka] In the formula, R 9 and R 10 independently represent hydrogen or hydrocarbyl.

[0098] The terms "polycyclyl," "polycycle," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, e.g., the rings are "fused rings." Each ring of a polycycle can be substituted or unsubstituted. In certain embodiments, each ring of a polycycle contains 3 to 10 atoms, preferably 5 to 7 atoms, within the ring.

[0099] The term "sulfate" is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

[0100] The term "sulfonamide" is art-recognized and has the general formula [ka] refers to a group represented by In the formula, R 9 and R 10 independently represent hydrogen or hydrocarbyl.

[0101] The term "sulfoxide" is art-recognized and refers to the group --S(O)--.

[0102] The term "sulfonate" is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

[0103] The term "sulfone" is art-recognized and refers to a -S(O)2- group.

[0104] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more backbone carbons. It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is consistent with the permissible valencies of the substituted atom and substituent, and that the substitution results in a stable compound that does not undergo spontaneous transformation, e.g., by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In one broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. The substituents may include any of the substituents described herein, such as halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

[0105] The term "thioalkyl," as used herein, refers to an alkyl group substituted with a thiol group.

[0106] The term "thioester" as used herein refers to a group consisting of -C(O)SR 9 group or -SC(O)R 9 refers to a group, wherein R 9 represents a hydrocarbyl.

[0107] The term "thioether" as used herein is equivalent to an ether where the oxygen has been replaced with sulfur.

[0108] The term "urea" is art-recognized and has the general formula [ka] may be expressed as In the formula, R 9 and R 10 independently represent hydrogen or hydrocarbyl.

[0109] As used herein, the term "modulate" includes the inhibition or suppression of a function or activity (eg, cell proliferation), as well as the enhancement of a function or activity.

[0110] As used herein, the term "inhibit" includes suppression of function or activity. In certain embodiments, the compounds disclosed herein inhibit complement factors. Inhibition of complement factors may be measured according to techniques known to those of skill in the art, such as enzymatic assays. For example, inhibition of C1s can be determined according to the enzymatic assay disclosed herein in Example 93. In some embodiments, a compound inhibits C1s if the pIC50, determined according to the procedure described in Example 93, is at least 5, at least 5.5, at least 6, at least 6.5, at least 7, at least 7.5, at least 8, at least 8.5, or at least 9.

[0111] The phrase "pharmaceutically acceptable" is art-recognized. In certain embodiments, this term includes compositions, excipients, adjuvants, polymers, and other materials and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0112] "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 for the treatment of patients.

[0113] As used herein, the term "pharmaceutically acceptable acid addition salt" refers to any non-toxic organic or inorganic salt of any of the main agents represented by Formula I or II. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, and salicylic acid, as well as sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. Either mono- or di-acid salts are formed, and such salts may exist in either hydrated, solvated, or substantially anhydrous form. In general, acid addition salts of compounds of formula I or II have higher solubility in water and various hydrophilic organic solvents and generally exhibit higher melting points than their free base forms.The selection of appropriate salts will be known to those skilled in the art.Other pharmaceutically unacceptable salts, such as oxalates, may be used, for example, for laboratory use or to isolate compounds of formula I or II for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0114] As used herein, the term "pharmaceutically acceptable base addition salt" refers to any non-toxic organic or inorganic base addition salt of any acid compound represented by Formula I or II or any of their intermediates. Exemplary inorganic bases that form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine, and picoline or ammonia. The selection of appropriate salts is within the skill of the art.

[0115] Many of the compounds useful in the methods and compositions of the present disclosure have at least one stereocenter in their structure. This stereocenter may exist in either the R or S configuration, and the R and S designations are used in accordance with the conventions set forth in Pure Appl. Chem. (1976), 45, 11-30. The present disclosure contemplates all stereoisomeric forms, such as enantiomeric and diastereomeric forms, of the compounds, salts, prodrugs, or mixtures thereof, including all possible mixtures of stereoisomers. See, e.g., WO 01 / 062726.

[0116] Furthermore, certain compounds containing alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each case, the present disclosure includes both mixtures and separate individual isomers.

[0117] Some compounds may exist in tautomeric forms, and such forms, although not explicitly shown in the formulas set forth herein, are intended to be included within the scope of the present disclosure.

[0118] A "prodrug" or "pharmaceutically acceptable prodrug" refers to a compound that is metabolized in the host after administration, e.g., hydrolyzed or oxidized, to form a compound of the present disclosure (e.g., a compound of Formula I or II). Typical examples of prodrugs include compounds that have a biologically labile or cleavable (protecting) group on the functional portion 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 to yield the active compound. Examples of prodrugs that use esters or phosphoramidates as biologically labile or cleavable (protecting) groups are disclosed in U.S. Patent Nos. 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of the present disclosure are metabolized to produce a compound of Formula I or II. The present disclosure includes within its scope prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in "Design of Prodrugs", Ed. H. Bundgaard, Elsevier, 1985.

[0119] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filter, diluent, excipient, solvent, or encapsulating material, useful in formulating a drug for pharmaceutical or therapeutic use.

[0120] As used herein, the terms "logarithm of solubility," "LogS," or "logS" are used in the art to quantify the aqueous solubility of a compound. The aqueous solubility of a compound significantly affects its absorption and distribution properties. Low solubility often results in poor absorption. The LogS value is the unit-removed logarithm (base 10) of the solubility measured in moles / liter.

[0121] Pharmaceutical Composition The compositions and methods of the present invention may be used to treat individuals in need thereof. In certain embodiments, the individual is a mammal, such as a human or a non-human animal. When administered to an animal, such as a human, the composition or compound is preferably administered as a pharmaceutical composition, for example, comprising a compound of the present 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 physiologically buffered saline, or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are intended for human administration, particularly invasive routes of administration (i.e., routes such as injection or implantation that avoid transport or diffusion across epithelial barriers), the aqueous solutions are pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to provide delayed release of the drug or to selectively target one or more cells, tissues, or organs. Pharmaceutical compositions can be in unit dosage forms such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized forms for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The compositions can also be present in transdermal delivery systems, e.g., skin patches. The compositions can also be present in solutions suitable for topical administration, such as lotions, creams, or ointments. The pharmaceutically acceptable carrier can contain, for example, physiologically acceptable agents that act to stabilize, increase solubility, or enhance 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 dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low-molecular-weight proteins, or other stabilizers or excipients. The choice of pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system.The pharmaceutical compositions (preparations) can also be liposomes or other polymer matrices into which, for example, the compounds of the invention can be incorporated. For example, liposomes comprising phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively easy to make and administer.

[0122] In some cases, the pharmaceutical composition may be a solid dispersion. The term "solid dispersion" refers to a system in a solid state containing at least two components, one component dispersed throughout the other. For example, the solid dispersion may be an amorphous solid dispersion. As used herein, the term "amorphous solid dispersion" refers to a stable solid dispersion containing an amorphous drug substance and a polymer. "Amorphous drug substance" means that the amorphous solid dispersion contains the drug substance in a substantially amorphous solid state.

[0123] As used herein, the phrase "pharmaceutically acceptable" is employed to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0124] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as, for example, a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful 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, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; and (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and da (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, 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) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic, compatible substances employed in pharmaceutical formulations.

[0125] Pharmaceutical compositions (preparations) can be administered to a subject by any of a number of routes of administration, including, for example, orally (e.g., as a drench such as an aqueous or non-aqueous solution or suspension, a tablet, a capsule (including sprinkle capsules and gelatin capsules), a bolus, a powder, a granule, a paste for application to the tongue), absorption through the oral mucosa (e.g., sublingually), subcutaneously, transdermally (e.g., as a patch applied to the skin), and topically (e.g., as a cream, ointment, or spray applied to the skin). Compounds may also be formulated for inhalation. In certain embodiments, the compounds may simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found, for example, in U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896, as well as the patents cited therein.

[0126] The formulations may be conveniently presented in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of compound that produces a therapeutic effect. Generally, out of 100 percent, this amount will range from about 1 percent to about 99 percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0127] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the present 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 present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0128] Formulations of the present invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), lyophilizates, powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as lozenges (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, etc., each containing a predetermined amount of a compound of the present invention as an active ingredient. The composition or compound may also be administered as a bolus, electuary, or paste.

[0129] To prepare solid dosage forms for oral administration (such as capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active ingredient can be combined with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; and (4) disintegrants, such as agar-agar, calcium carbonate, potato starch, or tapioca starch. (5) dissolution retarders, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, 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 to make amorphous solid dispersions; and (12) coloring agents. For capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers for soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0130] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface-active agents, or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0131] Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may also be formulated to sustain or control the release of the active ingredient therein, using, for example, hydroxypropylmethylcellulose in various proportions to produce the desired release profile, other polymer matrices, liposomes, and / or microspheres. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents, and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0132] The liquid dosage form useful for oral administration includes pharmaceutically acceptable emulsion, lyophilized product for reconstitution, microemulsion, solution, suspension, syrup and elixir.In addition to active ingredient, liquid dosage form can contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrin and its derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, and mixtures thereof.

[0133] 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.

[0134] Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0135] 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 that may be required.

[0136] The ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0137] 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.

[0138] Transdermal patches have the additional advantage of providing controlled delivery of the compound of the present invention to the body.Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium.Absorption enhancers can also be used to increase the flux of the compound across the skin.The rate of such flux can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0139] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to 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, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile, isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that may be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0140] Examples of suitable aqueous and non-aqueous carriers that may be employed in the pharmaceutical compositions of the present invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), 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 the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0141] These compositions may contain auxiliary agents such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial activity may be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc., in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0142] In some cases, it is desirable to delay the absorption of a drug from subcutaneous or intramuscular injection to prolong its effect. This can be achieved by using a liquid suspension of crystalline or amorphous material that is poorly water-soluble. The rate of absorption of a drug depends on its dissolution rate, which in turn depends on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0143] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on 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 can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0144] For use in the methods of the present invention, the active compound may be provided per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0145] The method of introduction may be provided by a rechargeable or biodegradable device. A variety of sustained-release polymeric devices have been developed and investigated in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form implants for sustained release of compounds at specific target sites.

[0146] Actual dosage levels of the active ingredient in the pharmaceutical compositions may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0147] The selected dosage level will depend upon the activity of the particular compound or combination of compounds employed, or their esters, salts, or amides, the route of administration, the time of administration, the rate of excretion of the particular compound(s) employed, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health, and medical history of the patient being treated, and similar factors, including similar factors well known in the medical arts.

[0148] A physician or veterinarian of ordinary skill in the art can easily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, a physician or veterinarian may start by administering a pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. A "therapeutically effective amount" refers to the concentration of a compound sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of a compound will vary depending on the subject's weight, sex, age, and medical history. Other factors that affect the effective amount may 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, other therapeutic agents administered together with the compound of the present invention. Multiple administrations of the drug can deliver a larger total dose. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, incorporated herein by reference).

[0149] Generally, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0150] If desired, the effective daily dose of the active compound can be administered as 1, 2, 3, 4, 5, 6 or more subdoses at appropriate intervals throughout the day, or optionally in unit dosage form.In certain embodiments of the present invention, the active compound can be administered 2 or 3 times a day.In a preferred embodiment, the active compound will be administered once a day.

[0151] Patients receiving this treatment may be any animal in need of treatment, including primates, particularly humans; and other mammals such as horses, cows, pigs, sheep, cats, dogs, poultry, and pets in general.

[0152] In certain embodiments, the compounds of the present invention may be used alone or may be administered in combination with other types of therapeutic agents.

[0153] The present disclosure includes the use of pharmaceutically acceptable salts of the compounds of the present invention (Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19) in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, L-arginine, benentamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, salts of Na, Ca, K, Mg, Zn or other metals.In certain embodiments, contemplated salts of the present invention include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, l-ascorbic acid, l-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucoheptan-1,2-one ... and hydroxybenzoates such as hydroxybenzoates, ...

[0154] Pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates can also be prepared. The source of such solvates can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0155] Wetting agents, emulsifying agents, and lubricating agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0156] 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 hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine.

[0157] Treatment method In certain aspects, the present disclosure provides methods for treating a disease or condition associated with complement activation in an individual in need thereof, comprising administering a therapeutically effective amount of a compound provided herein. Without being bound by theory, it is believed that the compounds disclosed herein act as C1s inhibitors, thus preventing complement activation and thus treating diseases associated with complement activation.

[0158] In certain embodiments, the disease or condition is selected from a neurodegenerative disorder, an inflammatory disease, an autoimmune disease, an ocular disease, and a metabolic disease. Those skilled in the art will appreciate that many diseases or conditions can fall into more than one of the aforementioned disease categories. For example, a condition can be both neurological and autoimmune, autoimmune and inflammatory, ocular and neurological, etc.

[0159] In certain embodiments, the disease or condition is Duchenne muscular dystrophy, Becker muscular dystrophy, limb-girdle muscular dystrophies (LGMDs) (e.g., sarcoglycanopathies, dystroglycanopathies, and dysferlinopathies), type VI collagen-related disorders (e.g., Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD)), congenital muscular dystrophies (CMDs) and congenital myopathies, distal muscular dystrophy / myopathy (e.g., Miyoshi myopathy).

[0160] Diseases or conditions associated with complement activation that may be treated according to the present methods include, but are not limited to: Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, progressive multiple sclerosis, glaucoma, myotonic dystrophy, Duchenne muscular dystrophy, Guillain-Barré 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, and rheumatoid arthritis. Pemphigus foliaceus, pemphigus foliaceus, bullous pemphigoid, immune-mediated necrotizing myopathy, vitiligo, paraneoplastic syndromes, vasculitic diseases, hypocomplementemic urticarial vasculitis, chronic spontaneous urticaria, remote tissue damage 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, cardioprotection-induced coronary endothelial dysfunction, type II membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure, cryoglobulinemia, antiphospholipid syndrome, chronic open-angle glaucoma, acute angle-closure glaucoma, macular degenerative disease, wet age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, choroidal neovascularization, uveitis, diabetic retinopathy, ischemia-related retinopathy, endophthalmitis, intraocular neovascular disease, diabetic macular edema, pathological myopia, von Hippel-Lindau disease, ocular histoplasmosis, neuromyelitis optica, retinal These include central vein occlusion, corneal neovascularization, retinal neovascularization, Leber's hereditary optic neuropathy, optic neuritis, Behcet's retinopathy, ischemic optic neuropathy, retinal vasculitis, ANCA vasculitis, Wegener's granulomatosis, Purtscher's 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, thermal autoimmune hemolytic anemia, and coronary artery disease.

[0161] In certain embodiments, diseases or conditions associated with complement activation that may be treated according to the present methods include Guillain-Barré syndrome, amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), geographic atrophy, cold agglutinin disease, thermal autoimmune hemolytic anemia, lupus nephritis, and multifocal motor neuropathy.

[0162] In certain embodiments, the complement activation-associated disease or condition that may be treated according to the method is Guillain-Barré syndrome. In certain embodiments, the complement activation-associated disease or condition that may be treated according to the method is ALS. In certain embodiments, the complement activation-associated disease or condition that may be treated according to the method is HD. In certain embodiments, the complement activation-associated disease or condition that may be treated according to the method is geographic atrophy. In certain embodiments, the complement activation-associated disease or condition that may be treated according to the method is cold agglutinin disease. In certain embodiments, the complement activation-associated disease or condition that may be treated according to the method is hyperthermic autoimmune hemolytic anemia. In certain embodiments, the complement activation-associated disease or condition that may be treated according to the method is lupus nephritis. In certain embodiments, the complement activation-associated disease or condition that may be treated according to the method is multifocal motor neuropathy.

[0163] In certain embodiments, the disease or condition is a neurodegenerative disorder, for example, a disorder associated with synapse loss or loss of neural connections that is dependent on C1q, C1 complex, CR1, C3, CR3, C4, or CR4, pathological activity-dependent synapse loss, or microglial synapse phagocytosis. In certain embodiments, the neurodegenerative disorder is associated with dysregulation of C1s. In certain embodiments, the neurodegenerative disorder is associated with activation or dysregulation of C1s. In certain embodiments, the neurodegenerative disorder is associated with activation of C1s.

[0164] In certain embodiments, the neurodegenerative disorder is selected from Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, progressive multiple sclerosis, glaucoma, myotonic dystrophy, Guillain-Barré syndrome (GBS), myasthenia gravis, spinal muscular atrophy, Down's syndrome, Parkinson's disease, Huntington's disease (HD), traumatic brain injury, epilepsy, age-related macular degeneration, immune-mediated necrotizing myopathy (IMNM), and frontotemporal dementia.

[0165] In certain embodiments, the neurodegenerative disorder is selected from Guillain-Barré syndrome, Huntington's disease, amyotrophic lateral sclerosis, and geographic atrophy. Age-related macular degeneration (AMD) includes wet AMD and dry AMD. Furthermore, dry AMD has early, intermediate, and late stages, the latter of which is called geographic atrophy and refers to the progressive loss of cells in the retina.

[0166] In certain embodiments, the disease or condition is an inflammatory disease, an autoimmune disease, a metabolic disease, or an ocular disease. In certain embodiments, the inflammatory disease, autoimmune disease, metabolic disease, or ocular disease is associated with activation or dysregulation of C1s.

[0167] In certain embodiments, the inflammatory disease, autoimmune disease, metabolic disease, or eye disease is selected from the group consisting of diabetes, obesity, atherosclerosis, rheumatoid arthritis, acute respiratory distress syndrome, pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, remote tissue injury after ischemia-reperfusion, complement activation during cardiopulmonary bypass surgery, dermatomyositis, pemphigus, lupus nephritis and its resulting glomerulonephritis and vasculitis, renal fibrosis, systemic lupus erythematosus, Hashimoto's thyroiditis, Addison's disease, and celiac disease. Chronic leukemia, Crohn's disease, pernicious anemia, immune-mediated necrotizing myopathy, vitiligo, paraneoplastic syndromes, vasculitic disorders, hypocomplementemic urticarial vasculitis, chronic spontaneous urticaria, chronic idiopathic demyelinating polyneuropathy, polymyalgia rheumatica, multifocal motor neuropathy, immune thrombocytopenia, heparin-induced thrombocytopenia, idiopathic thrombocytopenic purpura, cardioprotection-induced coronary endothelial dysfunction, type II membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure, cryoglobulinemia, antiphospholipid glaucoma syndrome, chronic open-angle glaucoma, acute angle-closure glaucoma, macular degenerative disease, wet age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, choroidal neovascularization, 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 disease The present invention relates to retinal disease, including retinal vasculitis, ischemic optic neuropathy, retinal vasculitis, ANCA vasculitis, Wegener's granulomatosis, Purtscher's retinopathy, Sjogren's disease dry eye, sarcoidosis, temporal arteritis, polyarteritis nodosa, multiple sclerosis, progressive multiple sclerosis, allograft, hyperacute rejection, hemodialysis, chronic obstructive pulmonary distress syndrome, asthma, aspiration pneumonia, immune thrombocytopenia, autoimmune hemolytic anemia, cold agglutinin disease, thermal autoimmune hemolytic anemia, and coronary artery disease.

[0168] In some embodiments, the disease is cold agglutinin disease, thermal autoimmune hemolytic anemia, geographic atrophy, lupus nephritis, or multifocal motor neuropathy.

[0169] In certain embodiments, the disease is autoimmune hemolytic anemia, such as cold agglutinin disease or febrile autoimmune hemolytic anemia.

[0170] In certain embodiments, the present disclosure provides methods for inhibiting C1s, comprising contacting C1s with a compound disclosed herein. In certain embodiments, the present disclosure provides methods for inhibiting activated C1s, comprising contacting C1s with a compound disclosed herein.

[0171] In certain embodiments, contacting the C1s with the compound comprises administering the compound to the individual. [Example]

[0172] The invention having now generally been described, it will be more readily understood by reference to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention.

[0173] General Procedure Liquid chromatography-mass spectrometry method A (LC-MS method A) Total ion current (TIC) and DAD UV chromatographic traces, along with peak-associated MS and UV spectra, were acquired on a UPLC / MS Acquity™ system coupled to a Waters single quadrupole mass spectrometer equipped with a PDA detector and operated in alternating positive-negative electrospray ionization mode. [LC / MS-ES(+ / -): Analysis performed using an Acquity UPLC™ CSH, 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, stop time 2.0 min.] Positive ES 100-1000, negative ES 100-1000, UV detection DAD 210-350nm.

[0174] Liquid chromatography-mass spectrometry B (LC-MS method B) Total ion current (TIC) and DAD UV chromatographic traces, along with peak-associated MS and UV spectra, were acquired on a UPLC / MS Acquity™ system coupled to a Waters single quadrupole mass spectrometer equipped with a PDA detector and operated in alternating positive-negative electrospray ionization mode. [LC / MS-ES(+ / -): Analysis performed using an Acquity UPLC™ CSH, C18 column (50 × 2.1 mm, 1.7 μm particle size), column temperature 40 °C, mobile phase: A—water + 0.1% v / v aqueous ammonia 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, stop time 2.0 min.] Positive ES 100-1000, negative ES 100-1000, UV detection DAD 210-350nm.

[0175] Analysis method 1 H nuclear magnetic resonance (NMR) spectroscopy was performed using one of the following instruments: a Bruker Avance400 instrument equipped with a probe DUAL 400 MHz S1, probe 6 S1 400 MHz 5 mm 1 H- 13 Bruker Avance400 instrument equipped with C ID, Bruker Avance III 400 instrument with Nanobay equipped with probe Broadband BBFO 5mm direct, 400 MHz Agilent Direct Drive instrument equipped with ID AUTO-X PFG probe, or 5mm Triple Resonance operating at 500 MHz 1 H{ 13 C / 15Agilent VNMRS500 Direct Drive instrument equipped with a {N} cryoprobe. Spectra were acquired near room temperature in the solvents indicated unless otherwise noted. In all cases, the NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts per million using conventional abbreviations for major peak designations: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; br, broad line.

[0176] Where thin-layer chromatography (TLC) is used, it refers to silica gel TLC using silica gel F254 (Merck) plates. Rf is the distance traveled by the compound on the TLC plate divided by the distance traveled by the solvent. Column chromatography was performed using automated flash chromatography (Biotage SP1 or Isolera) systems on Biotage silica gel cartridges (KP-Sil, KP-NH, Sfar D, or Sfar NHD) or, for reverse-phase column chromatography, on Biotage C18 cartridges (KP-C18-HS or Sfar C18D).

[0177] Preparation of compounds Where the preparation of starting materials is not described, they are commercially available, known in the literature, or readily accessible by those skilled in the art using standard procedures. Where compounds are described as prepared similarly to previous examples or intermediates, those skilled in the art will understand that reaction times, number of equivalents of reagents, and temperatures can vary for each particular reaction, and that various workup or purification techniques may be necessary or desirable. When the reaction is carried out using microwave irradiation, the microwave used is a Biotage Initiator. The actual power supplied will vary over the course of the reaction to maintain a constant temperature. Additional details regarding the preparation of the following compounds can be found in U.S. Patent Application No. 17 / 379,334, filed July 19, 2021, the entire disclosure of which is incorporated herein by reference.

[0178] Example: Preparation of exemplary compounds Example 1: [3-(4-aminocinnolin-7-yl)-4-(1H-pyrazol-1-yl)phenyl]boronic acid (1) [ka] Step 1: Palladium(II) diacetate (1.36 mg, 0.010 mmol), 7-(5-chloro-2-pyrazol-1-ylphenyl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (57.0 mg, 0.120 mmol), potassium acetate (35.56 mg, 0.360 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (92.01 mg, 0.360 mmol) were dissolved in 1,4-dioxane (3 mL), and the mixture was degassed with Ar for 10 minutes. The mixture was then stirred at 95° C. for 1 hour. The mixture was filtered, washed with methanol, and the filtrate was concentrated in vacuo. LC-MS (Method A): Room temperature 0.88 min, MS (ESI) m / z=564.4[M+H] + .

[0179] Step 2: The crude material from Step 1 was dissolved in DCM (1.5 mL) and trifluoroacetic acid (1.5 mL), stirred at room temperature overnight, and then concentrated under reduced pressure. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge (5 g). The cartridge was washed with MeOH / HO (9:1), and the product was eluted from the SCX cartridge with a 2 M solution of NH in MeOH. The basic fractions were concentrated, and the residue was purified by column chromatography (KP-C18-HS, ​​6 g + 6 g consecutively) eluting with a 2% to 20% gradient of CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and concentrated to afford [3-(4-aminocinnolin-7-yl)-4-pyrazol-1-ylphenyl]boronic acid (15 mg, 0.045 mmol, 37.5% yield) as a white solid. 1H NMR (400MHz, DMSO-d6+TFA drop) δ6.33-6.38(m,1H),7.24(d,J=8.36Hz,1H),7.54(s,1H),7.58-7.67(m,2H) ),7.74-7.81(m,1H),8.02-8.09(m,2H),8.27(d,J=8.80Hz,1H),8.44(s,1H),9.70(s,1H),9.77(s,1H). LC-MS (method A): room temperature 0.41 min, MS (ESI) m / z=332.2[M+H] + .

[0180] Example 2: [3-(4-aminocinnolin-7-yl)-4-[4-(methylcarbamoyl)-1H-pyrazol-1-yl]phenyl]boronic acid formate (2) [ka] Step 1: Palladium(II) diacetate (1.8 mg, 0.010 mmol), 1-[4-chloro-2-[4-[(2,4-dimethoxyphenyl)methylamino]cinnolin-7-yl]phenyl]-N-methylpyrazole-4-carboxamide (85.0 mg, 0.160 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (6.13 mg, 0.010 mmol), potassium acetate (47.31 mg, 0.480 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (122.41 mg, 0.480 mmol) were dissolved in 1,4-dioxane (2 mL). The mixture was degassed with N2 for 10 min and then stirred for 2 h at 75° C. The mixture was filtered through a pad of Celite, washed with MeOH, and the filtrate was concentrated in vacuo.

[0181] 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 at room temperature overnight, 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 / HO (9:1), and then the product was eluted from the SCX cartridge with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​2 × SNAP12 in succession) eluting with a 2% to 25% gradient of CHCN (+0.1% HCOOH) in water (+0.1% HCOOH) to afford [3-(4-aminocinnolin-7-yl)-4-[4-(methylcarbamoyl)pyrazol-1-yl]phenyl]boronic acid formate (19 mg, 0.044 mmol, 27.23% yield) as a white powder. 1 H NMR (400MHz, DMSO-d6+2 drops of TFA) δ2.69(d,J=4.10Hz,3H),7.33(dd,J=8.80,1.64Hz,1H),7.62-7.70(m,2H),7.91 (s,1H), 8.03-8.10(m,3H), 8.13(s,0.8H from HCOOH), 8.21-8.35(m,2H), 8.47(s,1H), 9.75(s,1H), 9.81(s,1H). LC-MS (Method A): Room temperature 0.35 min, MS (ESI) m / z=389.19[M+H] + .

[0182] Example 3: [3-(4-aminocinnolin-7-yl)-4-(1H-pyrazol-1-yl)phenyl]boronic acid (3) [ka] Step 1: Palladium(II) diacetate (6.9 mg, 0.030 mmol), 7-(5-chloro-2-imidazol-1-ylphenyl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (290.0 mg, 0.610 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (23.43 mg, 0.050 mmol), potassium acetate (180.92 mg, 1.84 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (468.13 mg, 1.84 mmol) were dissolved in 1,4-dioxane (7 mL). The mixture was degassed with N2 for 10 min and then stirred for 2 h at 75° C. The mixture was filtered through a pad of Celite, washed with MeOH, and the filtrate was concentrated in vacuo.

[0183] Step 2: The crude material from Step 1 was dissolved in a mixture of DCM (6.8 mL) and trifluoroacetic acid (6.8 mL). The mixture was stirred at room temperature overnight, 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 / HO (9:1), and then the product was eluted from the SCX cartridge with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​2 × SNAP 12 g in succession) eluting with a 2% to 30% gradient of CHCN in water (+0.1% ammonium hydroxide). The appropriate fractions were collected and lyophilized to afford [3-(4-aminocinnolin-7-yl)-4-imidazol-1-ylphenyl]boronic acid (43 mg, 0.130 mmol, 21.13% yield) as a white powder. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ7.55(dd,J=8.80,1.66Hz,1H),7.73-7.78(m,3H),7.81(d,J=7.89Hz ,1H),8.12-8.17(m,2H),8.38(d,J=8.87Hz,1H),8.51(s,1H),9.35(s,1H),9.87(s,1H),9.94(s,1H). LC-MS (Method A): Room temperature 0.36 min, MS (ESI) m / z=331.83[M+H] + .

[0184] Example 4: [3-(4-aminocinnolin-7-yl)-4-[4-(methoxycarbonyl)-1H-imidazol-1-yl]phenyl]boronic acid (4) [ka] Step 1: A mixture of methyl 1-[4-chloro-2-(4-{[(2,4-dimethoxyphenyl)methyl]amino}cinnolin-7-yl)phenyl]-1H-imidazole-4-carboxylate (220.0 mg, 0.420 mmol), potassium acetate (122.22 mg, 1.25 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (316.25 mg, 1.25 mmol) in 1,4-dioxane (4.706 mL) was deoxygenated under argon for 10 minutes. Palladium(II) diacetate (4.66 mg, 0.020 mmol) and dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (15.83 mg, 0.030 mmol) were then added, and the mixture was stirred for 6 hours at 90° C. Additional 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (158.12 mg, 0.62 mmol), palladium(II) diacetate (2.33 mg, 0.010 mmol), and dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (7.91 mg, 0.015 mmol) were added, and the mixture was stirred for an additional 16 hours at 90° C. The mixture was filtered through Celite, washed with MeOH and EtOAc, and the filtrate was evaporated in vacuo. LC-MS (Method A): RT 0.83 min, MS (ESI) m / z=622.4 [M+H] + .

[0185] Step 2: The crude material from Step 1 was dissolved in DCM (3 mL) and trifluoroacetic acid (2.5 mL), and the mixture was stirred for 3 h. Additional trifluoroacetic acid (3 mL) was added, and the mixture was stirred for an additional 19 h. The volatiles were removed under reduced pressure, and the residue was dissolved in MeOH / water (9:1), loaded onto an SCX cartridge (10 g), washed with MeOH, and then eluted with a 7 M solution of ammonia in MeOH. Basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 30 g) eluting with a 1% to 25% gradient of MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give a white solid, which was subjected to semi-preparative HPLC purification (xBridge C18 (30 × 100 mm, 3 μm); 7.0% to 15.0% gradient of MeCN in 10 mM aqueous ammonium bicarbonate adjusted to pH 10 with ammonia) to give [3-(4-aminocinnolin-7-yl)-4-[4-(methoxycarbonyl)-1H-imidazol-1-yl]phenyl]boronic acid (14.2 mg, 0.036 mmol, 3.024% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6+TFA)δ3.74(s,3H),7.46(dd,J=8.83,1.64Hz,1H),7.66(d,J=7.73Hz,1H),7.72(d,J=1.59Hz,1H), 7.90-7.95(m,1H),8.06-8.11(m,2H),8.14-8.17(m,1H),8.33(d,J=8.82Hz,1H),8.47(s,1H),9.79(s,1H),9.85(s,1H). LC-MS (Method A): Room temperature 0.39 min, MS (ESI) m / z=390.1[M+H] + .

[0186] Example 5: [3-(4-aminocinnolin-7-yl)-4-(1H-1,2,4-triazol-1-yl)phenyl]boronic acid formate (5) [ka] Step 1: Palladium(II) diacetate (2.94 mg, 0.010 mmol), 7-[5-chloro-2-(1,2,4-triazol-1-yl)phenyl]-N-[(2,4-dimethoxyphenyl))methyl]cinnolin-4-amine (124.0 mg, 0.260 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (10.0 mg, 0.020 mmol), potassium acetate (77.2 mg, 0.790 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (199.75 mg, 0.790 mmol) were dissolved in 1,4-dioxane (3 mL). The mixture was degassed with N2 for 10 min and then stirred for 2 h at 75° C. The mixture was filtered through a pad of Celite, washed with MeOH, and the filtrate was concentrated in vacuo.

[0187] 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 at room temperature overnight, 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 / HO (9:1), and then the product was eluted from the SCX cartridge with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​2 × SNAP 12 g in succession) eluting with a 2% to 25% gradient of CHCN (+0.1% HCOOH) in water (+0.1% HCOOH) to afford [3-(4-aminocinnolin-7-yl)-4-(1,2,4-triazol-1-yl)phenyl]boronic acid formate (40 mg, 0.106 mmol, 40.34% yield) as a white powder. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ7.39(dd,J=8.86,1.64Hz,1H),7.66(d,J=1.59Hz,1H),7.70(d,J=7.93Hz,1H),8.07 -8.12(m,3H),8.13(s,0.84H from HCOOH),8.33(d,J=8.89Hz,1H),8.47(s,1H),8.70(s,1H),9.78(s,1H),9.86(s,1H). LC-MS (Method A): Room temperature 0.33 min, MS (ESI) m / z=333.09[M+H] + .

[0188] Example 6: [3-(4-aminocinnolin-7-yl)-4-[3-(methylcarbamoyl)-1H-pyrazol-1-yl]phenyl]boronic acid (6) [ka] Step 1: Palladium(II) diacetate (6.05 mg, 0.030 mmol), 1-[4-chloro-2-[4-[(2,4-dimethoxyphenyl)methylamino]cinnolin-7-yl]phenyl]-N-methylpyrazole-3-carboxamide (285.0 mg, 0.540 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (20.55 mg, 0.040 mmol), potassium acetate (158.62 mg, 1.62 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (410.44 mg, 1.62 mmol) were dissolved in 1,4-dioxane (7 mL). The mixture was degassed with Ar for 10 min and then stirred for 2 h at 75° C. The mixture was filtered through a pad of Celite, washed with EtOAc, and the filtrate was concentrated in vacuo.

[0189] Step 2: The crude material from Step 1 was dissolved in a mixture of DCM (7 mL) and trifluoroacetic acid (7 mL). The mixture was stirred at room temperature overnight, 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 / HO (9:1), and the product was eluted from the SCX cartridge with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​SNAP 30 g) eluting with a 2% to 25% gradient of CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). Fractions containing the partially purified product were collected and evaporated. The collected solid was subjected to semi-preparative HPLC purification (xBridge C18 (30 × 100 mm), 3 μm, 8% to 15% gradient of CHCN in 10 mM aqueous ammonium bicarbonate adjusted to pH 10 with ammonia, over 10 min). Fractions containing the desired compound were collected and lyophilized to give [3-(4-aminocinnolin-7-yl)-4-[3-(methylcarbamoyl)pyrazol-1-yl]phenyl]boronic acid (34 mg, 0.088 mmol, 16.26% yield) as a white powder. 1 H NMR (400MHz, DMSO-d6+2 drops of TFA) δ2.72(d,J=4.67Hz,3H),6.67(d,J=2.44Hz,1H),7.33(dd,J=8.85,1.64Hz,1H),7.68(d ,J=1.63Hz,1H),7.70-7.74(m,2H),8.01-8.11(m,3H),8.32(d,J=8.87Hz,1H),8.47(s,1H),9.76(s,1H),9.81(s,1H). LC-MS (Method A): Room temperature 0.38 min, MS (ESI) m / z=389.22[M+H] + .

[0190] Example 7: [3-(4-aminocinnolin-7-yl)-4-(1H-pyrazol-3-yl)phenyl]boronic acid (7) [ka] Palladium(II) diacetate (3.028 mg, 0.013 mmol), 7-[5-chloro-2-[1-(oxan-2-yl)pyrazol-3-yl]phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (150 mg, 0.270 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (12.8 A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (205.51 mg, 0.809 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (205.51 mg, 0.809 mmol) was dissolved in 1,4-dioxane (2.33 mL) in a microwave vial and degassed with N for 10 minutes. The resulting reaction mixture was stirred at 80 °C for 2 hours, then cooled to room temperature, filtered through Celite, and washed 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 and then evaporated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge, which was left for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 2 M 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 1% to 70% gradient of MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [3-(4-aminocinnolin-7-yl)-4-(1H-pyrazol-3-yl)phenyl]boronic acid (13 mg, 0.039 mmol, 14.44% yield) as a white powder. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ5.99(d,J=2.18Hz,1H),7.51(dd,J=8.80,1.54Hz,1H),7.62-7.66(m,1H),7.72(d,J=7.70Hz,1H),7.74(d,J= 1.32Hz,1H),7.92(s,1H),7.98(dd,J=7.70,1.10Hz,1H),8.09(s,1H),8.32(d,J=8.85Hz,1H),8.46(s,1H),9.69(br.s,1H),9.79(br.s,1H). LC-MS (method A): room temperature 0.39 min, MS (ESI) m / z=332.1[M+H] + .

[0191] Example 8: [5-(4-aminocinnolin-7-yl)-2-methyl-4-(1H-pyrazol-1-yl)phenyl]boronic acid (8) [ka] Step 1: Palladium(II) diacetate (1.69 mg, 0.010 mmol), 7-(5-chloro-4-methyl-2-pyrazol-1-ylphenyl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (73.0 mg, 0.150 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (5.73 mg, 0 4,4,5,5-Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (114.44 mg, 0.450 mmol), potassium acetate (44.23 mg, 0.450 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (114.44 mg, 0.450 mmol) were dissolved in 1,4-dioxane (4.05 mL) in a microwave vial, and the mixture was degassed with Ar for 10 minutes. The mixture was then stirred at 100° C. for 2 hours. The mixture was filtered, washed with MeOH, and the filtrate was concentrated in vacuo. LC-MS (Method A): RT 0.94 min, MS (ESI) m / z = 578.3 [M+H] + .

[0192] Step 2: The crude material from Step 1 was dissolved in DCM (2 mL) and trifluoroacetic acid (1.5 mL), and the mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge (5 g). The cartridge was washed with MeOH / HO (9:1), and the product was eluted from the SCX cartridge with a 2 M solution of NH in MeOH. The basic fractions were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​2 × 6 g in succession) eluting with a 2% to 30% gradient of MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and concentrated to afford [5-(4-aminocinnolin-7-yl)-2-methyl-4-pyrazol-1-ylphenyl]boronic acid (6.3 mg, 0.018 mmol, 12% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6+2 drops of TFA) δ2.56(s,3H),6.38(t,J=1.98Hz,1H),7.22(dd,J=8.91,1.65Hz,1H),7.43(s,1H),7.57(d,J=1.76H) z,1H),7.62(d,J=1.32Hz,1H),7.74(s,1H),7.80(d,J=2.42Hz,1H),8.26(d,J=9.02Hz,1H),8.45(s,1H),9.68(s,1H),9.79(s,1H). LC-MS (Method A): Room temperature 0.45 min, MS (ESI) m / z=346.2[M+H] + .

[0193] Example 9: [3-(4-aminocinnolin-7-yl)-4-[4-(difluoromethyl)-1H-pyrazol-1-yl]phenyl]boronic acid (9) [ka] Step 1: Palladium(II) diacetate (2.69 mg, 0.010 mmol), 7-[5-chloro-2-[4-(difluoromethyl)pyrazol-1-yl]phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (125.0 mg, 0.240 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (9.13 mg, 0.020 mmol), potassium acetate (70.51 mg, 0.720 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (182.45 mg, 0.720 mmol) were dissolved in 1,4-dioxane (3 mL). The mixture was degassed with N2 for 10 min and then stirred for 2 h at 75° C. The mixture was filtered through a pad of Celite, washing with EtOAc, and the filtrate was concentrated in vacuo.

[0194] 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 at room temperature overnight, 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 / HO (9:1), and then the product was eluted from the SCX cartridge with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​2 × SNAP 12 g in succession) eluting with a 2% to 25% gradient of CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give the partially purified product, which was further purified by column chromatography (KP-C18-HS, ​​2 × 12 g in succession) eluting with a gradient of 2% to 25% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [3-(4-aminocinnolin-7-yl)-4-[4-(difluoromethyl)pyrazol-1-yl]phenyl]boronic acid (21 mg, 0.055 mmol, 23.01% yield) as a white powder. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ6.97(t,J=55.85Hz,1H),7.29(dd,J=8.81,1.66Hz,1H),7.61-7.72(m,2H), 7.79(s,1H),8.02-8.09(m,2H),8.26(s,1H),8.30(d,J=8.88Hz,1H),8.46(s,1H),9.74(s,1H),9.81(s,1H). 19 F NMR (377MHz, DMSO-d6) δ-105.33 (d,J=55.84Hz). LC-MS (method A): room temperature 0.48 min, MS (ESI) m / z=382.14[M+H] + .

[0195] Example 10: [3-(4-aminocinnolin-7-yl)-4-(4-acetamido-1H-pyrazol-1-yl)phenyl]boronic acid formate (10) [ka] Step 1: Palladium(II) diacetate (3.61 mg, 0.020 mmol), N-[1-[4-chloro-2-[4-[(2,4-dimethoxyphenyl)methylamino]cinnolin-7-yl]phenyl]pyrazol-4-yl]acetamide (170.0 mg, 0.320 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (12.26 mg, 0.030 mmol), potassium acetate (94.62 mg, 0.960 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (244.82 mg, 0.960 mmol) were dissolved in 1,4-dioxane (4 mL). The mixture was degassed with N2 for 10 min and then stirred for 2 h at 75° C. The mixture was filtered through a pad of Celite, washing with EtOAc, and the filtrate was concentrated in vacuo.

[0196] Step 2: The crude material from Step 1 was dissolved in a mixture of DCM (4 mL) and trifluoroacetic acid (4 mL). The mixture was stirred at room temperature overnight, 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 / HO (9:1), and then the product was eluted from the SCX cartridge with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​2 × SNAP 12 g in succession) eluting with a gradient of 2% to 20% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to afford [4-(4-acetamidopyrazol-1-yl)-3-(4-aminocinnolin-7-yl)phenyl]boronic acid formate (58 mg, 0.134 mmol, 41.56% yield) as a pale yellow powder. 1 H NMR (400MHz, DMSO-d6+2 drops of TFA) δ1.95(s,3H),7.32(dd,J=8.80,1.62Hz,1H),7.54(s,1H),7.62(d,J=8.47Hz,1H),7.69(d,J=1.61Hz,1H) ,7.95(s,1H),8.00-8.07(m,2H),8.14(s,0.89H derived from HCOOH),8.31(d,J=8.89Hz,1H),8.47(s,1H),9.74(s,1H),9.81(s,1H),10.03(s,1H). LC-MS (Method A): Room temperature 0.36 min, MS (ESI) m / z=389.12[M+H] + .

[0197] Example 11: [3-(4-aminocinnolin-7-yl)-4-(4-fluoro-1H-pyrazol-1-yl)phenyl]boronic acid formate (11) [ka] Step 1: Palladium(II) diacetate (2.98 mg, 0.010 mmol), 7-[5-chloro-2-(4-fluoropyrazol-1-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (130.0 mg, 0.270 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (10.12 mg, 0.020 mmol), potassium acetate (78.12 mg, 0.800 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (202.14 mg, 0.800 mmol) were dissolved in 1,4-dioxane (3 mL). The mixture was degassed with N2 for 10 min and then stirred for 2 h at 75° C. The mixture was filtered through a pad of Celite, washing with EtOAc, and the filtrate was concentrated in vacuo.

[0198] 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 at room temperature overnight, 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 / HO (9:1), and then the product was eluted from the SCX cartridge with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​2 × SNAP 12 g in succession) eluting with a gradient of 2% to 25% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to afford [3-(4-aminocinnolin-7-yl)-4-(4-fluoropyrazol-1-yl)phenyl]boronic acid formate (40 mg, 0.101 mmol, 38.15% yield) as a white powder. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ7.35(dd,J=8.83,1.63Hz,1H),7.61-7.68(m,3H),8.04-8.08(m,2H),8.10( d,J=4.57Hz,1H),8.14(s,0.76H derived from HCOOH),8.34(d,J=8.88Hz,1H),8.48(s,1H),9.75(s,1H),9.83(s,1H). LC-MS (Method A): Room temperature 0.45 min, MS (ESI) m / z=350.04[M+H] + .

[0199] Example 12: [3-(4-aminocinnolin-7-yl)-4-(2H-1,2,3,4-tetrazol-2-yl)phenyl]boronic acid (12) [ka] Palladium(II) diacetate (5.92 mg, 0.030 mmol), 7-[5-chloro-2-(tetrazol-2-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (250.0 mg, 0.530 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (25.15 mg, 0.050 mmol), potassium acetate (155.31 mg, 1.58 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (401.88 mg, 1.58 mmol) were dissolved in 1,4-dioxane (4.5 mL) in a microwave vial and degassed with N for 10 minutes. The resulting reaction mixture was stirred at 80 °C for 2 hours, then cooled to room temperature, filtered through Celite, and washed 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 and then evaporated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge, which was left for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 2 M methanolic ammonia solution. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by flash chromatography (Sfar C18D, 30 g) eluting with a gradient of 1% to 70% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [3-(4-aminocinnolin-7-yl)-4-(tetrazol-2-yl)phenyl]boronic acid (53.7 mg, 0.161 mmol, 30.37% yield) as a white powder. 1H NMR (400MHz, DMSO-d6+1 drop of TFA) δ7.36(d,J=8.82Hz,1H),7.53(d,J=1.32Hz,1H),7.81(d,J=7.79Hz,1H),8 .12-8.18(m,2H),8.34(d,J=8.81Hz,1H),8.42(s,1H),9.01(br.s,1H),9.73(br.s,1H),9.83(br.s,1H). LC-MS (method A): room temperature 0.39 min, MS (ESI) m / z=334.1[M+H] + .

[0200] Example 13: [5-(4-aminocinnolin-7-yl)-6-(1H-pyrazol-1-yl)pyridin-3-yl]boronic acid (13) [ka] Step 1: 7-[5-chloro-2-(1H-pyrazol-1-yl)pyridin-3-yl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (150.0 mg, 0.180 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (137.73 mg, 0.540 mmol) and A mixture of 1,4-dioxane (5 mL) and potassium acetate (53.23 mg, 0.540 mmol) was degassed under argon for 10 min, then dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (6.89 mg, 0.010 mmol) and palladium(II) diacetate (2.03 mg, 0.010 mmol) were added, and the reaction mixture was stirred at 95 °C for 2 h. The mixture was cooled to room temperature, then diluted with EtOAc, filtered through Celite, washed with MeOH and EtOAc, and the filtrate was concentrated in vacuo. LC-MS (Method A): RT 0.61 min, MS (ESI) m / z = 483.3 [M+H] + .

[0201] Step 2: The crude material from Step 1 was dissolved in DCM (2 mL) and trifluoroacetic acid (1.5 mL), and the mixture was stirred at room temperature for 32 hours. The volatiles were removed, and the residue was dissolved in MeOH / water (9:1) and loaded onto an SCX cartridge (5 g), which was washed with MeOH and then eluted with a 7 M solution of 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 MeCN in 10 mM aqueous ammonium bicarbonate adjusted to pH 10 with ammonia to give [5-(4-aminocinnolin-7-yl)]-6-(1H-pyrazol-1-yl)pyridin-3-yl]boronic acid (8 mg, 0.024 mmol, 13.33% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6+TFA)δ6.33-6.39(m,1H),7.31(dd,J=8.88,1.25Hz,1H),7.35(d,J=1.66Hz,1H),7. 71(d,J=1.63Hz,1H),8.24-8.32(m,2H),8.36(s,1H),8.41(s,1H),8.89(s,1H),9.59(s,1H),9.69(s,1H). LC-MS (Method A): Room temperature 0.35 min, MS (ESI) m / z=333.1[M+H] + .

[0202] Example 14: [3-(4-aminocinnolin-7-yl)-4-[3-(difluoromethyl)-1H-pyrazol-1-yl]phenyl]boronic acid formate (14) [ka] Step 1: Palladium(II) diacetate (4.95 mg, 0.020 mmol), 7-[5-chloro-2-[3-(difluoromethyl)pyrazol-1-yl]phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (230.0 mg, 0.440 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (16.81 mg, 0.040 mmol), potassium acetate (129.74 mg, 1.32 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (335.7 mg, 1.32 mmol) were dissolved in 1,4-dioxane (6 mL). The mixture was degassed with N2 for 10 min and then stirred for 2 h at 75° C. The mixture was filtered through a pad of Celite, washing with EtOAc, and the filtrate was concentrated in vacuo.

[0203] Step 2: The crude material from Step 1 was dissolved in a mixture of DCM (4 mL) and trifluoroacetic acid (4 mL). The mixture was stirred at room temperature overnight, 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 / HO (9:1), and then the product was eluted from the SCX cartridge with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​2 × SNAP 12 g in succession) eluting with a 2% to 25% gradient of CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [3-(4-aminocinnolin-7-yl)-4-[3-(difluoromethyl)pyrazol-1-yl]phenyl]boronic acid formate (63 mg, 0.147 mmol, 33.47% yield) as a white powder. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ6.64(d,J=2.47Hz,1H),6.91(t,J=54.49Hz,1H),7.27(dd,J=8.81,1.64Hz,1H),7.68(d,J=1.64Hz,1H),7.70(d,J =8.29Hz,1H),7.94(d,J=2.51Hz,1H),8.07-8.11(m,2H),8.14(s,HCOOH 0.64H), 8.31 (d, J=8.86Hz, 1H), 8.48 (s, 1H), 9.76 (s, 1H), 9.83 (s, 1H). LC-MS (method A): room temperature 0.49 min, MS (ESI) m / z=382.06[M+H] + .

[0204] Example 15: [3-(4-aminocinnolin-7-yl)-4-(2H-1,2,3-triazol-1-yl)phenyl]boronic acid formate (15) [ka] Step 1: Palladium(II) diacetate (4.75 mg, 0.020 mmol), 7-[5-chloro-2-(triazol-2-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (200.0 mg, 0.420 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (16.13 mg, 0.030 mmol), potassium acetate (124.51 mg, 1.27 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (322.17 mg, 1.27 mmol) were dissolved in 1,4-dioxane (5 mL). The mixture was degassed with N2 for 10 min and then stirred for 2 h at 75° C. The mixture was filtered through a pad of Celite, washing with EtOAc, and the filtrate was concentrated in vacuo.

[0205] Step 2: The crude material from Step 1 was dissolved in a mixture of DCM (4 mL) and trifluoroacetic acid (4 mL). The mixture was stirred at room temperature overnight, 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 / HO (9:1), and then the product was eluted from the SCX cartridge with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​2 × SNAP 12 g in succession) eluting with a 2% to 25% gradient of CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to afford [3-(4-aminocinnolin-7-yl)-4-(triazol-2-yl)phenyl]boronic acid formate (51 mg, 0.135 mmol, 31.89% yield) as a white powder. 1 H NMR (400MHz, DMSO-d6+2 drops of TFA) δ7.33(dd,J=8.81,1.65Hz,1H),7.57(d,J=1.67Hz,1H),7.80(d,J=7.80Hz,1H),7.97 (s,2H),8.07-8.13(m,2H),8.13(s,0.69H from HCOOH),8.33(d,J=8.84Hz,1H),8.47(s,1H),9.76(s,1H),9.84(s,1H). LC-MS (Method A): Room temperature 0.40 min, MS (ESI) m / z=333.05[M+H] + .

[0206] Example 16: [3-(4-aminocinnolin-7-yl)-4-(1H-1,2,3-triazol-1-yl)phenyl]boronic acid (16) [ka] Step 1: Palladium(II) diacetate (6.65 mg, 0.030 mmol), 7-[5-chloro-2-(triazol-1-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (280.0 mg, 0.590 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (22.58 mg, 0.050 mmol), potassium acetate (174.31 mg, 1.78 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (451.04 mg, 1.78 mmol) were dissolved in 1,4-dioxane (7 mL). The mixture was degassed with N2 for 10 min and then stirred for 2 h at 75° C. The mixture was filtered through a pad of Celite, washing with EtOAc, and the filtrate was concentrated in vacuo.

[0207] Step 2: The crude material from Step 1 was dissolved in a mixture of DCM (5 mL) and trifluoroacetic acid (5 mL). The mixture was stirred at room temperature overnight, 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 / HO (9:1), and then the product was eluted from the SCX cartridge with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​2 × SNAP 12 g in succession) eluting with a gradient of 2% to 25% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). Fractions containing the desired compound were collected and lyophilized to afford [3-(4-aminocinnolin-7-yl)-4-(triazol-1-yl)phenyl]boronic acid (46 mg, 0.139 mmol, 23.39% yield) as a white powder. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ7.34(dd,J=8.79,1.66Hz,1H),7.63(d,J=1.64Hz,1H),7.71(d,J=8.31Hz,1H),7.83(d,J =1.13Hz,1H),8.10-8.18(m,2H),8.31(d,J=8.86Hz,1H),8.34(d,J=1.14Hz,1H),8.47(s,1H),9.79(s,1H),9.86(s,1H). LC-MS (Method A): Room temperature 0.35 min, MS (ESI) m / z=333.05[M+H] + .

[0208] Example 17: [3-(4-aminocinnolin-7-yl)-4-(3-cyano-1H-pyrazol-1-yl)phenyl]boronic acid (17) [ka] Step 1: 1-[4-chloro-2-(4-{[(2,4-dimethoxyphenyl)methyl]amino}cinnolin-7-yl)phenyl]-1H-pyrazole-3-carbonitrile (44.0 mg, 0.090 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (67.45 mg, 0.270 mmol), A mixture of 1,4-dioxane (1.5 mL) and potassium acetate (26.07 mg, 0.270 mmol) was degassed under argon for 10 min. Then dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (3.38 mg, 0.010 mmol) and palladium(II) diacetate (0.99 mg, 0.004 mmol) were added, and the reaction mixture was stirred at 85 °C for 2 h. The mixture was cooled to room temperature, diluted with EtOAc, filtered through Celite, washed with MeOH and EtOAc, and the filtrate was concentrated in vacuo. LC-MS (Method A): RT 0.68 min, MS (ESI) m / z = 507.2 [M+H] + .

[0209] Step 2: The crude material from Step 1 was dissolved in DCM (1 mL) and trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 12 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in MeOH / water (9:1) and loaded onto an SCX cartridge (5 g), which was washed with MeOH / water (9:1) and then eluted with a 7 M solution of 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 1% to 25% gradient of MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [3-(4-aminocinnolin-7-yl)-4-(3-cyano-1H-pyrazol-1-yl)phenyl]boronic acid (8 mg, 0.022 mmol, 24.72% yield) as a beige solid, which contained approximately 5 w / w% of 1-[2-(4-aminocinnolin-7-yl)-4-hydroxyphenyl]-1H-pyrazole-3-carbonitrile by-product. 1 H NMR(400MHz,DMSO-d6+TFA)δ6.98(d,J=2.51Hz,1H),7.35(dd,J=8.82,1.49Hz,1H),7.60(d,J=1.44Hz,1H),7.66(d,J= 7.82Hz,1H), 8.02(d,J=2.56Hz,1H),8.04-8.09(m,2H),8.34(d,J=8.88Hz,1H),8.45(s,1H),9.73(s,1H),9.81(s,1H). LC-MS (Method A): Room temperature 0.46 min, MS (ESI) m / z=357.1[M+H] + .

[0210] Example 18: [3-(4-aminocinnolin-7-yl)-4-(5-methyl-1,2,4-thiadiazol-3-yl)phenyl]boronic acid (18) [ka] Palladium(II) diacetate (1.78 mg, 0.010 mmol), 7-[5-chloro-2-(5-methyl-1,2,4-thiadiazol-3-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (80.0 mg, 0.160 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (7.5 A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (120.92 mg, 0.480 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (120.92 mg, 0.480 mmol) was dissolved in 1,4-dioxane (1.439 mL) in a microwave vial and degassed with N for 10 minutes. The resulting reaction mixture was stirred at 75 °C for 2 hours, then cooled to room temperature, filtered through Celite, and washed 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 and then evaporated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge, which was left for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 2 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 70% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [3-(4-aminocinnolin-7-yl)-4-(5-methyl-1,2,4-thiadiazol-3-yl)phenyl]boronic acid (25 mg, 0.069 mmol, 43.12% yield) as a white powder. 1H NMR(400MHz,DMSO-d6)δ2.60(s,3H),7.27(br.s,2H),7.37(dd,J=8.64,1.79Hz,1H),7.92(d,J=7. 69Hz, 1H), 7.96-7.99 (m, 1H), 8.00-8.02 (m, 1H), 8.13-8.20 (m, 2H), 8.40 (br.s, 2H), 8.64 (s, 1H). LC-MS (Method A): Room temperature 0.40 min, MS (ESI) m / z=364.1[M+H] + .

[0211] Example 19: [3-(4-aminocinnolin-7-yl)-4-[5-(trifluoromethyl)-1H-pyrazol-3-yl]phenyl]boronic acid (19) [ka] Palladium(II) diacetate (4.44 mg, 0.020 mmol), 7-[5-chloro-2-[1-(oxan-2-yl)-5-(trifluoromethyl)pyrazol-3-yl]phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (247.0 mg, 0.400 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphazene Fin (18.87 mg, 0.040 mmol), potassium acetate (116.53 mg, 1.19 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (301.53 mg, 1.19 mmol) were dissolved in 1,4-dioxane (3.95 mL) in a microwave vial and degassed with N for 10 minutes. The resulting reaction mixture was stirred at 80 °C for 2 hours, then cooled to room temperature, filtered through Celite, and washed 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 overnight and then evaporated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge. The cartridge was left for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 2 M 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 1% to 70% gradient of MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [3-(4-aminocinnolin-7-yl)-4-[5-(trifluoromethyl)-1H-pyrazol-3-yl]phenyl]boronic acid (54 mg, 0.135 mmol, 33.75% yield) as a white powder. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ6.40(s,1H),7.49(dd,J=8.91,1.43Hz,1H),7.67(d,J=7.62Hz,1H),7.77(d,J=1.57Hz,1H),7 .99(s,1H),8.03(dd,J=7.70,0.88Hz,1H),8.11(s,1H),8.33(d,J=8.84Hz,1H),8.48(s,1H),9.75(br.s,1H),9.83(br.s,1H). LC-MS (Method A): Room temperature 0.54 min, MS (ESI) m / z=400.3[M+H] + .

[0212] Example 20: [3-(4-aminocinnolin-7-yl)-4-(1H-1,2,4-triazol-3-yl)phenyl]boronic acid (20) [ka] Step 1: Palladium(II) diacetate (3.12 mg, 0.010 mmol), 7-[5-chloro-2-[1-(oxan-2-yl)-1,2,4-triazol-3-yl]phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (155.0 mg, 0.280 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]methyl]cinnolin-4-amine [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text] [Chemical formula - see original text]

[0213] 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 at room temperature overnight, 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 / HO (9:1), and then the product was eluted from the SCX cartridge with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​2 × SNAP 12 g in succession) eluting with a gradient of 2% to 20% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized. The partially purified product was further purified by column chromatography (KP-C18-HS, ​​2 × 12 g in succession) eluting with a gradient of 2% to 15% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [3-(4-aminocinnolin-7-yl)-4-(1H-1,2,4-triazol-3-yl)phenyl]boronic acid (23 mg, 0.069 mmol, 24.89% yield) as a white powder. 1 H NMR (400MHz, DMSO-d6+2 drops of TFA) δ7.53(dd,J=8.79,1.61Hz,1H),7.69(d,J=1.62Hz,1H),7.89(d,J=7.70Hz,1H),7.94(s,1H),8.01 (dd,J=7.72,1.24Hz,1H),8.13(s,1H),8.32(d,J=8.81Hz,1H),8.39(br.s,J=1.56Hz,1H),8.47(s,1H),9.71(s,1H),9.81(s,1H). LC-MS (Method A): Room temperature 0.31 min, MS (ESI) m / z=333.09[M+H] + .

[0214] Example 21: [3-(4-aminocinnolin-7-yl)-4-(4-methanesulfonamido-1H-pyrazol-1-yl)phenyl]boronic acid (21) [ka] Step 1: Palladium(II) diacetate (1.48 mg, 0.010 mmol), N-[1-[4-chloro-2-[4-[(2,4-dimethoxyphenyl)methylamino]cinnolin-7-yl]phenyl]pyrazol-4-yl]methanesulfonamide (75.0 mg, 0.130 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (5 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (100.11 mg, 0.394 mmol) were dissolved in 1,4-dioxane (2 mL) in a microwave vial, and the mixture was degassed with Ar for 10 minutes. The mixture was then stirred at 90° C. for 2 hours. The mixture was filtered, washed with MeOH, and the filtrate was concentrated in vacuo. LC-MS (Method A): RT 0.85 min, MS (ESI) m / z = 657.4 [M+H] + .

[0215] Step 2: The crude material from Step 1 was dissolved in DCM (1.5 mL) and trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge (2 g). The cartridge was washed with MeOH / HO (9:1), and the product was eluted from the SCX cartridge with a 7 M solution of NH in MeOH. The basic fractions were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​2 × 6 g in succession) eluting with a gradient of 2% to 20% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were concentrated to give [3-(4-aminocinnolin-7-yl)-4-[4-(methanesulfonamido)pyrazol-1-yl]phenyl]boronic acid (8.5 mg, 0.020 mmol, 15.4% yield) as a yellowish solid. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ2.78(s,3H),7.35(dd,J=8.80,1.54Hz,1H),7.47(s,1H),7.56(s,1H),7.61(d,J=1.54Hz,1 H),7.67(d,J=8.14Hz,1H),8.03-8.08(m,2H),8.33(d,J=9.02Hz,1H),8.46(s,1H),9.20(s,1H),9.73(s,1H),9.83(s,1H). LC-MS (Method A): Room temperature 0.37 min, MS (ESI) m / z=425.1[M+H] + .

[0216] Example 22: [3-(4-aminocinnolin-7-yl)-4-(5-cyano-1H-pyrazol-1-yl)phenyl]boronic acid (22) [ka] Step 1: 1-[4-chloro-2-(4-{[(2,4-dimethoxyphenyl)methyl]amino}cinnolin-7-yl)phenyl]-1H-pyrazole-5-carbonitrile (170.0 mg, 0.340 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (260.61 mg, 1.03 mmol) A mixture of 1,4-dioxane (6 mL) and potassium acetate (100.72 mg, 1.03 mmol) was degassed under argon for 10 minutes, then dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (13.05 mg, 0.030 mmol) and palladium(II) diacetate (3.84 mg, 0.020 mmol) were added, and the reaction mixture was stirred at 85 °C for 2 hours. The mixture was cooled to room temperature, diluted with EtOAc, filtered through Celite, washed with MeOH and EtOAc, and the filtrate was concentrated in vacuo. LC-MS (Method A): RT 0.66 min, MS (ESI) m / z = 507.2 [M+H] + .

[0217] Step 2: The crude material from Step 1 was dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL), and the mixture was stirred at room temperature for 12 hours. Volatiles were removed under reduced pressure, and the crude was dissolved in MeOH / water (9:1) and then loaded onto an SCX cartridge (10 g), which was washed with MeOH / water (9:1) and then eluted with a 7 M solution of ammonia in MeOH. 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 MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give an off-white solid, which was subjected to semi-preparative HPLC purification (first purification: xBridge C18 (30 × 100 mm, 3 μm), 10.0% to 30.0% gradient of MeCN in 10 mM aqueous ammonium bicarbonate adjusted to pH 10 with ammonia; second purification: Chiralcel OJ-H (25 × 2.0 cm), 5 μm, n-hexane / (EtOH + 0.1% isopropylamine) 65 / 35% v / v) to give [3-(4-aminocinnolin-7-yl)-4-(5-cyano-1H-pyrazol-1-yl)phenyl]boronic acid (6.9 mg, 0.019 mmol, 5.59% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6+TFA)δ7.30(d,J=2.13Hz,1H),7.44(dd,J=8.81,1.68Hz,1H),7.49(d,J=1.68Hz,1H),7.76(d,J= 7.82Hz,1H), 7.90(d,J=2.16Hz,1H),8.12-8.17(m,2H),8.38(d,J=8.82Hz,1H),8.45(s,1H),9.80(s,1H),9.89(s,1H). LC-MS (Method A): Room temperature 0.45 min, MS (ESI) m / z=357.1[M+H] + .

[0218] Example 23: [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(1H-pyrazol-1-yl)phenyl]boronic acid (23) [ka] Palladium(II) diacetate (5.59 mg, 0.020 mmol), 7-(5-chloro-4-methoxy-2-pyrazol-1-ylphenyl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (250.0 mg, 0.500 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (23.74 mg , 0.050 mmol), potassium acetate (146.64 mg, 1.49 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (379.42 mg, 1.49 mmol) were dissolved in 1,4-dioxane (4.98 mL) in a microwave vial and degassed with N for 10 minutes. The resulting reaction mixture was stirred at 75 °C for 2 hours, then cooled to room temperature, filtered through Celite, and washed 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 overnight and then evaporated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge, and the cartridge was left for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 2 M methanolic ammonia solution. The basic fractions were collected and evaporated under reduced pressure. The residue was subjected to semi-preparative HPLC purification (Chiralpak OJ-H (25 × 0.46 cm), 5 μm, n-hexane / (EtOH + 0.1% isopropylamine) 80 / 20% v / v). The appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-2-methoxy-4-pyrazol-1-ylphenyl]boronic acid (9 mg, 0.025 mmol, 5% yield) as a white solid. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ3.93(s,3H),6.35-6.40(m,1H),7.11-7.15(m,1H),7.21(s,1H),7.57-7.61( m,2H),7.78(s,1H),7.79-7.83(m,1H),8.23(d,J=8.88Hz,1H),8.42(s,1H),9.65(br.s,1H),9.73(br.s,1H). LC-MS (Method A): Room temperature 0.43 min, MS (ESI) m / z=362.0[M+H] + .

[0219] Example 24: [3-(4-aminocinnolin-7-yl)-4-(1,3-thiazol-2-yl)phenyl]boronic acid formate (24) [ka] Step 1: Palladium(II) diacetate (4.13 mg, 0.020 mmol), 7-[5-chloro-2-(1,3-thiazol-2-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (180.0 mg, 0.370 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (14.04 mg, 0.030 mmol), potassium acetate (108.38 mg, 1.1 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (280.43 mg, 1.1 mmol) were dissolved in 1,4-dioxane (5 mL). The mixture was degassed with N2 for 10 min and then stirred for 2 h at 75° C. The mixture was filtered through a pad of Celite, washing with EtOAc, and the filtrate was concentrated in vacuo.

[0220] 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 at room temperature overnight, and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH / HO (9:1), and then the product was eluted from the SCX cartridge with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​2 × SNAP 12 g in succession) eluting with a 2% to 20% gradient of CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to afford [3-(4-aminocinnolin-7-yl)-4-(1,3-thiazol-2-yl)phenyl]boronic acid formate (22 mg, 0.056 mmol, 15.16% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d6+2 drops of TFA) δ7.58(dd,J=8.76,1.61Hz,1H),7.72-7.78(m,3H),7.91(d,J=7.78Hz,1H),7.94(d,J=1.20Hz,1 H),8.04(dd,J=7.76,1.29Hz,1H),8.13(s,0.77H,1H derived from HCOOH),8.37(d,J=8.81Hz,1H),8.49(s,1H),9.77(s,1H),9.86(s,1H). LC-MS (method A): room temperature 0.46 min, MS (ESI) m / z=349.04[M+H] + .

[0221] Example 25: [3-(4-aminocinnolin-7-yl)-4-(1,3-oxazol-2-yl)phenyl]boronic acid formate (25) [ka] Step 1: Palladium(II) diacetate (2.61 mg, 0.010 mmol), 7-[5-chloro-2-(1,3-oxazol-2-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (110.0 mg, 0.230 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (8.87 mg, 0.020 mmol), potassium acetate (68.48 mg, 0.700 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (177.2 mg, 0.700 mmol) were dissolved in 1,4-dioxane (5 mL). The mixture was degassed with N2 for 10 min and then stirred for 2 h at 75° C. The mixture was filtered through a pad of Celite, washed with MeOH, and the filtrate was concentrated in vacuo.

[0222] 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 at room temperature overnight, and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH / HO (9:1), and then the product was eluted from the SCX cartridge with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​2 × SNAP 12 g in succession) eluting with a 2% to 25% gradient of CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to afford [3-(4-aminocinnolin-7-yl)-4-(1,3-oxazol-2-yl)phenyl]boronic acid formate (30 mg, 0.079 mmol, 34.3% yield) as a white solid. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ7.25(s,1H),7.63(dd,J=8.77,1.66Hz,1H),7.73(d,J=1.61Hz,1H),7.94(s,1H),7.98-8.08(m,3H),8.1 2(s,HCOOH derived 0.72H,1H),8.40(d,J=8.83Hz,1H),8.49(s,1H),9.75(s,1H),9.86(s,1H)LC-MS(Method A): Room temperature 0.42 min, MS(ESI) m / z=333.11[M+H] + .

[0223] Example 26: [3-(4-aminocinnolin-7-yl)-4-(pyrimidin-2-yl)phenyl]boronic acid formate (26) [ka] Palladium(II) diacetate (1.28 mg, 0.010 mmol), 7-(5-chloro-2-pyrimidin-2-ylphenyl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (55.0 mg, 0.110 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (5.42 mg, 0.01 0 mmol), potassium acetate (33.46 mg, 0.340 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (86.58 mg, 0.340 mmol) were dissolved in 1,4-dioxane (1.136 mL) in a microwave vial and degassed with N for 10 minutes. The resulting reaction mixture was stirred at 75 °C for 2 hours, then cooled to room temperature, filtered through Celite, and washed 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 4 hours and then evaporated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge, and the cartridge was left for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 7 M methanolic ammonia solution. The basic fractions were collected and evaporated under reduced pressure. The residue was subjected to semi-preparative HPLC purification [CSH C18 (30 × 100 mm, 3 μm) 10 min gradient of 3.0% to 13.0% MeCN in water (+0.1% HCOOH), flow rate: 40.00 mL / min]. The appropriate fractions were collected and lyophilized to give [3-(4-aminocinnolin-7-yl)-4-pyrimidin-2-ylphenyl]boronic acid formate (2.5 mg, 0.006 mmol, 5.45% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6 + 2 drops of TFA) δ 7.33 (t, J = 4.95 Hz, 1H), 7.44 (dd, J = 8.80, 1.10 Hz, 1H), 7.61 (d, J = 1.32 Hz, 1H), 7.94 (d, J = 7.70 Hz, 1H), 8.00 (s, 1H), 8.05 (d, J = 7.72 Hz, 1H), 8.09 (s, 1H from HCOOH), 8.28 (d, J = 8.84 Hz, 1H), 8.44 (s, 1H), 8.67 (d, J = 4.84 Hz, 2H), 9.67 (br.s, 1H), 9.75 (br.s, 1H). LC-MS (Method A): Room temperature 0.37 min, MS (ESI) m / z=344.15[M+H] + .

[0224] Example 27: [5-(4-aminocinnolin-7-yl)-2-(difluoromethoxy)-4-(1H-pyrazol-1-yl)phenyl]boronic acid formate (27) [ka] Palladium(II) diacetate (7.3 mg, 0.030 mmol), 7-[5-chloro-4-(difluoromethoxy)-2-pyrazol-1-ylphenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (350.0 mg, 0.650 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (31.0 mg, 0.650 mmol), 2 mg, 0.070 mmol), potassium acetate (191.55 mg, 1.95 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (495.65 mg, 1.95 mmol) were dissolved in 1,4-dioxane (6.97 mL) in a microwave vial and degassed with N for 10 minutes. The resulting reaction mixture was stirred at 85 °C for 6 hours, then cooled to room temperature, filtered through Celite, and washed 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 and then evaporated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge, and the cartridge was left for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 2 M methanolic ammonia solution. Basic fractions were collected and evaporated under reduced pressure. The residue was purified by column chromatography (Sfar C18D, 30 g) eluting with a 2% to 25% gradient of MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-2-(difluoromethoxy)-4-pyrazol-1-ylphenyl]boronic acid formate (5.5 mg, 0.012 mmol, 1.85% yield) as a white powder. 1H NMR(400MHz,DMSO-d6+TFA)δ6.34(t,J=2.19Hz,1H),7.23(d,J=8.99Hz,1H),7.26(t,J=73.95Hz,1H),7.41(s,1H),7.57-7.61(m,1H),7.64 -7.67(m,1H),7.72-7.77(m,1H),7.80(s,1H),8.09(s,1H from HCOOH),8.28(d,J=8.90Hz,1H),8.45(s,1H),9.71(br.s,1H),9.78(br.s,1H). LC-MS (Method A): Room temperature 0.47 min, MS (ESI) m / z=398.1[M+H] + .

[0225] Example 28: [3-(4-aminocinnolin-7-yl)-4-(4-methoxy-1H-pyrazol-1-yl)phenyl]boronic acid formate (28) [ka] Palladium(II) diacetate (3.22 mg, 0.010 mmol), 7-[5-chloro-2-(4-methoxypyrazol-1-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (144.0 mg, 0.290 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (13.68 m g, 0.030 mmol), potassium acetate (84.46 mg, 0.860 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (218.55 mg, 0.860 mmol) were dissolved in 1,4-dioxane (2.8 mL) in a microwave vial and degassed with N for 10 minutes. The resulting reaction mixture was stirred at 90 °C for 2 hours, then cooled to room temperature, filtered through Celite, and washed 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 and then evaporated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge, and the cartridge was left for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 2 M methanolic ammonia solution. 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 3-(4-aminocinnolin-7-yl)-4-(4-methoxypyrazol-1-yl)phenyl]boronic acid formate (12 mg, 0.029 mmol, 10% yield) as a white powder. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ3.60(s,3H),7.27(d,J=8.90Hz,1H),7.31(s,1H),7.52-7.59(m,2H),7.67(s,1H) ,7.99-8.06(m,2H),8.07(s,1H derived from HCOOH),8.30(d,J=8.87Hz,1H),8.44(s,1H),9.67(br.s,1H),9.75(br.s,1H). LC-MS (Method A): Room temperature 0.44 min, MS (ESI) m / z=362.3[M+H] + .

[0226] Example 29: [5-(4-aminocinnolin-7-yl)-4-[4-(difluoromethyl)-1H-pyrazol-1-yl)methoxyphenyl]boronic acid formate (29) [ka] Step 1: Palladium(II) diacetate (6.02 mg, 0.030 mmol), 7-[5-chloro-2-[4-(difluoromethyl)pyrazol-1-yl]-4-methoxyphenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (296.0 mg, 0.540 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (20.45 mg, 0.040 mmol), potassium acetate (157.89 mg, 1.61 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (408.53 mg, 1.61 mmol) were dissolved in 1,4-dioxane (8 mL). The mixture was degassed with N2 for 10 min and then stirred for 2 h at 75° C. The mixture was filtered through a pad of Celite, washed with MeOH, and the filtrate was concentrated in vacuo.

[0227] Step 2: The crude material from Step 1 was dissolved in a mixture of DCM (4 mL) and trifluoroacetic acid (4 mL). The mixture was stirred at room temperature overnight, and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH / HO (9:1), and then the product was eluted from the SCX cartridge with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​2 x SNAP 12 g in succession) eluting with a 2% to 20% gradient of MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give the partially purified product, which was subjected to semi-preparative HPLC purification [CSH C18 (2.1 × 50 mm, 1.7 μm), gradient of 3% to 99.9% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH) over 1.5 min]. The appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-4-[4-(difluoromethyl)pyrazol-1-yl]-2-methoxyphenyl]boronic acid formate (10 mg, 0.022 mmol, 4.079% yield) as a white powder. 1 H NMR (400MHz, DMSO-d6+2 drops of TFA) δ3.94(s,3H),7.00(t,J=55.85Hz,1H),7.19(d,J=8.73Hz,1H),7.28(s,1H),7.63(s,1H),7.78( s,1H),7.81(s,1H),8.13(s,0.64H,1H derived from HCOOH),8.26(d,J=8.87Hz,1H),8.33(s,1H),8.45(s,1H),9.70(s,1H),9.77(s,1H). LC-MS (Method A): Room temperature 0.50 min, MS (ESI) m / z=412.16[M+H] + .

[0228] Example 30: [3-(4-aminocinnolin-7-yl)-4-[4-(difluoromethyl)-1H-pyrazol-1-yl)-5-methoxyphenyl]boronic acid formate (30) [ka] Step 1: Palladium(II) diacetate (2.52 mg, 0.010 mmol), 7-[5-chloro-2-[4-(difluoromethyl)pyrazol-1-yl]-3-methoxyphenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (124.0 mg, 0.220 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (8.57 mg, 0.020 mmol), potassium acetate (66.14 mg, 0.670 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (171.14 mg, 0.670 mmol) were dissolved in 1,4-dioxane (3 mL). The mixture was degassed with N2 for 10 min and then stirred for 2 h at 75° C. The mixture was filtered through a pad of Celite, washed with MeOH, and the filtrate was concentrated in vacuo.

[0229] Step 2: The crude material from Step 1 was dissolved in a mixture of DCM (5 mL) and trifluoroacetic acid (5 mL). The mixture was stirred at room temperature overnight, and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH / HO (9:1), and then the product was eluted from the SCX cartridge with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​2 x SNAP 12 g in succession) eluting with a 2% to 20% gradient of MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [3-(4-aminocinnolin-7-yl)-4-[4-(difluoromethyl)pyrazol-1-yl]-5-methoxyphenyl]boronic acid formate (11 mg, 0.024 mmol, 15.18% yield) as a white solid. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ3.85(s,3H),6.97(t,J=55.82Hz,1H),7.31(dd,J=8.79,1.63Hz,1H),7.61-7.66(m,2H),7.69( s,1H),7.79(s,1H),8.12(s,0.81H,1H derived from HCOOH),8.23(s,1H),8.26(d,J=8.90Hz,1H),8.44(s,1H),9.73(s,1H),9.80(s,1H). LC-MS (Method A): Room temperature 0.51 min, MS (ESI) m / z=412.17[M+H] + .

[0230] Example 31: [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(1H-1,2,4-triazol-3-yl)phenyl]boronic acid (31) [ka] Step 1: Palladium(II) diacetate (10.23 mg, 0.050 mmol), 7-[5-chloro-4-methoxy-2-[1-(oxan-2-yl)-1,2,4-triazol-3-yl]phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (535.0 mg, 0.910 mmol), dicyclohexyl-[2-[2,4,6-tri(propane-2-yl)]methyl]cinnolin-4-amine (535.0 mg, 0.910 mmol),

[0111] 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane) ...

[0231] Step 2: The crude material from Step 1 was dissolved in a mixture of DCM (5 mL) and trifluoroacetic acid (5 mL). The mixture was stirred at room temperature overnight, and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH / HO (9:1), and then the product was eluted from the SCX cartridge with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​2 x SNAP 30 g in succession) eluting with a 2% to 15% gradient of MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(1H-1,2,4-triazol-3-yl)phenyl]boronic acid (51 mg, 0.141 mmol, 10.06% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6+2 drops of TFA) δ3.93(s,3H),7.44-7.49(m,2H),7.64(d,J=1.64Hz,1H),7.67(s ,1H),8.28(d,J=8.86Hz,1H),8.44(s,1H),8.45(s,1H),9.67(s,1H),9.77(s,1H),15.16(s,1H). LC-MS (Method A): Room temperature 0.34 min, MS (ESI) m / z=363.11[M+H] + .

[0232] Example 32: [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(1,3-oxazol-2-yl)phenyl]boronic acid formate (32) [ka] Palladium(II) diacetate (7.54 mg, 0.030 mmol), 7-[5-chloro-4-methoxy-2-(1,3-oxazol-2-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (338.0 mg, 0.670 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (32. 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (511.97 mg, 2.02 mmol) were dissolved in 1,4-dioxane (6.07 mL) in a microwave vial and degassed with N for 10 minutes. The resulting reaction mixture was stirred at 90 °C for 2 hours, then cooled to room temperature, filtered through Celite, and washed 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 and then evaporated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge, which was left for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 2 M methanolic ammonia solution. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by semi-preparative HPLC [CSH C18 (30 × 100 mm, 3 μm), 10 min gradient of 3.0% to 20.0% MeCN in water (+0.1% HCOOH), flow rate: 40.00 mL / min]. The appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(1,3-oxazol-2-yl)phenyl]boronic acid formate (62 mg, 0.152 mmol, 22.68% yield) as a white solid. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ3.94(s,3H),7.22(s,1H),7.48-7.58(m,2H),7.69(s,2H),7.94( s, 1H), 8.07 (s, derived from HCOOH), 8.36 (d, J=8.87Hz, 1H), 8.46 (s, 1H), 9.67 (br.s, 1H), 9.79 (br.s, 1H). LC-MS (Method A): Room temperature 0.44 min, MS (ESI) m / z=363.08[M+H] + .

[0233] Example 33: [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl]boronic acid (33) [ka] Step 1: 7-[5-chloro-4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (85.0 mg, 0.170 mmol, batch with 57% a / a purity by LC-MS), potassium acetate (49.76 mg, 0.510 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (128.75 mg, 0.510 mmol) were dissolved in 1,4-dioxane (4 mL) and the mixture was deoxygenated under argon for 10 min. Next, palladium(II) diacetate (1.9 mg, 0.010 mmol) and dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (8.06 mg, 0.020 mmol) were added, and the mixture was stirred at 85 °C for 24 h. Additional potassium acetate (24.88 mg, 0.255 mmol), palladium(II) diacetate (0.95 mg, 0.005 mmol), and dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (4.03 mg, 0.010 mmol) were added, and the mixture was stirred for an additional 5 h. Since no conversion to product was observed, the mixture was filtered through a pad of Celite, dried under vacuum, and purified by column chromatography (Sfar Amino) eluting with a gradient of 0% to 100% EtOAc in cyclohexane. Purification by HPLC (HPLC-MS, 28 g) afforded recovered 7-[5-chloro-4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (164 mg, 0.326 mmL, 80% a / a purity batch by LC-MS) as a yellow solid, combined with recovered 7-[5-chloro-4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine from a similar reaction performed with another batch of 7-[5-chloro-4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine which also resulted in no conversion.The combined recovered 7-[5-chloro-4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (200 mg, 0.397 mmol) was dissolved in 1,4-dioxane (5 mL) and treated with potassium acetate (116.88 mg, 1.191 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3 (2-Dioxaborolan-2-yl)-1,3,2-dioxaborolane (302.44 mg, 1.191 mmol), palladium(II) diacetate (4.46 mg, 0.020 mmol), and dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (18.93 mg, 0.040 mmol) were added, and the mixture was deoxygenated under argon for 10 minutes before stirring at 85 °C overnight. The mixture was filtered through Celite, washed with MeOH and EtOAc, and the filtrate was concentrated to dryness. LC-MS (Method A): RT 0.67 min, MS (ESI) m / z = 513.1 [M+H]. + .

[0234] Step 2: The crude material from Step 1 was dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL). The resulting mixture was stirred at room temperature for 24 hours, and then the volatile components were evaporated under reduced pressure. The residue was dissolved in MeOH / water (9:1) and loaded onto an SCX cartridge (10 g), which was washed with a mixture of MeOH / water (9:1) and then eluted with a 2 M ammonia solution 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 20% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(2H-1,2,3-triazol-2-yl)phenyl]boronic acid (20 mg, 0.055 mmol, 13.8% yield) as a beige solid. 1H NMR(400MHz,DMSO-d6+TFA)δ3.93(s,3H),7.21(dd,J=8.83,1.54Hz,1H),7.35(s,1H),7.50(d,J=1. 44Hz,1H),7.80(s,1H),7.95(s,2H),8.27(d,J=8.86Hz,1H),8.43(s,1H),9.68(s,1H),9.77(s,1H). LC-MS (Method A): Room temperature 0.43 min, MS (ESI) m / z=363.1[M+H] + .

[0235] Example 34: [5-(4-aminocinnolin-7-yl)-2-(3,3-difluorocyclobutoxy)-4-(1H-pyrazol-1-yl)phenyl]boronic acid formate (34) [ka] Palladium(II) diacetate (4.08 mg, 0.020 mmol), 7-[5-chloro-4-(3,3-difluorocyclobutyl)oxy-2-pyrazol-1-ylphenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (210.0 mg, 0.360 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (17.32 mg, 0.040 mmol), potassium acetate (106.97 mg, 1.09 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (276.78 mg, 1.09 mmol) were dissolved in 1,4-dioxane (3.63 mL) in a microwave vial and degassed with N for 10 minutes. The resulting reaction mixture was stirred at 90 °C for 2 hours, then cooled to room temperature, filtered through Celite, and washed 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 and then evaporated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge, and the cartridge was left for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 2 M methanolic ammonia solution. The basic fractions were collected and evaporated under reduced pressure. The residue was subjected to semi-preparative HPLC purification [CSH C18 (30 × 100 mm, 3 μm) gradient of 3.0% to 20.0% MeCN in water (+0.1% HCOOH) over 10 min, flow rate: 40.00 mL / min]. The appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-2-(3,3-difluorocyclobutyl)oxy-4-pyrazol-1-ylphenyl]boronic acid formate (9.5 mg, 0.020 mmol, 5.55% yield) as a white solid. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ2.72-2.99(m,2H),3.13-3.29(m,2H),4.90-5.04 (m,1H),6.38-6.42(m,1H),7.09(s,1H),7.12(dd,J=8.89,1.61Hz,1H),7.56(d,J= 1.54Hz,1H),7.59(d,J=1.32Hz,1H),7.76(s,1H),7.83-7.91(m,1H),8.11(s,HCOO) 0.6H derived from H), 8.22 (d, J=8.93Hz, 1H), 8.43 (s, 1H), 9.67 (br.s, 1H), 9.74 (br.s, 1H). LC-MS (Method A): Room temperature 0.55 min, MS (ESI) m / z=438.26[M+H] + .

[0236] Example 35: 7-[4-methoxy-2-pyrazol-1-yl-5-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0 2,6 ]Decan-4-yl]phenyl]cinnoline-4-amine (35) [ka] A suspension of (1S,3R,4S,5S)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol (165.93 mg, 0.970 mmol) and [5-(4-aminocinnolin-7-yl)-2-methoxy-4-pyrazol-1-ylphenyl]boronic acid (320.0 mg, 0.890 mmol) in THF (28 mL) was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in MeOH, and the solution was loaded onto an SCX cartridge, which was washed with MeOH and then eluted with 7 M ammonia solution in MeOH. The basic fractions were collected and evaporated under reduced pressure. The resulting solid was dried in an oven at 60°C for 48 hours to give 7-[4-methoxy-2-pyrazol-1-yl-5-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0 2,6]decan-4-yl]phenyl]cinnolin-4-amine (349.2 mg, 0.705 mmol, 79.56% yield) was obtained as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ0.87(s,3H),1.13-1.19(m,1H),1.28(s,3H),1.44(s,3H),1.79-1.89(m,1H),1.89 -1.95(m,1H),2.06-2.12(m,1H),2.17-2.28(m,1H),2.34-2.42(m,1H),3.88(s,3H),4.53(dd,J=8.73,1.9 0Hz,1H),6.33(t,J=2.11Hz,1H),6.95(dd,J=8.71,1.85Hz,1H),7.13(s,2H),7.21(s,1H),7.61(d,J=1.74 Hz,1H),7.65(d,J=2.41Hz,1H),7.77(s,1H),7.79(d,J=1.81Hz,1H),7.99(d,J=8.81Hz,1H),8.57(s,1H). LC-MS (Method A): Room temperature 0.80 min, MS (ESI) m / z=496.16[M+H] + .

[0237] Example 36: [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(1H-pyrazol-3-yl)phenyl]boronic acid formate (36) [ka] Step 1: Two microwave vials were each charged with 7-{5-chloro-4-methoxy-2-[1-(oxan-2-yl)-1H-pyrazol-3-yl]phenyl}-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (610.0 mg, 1.04 mmol), potassium acetate (306.44 mg, 3.12 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (792.91 mg, 3.12 mmol) in 1,2-dimethoxyethane (15 mL), and the mixture was deoxygenated under argon for 10 minutes. Palladium(II) diacetate (11.68 mg, 0.050 mmol) and dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (49.62 mg, 0.100 mmol) were then added to each vial, and the two reactions were stirred at 65° C. for 15 h. The two crude reaction mixtures were combined, diluted with MeOH, filtered through Celite, washed with MeOH and EtOAc, and the filtrate was concentrated to dryness. LC-MS (Method A): RT 0.76 min, MS (ESI) m / z = 596.3 [M+H] + .

[0238] Step 2: The crude material from Step 1 was dissolved in DCM (3 mL) and trifluoroacetic acid (1.5 mL), and the mixture was stirred at room temperature for 18 h. The volatiles were evaporated under reduced pressure, and the residue was dissolved in a mixture of MeOH / water (9:1) and loaded onto an SCX cartridge (10 g), which was then washed with a mixture of MeOH / water (9:1) and eluted with 2N ammonia solution in MeOH. The volatiles were removed under reduced pressure, and the residue was purified by column chromatography (Sfar C18D, 30 g) eluting with a gradient of 1% to 15% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give a solid, which was subjected to semi-preparative HPLC (CSH C18 (2.1 × 50 mm, 1.7 μm); gradient of 3% to 99.9% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH)). The appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(1H-pyrazol-3-yl)phenyl]boronic acid formate (16 mg, 0.039 mmol, 3.775% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6+TFA)δ3.93(s,3H),5.96(d,J=2.24Hz,1H),7.30(s,1H),7.44(dd,J=8.81,1.36Hz,1H),7.60(d,J=2.31Hz) ,1H),7.66(s,1H),7.70(d,J=1.24Hz,1H),8.10(s,1H derived from HCOOH),8.27(d,J=8.84Hz,1H),8.44(s,1H),9.65(s,1H),9.75(s,1H). LC-MS (Method A): Room temperature 0.43 min, MS (ESI) m / z=362.1[M+H] + .

[0239] Example 37: [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(4-methoxypyrazol-1-yl)phenyl]boronic acid formate (37) [ka] Palladium(II) diacetate (8.19 mg, 0.040 mmol), 7-[5-chloro-4-methoxy-2-(4-methoxypyrazol-1-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (388.0 mg, 0.730 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (34 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (555.62 mg, 2.19 mmol) were dissolved in 1,4-dioxane (8 mL) in a microwave vial and degassed under N for 10 minutes. The resulting reaction mixture was stirred at 80 °C for 2 hours, then cooled to room temperature, filtered through Celite, and washed with MeOH. The filtrate was concentrated 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 overnight and then concentrated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge, and the cartridge was left for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 2 M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 30 g) eluting with a gradient of 2% to 30% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give the partially purified product, which was subjected to semi-preparative HPLC purification (Column: CSH C18 (2.1 × 50 mm, 1.7 μm)). Conditions: [Solvent 1: Water (+0.1% HCOOH)]; [Solvent 2: MeCN (+0.1% HCOOH)]. Gradient: 3% to 99.9%. The appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(4-methoxypyrazol-1-yl)phenyl]boronic acid formate (13 mg, 0.030 mmol, 4.10% yield) as a yellow powder. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ3.63(s,3H),3.94(s,3H),7.18(dd,J=9.80,1.61Hz,1H),7.19(s,1H),7.36(s,1H),7.62(d,J=1.64H) z,1H),7.68(s,1H),7.78(s,1H),8.11(s,HCOOH derived 0.8H,1H),8.26(d,J=8.91Hz,1H),8.44(s,1H),9.65(br.s,1H),9.72(br.s,1H). LC-MS (Method A): Room temperature 0.47 min, MS (ESI) m / z=392.31[M+H] + .

[0240] Example 38: [5-(4-aminocinnolin-7-yl)-2-methoxy-4-thiazol-2-yl)phenyl]boronic acid formate (38) [ka] 7-(5-Bromo-4-methoxy-2-thiazol-2-yl-phenyl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (485.0 mg, 0.860 mmol), potassium acetate (426.71 mg, 4.3 mmol), and bis[(+)-pinanediolate]diboron (924.66 mg, 2.58 mmol) were dissolved in 1,4-dioxane (8.87 mL) in a microwave vial and degassed under N for 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (63.15 mg, 0.090 mmol) was added to the mixture, and the resulting reaction mixture was stirred at 90 °C for 2.5 h, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX cartridge, washed first with MeOH, and then eluted with 2 M methanolic NH solution. The basic fractions were concentrated in vacuo, and the residue was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (4 mL). The resulting mixture was stirred at room temperature overnight and then evaporated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge, and the cartridge was left for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 2 M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 30 g) eluting with a 2% to 25% gradient of CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-2-methoxy-4-thiazol-2-yl-phenyl]boronic acid formate (53.8 mg, 0.127 mmol, 25.4% yield) as a pale yellow solid. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ3.94(s,3H),7.44(s,1H),7.49(dd,J=8.69,1.43Hz,1H),7.69(s,1H),7.70(d,J=3.29Hz,1H),7.72 (d,J=1.32Hz,1H),7.78(d,J=3.26Hz,1H),8.09(s,HCOOH origin),8.33(d,J=8.81Hz,1H),8.45(s,1H),9.70(br.s,1H),9.80(br.s,1H). LC-MS (Method A): Room temperature 0.47 min, MS (ESI) m / z=379.16[M+H] + .

[0241] Example 39: [5-(4-aminocinnolin-7-yl)-2-propan-2-yloxy-4-pyrazol-1-ylphenyl]boronic acid formate (39) [ka] Potassium acetate (138.08 mg, 1.39 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (212.18 mg, 0.840 mmol), and 7-(5-bromo-4-propan-2-yloxy-2-pyrazol-1-ylphenyl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (160.0 mg, 0.280 mmol) were dissolved in 1,2-dimethoxyethane (7 mL) and degassed under N for 10 min. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20.44 mg, 0.030 mmol) was then added, and the resulting reaction mixture was stirred at 85 °C for 2.5 h. The mixture was then cooled to room temperature, filtered through Celite, and washed with MeOH. The filtrate was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (1.8 mL) and trifluoroacetic acid (1.8 mL). The resulting mixture was stirred at room temperature overnight and then evaporated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge, and the cartridge was left for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 2 M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18D, 30 g) eluting with a gradient of 1% to 15% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-2-propan-2-yloxy-4-pyrazol-1-ylphenyl]boronic acid formate (15 mg, 0.034 mmol, 12.1% yield) as a pale yellow solid. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ1.37(d,J=6.00Hz,6H),4.87(hept,J=5.96Hz,1H) ,6.40(t,J=2.15Hz,1H),7.12(dd,J=8.84,1.66Hz,1H),7.24(s,1H),7.58(d,J=1.7 9Hz,1H),7.59(d,J=1.63Hz,1H),7.80(s,1H),7.84(d,J=2.47Hz,1H),8.12(s,HCOO) 0.56H derived from H), 8.23 ​​(d, J = 8.91Hz, 1H), 8.43 (s, 1H), 9.67 (br.s, 1H), 9.74 (br.s, 1H). LC-MS (Method A): Room temperature 0.65 min, MS (ESI) m / z=390.19[M+H] + .

[0242] Example 40: [5-(4-aminocinnolin-7-yl)-4-(4-fluoropyrazol-1-yl)-2-methoxyphenyl]boronic acid (40) [ka] [7-[5-chloro-2-(4-fluoropyrazol-1-yl)-4-methoxyphenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (434.0 mg, 0.810 mmol), potassium acetate (238.38 mg, 2.43 mmol), and bis[(+)-pinanediolate]diboron (869.79 mg, 2.43 mmol) were dissolved in 1,2-dimethoxyethane (8 mL) in a microwave vial and degassed under Ar for 10 min. Next, dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (38.6 mg, 0.080 mmol) and palladium(II) diacetate (9.09 mg, 0.040 mmol) were added, and the mixture was stirred at 65° C. for 32 hours, then filtered through Celite, washed with MeOH, and concentrated in vacuo. The residue was dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL), and the resulting mixture was stirred at room temperature for 17 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in MeOH / water (9:1) and then loaded onto an SCX cartridge, which was washed with a mixture of MeOH / water (9:1) and then eluted with 2 M ammonia solution in MeOH. The basic fractions were concentrated under reduced pressure, and the residue was purified by column chromatography (Sfar C18 D, 30 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 the partially purified product, which was subjected to semi-preparative HPLC [CSH C18 (2.1 × 50 mm, 1.7 μm); gradient of 3% to 99.9% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH)] to give [5-(4-aminocinnolin-7-yl)-4-(4-fluoropyrazol-1-yl)-2-methoxyphenyl]boronic acid (6.5 mg, 0.017 mmol, 2.1% yield) as a beige solid. 1H NMR(400MHz,DMSO-d6+TFA)δ3.92(s,3H),7.20(s,1H),7.22(dd,J=8.84,1.48Hz,1H),7.58(d,J=4.02Hz,1H),7.60(d,J=1.40Hz,1H) ,7.79(s,1H),8.00(d,J=4.50Hz,1H),8.07(s,0.4H derived from HCOOH),8.28(d,J=8.85Hz,1H),8.42(s,1H),9.64(br.s,1H),9.73(br.s,1H). LC-MS (method A): room temperature 0.47 min, MS (ESI) m / z=380.1[M+H] + .

[0243] Example 41: [5-(4-aminocinnolin-7-yl)-2-methyl-4-(1H-pyrazol-3-yl)phenyl]boronic acid (41) [ka] 7-[5-chloro-4-methyl-2-[1-(oxan-2-yl)pyrazol-3-yl]phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (310.0 mg, 0.540 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (0.41 g, A mixture of dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (20.74 mg, 0.040 mmol) and potassium acetate (160.1 mg, 1.63 mmol) in 1,2-dimethoxyethane (9 mL) was degassed under Ar for 10 minutes, then dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (20.74 mg, 0.040 mmol) and palladium(II) diacetate (6.1 mg, 0.030 mmol) were added. The resulting reaction mixture was stirred at 85° C. for 90 minutes, then cooled to room temperature, diluted with EtOAc, filtered through Celite, and washed with MeOH. The filtrate was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1.5 mL). The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in MeOH / water (9:1) and loaded onto an SCX cartridge, which was washed with MeOH / water (9:1) and then eluted with a 2M solution of ammonia in MeOH. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 30 g) eluting with a gradient of 1% to 15% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized. The resulting material was dissolved in MeOH, and the solution was loaded onto an SCX cartridge, which was washed with MeOH and then eluted with a 2M solution of ammonia in MeOH. The basic fractions were collected and concentrated in vacuo to give [5-(4-aminocinnolin-7-yl)-2-methyl-4-(1H-pyrazol-3-yl)phenyl]boronic acid (8 mg, 0.023 mmol, 4.25% yield) as a beige solid. 1H NMR(400MHz,DMSO-d6+TFA)δ2.52(s,3H),5.96(d,J=1.65Hz,1H),7.47(dd,J=8.80,1.48Hz,1H),7.50(s,1H),7.59(s, 1H),7.60-7.62(m,1H),7.71(d,J=1.36Hz,1H),8.29(d,J=8.83Hz,1H),8.45(s,1H),9.66(br.s,1H),9.76(br.s,1H). LC-MS (method A): room temperature 0.42 min, MS (ESI) m / z=346.3[M+H] + .

[0244] Example 42: [5-(4-aminocinnolin-7-yl)-2-methyl-4-oxazol-2-yl-phenyl]boronic acid formate (42) [ka] Palladium(II) diacetate (8.41 mg, 0.040 mmol), 7-[5-chloro-4-methyl-2-(1,3-oxazol-2-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (365.0 mg, 0.750 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (35.73 mg , 0.070 mmol), potassium acetate (220.69 mg, 2.25 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (571.03 mg, 2.25 mmol) were dissolved in 1,2-dimethoxyethane (8.295 mL) in a microwave vial and degassed under N for 10 minutes. The resulting reaction mixture was stirred at 75 °C for 2.5 hours, then cooled to room temperature, filtered through Celite, and washed with MeOH. The filtrate was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (6.2 mL) and trifluoroacetic acid (6.2 mL). The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX cartridge, which was washed with MeOH / water (9:1) and then eluted with 2 M ammonia solution in MeOH. Basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 12 g + 12 g consecutively) eluting with a 2% to 15% gradient of CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-2-methyl-4-oxazol-2-yl-phenyl]boronic acid formate (9.16 mg, 0.023 mmol, 3.1% yield) as a white solid. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ2.55(s,3H),7.24(s,1H),7.59(dd,J=8.78,1.61Hz,1H),7.61(s,1H),7.70(d,J=1.63Hz,1H ),7.79(s,1H),8.02(s,1H),8.12(s,0.75H derived from HCOOH),8.37(d,J=8.89Hz,1H),8.48(s,1H),9.73(br.s,1H),9.84(br.s,1H). LC-MS (Method A): Room temperature 0.44 min, MS (ESI) m / z=347.23[M+H] + .

[0245] Example 43: 7-[4-Methoxy-2-pyrazol-1-yl-5-[(1S,2S,6R,8S)-2,6,9,9-tetramethyl-3,5-dioxa-4-boratricyclo][6.1.1.0 2,6 ]Decan-4-yl]phenyl]cinnoline-4-amine (43) [ka] A suspension of [[5-(4-aminocinnolin-7-yl)-2-methoxy-4-pyrazol-1-ylphenyl]boronic acid (20.93 mg, 0.060 mmol) and (1S,3R,4S,5S)-3,4,6,6-tetramethylbicyclo[3.1.1]heptane-3,4-diol (10.68 mg, 0.060 mmol) in THF (1 mL) was stirred at 50° C. for 18 hours, and then it was concentrated in vacuo. The residue was dissolved in MeOH, and the solution was loaded onto an SCX cartridge, which was washed with MeOH and then eluted with 2 M ammonia solution in MeOH. The basic fractions were collected and dried using a V10 apparatus to give 7-[4-methoxy-2-pyrazol-1-yl-5-[(1S,2S,6R,8S)-2,6,9,9-tetramethyl]-3,5-dioxa-4-boratricyclo[6.1.1.0 2,6 ]decan-4-yl]phenyl]cinnolin-4-amine (29 mg, 0.057 mmol, 98.25% yield) was obtained as a white solid. 1H NMR(400MHz,DMSO-d6)δ0.88(s,3H),1.27(s,3H),1.36-1.39(m,1H),1.41(s,3H),1.45(s,3H),1.91 -1.97(m,2H),2.02-2.11(m,1H),2.14-2.20(m,1H),2.27(dd,J=14.88,4.24Hz,1H),3.87(s,3H),6.3 2(t,J=2.11Hz,1H),6.93(dd,J=8.75,1.82Hz,1H),7.15(br.s,2H),7.19(s,1H),7.61(d,J=1.78Hz,1 H),7.64(d,J=2.43Hz,1H),7.73(s,1H),7.79(d,J=1.83Hz,1H),7.98(d,J=8.73Hz,1H),8.58(s,1H). LC-MS (Method A): Room temperature 0.83 min, MS (ESI) m / z=510.33[M+H] + .

[0246] Example 44: 7-{5-[(3aR,6aS)-3a,6a-dimethyl-hexahydrocyclopenta[d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1H-pyrazol-1-yl)phenyl}cinnolin-4-amine (44) [ka] A suspension of [5-(4-aminocinnolin-7-yl)-2-methoxy-4-pyrazol-1-ylphenyl]boronic acid (20.0 mg, 0.060 mmol) and (1R,2S)-1,2-dimethylcyclopentane-1,2-diol (10.81 mg, 0.080 mmol) in THF (1 mL) was stirred at 45 °C for 18 hours, and then it was concentrated in vacuo. The residue was dissolved in MeOH, and the solution was loaded onto an SCX cartridge, which was washed with MeOH and then eluted with a 2 M solution of ammonia in MeOH. The basic fractions were collected and concentrated under reduced pressure. The resulting solid was dried in an oven at 60 °C for 48 h to give 7-{5-[(3aR,6aS)-3a,6a-dimethyl-hexahydrocyclopenta[d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1H-pyrazol-1-yl)phenyl}cinnolin-4-amine (22 mg, 0.048 mmol, 87.25% yield) as a beige solid. 1 H NMR(400MHz,DMSO-d6)δ1.37(s,6H),1.45-1.71(m,4H),1.89-2.14(m,2H),3.87(s,3H),6.32(t,J=2.17Hz,1H),6.94(dd,J=8.72,1.81Hz,1H),7.1 3(br.s,2H),7.19(s,1H),7.61(d,J=1.76Hz,1H),7.64(d,J=2.42Hz,1H), 7.75(s,1H),7.79(d,J=1.83Hz,1H),7.99(d,J=8.76Hz,1H),8.58(s,1H). LC-MS (Method A): Room temperature 0.66 min, MS (ESI) m / z=456.3[M+H] + .

[0247] Example 45: [5-(4-aminocinnolin-7-yl)-4-(1H-imidazol-4-yl)-2-methoxyphenyl]boronic acid (45) [ka] 7-[5-Chloro-4-methoxy-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (220.0 mg, 0.350 mmol), potassium acetate (102.45 mg, 1.04 mmol), and bis[(+)-pinanediolate]diboron (373.82 mg, 1.04 mmol) were dissolved in 1,2-dimethoxyethane (4 mL), and the mixture was deoxygenated under Ar for 10 min. Next, dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (16.59 mg, 0.030 mmol) and palladium(II) diacetate (3.91 mg, 0.020 mmol) were added, and the mixture was stirred at 90 °C for 20 h. LC-MS check of the reaction indicated no conversion. Therefore, the mixture was filtered through Celite and purified by column chromatography (Sfar Amino D, 28 g) eluting with a gradient of 0% to 100% EtOAc in cyclohexane to give the recovered 7-[5-chloro-4-methoxy-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-4-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine as a yellowish solid, which was redissolved in 1,2-dimethoxyethane (4 mL). Bis[(+)-pinanediolate]diboron (373.82 mg, 1.04 mmol), potassium acetate (102.45 mg, 1.04 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (16.59 mg, 0.030 mmol), and palladium(II) diacetate (3.91 mg, 0.020 mmol) were added, and the mixture was stirred at 90 °C for 3 h. The mixture was filtered through Celite and washed with MeOH and EtOAc. The filtrate was concentrated under reduced pressure, and the residue was dissolved in DCM (2 mL) and trifluoroacetic acid (1.5 mL). The mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was dissolved in MeOH / water (9:1) and loaded onto an SCX cartridge, which was washed with MeOH / water (9:1) and then eluted with 2 M ammonia solution in MeOH.The volatiles were removed under reduced pressure to give a yellowish solid, which was subjected to semi-preparative HPLC purification [CSH C18 (2.1 × 50 mm, 1.7 μm); gradient of 3% to 99.9% MeCN (+0.1% HCOOH) in water (+0.1% HCOOH)]. The appropriate fractions were collected and lyophilized to give a yellowish residue. This material was dissolved in MeOH, loaded onto an SCX cartridge, washed with MeOH, and then eluted with 2 M ammonia solution in MeOH to give [5-(4-aminocinnolin-7-yl)-4-(1H-imidazol-4-yl)-2-methoxyphenyl]boronic acid (3.6 mg, 0.010 mmol, 2.85% yield) as a yellowish solid. 1 H NMR(400MHz,DMSO-d6+TFA)3.95(s,3H),7.30(s,1H),7.39(d,J=1.32Hz,1H),7.56(dd,J=8.82,1.67Hz,1H),7.70(d,J= 1.64Hz,1H),7.72(s,1H),8.34(d,J=8.85Hz,1H),8.49(s,1H),9.12(d,J=1.31Hz,1H),9.74(br.s,1H),9.86(br.s,1H). LC-MS (method A): room temperature 0.48 min, MS (ESI) m / z=362.1[M+H] + .

[0248] Example 46: [5-(4-aminocinnolin-7-yl)-4-(1H-imidazol-2-yl)-2-methoxyphenyl]boronic acid (46) [ka] 7-[5-Chloro-4-methoxy-2-[1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (113.0 mg, 0.180 mmol), potassium acetate (52.62 mg, 0.540 mmol), and bis[(+)-pinanediolate]diboron (192.01 mg, 0.540 mmol) were dissolved in 1,2-dimethoxyethane (2 mL) and degassed under argon for 10 minutes. Dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (8.52 mg, 0.020 mmol) and palladium(II) diacetate (2.01 mg, 0.010 mmol) were then added, and the mixture was stirred at 90° C. for 18 hours, then cooled to room temperature, filtered through Celite, and washed with MeOH and EtOAc. The filtrate was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1.5 mL). The resulting mixture was stirred at room temperature for 18 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in MeOH / water (9:1) and loaded onto an SCX cartridge. The cartridge was washed with a mixture of MeOH / water (9:1) and then eluted with a 2 M ammonia solution in MeOH. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 30 g) eluting with a gradient of 0% to 35% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized. The resulting material was subjected to semi-preparative HPLC (column Chiralpak OJ-H (25 × 0.46 cm), 5 μL mobile phase n-hexane / (ethanol + 0.1% isopropylamine) 82 / 18% v / v). Appropriate fractions were collected and evaporated to give [5-(4-aminocinnolin-7-yl)-4-(1H-imidazol-2-yl)-2-methoxy-phenyl]boronic acid (7 mg, 0.019 mmol, 10.55% yield) as a pale yellow solid. 1H NMR(400MHz,DMSO-d6+TFA)δ3.93(s,3H),7.43(dd,J=8.83,1.34Hz,1H),7.46(s,1H),7.60(d,J=1.27Hz,1 H),7.69-7.72(m,2H),7.82(s,1H),8.35(d,J=8.92Hz,1H),8.47(s,1H),9.77(br.s,1H),9.87(br.s,1H). LC-MS (Method A): Room temperature 0.44 min, MS (ESI) m / z=362.1[M+H] + .

[0249] Example 47: [5-(1-amino-4-methyl-phthalazin-6-yl)-2-methoxy-4-pyrazol-1-yl-phenyl]boronic acid (47) [ka] N-[(2,4-dimethoxyphenyl)methyl]-6-[4-methoxy-2-(1H-pyrazol-1-yl)-5-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0 2,6[Decan-4-yl]phenyl]-4-methylphthalazin-1-amine (700.0 mg, 1.06 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (3 mL). The resulting mixture was stirred at room temperature for 18 hours. The volatiles were then removed under reduced pressure, and the residue was dissolved in MeOH / water (9:1) and loaded onto an SCX cartridge, which was washed with MeOH / water (9:1) and then eluted with a 7 M solution of ammonia in MeOH. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by flash chromatography (Sfar C18 D, 30 g) eluting with a 0% to 35% gradient of CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and then lyophilized. The resulting material was dissolved in MeOH, and the solution was loaded onto an SCX cartridge, which was washed with MeOH and then eluted with a 2 M solution of ammonia in MeOH. The basic fractions were collected and evaporated in vacuo to give [5-(1-amino-4-methyl-phthalazin-6-yl)-2-methoxy-4-pyrazol-1-yl-phenyl]boronic acid (32 mg, 0.085 mmol, 8.037% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6+TFA)δ2.49(s,3H),3.91(s,3H),6.31(t,J=2.18Hz,1H),7.20(s,1H),7.53(d,J=1.78Hz,1H),7.59(d, J=1.40Hz,1H),7.67(d,J=2.37Hz,1H),7.70(dd,J=8.58,1.56Hz,1H),7.88(s,1H),8.52(d,J=8.56Hz,1H),9.00(br.s,2H). LC-MS (Method A): Room temperature 0.48 min, MS (ESI) m / z=376.3[M+H] + .

[0250] Example 48: [5-(1-amino-6-isoquinolyl)-2-methoxy-4-pyrazol-1-yl-phenyl]boronic acid formate (48) [ka] 6-(5-Bromo-4-methoxy-2-pyrazol-1-yl-phenyl)-N-[(2,4-dimethoxyphenyl)methyl]isoquinolin-1-amine (246.55 mg, 0.450 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (33.17 mg, 0.050 mmol), potassium acetate (224.1 mg, 2.26 mmol), and bis[(+)-pinanediolate]diboron (485.61 mg, 1.36 mmol) were dissolved in 1,4-dioxane (4.52 mL) in a microwave vial and degassed under N for 10 min. The resulting reaction mixture was stirred at 90 °C for 2.5 h, then cooled to room temperature, filtered through Celite, and washed with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (4 mL). The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge. The cartridge was allowed to stand for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 2 M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 30 g) eluting with a 2% to 30% gradient of CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [5-(1-amino-6-isoquinolyl)-2-methoxy-4-pyrazol-1-yl-phenyl]boronic acid formate (33.24 mg, 0.082 mmol, 18.22% yield) as a white powder. 1 H NMR (400MHz, DMSO-d6+2 drops of TFA) δ3.93(s,3H),6.31-6.39(m,1H),7.08-7.18(m,2H),7.20(s,1H),7.58(s,1H),7. 62(d,J=6.66Hz,1H),7.67-7.77(m,2H),7.80(s,1H),8.10(s,1H derived from HCOOH),8.34(d,J=8.76Hz,1H),8.94(s,2H). LC-MS (method A): room temperature 0.48 min, MS (ESI) m / z=361.25[M+H] + .

[0251] Example 49: 7-{5-[(3aR,6aS)-3a,6a-diethyl-hexahydrocyclopenta[d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1H-pyrazol-)1-yl)phenyl}cinnolin-4-amine (49) [ka] A mixture of [5-(4-aminocinnolin-7-yl)-2-methoxy-4-pyrazol-1-ylphenyl]boronic acid formate (265.0 mg, 0.650 mmol) and (1R,2S)-1,2-diethylcyclopentane-1,2-diol (154.47 mg, 0.980 mmol) in THF (13.5 mL) and MeOH (1.5 mL) was stirred at 25 °C overnight. The volatiles were removed under reduced pressure. The residue was dissolved in MeOH and loaded onto an SCX cartridge, which was washed with MeOH and then eluted with 2 M ammonia solution in MeOH. The basic fractions were concentrated under reduced pressure to give a beige solid, which was purified by column chromatography (Sfar C18D, 30 g) eluting with a gradient of 2% to 98% MeCN in water to give 7-{5-[(3aR,6aS)-3a,6a-diethyl-hexahydrocyclopenta[d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1H-pyrazol-1-yl)phenyl}cinnolin-4-amine (195 mg, 0.403 mmol, 61.99% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ1.03(t,J=7.35Hz,6H),1.44-1.66(m,6H),1.65-1.82(m,2H),1.89-2.09(m,2H),3.87(s,3H),6.32(t,J=2.18Hz,1H),6.9 5(dd,J=8.68,1.80Hz,1H),7.13(s,2H),7.19(s,1H),7.58-7.68(m,2H), 7.73(s,1H),7.80(d,J=1.76Hz,1H),7.99(d,J=8.80Hz,1H),8.58(s,1H). LC-MS (Method A): Room temperature 0.82 min, MS (ESI) m / z=484.4[M+H] + .

[0252] Example 50 and Example 52: [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(5-methylthiazol-2-yl)phenyl]boronic acid formate (50) and 7-[4-methoxy-2-(5-methylthiazol-2-yl)-5-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratocyclo[6.1.1.0 2,6 ]Decan-4-yl]phenyl]cinnoline-4-amine (52) [ka] Palladium(II) diacetate (3.33 mg, 0.010 mmol), 7-[5-chloro-4-methoxy-2-(5-methylthiazol-2-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (158.0 mg, 0.300 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (14.13 mg, 0.030 mmol), potassium acetate (87.27 mg, 0.890 mmol), and bis[(+)-pinanediolate]diboron (318.43 mg, 0.890 mmol) were dissolved in 1,2-dimethoxyethane (5 mL) in a microwave vial and degassed under N for 10 min. The resulting reaction mixture was stirred at 80°C for 4 hours, then cooled to room temperature, filtered through Celite, and washed with MeOH. The filtrate was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1.5 mL). The resulting mixture was stirred at room temperature overnight and then evaporated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX cartridge, which was washed with MeOH / water (9:1) and then eluted with a 2 M ammonia solution in MeOH. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18D, 30 g) eluting with a gradient of 1% to 15% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(5-methylthiazol-2-yl)phenyl]boronic acid formate (1.8 mg, 0.004 mmol, 1.158% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d6+2 drops of TFA) δ2.37(s,3H),3.93(s,3H),7.39(s,1H),7.47(d,J=1.45Hz,1H),7.51(dd,J=8.69,1.65Hz,1H),7 .62(s,1H),7.73(d,J=1.67Hz,1H),8.12(s,H from HCOOH),8.33(d,J=8.89Hz,1H),8.47(s,1H),9.72(br.s,1H),9.81(br.s,1H). LC-MS (Method A): Room temperature 0.52 min, MS (ESI) m / z=393.2[M+H]+ .

[0253] Other fractions from the chromatography were lyophilized to give the partially purified boronic ester 7-[4-methoxy-2-(5-methylthiazol-2-yl)-5-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0 2,6 ]decan-4-yl]phenyl]cinnolin-4-amine (14 mg) was obtained, which was then subjected to semi-preparative HPLC (column Chiralpak AD-H (25 × 2.0 cm), 5μ, mobile phase n-hexane / (ethanol + 0.1% isopropylamine) 75 / 25% v / v). The appropriate fractions were collected and concentrated to give 7-[4-methoxy-2-(5-methylthiazol-2-yl)-5-[rac-(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0]. 2,6 ]decan-4-yl]phenyl]cinnolin-4-amine (8.2 mg, 0.016 mmol, 4.391% yield) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δ0.86(s,3H),1.14(d,J=10.72Hz,1H),1.27(s,3H),1.42(s,3H),1.78-1.87( m,1H),1.88-1.93(m,1H),2.06(t,J=5.49Hz,1H),2.17-2.28(m,1H),2.30(s,3H),2.32-2.42(m,1H) ,3.88(s,3H),4.51(dd,J=8.67,1.92Hz,1H),7.21(s,2H),7.33(dd,J=8.64,1.82Hz,1H),7.51(d,J= 1.36Hz,1H),7.52(s,1H),7.60(s,1H),7.90(d,J=1.78Hz,1H),8.13(d,J=8.66Hz,1H),8.62(s,1H). LC-MS (Method A): Room temperature 0.85 min, MS (ESI) m / z=527.37[M+H] + .

[0254] Example 51: 7-[4-methyl-2-(1,3-thiazol-2-yl)-5-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0 2,6 ]Decan-4-yl]phenyl]cinnoline-4-amine (51) [ka] A mixture of 7-(5-chloro-4-methyl-2-thiazol-2-ylphenyl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (790.0 mg, 1.57 mmol), potassium acetate (0.47 g, 4.71 mmol), and bis[(+)-pinanediolate]diboron (1.69 g, 4.71 mmol) in 1,2-dimethoxyethane (20 mL) was degassed under Ar for 10 min, followed by the addition of palladium(II) diacetate (17.63 mg, 0.080 mmol) and dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (76.27 mg, 0.16 mmol). The resulting reaction mixture was stirred at 85 °C for 17 h, then cooled to room temperature, filtered through Celite, and washed with EtOAc and MeOH. The filtrate was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (3 mL). The resulting mixture was stirred at room temperature for 10 hours and then evaporated in vacuo. The residue was dissolved in MeOH / water (9:1) and loaded onto an SCX cartridge, which was washed with a mixture of MeOH / water (9:1) and then eluted with a 2 M ammonia solution in MeOH. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18D, 60 g) eluting with a gradient of 2% to 50% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized. The resulting material was triturated with EtO, filtered, and purified to give 7-[4-methyl-2-(1,3-thiazol-2-yl)-5-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0 2,6]decan-4-yl]phenyl]cinnolin-4-amine (80 mg, 0.161 mmol, 5.21% yield) was obtained as a beige solid. 1 H NMR(400MHz,DMSO-d6)δ0.87(s,3H),1.14(d,J=10.73Hz,1H),1.28(s,3H),1.46(s,3H),1.82-1.9 7(m,2H),2.10(t,J=5.46Hz,1H),2.19-2.31(m,1H),2.35-2.46(m,1H),2.61(s,3H),4.56(dd,J=8 .77,1.89Hz,1H),7.21(s,2H),7.31(dd,J=8.69,1.77Hz,1H),7.65(d,J=3.25Hz,1H),7.74(s,1H) ,7.80(d,J=3.25Hz,1H),7.83(s,1H),7.91(d,J=1.69Hz,1H),8.12(d,J=8.64Hz,1H),8.62(s,1H). LC-MS (Method A): Room temperature 0.95 min, MS (ESI) m / z=497.3[M+H] + .

[0255] Example 53: [5-(4-aminocinnolin-7-yl)-2-methyl-4-thiazol-2-yl-phenyl]boronic acid formate (53) [ka] 7-[4-methyl-2-(1,3-thiazol-2-yl)-5-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0 2,6[Decan-4-yl]phenyl]cinnolin-4-amine (66.0 mg, 0.130 mmol) and methylboronic acid (39.39 mg, 0.660 mmol) were dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL). The resulting mixture was stirred at room temperature for 3 days, during which time methylboronic acid and trifluoroacetic acid were added two more times. The volatiles were removed under reduced pressure, and the residue was dissolved in MeOH / water (9:1) and loaded onto an SCX cartridge, which was washed with a mixture of MeOH / water (9:1) and then eluted with 2 M ammonia solution in MeOH. Basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18D, 30 g) eluting with a 2% to 35% gradient of CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-2-methyl-4-thiazol-2-yl-phenyl]boronic acid formate (10.5 mg, 0.026 mmol, 19.54% yield) as a beige solid. 1 H NMR(400MHz,DMSO-d6+TFA)δ2.55(s,3H),7.52(dd,J=8.61,1.74Hz,1H),7.61(s,1H),7.66(s,1H),7.69 -7.77(m,3H),8.11(s,from HCOOH),8.33(d,J=8.82Hz,1H),8.46(s,1H),9.72(br.s,1H),9.82(br.s,1H). LC-MS (Method A): Room temperature 0.47 min, MS (ESI) m / z=363.2[M+H] + .

[0256] Example 54: [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(1H-pyrazol-4-yl)phenyl]boronic acid (54) [ka] Palladium(II) diacetate (5.92 mg, 0.030 mmol), 7-[5-chloro-4-methoxy-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (309.0 mg, 0.530 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (25.13 mg, 0.050 mmol), potassium acetate (155.23 mg, 1.58 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (401.66 mg, 1.58 mmol) were dissolved in 1,2-dimethoxyethane (6 mL) in a microwave vial and degassed under N for 10 minutes. The resulting reaction mixture was stirred at 80 °C for 5 hours, then cooled to room temperature, filtered through Celite, and washed with MeOH. The filtrate was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (5 mL). The resulting mixture was stirred at room temperature overnight and then evaporated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX cartridge, which was washed with MeOH / water (9:1) and then eluted with 2 M ammonia solution in MeOH. Basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 30 g) eluting with a 2% to 15% gradient of CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(1H-pyrazol-4-yl)phenyl]boronic acid (59 mg, 0.163 mmol, 30.7% yield) as an off-white solid. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ3.94(s,3H),7.16(s,1H),7.47(s,1H),7.49(dd,J=8.97,1.35Hz,1H),7.61(s, 1H),7.73(d,J=1.61Hz,1H),8.13(s,1H),8.30(d,J=8.83Hz,1H),8.47(s,1H),9.67(br.s,1H),9.77(br.s,1H). LC-MS (Method A): Room temperature 0.42 min, MS (ESI) m / z=362.20[M+H] + .

[0257] Example 55: 7-{5-[(3aR,6aS)-3a,6a-dimethyl-hexahydrocyclopenta[d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1,3-thiazol-2-yl)phenyl}cinnolin-4-amine (55) [ka] A suspension of [5-(4-aminocinnolin-7-yl)-2-methoxy-4-thiazol-2-yl-phenyl]boronic acid formate (10.0 mg, 0.020 mmol) and (1R,2S)-1,2-dimethylcyclopentane-1,2-diol (4.6 mg, 0.040 mmol) in THF (0.50 mL) was stirred at 45° C. for 18 hours and then concentrated in vacuo. The residue was dissolved in MeOH, and the solution was loaded onto an SCX cartridge, which was washed with MeOH and then eluted with a 2 M solution of ammonia in MeOH. The basic fractions were collected and dried using a V10 apparatus to give 7-{5-[(3aR,6aS)-3a,6a-dimethyl-hexahydrocyclopenta[d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1,3-thiazol-2-yl)phenyl}cinnolin-4-amine (9.59 mg, 0.020 mmol, 86.13% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ1.36(s,6H),1.51-1.68(m,4H),1.92-2.00(m,2H),3.90(s,3H),7.27-7.36(m,3H),7.56(s,1H), 7.62(s,1H),7.67(d,J=3.22Hz,1H),7.84(d,J=3.24Hz,1H),7.90(d,J=1.76Hz,1H),8.14(d,J=8.69Hz,1H),8.62(s,1H). LC-MS (method A): room temperature 0.71 min, MS (ESI) m / z=473.30[M+H] + .

[0258] Example 56: rac-7-{5-[(3aS,6aS)-3a-(propan-2-yl)-hexahydrocyclopenta[d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1H-pyrazol-1-yl)phenyl}cinnolin-4-amine (56) [ka] A suspension of [5-(4-aminocinnolin-7-yl)-2-methoxy-4-pyrazol-1-ylphenyl]boronic acid formate (11.0 mg, 0.030 mmol) and rac-(1S,2S)-1-(propan-2-yl)cyclopentane-1,2-diol (15.58 mg, 0.10 mmol) in THF (1 mL) containing a few drops of MeOH was stirred at room temperature overnight. Additional rac-(1S,2S)-1-(propan-2-yl)cyclopentane-1,2-diol (7.79 mg, 0.050 mmol) was added, and the resulting mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was dissolved in MeOH, and the solution was loaded onto an SCX cartridge, which was washed with MeOH and then eluted with a 2 M solution of ammonia in MeOH. The basic fractions were collected and concentrated under reduced pressure to give rac-7-{5-[(3aS,6aS)-3a-(propan-2-yl)-hexahydrocyclopenta[d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1H-pyrazol-1-yl)phenyl}cinnolin-4-amine (9.5 mg, 0.020 mmol, 74.93% yield) as a beige solid.1 H NMR (400MHz, methanol-d4) δ1.03(d,J=6.60Hz,3H),1.04(d,J=6.82Hz,3H),1.52- 1.80(m,4H),1.85-2.06(m,3H),3.94(s,3H),4.71-4.74(m,1H),6.34(t,J=2.1 4Hz,1H),7.10(dd,J=8.76,1.81Hz,1H),7.23(s,1H),7.48(d,J=2.74Hz,1H),7 .65(d,J=1.71Hz,1H),7.90-7.92(m,2H),7.94(d,J=8.82Hz,1H),8.55(s,1H). LC-MS (method A): room temperature 0.73 min, MS (ESI) m / z=470.5[M+H] + .

[0259] Example 57: 7-[4-methoxy-2-(1H-pyrazol-3-yl)-5-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0 2,6 ]Decan-4-yl]phenyl]cinnolin-4-amine (57) [ka] 7-{5-chloro-4-methoxy-2-[1-(oxan-2-yl)-1H-pyrazol-3-yl]phenyl}-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (2.48 g, 4.22 mmol), potassium acetate (1.26 g, 12.67 mmol), palladium(II) diacetate (47.42 mg, 0.210 mmol), dicyclohexyl-[2-[2,4,6-tri(propane)]-2-yl)phenyl]phenyl]phosphine (201.38 mg, 0.1 mmol), and bis[(+)-pinanediolate]diboron (4.54 g, 12.67 mmol) were solubilized in 1,2-dimethoxyethane (50 mL) and degassed under N for 10 min. The resulting reaction mixture was stirred at 85°C for 3 hours, then cooled to room temperature, filtered through Celite, and washed with MeOH and EtOAc. The filtrate was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (7.5 mL). The resulting mixture was stirred at room temperature for 26 hours and then concentrated in vacuo. The residue was dissolved in MeOH / water (9:1) and loaded onto an SCX cartridge, which was washed with a mixture of MeOH / water (9:1) and then eluted with a 2M ammonia solution in MeOH. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 120 g) eluting with a 2% to 50% gradient of CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized. The resulting solid was dissolved in MeOH, and the resulting solution was loaded onto an SCX cartridge, which was washed with MeOH and then eluted with a 2 M solution of ammonia in MeOH. The basic fractions were collected and concentrated under reduced pressure to give 7-[4-methoxy-2-(1H-pyrazol-3-yl)-5-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0]. 2,6 ]decan-4-yl]phenyl]cinnolin-4-amine (120 mg, 0.242 mmol, 5.73% yield) was obtained as a beige solid. 1H NMR(400MHz,DMSO-d6)δ0.87(s,3H),1.16(d,J=10.70Hz,1H),1.28(s,3H),1.43(s,3H),1.80-1.88(m ,1H),1.89-1.95(m,1H),2.08(t,J=5.51Hz,1H),2.16-2.31(m,1H),2.34-2.45(m,1H),3.88(s,3H),4. 51(dd,J=8.73,1.88Hz,1H),5.73(d,J=2.17Hz,1H),7.14(s,2H),7.24(d,J=8.69Hz,1H),7.35(s,1H) ,7.55(s,1H),7.62(s,1H),7.85(d,J=1.77Hz,1H),8.04(d,J=8.73Hz,1H),8.60(s,1H),12.85(s,1H). LC-MS (Method A): Room temperature 0.77 min, MS (ESI) m / z=496.4[M+H] + .

[0260] Example 58: [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(4-morpholinopyrazol-1-yl)phenyl]boronic acid formate (58) [ka] 7-[5-Bromo-4-methoxy-2-(4-morpholinopyrazol-1-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (63.0 mg, 0.100 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.32 mg, 0.010 mmol), potassium acetate (49.46 mg, 0.500 mmol), and bis[(+)-pinanediolate]diboron (107.17 mg, 0.300 mmol) were dissolved in 1,2-dimethoxyethane (1.5 mL) in a microwave vial and degassed under N for 10 min. The resulting reaction mixture was stirred at 90 °C for 3 h, then cooled to room temperature and filtered through Celite, rinsing with EtOAc and MeOH. The filtrate was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (2.5 mL) and trifluoroacetic acid (1.5 mL). The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in MeOH / water (9:1) and loaded onto an SCX cartridge, which was washed with a mixture of MeOH / water (9:1) and then eluted with a 2 M ammonia solution in MeOH. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 12 g) eluting with a gradient of 1% to 15% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(4-morpholinopyrazol-1-yl)phenyl]boronic acid formate (7 mg, 0.014 mmol, 14% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6+2 drops of TFA) δ2.82-2.94(m,4H),3.63-3.73(m,4H),3.94(s,3H),7.15(dd,J=8.91,1.50Hz,1H),7.18(s,1H),7. 45(s,1H),7.56-7.67(m,2H),7.77(s,1H),8.11(s,HCOOH derived),8.25(d,J=8.89Hz,1H),8.44(s,1H),9.65(br.s1H),9.73(br.s,1H). LC-MS (Method A): Room temperature 0.49 min, MS (ESI) m / z=447.2[M+H] + .

[0261] Example 59: 7-{5-[(3aR,6aS)-3a,6a-diethyl-hexahydrocyclopenta[d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1,3-thiazol-2-yl)phenyl}cinnolin-4-amine (59) [ka] [5-(4-aminocinnolin-7-yl)-2-methoxy-4-thiazol-2-yl-phenyl]boronic acid formate (10.0 mg, 0.020 mmol) and (1R,2S)-1,2-diethylcyclopentane-1,2-diol (7.46 mg, 0.050 mmol) were dissolved in THF (1 mL) containing a few drops of MeOH. The resulting reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in MeOH, and the solution was loaded onto an SCX cartridge, which was washed with MeOH and then eluted with a 2 M solution of ammonia in MeOH. The basic fractions were collected and concentrated under reduced pressure to give 7-{5-[(3aR,6aS)-3a,6a-diethyl-hexahydrocyclopenta[d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1,3-thiazol-2-yl)phenyl}cinnolin-4-amine (9.8 mg, 0.020 mmol, 83.08% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ1.02(t,J=7.28Hz,6H),1.41-1.62(m,6H),1.66-1. 83(m,2H),1.92-2.04(m,2H),3.89(s,3H),7.21(br.s,2H),7.31(dd,J=8.6 8,1.80Hz,1H),7.55(s,1H),7.60(s,1H),7.66(d,J=3.23Hz,1H),7.83(d,J =3.26Hz,1H),7.91(d,J=1.74Hz,1H),8.12(d,J=8.64Hz,1H),8.62(s,1H). LC-MS (method A): room temperature 0.84 min, MS (ESI) m / z=501.4[M+H] + .

[0262] Example 60: rac-7-{5-[(3aS,6aS)-3a-isopropyl-6a-methyl-dihydro-4H-cyclopenta[d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(pyrazol-1-yl)phenyl}cinnolin-4-amine (60) [ka] [5-(4-aminocinnolin-7-yl)-2-methoxy-4-pyrazol-1-ylphenyl]boronic acid formate (10.0 mg, 0.020 mmol) and rac-(1S,2S)-1-methyl-2-(propan-2-yl)cyclopentane-1,2-diol (11.66 mg, 0.070 mmol) were dissolved in THF (1 mL) containing a few drops of MeOH. The resulting reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in MeOH, and the solution was loaded onto an SCX cartridge, which was washed with MeOH and then eluted with a 2 M solution of ammonia in MeOH. The basic fractions were collected and concentrated under reduced pressure to give rac-7-{5-[(3aS,6aS)-3a-isopropyl-6a-methyl-dihydro-4H-cyclopenta[d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(pyrazol-1-yl)phenyl}cinnolin-4-amine (10.5 mg, 0.022 mmol, 88.45% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ0.96(d,J=6.69Hz,3H),1.00(d,J=6.51Hz,3H),1.47(s,3H),1.5 4-1.70(m,4H),1.79-1.89(m,1H),1.91-2.13(m,2H),3.88(s,3H),6.32-6.35(m,1H),6.9 5(dd,J=8.76,1.83Hz,1H),7.14(br.s,2H),7.20(s,1H),7.62(d,J=1.79Hz1H),7.65(d, J=2.47Hz,1H),7.74(s,1H),7.81(d,J=1.86Hz,1H),8.00(d,J=8.79Hz,1H),8.59(s,1H). LC-MS (Method A): Room temperature 0.78 min, MS (ESI) m / z=484.4[M+H] + .

[0263] Example 61: 7-{5-[(3aR,6aS)-3a,6a-dimethyl-hexahydrocyclopenta[d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1H-pyrazol-3-yl)phenyl}cinnolin-4-amine (61) [ka] A mixture of [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(1H-pyrazol-3-yl)phenyl]boronic acid formate (10.0 mg, 0.020 mmol) and (1R,2S)-1,2-dimethylcyclopentane-1,2-diol (4.8 mg, 0.040 mmol) in THF (1 mL) containing 2 drops of MeOH was stirred at 25° C. overnight and then concentrated in vacuo. The residue was dissolved in MeOH, and the solution was loaded onto an SCX cartridge, which was washed with MeOH and then eluted with a 2 M solution of ammonia in MeOH. The basic fractions were concentrated to give 7-{5-[(3aR,6aS)-3a,6a-dimethyl-hexahydrocyclopenta[d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1H-pyrazol-3-yl)phenyl}cinnolin-4-amine (9.1 mg, 0.020 mmol, 81.38% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ1.35(s,6H),1.52-1.70(m,4H),1.86-2.07(m,2H),3.86(s,3H),5.71(d,J=2.11Hz,1H),7.14(br.s,2H) ,7.22(d,J=7.93Hz,1H),7.34(s,1H),7.54(s,1H),7.58(s,1H),7.84(s,1H),8.04(d,J=8.69Hz,1H),8.59(s,1H),12.84(s,1H). LC-MS (method A): room temperature 0.67 min, MS (ESI) m / z=456.30[M+H] + .

[0264] Example 62: 7-{5-[(3aR,6aS)-3a,6a-diethyl-hexahydrocyclopenta[d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1H-pyrazol-3-yl)phenyl}cinnolin-4-amine (62) [ka] A mixture of [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(1H-pyrazol-3-yl)phenyl]boronic acid formate (10.0 mg, 0.020 mmol) and (1R,2S)-1,2-diethylcyclopentane-1,2-diol (5.83 mg, 0.040 mmol) in THF (1 mL) containing 2 drops of MeOH was stirred at 25° C. overnight and then concentrated in vacuo. The residue was dissolved in MeOH, and the solution was loaded onto an SCX cartridge, which was washed with MeOH and then eluted with a 2 M solution of ammonia in MeOH. The basic fractions were concentrated to give 7-{5-[(3aR,6aS)-3a,6a-diethyl-hexahydrocyclopenta[d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1H-pyrazol-3-yl)phenyl}cinnolin-4-amine (6.5 mg, 0.013 mmol, 54.76% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ1.02(t,J=7.29Hz,6H),1.36-1.62(m,4H),1.64-1.81(m,4H),1.87-2.01(m,2H),3.86(s,3H),5.70(d,J=2.18Hz,1H),7.1 4(br.s,2H),7.20-7.26(m,1H),7.30-7.36(m,1H),7.49-7.59(m,2H),7. 84(d,J=1.54Hz,1H),8.03(d,J=8.76Hz,1H),8.59(s,1H),12.84(s,1H). LC-MS (Method A): Room temperature 0.81 min, MS (ESI) m / z=484.4[M+H] + .

[0265] Example 63: [3-(4-aminocinnolin-7-yl)-4-(2-pyridyl)phenyl]boronic acid formate (63) [ka] Palladium(II) diacetate (6.58 mg, 0.030 mmol), 7-[5-chloro-2-(2-pyridyl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (283.0 mg, 0.590 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (27.93 mg, 0.060 mmol), potassium acetate (172.52 mg, 1.76 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (446.4 mg, 1.76 mmol) were dissolved in 1,2-dimethoxyethane (5.6 mL) in a microwave vial and degassed under N for 10 min. The resulting reaction mixture was stirred at 90°C for 2 hours, then cooled to room temperature, filtered through Celite, and washed with EtOAc. The filtrate was concentrated 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 overnight and then concentrated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge. The cartridge was allowed to stand for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 2 M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 12 g) eluting with a 2% to 30% gradient of CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [3-(4-aminocinnolin-7-yl)-4-(2-pyridyl)phenyl]boronic acid formate (35 mg, 0.090 mmol, 15.2% yield) as a white solid. 1H NMR (400MHz, DMSO-d6 + 2 drops of TFA) δ7.53 (dd, J=8.66, 2.01Hz, 1H), 7.66 (s, 1H), 7.76-7.81 (m, 2H), 7.87-7.94 (m, 1H), 8.08 (s, derived from HCOOH), 8 .12-8.17(m,2H),8.32(d,J=9.11Hz,1H),8.36(d,J=7.92Hz,1H),8.45(s,1H),8.82(d,J=5.71Hz,1H),9.75(br.s,1H),9.85(br.s,1H). LC-MS (Method B): Room temperature 0.39 min, MS (ESI) m / z=343.24[M+H] + .

[0266] Example 64: [5-(4-aminocinnolin-7-yl)-2-phenoxy-4-pyrazol-1-yl-phenyl]boronic acid formate (64) [ka] Palladium(II) diacetate (1.49 mg, 0.010 mmol), 7-(5-chloro-4-phenoxy-2-pyrazol-1-yl-phenyl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (75.0 mg, 0.130 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (6.34 mg, 0.010 mmol), potassium acetate (39.15 mg, 0.400 mmol), and bis[(+)-pinanediolate]diboron (142.85 mg, 0.400 mmol) were dissolved in 1,2-dimethoxyethane (2.507 mL) in a microwave vial and degassed under N for 10 min. The resulting reaction mixture was stirred at 85 °C for 3 hours, then cooled to room temperature, filtered through Celite, and washed with MeOH. The filtrate was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (3 mL). The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX cartridge, which was washed with MeOH / water (9:1) and then eluted with a 2 M ammonia solution in MeOH. The basic fractions were concentrated under reduced pressure, and the residue was purified by column chromatography (Sfar C18D, 12 g + 12 g consecutively) eluting with a 1% to 20% gradient of CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were lyophilized to give [5-(4-aminocinnolin-7-yl)-2-phenoxy-4-pyrazol-1-yl-phenyl]boronic acid formate (6 mg, 0.013 mmol, 10% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6 + 2 drops of TFA) δ6.27-6.30(m,1H),6.92(s,1H),7.15-7.24(m,4H),7.40-7.47(m,2H),7.54(s,1H),7.58-7.63(m, 1H),7.65(d,J=1.65Hz,1H),7.84(s,1H),8.11(s,derived from HCOOH),8.27(d,J=8.92Hz,1H),8.45(s,1H),9.70(br.s,1H),9.77(br.s,1H). LC-MS (Method A): Room temperature 0.60 min, MS (ESI) m / z=424.27[M+H] + .

[0267] Example 65: [[10-(4-aminocinnolin-7-yl)-4,5-dihydropyrazolo[5,1-d][1,5]benzoxazepin-8-yl]boronic acid formate (65) [ka] Potassium acetate (225.7 mg, 2.28 mmol), 7-(8-chloro-4,5-dihydropyrazolo[5,1-d][1,5]benzoxazepin-10-yl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (234.0 mg, 0.460 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (21.7 mg, 0.050 mmol), and palladium(II) diacetate (5.11 mg, 0.020 mmol) were solubilized in 1,2-dimethoxyethane (6 mL) and degassed under N for 10 min. The resulting reaction mixture was stirred at 75 °C for 3 h, then cooled to room temperature, filtered through Celite, and washed with MeOH. The filtrate was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (3 mL). The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX cartridge, which was washed with MeOH / water (9:1) and then eluted with a 2 M ammonia solution in MeOH. The basic fractions were concentrated under reduced pressure, and the residue was purified by column chromatography (Sfar C18 D, 12 g + 12 g consecutively) eluting with a gradient of 1% to 20% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [[10-(4-aminocinnolin-7-yl)-4,5-dihydropyrazolo[5,1-d][1,5]benzoxazepin-8-yl]boronic acid formate (36 mg, 0.086 mmol, 18.69% yield) as a white solid. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ3.20(t,J=6.57Hz,2H),4.53(t,J=6.53Hz,2H), 6.38(d,J=1.74Hz,1H),7.21(dd,J=8.81,1.63Hz,1H),7.31(d,J=1.73Hz,1H),7 .69(d,J=1.65Hz,1H),7.81(d,J=1.34Hz,1H),7.86(d,J=1.37Hz,1H),8.13(s,H COOH origin), 8.23 ​​(d, J=8.90Hz, 1H), 8.46 (s, 1H), 9.70 (br.s, 1H), 9.78 (br.s, 1H). LC-MS (Method A): Room temperature 0.42 min, MS (ESI) m / z=374.23[M+H] + .

[0268] Example 66: rac-7-{5-[(3aS,6aS)-3a-methyl-6a-(propan-2-yl)-hexahydrocyclopenta[d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1H-pyrazol-3-yl)phenyl}cinnolin-4-amine (66) [ka] [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(1H-pyrazol-3-yl)phenyl]boronic acid formate (13.0 mg, 0.030 mmol) was dissolved in THF (1.2 mL) containing a few drops of MeOH, and then rac-(1S,2S)-1-methyl-2-(propan-2-yl)cyclopentane-1,2-diol (15.16 mg, 0.100 mmol) was added, and the mixture was stirred overnight. The volatiles were evaporated under reduced pressure, and the residue was dissolved in MeOH and loaded onto an SCX cartridge (1 g), which was washed with MeOH and then eluted with 2 M ammonia solution in MeOH. The basic fractions were concentrated under reduced pressure to give rac-7-{5-[(3aS,6aS)-3a-methyl-6a-(propan-2-yl)-hexahydrocyclopenta[d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1H-pyrazol-3-yl)phenyl}cinnolin-4-amine (12 mg, 0.025 mmol, 77.76% yield) as a white solid.1 H NMR(400MHz,DMSO-d6)δ0.95(d,J=6.66Hz,3H),0.99(d,J=6.50Hz,3H),1.45( s,3H),1.50-1.73(m,4H),1.75-1.87(m,1H),1.88-2.04(m,2H),3.86(s,3H),5 .71(d,J=2.19Hz,1H),7.13(s,2H),7.22(d,J=8.68Hz,1H),7.34(s,1H),7.50 -7.62(m,2H),7.84(s,1H),8.03(d,J=8.72Hz,1H),8.59(s,1H),12.83(s,1H). LC-MS (Method A): Room temperature 0.76 min, MS (ESI) m / z=484.3[M+H] + .

[0269] Example 67: 7-{5-[(3aR,6aS)-3a,6a-diethyl-tetrahydro-2H-furo[3,4-d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1H-pyrazol-1-yl)phenyl}cinnolin-4-amine (67) [ka] [5-(4-aminocinnolin-7-yl)-2-methoxy-4-pyrazol-1-ylphenyl]boronic acid formate (15.0 mg, 0.040 mmol) was dissolved in THF (1.5 mL) containing 3 drops of MeOH, and then (3R,4S)-3,4-diethyltetrahydrofuran-3,4-diol (11.69 mg, 0.070 mmol) was added, and the mixture was stirred overnight. The volatiles were evaporated under reduced pressure, and the residue was dissolved in MeOH and loaded onto an SCX cartridge (1 g), which was washed with MeOH and then eluted with 2 M ammonia in MeOH. The basic fraction was concentrated under reduced pressure to give 7-{5-[(3aR,6aS)-3a,6a-diethyl-tetrahydro-2H-furo[3,4-d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1H-pyrazol-1-yl)phenyl}cinnolin-4-amine (14 mg, 0.029 mmol, 79.1% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.00 (t, J = 7.33 Hz, 6H), 1.56-1.89 (m, 4H), 3.45 (d, J = 10.45 Hz, 2H), 3.89 (s, 3H), 4.01 (d, J = 10.47 Hz, 2H), 6.32 (t, J = 2.15 Hz, 1H), 6.95 (dd, J = 8.74,1.81Hz,1H),7.14(s,2H),7.22(s,1H),7.62(d,J=1.82Hz,1H),7.64(d,J=2.4 5Hz,1H),7.77(s,1H),7.80(d,J=1.76Hz,1H),8.00(d,J=8.73Hz,1H),8.58(s,1H). LC-MS (Method A): Room temperature 0.68 min, MS (ESI) m / z=486.3[M+H] + .

[0270] Example 68: [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(5-methoxy-1,3-thiazol-2-yl)phenyl]boronic acid formate (68) [ka] Palladium(II) diacetate (7.67 mg, 0.030 mmol), 7-[5-chloro-4-methoxy-2-(5-methoxythiazol-2-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (375.0 mg, 0.680 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (32.56 mg, 0.070 mmol), potassium acetate (201.09 mg, 2.05 mmol), and bis[(+)-pinanediolate]diboron (733.74 mg, 2.05 mmol) were dissolved in 1,2-dimethoxyethane (10 mL) in a microwave vial, and the resulting mixture was deoxygenated under N for 10 min. The mixture was then stirred at 80 °C for 4 h. The volatiles were evaporated under reduced pressure, and the residue was dissolved in MeOH and loaded onto an SCX cartridge (10 g), which was washed with MeOH and then eluted with 2 M ammonia in MeOH. The basic fractions were concentrated in vacuo, and the residue was dissolved in DCM (1 mL) and trifluoroacetic acid (1 mL), stirred at room temperature overnight, and then evaporated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX cartridge, which was first washed with a 9:1 solution of MeOH / water and then eluted with a 2 M methanolic NH solution. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18D, 12 g + 12 g consecutively) eluting with a 1% to 20% gradient of CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(5-methoxythiazol-2-yl)phenyl]boronic acid formate (27 mg, 0.059 mmol, 8.7% yield) as a pale yellow solid. 1H NMR(400MHz,DMSO-d6+TFA)δ3.86(s,3H),3.94(s,3H),7.18(d,J=1.61Hz,1H),7.35(s,1H),7.56(dd,J=8.78,1.56Hz,1H),7. 62(s,1H),7.74(d,J=1.62Hz,1H),8.13(s,HCOOH derived 0.51H,1H),8.36(d,J=8.86Hz,1H),8.48(s,1H),9.73(s,1H),9.83(s,1H). LC-MS (Method A): Room temperature 0.53 min, MS (ESI) m / z=409.15[M+H] + .

[0271] Example 69: 7-{5-[(3aR,6aS)-3a,6a-diethyl-tetrahydro-2H-thieno[3,4-d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1H-pyrazol-1-yl)phenyl}cinnolin-4-amine (69) [ka] [5-(4-aminocinnolin-7-yl)-2-methoxy-4-pyrazol-1-ylphenyl]boronic acid formate (20.0 mg, 0.050 mmol) was dissolved in THF (1.9 mL) containing 3 drops of MeOH, and then (3R,4S)-3,4-diethyltetrahydrothiophene-3,4-diol (19.24 mg, 0.100 mmol) was added, and the mixture was stirred overnight. The volatiles were evaporated under reduced pressure, and the residue was dissolved in MeOH and loaded onto an SCX cartridge (1 g), which was washed with MeOH and then eluted with 2 M ammonia solution in MeOH. The basic fractions were collected and concentrated under reduced pressure to give 7-{5-[(3aR,6aS)-3a,6a-diethyl-4,6-dihydrothieno[3,4-d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-pyrazol-1-yl-phenyl}cinnolin-4-amine (6.8 mg, 0.014 mmol, 27.61% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ1.06(t,J=7.37Hz,6H),1.54-1.67(m,2H),1.74-1.87(m,2H ),2.84(d,J=13.20Hz,2H)2.99(d,J=13.42Hz,2H),3.88(s,3H),6.28-6.37(m,1H), 6.94(dd,J=8.58,1.76Hz,1H),7.15(s,2H),7.19-7.23(m,1H),7.62(d,J=1.54Hz,1 H),7.65(d,J=2.20Hz,1H),7.76-7.82(m,2H),8.00(d,J=8.80Hz,1H),8.59(s,1H). LC-MS (Method A): Room temperature 0.76 min, MS (ESI) m / z=502.2[M+H] + .

[0272] Example 70: 8-(4-aminocinnolin-7-yl)-7-(1H-pyrazol-1-yl)-3,4-dihydro-1H-2,5,1-benzodioxaborepin-1-ol (70) [ka] Potassium acetate (391.89 mg, 3.95 mmol), bis[(+)-pinanediolate]diboron (849.21 mg, 2.37 mmol), and 7-[5-bromo-4-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-2-pyrazol-1-yl-phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (546.0 mg, 0.790 mmol) were solubilized in 1,4-dioxane (12 mL), and the solution was degassed for 10 min. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (58.0 mg, 0.080 mmol) was added to the mixture, and the solution was heated to 100 °C for 5 h. The mixture was then concentrated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX cartridge, which was then eluted first with MeOH and then with 2M methanolic NH3 solution. The basic fractions were collected and concentrated under reduced pressure. The residue was dissolved in DCM (10 mL) and trifluoroacetic acid (10 mL), stirred at room temperature overnight, and then concentrated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX cartridge, which was then eluted first with a 9:1 solution of MeOH / water and then with 2M methanolic NH3 solution. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18D, 2 x 30 g in succession) eluting with a gradient of 1% to 15% MeCN (+0.1% NH4OH) in water (+0.1% NH4OH). The appropriate fractions were collected and lyophilized to give 7-(1-hydroxy-7-pyrazol-1-yl-3,4-dihydro-2,5,1-benzodioxaborepin-8-yl)cinnolin-4-amine (74 mg, 0.198 mmol, 24.1% yield) as a pale yellow solid. 1H NMR(400MHz,DMSO-d6)δ4.22-4.28(m,2H),4.42-4.48(m,2H),6.27-6.34(m,1H),6.96(dd,J=8.77,1.83Hz,1H),7.13(s,1H),7.19(s,2H) ),7.59(d,J=1.77Hz,1H),7.66(d,J=2.40Hz,1H),7.78(d,J=1.78Hz,1H),8.00(d,J=8.80Hz,1H),8.09(s,1H),8.57(s,1H),8.63(s,1H). LC-MS (Method A): Room temperature 0.46 min, MS (ESI) m / z=374.19[M+H] + .

[0273] Example 71: 7-(1-hydroxy-4-methyl-7-pyrazol-1-yl-3,4-dihydro-2,5,1-benzodioxaborepin-8-yl)cinnolin-4-amine (71) [ka] Step 1: 7-[5-Bromo-4-[2-[tert-butyl(dimethyl)silyl]oxy-1-methyl-ethoxy]-2-pyrazol-1-yl-phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (237 mg, approximately 45:55 mixture with N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine), potassium acetate (166.72 mg, 1.68 mmol), and bis[(+)-pinanediolate]diboron (361.28 mg, 1.01 mmol) were dissolved in 1,4-dioxane (5 mL), and the mixture was degassed under a N atmosphere for 10 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (24.67 mg, 0.030 mmol) was added, and the resulting reaction mixture was stirred at 100 °C for 2 h, then the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge, which was washed with MeOH, and then the product was eluted with a 2 M solution of NH in MeOH. The basic fractions were collected and concentrated in vacuo.

[0274] 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 at room temperature overnight, and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH / HO (9:1), and then the product was eluted with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​SNAP 30 g) eluting with a gradient of 1% to 15% CHCN (+0.1% NHOH) in water (+0.1% NHOH). Fractions containing the desired compound were collected and lyophilized to give 7-(1-hydroxy-4-methyl-7-pyrazol-1-yl-3,4-dihydro-2,5,1-benzodioxaborepin-8-yl)cinnolin-4-amine (13 mg) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ1.38(d,J=6.61Hz,3H),4.12(d,J=5.59Hz,2H),4.44 -4.52(m,1H),6.32(t,J=2.12Hz,1H),6.96(dd,J=8.76,1.83Hz,1H),7.08(s ,1H),7.13(s,2H),7.58(d,J=1.77Hz,1H),7.66(d,J=2.34Hz,1H),7.79(d,J =1.83Hz,1H),7.99(d,J=8.74Hz,1H),8.04(s,1H),8.57(s,1H),8.62(s,1H). LC-MS (Method A): Room temperature 0.53 min, MS (ESI) m / z=388.18[M+H] + .

[0275] Examples 72 and 73: 7-(1-hydroxy-3-methyl-7-pyrazol-1-yl-3,4-dihydro-2,5,1-benzodioxaborepin-8-yl)cinnolin-4-amine enantiomer 1 (72) and 7-(1-hydroxy-3-methyl-7-pyrazol-1-yl-3,4-dihydro-2,5,1-benzodioxaborepin-8-yl)cinnolin-4-amine enantiomer 2 (73) [ka] Step 1: 7-[5-Bromo-4-[2-[tert-butyl(dimethyl)silyl]oxypropoxy]-2-pyrazol-1-yl-phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (930 mg, 1.32 mmol), potassium acetate (654.22 mg, 6.6 mmol), and bis[(+)-pinanediolate]diboron (1.42 g, 3.96 mmol) were dissolved in 1,4-dioxane (5 mL), and the mixture was degassed under a N atmosphere for 10 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (96.83 mg, 0.130 mmol) was added, and the resulting reaction mixture was stirred at 100 °C for 2 hours, after which the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH and then the product was eluted with a 2M solution of NH3 in MeOH. The basic fractions were collected and concentrated in vacuo.

[0276] 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 at room temperature overnight, and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH / HO (9:1), and then the product was eluted with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (2 x KP-C18-HS, ​​SNAP 30 g) eluting with a gradient of 1% to 15% CHCN (+0.1% NHOH) in water (+0.1% NHOH). The appropriate fractions were collected and lyophilized to give racemic 7-(1-hydroxy-3-methyl-7-pyrazol-1-yl-3,4-dihydro-2,5,1-benzodioxaborepin-8-yl)cinnolin-4-amine. This material was subjected to semi-preparative chiral SFC purification (column: Chiralpak AS-H (25 × 2.0 cm), 5 μm, mobile phase (methanol + 0.1% isopropylamine), flow rate 18 mL / min). The fractions containing the two enantiomers were collected separately and evaporated under reduced pressure. The residue was dissolved in CHCN and water and lyophilized to give 7-(1-hydroxy-3-methyl-7-pyrazol-1-yl-3,4-dihydro-2,5,1-benzodioxaborepin-8-yl)cinnolin-4-amine enantiomer 1 (43 mg, 0.111 mmol, 13.73% yield) as a white powder and 7-(1-hydroxy-3-methyl-7-pyrazol-1-yl-3,4-dihydro-2,5,1-benzodioxaborepin-8-yl)cinnolin-4-amine enantiomer 2 (34 mg, 0.088 mmol, 10.86% yield) as a white solid.

[0277] Characterization of Enantiomer 1: 1H NMR(400MHz,DMSO-d6)δ1.27(d,J=6.60Hz,3H),4.24-4.39(m,2H),4.41-4. 50(m,1H),6.32(t,J=2.12Hz,1H),6.96(dd,J=8.77,1.84Hz,1H),7.13(s,1 H),7.14(s,2H),7.59(d,J=1.75Hz,1H),7.66(d,J=2.35Hz,1H),7.78(d,J= 1.79Hz,1H),7.99(d,J=8.74Hz,1H),8.09(s,1H),8.57(s,1H),8.59(s,1H). LC-MS (Method A): Room temperature 0.51 min, MS (ESI) m / z=388.19[M+H] + Analytical chiral SFC: Column: Chiralpak AS-H (25 x 0.46 cm), 5 μm. Mobile phase: 18% v / v methanol + 0.1% isopropylamine. Flow rate: 2.5 mL / min. DAD 220 nm loop: 5 μL. Enantiomer 1: 96.6% a / a by UV (11.2 min). Enantiomer 2: 3.4% a / a by UV (14.9 min).

[0278] Characterization of Enantiomer 2: 1 H NMR(400MHz,DMSO-d6)δ1.27(d,J=6.60Hz,3H),4.24-4.39(m,2H),4.41-4. 50(m,1H),6.32(t,J=2.12Hz,1H),6.96(dd,J=8.77,1.84Hz,1H),7.13(s,1 H),7.14(s,2H),7.59(d,J=1.75Hz,1H),7.66(d,J=2.35Hz,1H),7.78(d,J= 1.79Hz,1H),7.99(d,J=8.74Hz,1H),8.09(s,1H),8.57(s,1H),8.59(s,1H). LC-MS (method A): room temperature 0.51 min, MS (ESI) m / z=388.21[M+H] + Analytical chiral SFC: Column: Chiralpak AS-H (25 x 0.46 cm), 5 μm. Mobile phase: 18% v / v methanol + 0.1% isopropylamine. Flow rate: 2.5 mL / min. DAD 220 nm loop: 5 μL. Enantiomer 1: 0.2% a / a by UV (11.2 min); Enantiomer 2: 99.8% a / a by UV (13.7 min).

[0279] Example 74: 7-(1-hydroxy-7-oxazol-2-yl-3,4-dihydro-2,5,1-benzodioxaborepin-8-yl)cinnolin-4-amine (74) [ka] Step 1: Palladium(II) diacetate (8.15 mg, 0.040 mmol), 7-[4-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-5-chloro-2-oxazol-2-yl-phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (470 mg, 0.730 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (34.62 mg, 0.070 mmol), potassium acetate (213.8 mg, 2.18 mmol), and bis[(+)-pinanediolate]diboron (780.09 mg, 2.18 mmol) were dissolved in 1,2-dimethoxyethane (12 mL) in a microwave vial. The resulting mixture was degassed with N for 10 minutes and stirred at 70 °C for 4 hours. The volatiles were then evaporated and the residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH and then the product was eluted with a 2M solution of NH3 in MeOH. The basic fractions were collected and concentrated in vacuo.

[0280] Step 2: The crude material from Step 1 was dissolved in a mixture of DCM (7 mL) and trifluoroacetic acid (7 mL). The mixture was stirred at room temperature overnight, and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH / HO (9:1), and then the product was eluted with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​2 x SNAP 30 g in succession) eluting with a gradient of 1% to 15% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). Fractions containing the desired compound were collected and lyophilized to give a partially purified product, which was further purified by column chromatography (KP-C18-HS, ​​2 × SNAP 30 g in succession) eluting with a gradient of 1% to 15% CH3CN (+0.1% NH4OH) in water (+0.1% NH4OH). Fractions containing the desired compound were collected and lyophilized to give 7-(1-hydroxy-7-oxazol-2-yl-3,4-dihydro-2,5,1-benzodioxaborepin-8-yl)cinnolin-4-amine (86 mg, 0.230 mmol, 31.5% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ4.22-4.28(m,2H),4.42-4.47(m,2H),7.17(s,2H),7.25-7.29(m,2H),7.45( s,1H),7.83(d,J=1.78Hz,1H),7.99-8.01(m,2H),8.10(d,J=8.75Hz,1H),8.60(s,1H),8.64(s,1H). LC-MS (Method A): Room temperature 0.47 min, MS (ESI) m / z=375.15[M+H] + .

[0281] Example 75: [5-(4-aminocinnolin-7-yl)-4-(5-fluorothiazol-2-yl)-2-methoxy-phenyl]boronic acid (75) [ka] Step 1: Palladium(II) diacetate (1.36 mg, 0.010 mmol), 7-[5-chloro-2-(5-fluorothiazol-2-yl)-4-methoxyphenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (65 mg, 0.120 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (5.77 mg, 0.010 mmol), potassium acetate (35.64 mg, 0.360 mmol), and bis[(+)-pinanediolate]diboron (130.03 mg, 0.360 mmol) were dissolved in 1,2-dimethoxyethane (2 mL) in a microwave vial. The resulting mixture was degassed with N for 10 minutes and then stirred at 70 °C for 3 hours. The volatiles were evaporated and the residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH and then the product was eluted with a 2M solution of NH3 in MeOH. The basic fractions were collected and concentrated in vacuo.

[0282] 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 at room temperature overnight, and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH / HO (9:1), and then the product was eluted with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​SNAP 12 g) eluting with a 1% to 15% gradient of CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). Fractions containing the desired compound were collected and lyophilized to afford [5-(4-aminocinnolin-7-yl)-4-(5-fluorothiazol-2-yl)-2-methoxy-phenyl]boronic acid (8.5 mg, 0.021 mmol, 17.5% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ3.94(s,3H),7.24(s,2H),7.37(dd,J=8.61,1.83Hz,1H),7.46(s,1H),7.63(s,1H ),7.66(d,J=3.11Hz,1H),7.93(d,J=1.78Hz,1H),7.97(br.s,2OH),8.17(d,J=8.69Hz,1H),8.64(s,1H). LC-MS (Method A): Room temperature 0.54 min, MS (ESI) m / z=397.14[M+H] + .

[0283] Example 76: 7-(1-hydroxy-7-thiazol-2-yl-3,4-dihydro-2,5,1-benzodioxaborepin-8-yl)cinnolin-4-amine (76) [ka] Step 1: Palladium(II) diacetate (4.08 mg, 0.020 mmol), 7-[4-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-5-chloro-2-thiazol-2-yl-phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (241 mg, 0.360 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (17.32 mg, 0.040 mmol), potassium acetate (106.97 mg, 1.09 mmol), and bis[(+)-pinanediolate]diboron (390.32 mg, 1.09 mmol) were dissolved in 1,2-dimethoxyethane (7 mL) in a microwave vial. The resulting mixture was degassed with N for 10 minutes and stirred at 70 °C for 12 hours. The volatiles were evaporated and the residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH and then the product was eluted with a 2M solution of NH3 in MeOH. The basic fractions were collected and concentrated in vacuo.

[0284] 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 at room temperature overnight, and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH / HO (9:1), and then the product was eluted with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​2 x SNAP 30 g in succession) eluting with a gradient of 1% to 15% CHCN (+0.1% NHOH) in water (+0.1% NHOH). The fractions containing the desired compound were collected and lyophilized to give 7-(1-hydroxy-7-thiazol-2-yl-3,4-dihydro-2,5,1-benzodioxaborepin-8-yl)cinnolin-4-amine (33 mg, 0.085 mmol, 31.02% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ4.23-4.28(m,2H),4.42-4.47(m,2H),7.26(s,2H),7.30(dd,J=8.67,1.81Hz,1H),7.47(s,1H),7.68(d ,J=3.23Hz,1H),7.81(d,J=3.21Hz,1H),7.89(d,J=1.74Hz,1H),7.97(s,1H),8.12(d,J=8.71Hz,1H),8.59(s,1H),8.62(s,1H). LC-MS (method A): room temperature 0.49 min, MS (ESI) m / z=391.13[M+H] + .

[0285] Example 77: 7-(1-hydroxy-3,3-dimethyl-7-pyrazol-1-yl-4H-2,5,1-benzodioxaborepin-8-yl)cinnolin-4-amine (77) [ka] 7-[5-Bromo-4-[2-[tert-butyl(dimethyl)silyl]oxy-2-methyl-propoxy]-2-pyrazol-1-yl-phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (457.49 mg, 0.640 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (46.7 mg, 0.060 mmol), potassium acetate (315.54 mg, 3.18 mmol), and bis[(+)-pinanediolate]diboron (683.77 mg, 1.91 mmol) were dissolved in 1,4-dioxane (6.36 mL) in a microwave vial and degassed under N for 10 min. The resulting reaction mixture was stirred at 90 °C overnight, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was then washed with MeOH and eluted with 2M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (4 mL). The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge, and the cartridge was left for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 2M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18D, 12 g) eluting with a gradient of 1% to 40% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give 7-(1-hydroxy-3,3-dimethyl-7-pyrazol-1-yl-4H-2,5,1-benzodioxaborepin-8-yl)cinnolin-4-amine (14.5 mg, 0.036 mmol, 5.6% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ1.33(s,6H),4.24(s,2H),6.33(t,J=1.8Hz,1H),6.97(dd,J=8.7,1.8Hz,1H),7.14(s,2H),7.16(s,1H),7 .59(d,J=1.9Hz,1H),7.68(d,J=2.5Hz,1H),7.78(d,J=1.8Hz,1H),8.00(d,J=8.8Hz,1H),8.11(s,1H),8.46(s,1H),8.58(s,1H). LC-MS (Method A): Room temperature 0.55 min, MS (ESI) m / z=402.21[M+H] + .

[0286] Example 78: 7-[1-hydroxy-7-(1H-pyrazol-3-yl)-3,4-dihydro-2,5,1-benzodioxaborepin-8-yl]cinnolin-4-amine (78) [ka] Palladium(II) diacetate (5.89 mg, 0.030 mmol), 7-[4-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-5-chloro-2-(1-tetrahydropyran-2-ylpyrazol-3-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (383.0 mg, 0.520 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (25.0 mg, 0.050 mmol), potassium acetate (154.39 mg, 1.57 mmol), and bis[(+)-pinanediolate]diboron (563.34 mg, 1.57 mmol) were dissolved in 1,2-dimethoxyethane (11.12 mL) in a microwave vial and degassed under N for 10 min. The resulting reaction mixture was stirred at 80°C for 30 hours, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was then washed with MeOH and eluted with 2M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (1.5 mL). The resulting mixture was stirred overnight at room temperature and then concentrated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge, and the cartridge was left for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 7M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 12 g) eluting with a gradient of 1% to 40% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give the partially purified product, which was further purified by column chromatography (Sfar C18 D, 12 g) eluting with a gradient of 1% to 40% CHCN (+0.1% NHOH) in water (+0.1% NHOH).The appropriate fractions were collected and lyophilized to give 7-[1-hydroxy-7-(1H-pyrazol-3-yl)-3,4-dihydro-2,5,1-benzodioxaborepin-8-yl]cinnolin-4-amine (8.5 mg, 0.023 mmol, 4.42% yield) as a white solid. 1 H NMR (400MHz, DMSO+2 drops of TFA) δ4.18-4.26(m,2H),4.36-4.44(m,2H),6.00(d,J=2.3Hz,1H),7.26(s,1H),7.43(dd,J=8.7,1.6Hz ,1H),7.62(d,J=2.3Hz,1H),7.72(d,J=1.6Hz,1H),7.97(s,1H),8.27(d,J=8.9Hz,1H),8.44(s,1H),9.62(s,1H),9.73(s,1H). LC-MS (Method B): Room temperature 0.41 min, MS (ESI) m / z=374.1[M+H] + .

[0287] Example 79: 7-{5-[(3aR,6aS)-3a,6a-dicyclopropyl-tetrahydro-2H-furo[3,4-d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1H-pyrazol-1-yl)phenyl}cinnolin-4-amine (79) [ka] [5-(4-aminocinnolin-7-yl)-2-methoxy-4-pyrazol-1-ylphenyl]boronic acid (10.0 mg, 0.030 mmol) was dissolved in THF (1 mL) and 3 drops of MeOH. (3R,4S)-3,4-dicyclopropyltetrahydrofuran-3,4-diol (15.3 mg, 0.080 mmol) was then added, and the mixture was stirred at room temperature overnight. Additional 3,4-dicyclopropyltetrahydrofuran-3,4-diol (5 mg) was added, and the mixture was stirred for another 5 hours. The volatiles were evaporated under reduced pressure, and the residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH and then eluted with 2 M ammonia in MeOH. The basic fractions were collected and concentrated under reduced pressure. The residue was dissolved in a minimum amount of MeOH, water was added, and the mixture was lyophilized to give 7-{5-[(3aR,6aS)-3a,6a-dicyclopropyl-tetrahydro-2H-furo[3,4-d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1H-pyrazol-1-yl)phenyl}cinnolin-4-amine (6.6 mg, 0.013 mmol, 46.8% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ0.34-0.43(m,2H),0.43-0.59(m,6H),1.16-1.28(m,2H),3.56 (d,J=10.90Hz,2H),3.87(s,3H),3.90(d,J=11.06Hz,2H),6.32(t,J=2.13Hz,1H),6.9 4(dd,J=8.74,1.81Hz,1H),7.13(s,2H),7.20(s,1H),7.62(d,J=1.7Hz,1H),7.65(d,J =2.4Hz,1H),7.67(s,1H),7.79(d,J=1.81Hz,1H),7.99(d,J=8.79Hz,1H),8.58(s,1H). LC-MS (Method A): Room temperature 0.75 min, MS (ESI) m / z=510.2[M+H] + .

[0288] Example 80: 7-{5-[(3aR,6aS)-3a,6a-bis(propan-2-yl)-tetrahydro-2H-furo[3,4-d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1H-pyrazol-1-yl)phenyl}cinnolin-4-amine (80) [ka] [5-(4-Aminocinnolin-7-yl)-2-methoxy-4-pyrazol-1-yl-phenyl]boronic acid formate (220.0 mg, 0.540 mmol) was dissolved in THF (15.38 mL) and 3 drops of MeOH, then (3R,4S)-3,4-diisopropyltetrahydrofuran-3,4-diol (132.23 mg, 0.700 mmol) was added and the resulting mixture was stirred for 24 hours at 50° C. The volatiles were evaporated under reduced pressure and the residue was dissolved in MeOH and loaded onto an SCX cartridge, which was then washed with MeOH and eluted with 2 M ammonia in MeOH. The basic fractions were collected and concentrated under reduced pressure to give 7-{5-[(3aR,6aS)-3a,6a-bis(propan-2-yl)-tetrahydro-2H-furo[3,4-d][1,3,2]dioxaborol-2-yl]-4-methoxy-2-(1H-pyrazol-1-yl)phenyl}cinnolin-4-amine (200 mg, 0.390 mmol, 72.1% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ0.98-1.05(m,12H),2.22-2.31(m,2H),3.74(d,J=10.6Hz, 2H),3.89(d,J=10.6Hz,2H),3.89(s,3H),6.33(t,J=2.1Hz,1H),6.96(dd,J=8.7,1 .8Hz,1H),7.13(s,2H),7.22(s,1H),7.61(dd,J=1.8,0.6Hz,1H),7.65(dd,J=2.5, 0.7Hz,1H),7.77(s,1H),7.81(d,J=1.8Hz,1H),7.99(d,J=8.8Hz,1H),8.58(s,1H). LC-MS (method A): room temperature 0.78 min, MS (ESI) m / z=514.33[M+H] + .

[0289] Example 81: 5-(4-aminocinnolin-7-yl)-2-methoxy-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]boronic acid formate (81) [ka] 7-[5-Bromo-4-methoxy-2-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (118.0 mg, 0.190 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.09 mg, 0.020 mmol), potassium acetate (95.21 mg, 0.960 mmol), and bis[(+)-pinanediolate]diboron (206.32 mg, 0.580 mmol) were dissolved in 1,2-dimethoxyethane (2.5 mL) and degassed under N for 10 min. The resulting reaction mixture was stirred at 100 °C for 3 h, then cooled to room temperature, filtered through Celite, and washed with MeOH. The filtrate was concentrated under reduced pressure, and the residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH and then eluted with 2M ammonia solution in MeOH. The basic fractions were collected and concentrated under reduced pressure. The residue was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL). The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge, and the cartridge was left for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 2M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 12 g) eluting with a 1% to 30% gradient of CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give the partially purified product, which was subjected to semi-preparative HPLC purification (Column: CSH C18 (2.1 × 50 mm, 1.7 μm)). Conditions: [Solvent 1: water + 0.1% HCOOH]; [Solvent 2: MeCN + 0.1% HCOOH]. Gradient: 15% to 50%. The product-containing fractions were collected and lyophilized to give 5-(4-aminocinnolin-7-yl)-2-methoxy-4-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]boronic acid formate (13.4 mg, 0.028 mmol, 14.7% yield) as a white solid. 1H NMR(400MHz,DMSO-d6+TFA)δ3.94(s,3H),7.21(dd,J=8.88,1.64Hz,1H),7.32(s,1H),7.61(d,J=1.68Hz,1H),7.78(s, 1H),7.99(s,1H),8.12(s,1H,1H derived from HCOOH),8.26(d,J=8.89Hz,1H),8.44(s,1H),8.72(s,1H),9.70(s,1H),9.77(s,1H). LC-MS (Method A): Room temperature 0.60 min, MS (ESI) m / z=430.1[M+H] + .

[0290] Example 82: [5-(4-aminocinnolin-7-yl)-2-ethoxy-4-pyrazol-1-yl-phenyl]boronic acid (82) [ka] Step 1: 7-(5-Bromo-4-ethoxy-2-pyrazol-1-yl-phenyl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (545 mg, 0.970 mmol), potassium acetate (482.09 mg, 4.86 mmol), and bis[(+)-pinanediolate]diboron (1.04 g, 2.92 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was degassed under a N atmosphere for 10 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (71.35 mg, 0.100 mmol) was added, and the resulting reaction mixture was stirred at 100 °C for 5 hours, after which the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH, and the product was then eluted with a 2 M solution of NH in MeOH. The basic fractions were collected and concentrated in vacuo.

[0291] Step 2: The crude material from Step 1 was dissolved in a mixture of DCM (8 mL) and trifluoroacetic acid (8 mL). The mixture was stirred at room temperature overnight, and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH / HO (9:1), and then the product was eluted with a 2 M solution of NH in MeOH. The volatiles were evaporated, and the residue was purified by column chromatography (KP-C18-HS, ​​SNAP 30 g) eluting with a gradient of 1% to 15% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). Fractions containing the desired compound were collected and lyophilized to afford [5-(4-aminocinnolin-7-yl)-2-ethoxy-4-pyrazol-1-yl-phenyl]boronic acid (43.61 mg, 0.116 mmol, 12.47% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6+2 drops of TFA) δ1.41(t,J=6.89Hz,3H),4.23(q,J=6.91Hz, 2H),6.40-6.36(m,1H),7.13(dd,J=8.86,1.58Hz,1H),7.22(s,1H),7.58(d, J=1.87Hz,1H),7.61(d,J=1.66Hz,1H),7.80(s,1H),7.81(d,J=2.56Hz,1H), 8.11(s,1H),8.24(d,J=8.90Hz,1H),8.43(s,1H),9.66(s,1H),9.73(s,1H). LC-MS (Method A): Room temperature 0.52 min, MS (ESI) m / z=376.16[M+H] + .

[0292] Example 83: [5-(4-aminocinnolin-7-yl)-2-methoxy-4-[5-(trifluoromethyl)thiazol-2-yl]phenyl]boronic acid (83) [ka] 7-[5-Bromo-4-methoxy-2-[5-(trifluoromethyl)thiazol-2-yl]phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (90 mg, 0.140 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10.46 mg, 0.010 mmol), potassium acetate (70.66 mg, 0.710 mmol), and bis[(+)-pinanediolate]diboron (153.11 mg, 0.430 mmol) were dissolved in 1,4-dioxane (1.34 mL) and degassed under N for 10 min. The resulting reaction mixture was stirred at 90 °C for 30 h, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH and eluted with 2 M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL), and the resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge, and the cartridge was left for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 7 M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 12 g) eluting with a gradient of 1% to 40% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-2-methoxy-4-[5-(trifluoromethyl)thiazol-2-yl]phenyl]boronic acid (7 mg, 0.016 mmol, 11.42% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ3.95(s,3H),7.24(br.s,2H),7.36(dd,J=8.7,1.8Hz,1H),7.57(s,1H),7.67(s ,1H),7.94(d,J=1.8Hz,1H),8.05(br.s,2H),8.16(d,J=8.7Hz,1H),8.44(d,J=1.4Hz,1H),8.64(s,1H). LC-MS (Method A): Room temperature 0.63 min, MS (ESI) m / z=447.15[M+H] + .

[0293] Example 84: [5-(4-aminocinnolin-7-yl)-4-[4-(difluoromethoxy)pyrazol-1-yl]-2-methoxy-phenyl]boronic acid formate (84) [ka] 7-[5-Bromo-2-[4-(difluoromethoxy)pyrazol-1-yl]-4-methoxyphenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (550 mg, 0.580 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10.46 mg, 0.010 mmol), potassium acetate (289.39 mg, 2.92 mmol), and bis[(+)-pinanediolate]diboron (627.1 mg, 1.75 mmol) were dissolved in 1,4-dioxane (8.209 mL). The resulting reaction mixture was degassed under N for 10 minutes and then stirred at 90 °C for 3 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH and eluted with 2 M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL). The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge, and the cartridge was left for 20 min. The cartridge was then washed with MeOH / HO (9:1) and eluted with 7 M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 12 g) eluting with a gradient of 1% to 40% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-4-[4-(difluoromethoxy)pyrazol-1-yl]-2-methoxy-phenyl]boronic acid formate (41 mg, 0.087 mmol, 15% yield) as a white solid. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ3.94(s,3H),6.85(t,J=73.5Hz,1H),7.19-7.24(m,2H),7.55-7.60(m,2H),7.80 (s,1H),7.91-7.99(m,1H),8.08(s,HCOOH derived 0.5H),8.28(d,J=8.9Hz,1H),8.43(s,1H),9.66(s,1H),9.75(s,1H). LC-MS (Method A): Room temperature 0.54 min, MS (ESI) m / z=428.17[M+H] + .

[0294] Example 85: 5-(4-aminocinnolin-7-yl)-2-methoxy-4-[4-(trifluoromethoxy)pyrazol-1-yl]phenyl]boronic acid formate (85) [ka] 7-[5-Bromo-4-methoxy-2-[4-(trifluoromethoxy)pyrazol-1-yl]phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (65 mg, 0.100 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (14.13 mg, 0.030 mmol), potassium acetate (51.12 mg, 0.520 mmol), and bis[(+)-pinanediolate]diboron (110.77 mg, 0.310 mmol) were dissolved in 1,4-dioxane (1.5 mL) and degassed under N for 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.57 mg, 0.010 mmol) was added, and the reaction was heated to 100 °C for 1 h. The mixture was cooled to room temperature, diluted with EtOAc, filtered through Celite, and washed with EtOAc and MeOH. The filtrate was concentrated 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 and then concentrated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge, and the cartridge was allowed to stand for 20 min. The cartridge was then washed with MeOH / HO (9:1) and eluted with 7 M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 12 g) eluting with a gradient of 1% to 15% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). Appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-2-methoxy-4-[4-(trifluoromethoxy)pyrazol-1-yl]phenyl]boronic acid formate (5 mg, 0.010 mmol, 10% yield) as an off-white solid. 1H NMR(400MHz,DMSO-d6+TFA)δ3.94(s,3H),7.20(dd,J=8.82,1.65Hz,1H),7.27(s,1H),7.57(d,J=1.65Hz,1H),7.73 -7.87(m,2H),8.12(s,0.5H from HCOOH),8.23(s,1H),8.28(d,J=8.89Hz,1H),8.45(s,1H),9.70(s,1H),9.79(s,1H). LC-MS (Method A): Room temperature 0.61 min, MS (ESI) m / z=446.1[M+H] + .

[0295] Example 86: [5-(4-aminocinnolin-7-yl)-4-[5-(difluoromethyl)thiazol-2-yl]-2-methoxy-phenyl]boronic acid (86) [ka] 7-[5-Bromo-2-[5-(difluoromethyl)thiazol-2-yl]-4-methoxyphenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (140 mg, 0.230 mmol), potassium acetate (113.14 mg, 1.14 mmol), and bis[(+)-pinanediolate]diboron (245.16 mg, 0.680 mmol) were dissolved in 1,4-dioxane (8.209 mL) and degassed under N for 10 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (16.74 mg, 0.020 mmol) was added. The resulting reaction mixture was stirred at 90 °C for 30 hours, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX cartridge. The cartridge was washed with MeOH and then eluted with 2 M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was dissolved in dichloromethane (1.5 mL) and trifluoroacetic acid (1.5 mL). The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge, and the cartridge was left for 20 min. The cartridge was then washed with MeOH / HO (9:1) and eluted with 7 M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 12 g) eluting with a gradient of 1% to 40% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-4-[5-(difluoromethyl)thiazol-2-yl]-2-methoxy-phenyl]boronic acid (16 mg, 0.037 mmol, 16% yield) as a white solid. 1H NMR (400MHz, DMSO-d6+2 drops of TFA) δ3.94(s,3H),7.28(t,J=55.7Hz,1H),7.45(s,1H),7.51(dd,J=8.7,1.6Hz,1H),7. 68(s,1H),7.74(d,J=1.6Hz,1H),8.04-8.10(m,1H),8.33(d,J=8.8Hz,1H),8.45(s,1H),9.71(s,1H),9.81(s,1H). LC-MS (Method A): Room temperature 0.56 min, MS (ESI) m / z=429.2[M+H] + .

[0296] Example 87: 7-[4-Methoxy-2-(1H-pyrazol-1-yl)-5-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)phenyl]cinnolin-4-amine (87) [ka] [5-(4-Aminocinnolin-7-yl)-2-methoxy-4-pyrazol-1-ylphenyl]boronic acid formate (20 mg, 0.050 mmol) was dissolved in THF (0.5 mL) and MeOH (0.5 mL), followed by the addition of 3,4-diethylhexane-3,4-diol (20 mg, 0.110 mmol), and the resulting mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure, and the residue was then dissolved in MeOH and loaded onto an SCX cartridge (2 g), which was washed with MeOH and then eluted with 2 M ammonia in MeOH. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 12 g) eluting with a gradient of 1% to 70% CH3CN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give 7-[4-methoxy-2-(1H-pyrazol-1-yl)-5-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)phenyl]cinnolin-4-amine (200 mg, 0.390 mmol, 72.1% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ0.94(t,J=7.4Hz,12H),1.65-1.81(m,8H),3.90(s,3H),6.40(t,J=2.1Hz,1H),7.06(dd,J=8.8,1.7Hz,1H),7.24( s,1H),7.61(d,J=1.7Hz,1H),7.71(d,J=1.7Hz,1H),7.73(s,1H),7.81(d,J=2.5Hz,1H),8.17(d,J=8.9Hz,1H),8.49(s,1H),9.02(s,2H). LC-MS (Method A): Room temperature 0.87 min, MS (ESI) m / z=500.36[M+H] + .

[0297] Example 88: [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(5-methyloxazol-2-yl)phenyl]boronic acid formate (88) [ka] Potassium acetate (103.31 mg, 1.04 mmol), bis[(+)-pinanediolate]diboron (223.87 mg, 0.630 mmol), and 7-[5-bromo-4-methoxy-2-(5-methyloxazol-2)-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (130.0 mg, 0.210 mmol) were solubilized in 1,4-dioxane (1.966 mL), and the solution was degassed for 10 minutes. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.29 mg, 0.020 mmol) was added to the mixture, and the solution was heated at 90 °C for 3 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was suspended in MeOH and filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (0.560 mL) and trifluoroacetic acid (0.560 mL), stirred at room temperature overnight, and then concentrated in vacuo. The residue was dissolved in MeOH / HO (9:1), loaded onto an SCX (10 g) cartridge, and allowed to absorb onto the SCX cartridge for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 2 M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 60 g) eluting with a gradient of 1% to 30% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). Fractions containing the desired compound were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(5-methyloxazol-2-yl)phenyl]boronic acid formate (6.59 mg, 0.016 mmol, 7.6% yield) as a yellowish solid. 1 H NMR(400MHz,DMSO-d6)δ2.11(d,J=1.2Hz,3H),3.94(s,3H),6.85-6.88(m,1H),7.16(s,2H),7.29(dd,J=8.7,1.8Hz,1H), 7.44(s,1H),7.68(s,1H),7.84(d,J=1.8Hz,1H),7.98(s,2H),8.09(d,J=8.7Hz,1H),8.17(s,HCOOH derived 0.8H),8.61(s,1H). LC-MS (Method A): Room temperature 0.50 min, MS (ESI) m / z=377.20[M+H]+ .

[0298] Example 89: [5-(4-aminocinnolin-7-yl)-2-(cyclopropoxy)-4-pyrazol-1-yl-phenyl]boronic acid formate (89) [ka] 7-[5-Bromo-4-(cyclopropoxy)-2-pyrazol-1-yl-phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (200.0 mg, 0.170 mmol), potassium acetate (0.09 g, 0.870 mmol), and bis[(+)-pinanediolate]diboron (0.19 g, 0.520 mmol) were solubilized in 1,4-dioxane (1.648 mL), and the solution was degassed for 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.01 g, 0.020 mmol) was added, and the mixture was heated at 100 °C for 3 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (3.862 mL) and trifluoroacetic acid (3.862 mL), stirred at room temperature overnight, and then concentrated in vacuo. The residue was dissolved in MeOH / HO (9:1), loaded onto an SCX (10 g) cartridge, and allowed to absorb onto the SCX cartridge for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 2 M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was dissolved in DCM (1.488 ml) and trifluoroacetic acid (0.074 ml), and to this solution was added methylboronic acid (25.26 mg, 0.420 mmol). The mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in MeOH / HO (9:1), loaded onto an SCX (10 g) cartridge, and allowed to absorb onto the SCX cartridge for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 2 M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (KP-Sfar C18, 30 g) eluting with a gradient of 1% to 20% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-2-(cyclopropoxy)-4-pyrazol-1-yl-phenyl]boronic acid formate (10 mg, 0.023 mmol, 13.5% yield) as a yellowish solid. 1H NMR (400 MHz, DMSO-d6 + 2 drops of TFA) δ 0.77-0.87 (m, 4H), 4.00-4.07 (m, 1H), 6.36-6.40 (m, 1H), 7.15 (dd, J = 8.89, 1.10 Hz, 1H), 7.49 (s, 1H), 7.60 (d, J = 1.66 Hz, 1H), 7.62 (d, J = 2.06 Hz, 1H), 7.73 (s, 1H), 7.80-7.75 (m, 1H), 8.12 (s, 0.5H from HCOOH), 8.23 ​​(d, J = 8.89 Hz, 1H), 8.43 (s, 1H), 9.68 (s, 1H), 9.75 (s, 1H). LC-MS (Method A): Room temperature 0.54 min, MS (ESI) m / z=388.23[M+H] + .

[0299] Example 90: [5-(4-aminocinnolin-7-yl)-4-[5-(difluoromethyl)oxazol-2-yl]-2-methoxy-phenyl]boronic acid formate (90) [ka] 7-[5-Bromo-2-[5-(difluoromethyl)oxazol-2-yl]-4-methoxyphenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (170 mg, 0.280 mmol), potassium acetate (0.14 g, 1.42 mmol), and bis[(+)-pinanediolate]diboron (0.31 g, 0.850 mmol) were dissolved in 1,4-dioxane (8.209 mL) and degassed under N for 10 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.02 g, 0.030 mmol) was added, and the resulting reaction mixture was stirred at 100 °C for 3 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (3.5 mL), stirred at room temperature overnight, and then concentrated in vacuo. The residue was dissolved in MeOH / HO (9:1) and loaded onto an SCX cartridge. The cartridge was allowed to absorb for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 7 M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 12 g) eluting with a gradient of 0% to 15% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to afford [5-(4-aminocinnolin-7-yl)-4-[5-(difluoromethyl)oxazol-2-yl]-2-methoxy-phenyl]boronic acid formate (5 mg, 0.011 mmol, 3.92% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6+TFA)δ3.95(s,3H),7.08(t,J=52.51Hz,1H),7.55(s,1H),7.61(dd,J=8.79,1.58Hz,1H),7.64(t,J=2.62H) z,1H),7.67(d,J=1.49Hz,1H),7.69(s,1H),8.11(s,1H derived from HCOOH),8.38(d,J=8.80Hz,1H),8.48(s,1H),9.72(s,1H),9.84(s,1H). LC-MS (Method A): Room temperature 0.53 min, MS (ESI) m / z=413.26[M+H] + .

[0300] Example 91: [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(1,2,4-thiadiazol-5-yl)phenyl]boronic acid formate (91) [ka] 7-[5-Bromo-4-methoxy-2-(5-methyloxazol-2-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (120.0 mg, 0.150 mmol), potassium acetate (75.88 mg, 0.770 mmol), and bis[(+)-pinanediolate]diboron (164.44 mg, 0.460 mmol) were solubilized in 1,4-dioxane (1.444 mL), and the solution was degassed for 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11.23 mg, 0.020 mmol) was added, and the mixture was heated at 100 °C for 3 h, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (3.394 mL) and trifluoroacetic acid (3.394 mL), stirred at room temperature overnight, and then concentrated in vacuo. The residue was dissolved in MeOH / HO (9:1), loaded onto an SCX (20 g) cartridge, and allowed to absorb onto the SCX cartridge for 20 minutes. The cartridge was then washed with MeOH / HO (9:1) and eluted with 7 M methanolic ammonia solution. The basic fractions were collected and concentrated under reduced pressure. The residue was purified by column chromatography (Sfar C18 D, 22 g) eluting with a gradient of 1% to 20% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and lyophilized to give [5-(4-aminocinnolin-7-yl)-2-methoxy-4-(1,2,4-thiadiazol-5-yl)phenyl]boronic acid formate (9.33 mg, 0.022 mmol, 14.6% yield) as a white solid. 1H NMR (400MHz, DMSO-d6+a few drops of TFA) δ3.96(s,1H),7.62-7.67(m,1H),7.76(d,J=1.7Hz,1H),8.12( s, 0.5H derived from HCOOH), 8.42 (d, J=8.8Hz, 1H), 8.49 (s, 1H), 8.86 (s, 1H), 9.81 (s, 1H), 9.91 (s, 1H). LC-MS (Method A): Room temperature 0.47 min, MS (ESI) m / z=380.19[M+H] + .

[0301] Example 92: Preparation of exemplary intermediates. Intermediate 1: 7-Bromocinnolin-1-ium-4-ol hydrochloride [ka] 1-(2-Amino-4-bromophenyl)ethanone (10.0 g, 46.72 mmol) was dissolved in concentrated hydrochloric acid (270.02 mL, 3240.2 mmol) and water (51 mL) and cooled to −5°C in an ice / brine bath. After 15 min, a solution of sodium nitrite (3380.0 mg, 48.99 mmol) in water (17 mL) was added dropwise. The reaction was stirred at −5°C for 30 min and then at room temperature for 30 min, after which the temperature was slowly increased to 60°C. The reaction mixture was heated at 60°C for 2 h, then cooled to room temperature. The resulting precipitate was filtered, washed with water, and dried in an oven at 50°C overnight to give 7-bromosinnoline-1-ium-4-ol hydrochloride (7.463 g, 28.54 mmol, 61.09% yield) as a brownish powder. 1 H NMR(400MHz,DMSO-d6) δppm 7.57(dd,J=8.58,1.76Hz,1H),7.76-7.80(m,2H),7.96(d,J=8.58Hz,1H),13.50(br.s,1H). LC-MS (Method A): 0.66 min at room temperature, MS (ESI) m / z=224.98 and 226.97 [M+H] + .

[0302] Intermediate 2: 7-Bromo-4-chlorocinnoline [ka] A solution of 7-bromocinnolin-1-ium-4-ol hydrochloride (7.85 g, 29.73 mmol) in phosphorus(V) oxychloride (24.0 mL, 256.7 mmol) was stirred at 90 °C for 4 h. The reaction was cooled to room temperature, and excess phosphorus(V) oxychloride was removed in vacuo. The residue was dissolved in DCM, the resulting mixture was cooled to 0 °C, and then a saturated aqueous solution of NaHCO was added. The phases were separated, and the organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (KP-Sil silica gel, SNAP 340 g) eluting with a gradient of 2% to 10% EtOAc in cyclohexane to give 7-bromo-4-chlorocinnoline (4.875 g, 20.02 mmol, 67.35% yield) as an orange foam. 1 H NMR (400MHz, DMSO-d6) δppm 8.18-8.21 (m, 2H), 8.85 (t, J = 1.21Hz, 1H), 9.66 (s, 1H). LC-MS (Method A): Room temperature 0.97 min, MS (ESI) m / z=242.97 and 244.97 [M+H] + .

[0303] Intermediate 3: 7-Bromo-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine [ka] (2,4-Dimethoxyphenyl)methanamine (5.55 mL, 37.54 mmol) was added to a solution of 7-bromo-4-chlorocinnoline (4.06 g, 15.02 mmol) in ethanol (60.94 mL), and the resulting mixture was stirred at 110 °C for 2.5 h. Further (2,4-dimethoxyphenyl)methanamine (1 mL) was added, and the mixture was stirred at 110 °C for 2.5 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc, and the suspension was filtered through a Hirsch funnel. The recovered powder was purified by column chromatography (KP-Sil silica gel, SNAP 340) eluting with a gradient of 0% to 10% MeOH in DCM to give 7-bromo-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (5.667 g, 15.14 mmol, 100.85% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δppm 3.74(s,3H),3.87(s,3H),4.50(d,J=5.72Hz,2H),6.46-6.52(m,1H),6.62(d,J=2.42Hz,1H),7.15(d,J=8.36Hz,1H) ,7.78(dd,J=8.91,2.09Hz,1H),8.16(t,J=5.72Hz,1H),8.29(d,J=1.98Hz,1H),8.32(d,J=9.24Hz,1H),8.54(s,1H). LC-MS (method A): room temperature 0.63 min, MS (ESI) m / z=374.05 and 376.08 [M+H] + .

[0304] Intermediate 4: N-[(2,4-dimethoxyphenyl)methyl]-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cinnolin-4-amine [ka] In a 2 L round-bottom flask, 7-bromo-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (50.0 g, 133.61 mmol), potassium acetate (39.34 g, 400.82 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (101.78 g, 400.82 mmol) were stirred in 1,4-dioxane (1334.9 mL) at room temperature. Three vacuum / N cycles (one full cycle for 1 min, followed by 30 s of N and 30 s of vacuum) were applied to the mixture.

[0305] Palladium(II) diacetate (1.5 g, 6.68 mmol) and dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (5.1 g, 10.69 mmol) were added, and the mixture was deoxygenated by three vacuum / N cycles (1 min for one full cycle, 30 s of N and 30 s of vacuum). The mixture was then stirred at 90 °C for 2 h. The reaction was cooled to room temperature, filtered through a Gooch funnel, and the filtrate was concentrated to dryness under reduced pressure.

[0306] The residue was triturated with EtOAc at room temperature for 1 hour, then filtered, and the collected solid was dried under high vacuum. The trituration procedure was repeated with EtO to give N-[(2,4-dimethoxyphenyl)methyl]-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cinnolin-4-amine (30.2 g, 71.68 mmol, 53.65% yield). 1H NMR(400MHz,DMSO-d6)δ1.16-1.18(m,12H),3.74(s,3H),3.87(s,3H),4.49(d,J=5.72Hz,2H),6.47(dd,J=8.36,2.20Hz,1H),6.63(d,J=2. 20Hz,1H),7.14(d,J=8.36Hz,1H),7.81(dd,J=8.36,1.10Hz,1H),8.02(t,J=5.72Hz,1H),8.33(d,J=8.36Hz,1H),8.40(s,1H),8.49(s,1H). LC-MS (method A): room temperature 0.55 min, MS (ESI) m / z=340.3[M-C6H 10 +H] + (The pinacolatolate ester hydrolyzes to the boronic acid by HPLC).

[0307] Intermediate 5: 1-(2-bromo-4-chlorophenyl)-1H-pyrazole [ka] A mixture of 2-bromo-4-chloro-1-fluorobenzene (750.0 mg, 3.58 mmol), pyrazole (292.5 mg, 4.3 mmol), and dicesium carbonate (1983.48 mg, 6.09 mmol) in DMA (7.5 mL) was stirred at 100 °C for 6 h and then cooled to room temperature. EtOAc and water were added, and the phases were separated. The organic phase was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (KP-Sil, SNAP 25 g + 25 g sequentially) eluting with a gradient of 0% to 30% EtOAc in cyclohexane to give 1-(2-bromo-4-chlorophenyl)pyrazole (525 mg, 2.039 mmol, 56.93% yield) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ6.51-6.56(m,1H),7.56(d,J=8.58Hz,1H),7.64(dd,J=8.3 6,2.42Hz,1H),7.76(d,J=1.32Hz,1H),8.00(d,J=2.20Hz,1H),8.09-8.13(m,1H). LC-MS (Method A): 1.06 min at room temperature, MS (ESI) m / z=257.0 and 259.0 [M+H]+ .

[0308] Intermediate 6: 7-[5-chloro-2-(1H-pyrazol-1-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine [ka] A mixture of N-[(2,4-dimethoxyphenyl)methyl]-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cinnolin-4-amine (490.82 mg, 1.17 mmol) and 1-(2-bromo-4-chlorophenyl)pyrazole (200.0 mg, 0.780 mmol) in 1,2-dimethoxyethane (20 mL) and 2N aqueous sodium carbonate (0.78 mL, 1.55 mmol) was degassed with Ar for 10 minutes. [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (50.78 mg, 0.080 mmol) was added, and the mixture was degassed for 10 minutes and then stirred at 80 °C for 28 hours. The mixture was cooled to room temperature, filtered through Celite, washed with EtOAc, and the solvent was evaporated. The residue was purified by column chromatography (KP-NH silica gel, SNAP 110 g) eluting with a gradient of 20% to 100% EtOAc in cyclohexane to give 7-(5-chloro-2-pyrazol-1-ylphenyl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (57 mg, 0.121 mmol, 15.55% yield) as a brownish foam. 1H NMR(400MHz,DMSO-d6)δ3.74(s,3H),3.87(s,3H),4.48(d,J=5.72Hz,2H),6.32(dd,J= 2.42,1.76Hz,1H),6.48(dd,J=8.47,2.31Hz,1H),6.62(d,J=2.42Hz,1H),7.12-7.18( m,2H),7.59-7.61(m,1H),7.63-7.67(m,2H),7.68-7.72(m,1H),7.81(d,J=2.20Hz,1H ),7.89(d,J=1.76Hz,1H),7.96(t,J=5.72Hz,1H),8.19(d,J=8.80Hz,1H),8.47(s,1H). LC-MS (Method A): Room temperature 0.76 min, MS (ESI) m / z=472.2[M+H] + .

[0309] Intermediate 7: Ethyl 1-(2-bromo-4-chlorophenyl)pyrazole-4-carboxylate [ka] A mixture of 2-bromo-4-chloro-1-fluorobenzene (1.0 g, 4.77 mmol), ethyl 1H-pyrazole-4-carboxylate (802.8 mg, 5.73 mmol), and dicesium carbonate (2.64 g, 8.12 mmol) in DMA (10 mL) was stirred at 100 °C for 12 h and then allowed to reach room temperature. EtOAc and water were added, the two phases were separated, and the organic phase was washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (KP-Sil silica gel, SNAP 50) eluting with a gradient of 0% to 40% EtOAc in cyclohexane to give ethyl 1-(2-bromo-4-chlorophenyl)pyrazole-4-carboxylate (850 mg, 2.579 mmol, 54.02% yield) as a colorless oil. 1H NMR(400MHz,DMSO-d6)δ1.30(t,J=7.08Hz,3H),4.27(q,J=7.10Hz,2H),7.61-7.70(m ,2H),8.04(dd,J=2.02,0.53Hz,1H),8.15(d,J=0.71Hz,1H),8.70(d,J=0.67Hz,1H). LC-MS (Method A): 1.19 min at room temperature, MS (ESI) m / z=329.01 and 330.98 [M+H] + .

[0310] Intermediate 8: Ethyl 1-[4-chloro-2-[4-[(2,4-dimethoxyphenyl)methylamino]cinnolin-7-yl]phenyl]pyrazole-4-carboxylate [ka] A mixture of ethyl 1-(2-bromo-4-chlorophenyl)pyrazole-4-carboxylate (300.0 mg, 0.910 mmol), N-[(2,4-dimethoxyphenyl)methyl]-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cinnolin-4-amine (498.53 mg, 1.18 mmol), and 2N aqueous sodium carbonate (0.91 mL, 1.82 mmol) in 1,2-dimethoxyethane (9 mL) was degassed under N for 10 minutes. Next, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (59.51 mg, 0.090 mmol) was added, and the resulting reaction mixture was stirred at 80 °C for 7 hours. The mixture was filtered through a pad of Celite and washed with MeOH. The organic phase was concentrated in vacuo, and the residue was purified by column chromatography (KP-Sil silica gel, SNAP 25) eluting with a gradient of 0% to 100% EtOAc in cyclohexane to give ethyl 1-[4-chloro-2-[4-[(2,4-dimethoxyphenyl)methylamino]cinnolin-7-yl]phenyl]pyrazole-4-carboxylate (152 mg, 0.279 mmol, 30.7% yield) as a brown powder. 1H NMR(400MHz,DMSO-d6)δ1.21(t,J=7.10Hz,3H),3.74(s,3H),3.87(s,3H),4.17(q,J=7.08Hz,2 H),4.48(d,J=5.68Hz,2H),6.47(dd,J=8.36,2.40Hz,1H),6.62(d,J=2.38Hz,1H),7.13(d,J=8. 37Hz,1H),7.23(dd,J=8.80,1.88Hz,1H),7.67-7.75(m,2H),7.83-7.86(m,1H),7.91(d,J=1.84 Hz,1H),7.93(s,1H),7.97(t,J=5.90Hz,1H),8.22(d,J=8.85Hz,1H),8.45(s,1H),8.48(s,1H). LC-MS (method A): room temperature 0.81 min, MS (ESI) m / z=544.29[M+H] +

[0311] Intermediate 9: 1-[4-chloro-2-[4-[(2,4-dimethoxyphenyl)methylamino]cinnolin-7-yl]phenyl]pyrazole-4-carboxylic acid [ka] Lithium hydroxide hydrate (14.07 mg, 0.340 mmol) was added to a solution of ethyl 1-[4-chloro-2-[4-[(2,4-dimethoxyphenyl)methylamino]cinnolin-7-yl]phenyl]pyrazole-4-carboxylate (152.0 mg, 0.280 mmol) in THF (4 mL) and water (1 mL), and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with water and partially evaporated under reduced pressure to remove THF. The residue was neutralized with 1 N HCl solution, and the resulting precipitate was collected by filtration through a Hirsch funnel to give 1-[4-chloro-2-[4-[(2,4-dimethoxyphenyl)methylamino]cinnolin-7-yl]phenyl]pyrazole-4-carboxylic acid (131 mg, 0.254 mmol, 90.87% yield) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ3.76(s,3H),3.83(s,3H),4.71(d,J=5.04Hz,2H),6.52(dd,J=8.38,2.39Hz,1H),6.63(d,J=2.38Hz,1H),7.24(d,J=8.38Hz, 1H),7.34(dd,J=8.82,1.74Hz,1H),7.72-7.79(m,2H),7.80(d,J=1.73Hz, 1H),7.84(d,J=2.08Hz,1H),7.88(s,1H),8.40-8.46(m,2H),8.65(s,1H). LC-MS (Method A): Room temperature 0.72 min, MS (ESI) m / z=516.26[M+H] + .

[0312] Intermediate 10: 1-[4-chloro-2-[4-[(2,4-dimethoxyphenyl)methylamino]cinnolin-7-yl]phenyl]-N-methylpyrazole-4-carboxamide [ka] A solution of 1-[4-chloro-2-[4-[(2,4-dimethoxyphenyl)methylamino]cinnolin-7-yl]phenyl]pyrazole-4-carboxylic acid (130.0 mg, 0.250 mmol), [dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylidene]-dimethylammonium hexafluorophosphate (143.71 mg, 0.380 mmol), a 2 M solution of methanamine in THF (138.58 μL, 0.280 mmol), and N,N-diisopropylethylamine (131.66 μL, 0.760 mmol) in DMF (2 mL) was stirred at room temperature for 4 h, then the mixture was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (KP-NH silica gel, SNAP 28) eluting with a gradient of 0% to 10% MeOH in DCM to give 1-[4-chloro-2-[4-[(2,4[-dimethoxyphenyl)methylamino]cinnolin-7-yl]phenyl]-N-methylpyrazole-4-carboxamide (85 mg, 0.161 mmol, 63.77% yield) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ2.65(d,J=4.57Hz,3H),3.74(s,3H),3.87(s,3H),4.49(d, J=5.74Hz,2H),6.47(dd,J=8.39,2.41Hz,1H),6.62(d,J=2.38Hz,1H),7.13(d,J=8 .38Hz,1H),7.18(dd,J=8.75,1.88Hz,1H),7.65-7.74(m,2H),7.83(d,J=2.24Hz,1 H),7.90-8.04(m,4H),8.14(d,J=0.67Hz,1H),8.21(d,J=8.80Hz,1H),8.48(s,1H). LC-MS (Method A): Room temperature 0.69 min, MS (ESI) m / z=529.29[M+H] + .

[0313] Intermediate 11: Nonane-3,7-dione [ka] Thionyl dichloride (4.14 mL, 56.77 mmol) was added to a suspension of pentanedioic acid (1.5 g, 11.35 mmol) in toluene (6.75 mL), and the mixture was stirred at 110 °C for 3 h. It was then cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was dissolved in THF (100 mL), and iron(III) acetylacetonate (120.25 mg, 0.340 mmol) was added under an argon atmosphere. Then, a 1 M solution of ethylmagnesium bromide in THF (22.7 mL, 22.7 mmol) was added dropwise over 30 min at room temperature. After stirring the mixture for 30 min, the reaction was quenched with 1 M aqueous HCl and extracted with EtOAc. The organic phase was washed with saturated NaHCO3 solution and then brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (Sfar D silica gel, 25 g) eluting with a gradient of 0% to 40% EtOAc in cyclohexane to give nonane-3,7-dione (400 mg, 2.56 mmol, 22.56% yield) as an off-white solid. 1 H NMR (400 MHz, chloroform-d) δ 1.05 (t, J = 7.34 Hz, 6H), 1.85 (quin, J = 7.09 Hz, 2H), 2.35-2.47 (m, 8H).

[0314] Intermediate 12: (1R,2S)-1,2-diethylcyclopentane-1,2-diol [ka] Titanium(IV) chloride (182.48 μL, 1.66 mmol) was added dropwise to a suspension of zinc (217.63 mg, 3.33 mmol) in THF (6 mL) under an argon atmosphere, and the mixture was heated to reflux for 1 h. Next, a solution of nonane-3,7-dione (400.0 mg, 2.56 mmol) in THF (2 mL) was added, and the resulting mixture was stirred at room temperature for 3 h. The mixture was quenched with saturated Na2CO3 solution and then filtered through Celite. The filtrate was extracted three times with ethyl acetate. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (Sfar D silica gel, 25 g) eluting with a 20–80% gradient of EtOAc in cyclohexane to give (1R,2S)-1,2-diethylcyclopentane-1,2-diol (84 mg, 0.531 mmol, 20.73% yield) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ0.88 (t, J = 7.38 Hz, 6H), 1.15-1.30 (m, 2H), 1.32-1.45 (m, 2H), 1.46-1.69 (m, 6H), 3.81 (s, 2H).

[0315] Intermediate 13: 1-(2-bromo-4-chlorophenyl)imidazole [ka] A mixture of 2-bromo-4-chloro-1-fluorobenzene (1.0 g, 4.77 mmol), imidazole (390.0 mg, 5.73 mmol), and dicesium carbonate (2.64 g, 8.12 mmol) in DMA (10 mL) was stirred at 100 °C for 12 h and then cooled to room temperature. EtOAc and water were added, the two phases were separated, and the organic phase was washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (KP-C18-HS, ​​SNAP 100 g) eluting with a gradient of 2% to 60% CHCN (+0.1% HCOOH) in water (+0.1% HCOOH). The appropriate fractions were collected and evaporated, and the resulting white powder was dissolved in DCM and washed with saturated aqueous NaHCO3 to give 1-(2-bromo-4-chlorophenyl)imidazole (850 mg, 3.301 mmol, 69.13% yield) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ7.11(t,J=1.14Hz,1H),7.42(t,J=1.31Hz,1H),7.56(d,J=8.46 Hz,1H),7.65(dd,J=8.49,2.35Hz,1H),7.88(t,J=1.13Hz,1H),8.03(d,J=2.30Hz,1H). LC-MS (Method A): 0.48 min at room temperature, MS (ESI) m / z=256.96 and 258.98 [M+H] + .

[0316] Intermediate 14: 7-(5-chloro-2-imidazol-1-ylphenyl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine [ka] A mixture of 1-(2-bromo-4-chlorophenyl)imidazole (350.0 mg, 1.36 mmol), N-[(2,4-dimethoxyphenyl)methyl]-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cinnolin-4-amine (744.4 mg, 1.77 mmol), and 2N aqueous sodium carbonate (1.36 mL, 2.72 mmol) in 1,2-dimethoxyethane (13 mL) was degassed under N for 10 minutes. Next, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (88.86 mg, 0.140 mmol) was added, and the resulting reaction mixture was stirred at 80 °C for 20 hours. The mixture was filtered through a pad of Celite and washed with MeOH. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (KP-NH silica gel, SNAP 55) eluting with a gradient of 0% to 100% EtOAc in cyclohexane to give 7-(5-chloro-2-imidazol)-1-ylphenyl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (290 mg, 0.614 mmol, 45.21% yield) as a brown powder. 1 H NMR(400MHz,DMSO-d6)δ3.73(s,3H),3.86(s,3H),4.48(d,J=5.74Hz,2H),6.47(dd,J=8.38,2.41 Hz,1H),6.62(d,J=2.41Hz,1H),6.90(t,J=1.14Hz,1H),7.13(d,J=8.36Hz,1H),7.16(t,J=1.32Hz ,1H),7.23(dd,J=8.73,1.86Hz,1H),7.55-7.64(m,2H),7.70(dd,J=8.47,2.42Hz,1H),7.80(d,J= 2.40Hz,1H),7.95(d,J=1.79Hz,1H),7.98(t,J=6.01Hz,1H),8.21(d,J=8.77Hz,1H),8.47(s,1H). LC-MS (Method A): Room temperature 0.94 min, MS (ESI) m / z=472.17[M+H] + .

[0317] Intermediate 15: 1-(2-bromo-4-chlorophenyl)-1H-imidazole-4-carboxylate methyl ester [ka] A mixture of 2-bromo-4-chloro-1-fluorobenzene (1.75 mL, 14.32 mmol), methyl 1H-imidazole-4-carboxylate (2.17 g, 17.19 mmol), and dicesium carbonate (7.93 g, 24.35 mmol) in DMF (25 mL) was stirred at 100° C. for 6 hours and then cooled to room temperature. A small amount of water was added to the flask, and the mixture was cooled to 4° C. over the weekend. The white solid was collected by filtration and washed with water to give methyl 1-(2-bromo-4-chlorophenyl)-1H-imidazole-4-carboxylate (880 mg, 2.789 mmol, 19.47% yield) as white needles. 1 H NMR(400MHz,DMSO-d6)δ3.79(s,3H),7.64(d,J=8.49Hz,1H),7.67(dd,J=8.54,2. 15Hz, 1H), 8.01 (d, J = 1.31Hz, 1H), 8.06 (d, J = 2.03Hz, 1H), 8.17 (d, J = 1.31Hz, 1H). LC-MS (method A): room temperature 0.93 min, MS (ESI) m / z=315.0 and 317.0 [M+H] + .

[0318] Intermediate 16: 1-[4-chloro-2-[4-{[(2,4-dimethoxyphenyl)methyl]amino}cinnolin-7-yl)phenyl]-1H-imidazole-4-carboxylate methyl ester [ka] A mixture of methyl 1-(2-bromo-4-chlorophenyl)-1H-imidazole-4-carboxylate (880.0 mg, 2.79 mmol), N-[(2,4-dimethoxyphenyl)methyl]-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cinnolin-4-amine (1.53 g, 3.63 mmol), and 2 M aqueous sodium carbonate (2.79 mL, 5.58 mmol) in 1,2-dimethoxyethane (27 mL) was degassed under argon for 10 minutes, then [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (182.32 mg, 0.280 mmol) was added, and the resulting mixture was stirred at 85° C. for 5 hours. The mixture was cooled to room temperature, diluted with MeOH, filtered through Celite, and washed with MeOH and EtOAc. The filtrate was concentrated, and the residue was purified by column chromatography (Sfar Amino D, 50 g) eluting with a gradient of 50% to 100% EtOAc in cyclohexane to give methyl 1-[4-chloro-2-(4-{[(2,4-dimethoxyphenyl)methyl]amino}cinnolin-7-yl)phenyl]-1H-imidazole-4-carboxylate (800 mg, 1.51 mmol, 54.13% yield) as a light brown solid. 1 H NMR(400MHz,DMSO-d6)δ3.70(s,3H),3.73(s,3H),3.86(s,3H),4.48(d,J=5.76Hz,2H),6.47 (dd,J=8.37,2.41Hz,1H),6.61(d,J=2.40Hz,1H),7.12(d,J=8.37Hz,1H),7.29(dd,J=8.76, 1.88Hz,1H),7.68(d,J=9.84Hz,1H),7.69(s,1H),7.73(dd,J=8.49,2.34Hz,1H),7.83(d,J= 2.34Hz, 1H), 7.94-8.02 (m, 2H), 8.03 (d, J = 1.31Hz, 1H), 8.22 (d, J = 8.82Hz, 1H), 8.48 (s, 1H). LC-MS (method A): room temperature 0.71 min, MS (ESI) m / z=530.3[M+H] + .

[0319] Intermediate 17: 1-(2-bromo-4-chlorophenyl)-1,2,4-triazole [ka] A mixture of 2-bromo-4-chloro-1-fluorobenzene (1.0 g, 4.77 mmol), 4H-1,2,4-triazole (395.67 mg, 5.73 mmol), and dicesium carbonate (2.64 g, 8.12 mmol) in DMA (10 mL) was stirred at 100 °C for 12 h and then cooled to room temperature. EtOAc and water were added, the two phases were separated, and the organic phase was washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (KP-Sil silica gel, SNAP 50) eluting with a gradient of 0% to 70% EtOAc in cyclohexane to give 1-(2-bromo-4-chlorophenyl)-1,2,4-triazole (620 mg, 2.398 mmol, 50.23% yield) as a white powder. 1 H NMR (400MHz, DMSO-d6) δ7.63-7.73 (m, 2H), 8.07 (d, J = 2.58Hz, 1H), 8.27 (s, 1H), 8.95 (s, 1H). LC-MS (Method A): Room temperature 0.88 min, MS (ESI) m / z=257.93 and 259.94 [M+H] + .

[0320] Intermediate 18: 7-[5-chloro-2-(1,2,4-triazol-1-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine [ka] A mixture of 1-(2-bromo-4-chlorophenyl)-1,2,4-triazole (150.0 mg, 0.580 mmol), N-[(2,4-dimethoxyphenyl)methyl]-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cinnolin-4-amine (317.81 mg, 0.750 mmol), and 2N aqueous sodium carbonate (0.58 mL, 1.16 mmol) in 1,2-dimethoxyethane (6 mL) was degassed under N for 10 minutes. Next, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (37.94 mg, 0.060 mmol) was added, and the resulting reaction mixture was stirred at 80 °C for 20 hours. The mixture was filtered through a pad of Celite and washed with MeOH. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (KP-NH silica gel, SNAP 28) eluting with a gradient of 0% to 100% EtOAc in cyclohexane to give 7-[5-chloro-2-(1,2,4-triazol-1-yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (124 mg, 0.262 mmol, 45.18% yield) as a brown powder. 1 H NMR(400MHz,DMSO-d6)δ3.74(s,3H),3.87(s,3H),4.49(d,J=5.84Hz,2H),6.48(dd, J=8.38,2.44Hz,1H),6.62(d,J=2.36Hz,1H),7.14(d,J=8.38Hz,1H),7.23(dd,J=8.8 0,1.87Hz,1H),7.70-7.79(m,2H),7.87(d,J=2.20Hz,1H),7.89(d,J=1.76Hz,1H),8. 01(t,J=5.90Hz,1H),8.08(s,1H),8.23(d,J=8.84Hz,1H),8.48(s,1H),8.59(s,1H). LC-MS (Method A): Room temperature 0.69 min, MS (ESI) m / z=473.22[M+H] + .

[0321] Intermediate 19: 1-(2-bromo-4-chlorophenyl)pyrazole-3-carboxylic acid [ka] A mixture of 2-bromo-4-chloro-1-fluorobenzene (1.0 g, 4.77 mmol), methyl 1H-pyrazole-3-carboxylate (722.43 mg, 5.73 mmol), and dicesium carbonate (2.64 g, 8.12 mmol) in DMA (10 mL) was stirred at 100 °C for 12 h and then cooled to room temperature. EtOAc and water were added, the two phases were separated, and the basic aqueous phase was washed twice with EtOAc to remove unreacted starting material and non-acidic by-products. The aqueous phase was acidified with 1 M HCl solution, and the resulting precipitate was filtered off, washed with water, and dried in an oven to give 1-(2-bromo-4-chlorophenyl)pyrazole-3-carboxylic acid (500 mg, 1.658 mmol, 34.73% yield) as a white powder. 1 H NMR (400MHz, DMSO-d6) δ6.93(d,J=2.52Hz,1H),7.57-7.71(m,2H),8.04(d,J=2.16Hz,1H),8.19(d,J=2.49Hz,1H),12.97(s,1H). LC-MS (method A): room temperature 0.93 min, MS (ESI) m / z=300.97 and 302.99 [M+] + .

[0322] Intermediate 20: 1-(2-bromo-4-chlorophenyl)-N-methylpyrazole-3-carboxamide [ka] A solution of 1-(2-bromo-4-chlorophenyl)pyrazole-3-carboxylic acid (500.0 mg, 1.66 mmol), [dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylidene]-dimethylammonium hexafluorophosphate (0.95 g, 2.49 mmol), a 2 M solution of methanamine in THF (0.91 mL, 1.82 mmol), and N,N-diisopropylethylamine (0.87 mL, 4.97 mmol) in DMF (10 mL) was stirred at room temperature for 4 hours, and then the mixture was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (KP-Sil silica gel, SNAP 50) eluting with a gradient of 0% to 50% EtOAc in cyclohexane to give 1-(2-bromo-4-chlorophenyl)-N-methylpyrazole-3-carboxamide (205 mg, 0.652 mmol, 39.3% yield) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ2.75(d,J=4.71Hz,3H),6.86(d,J=2.45Hz,1H),7.61-7.70 (m,2H),8.05(dd,J=2.02,0.58Hz,1H),8.16(d,J=2.46Hz,1H),8.22-8.30(m,1H). LC-MS (method A): room temperature 0.94 min, MS (ESI) m / z=314.00 and 316.00 [M+H] + .

[0323] Intermediate 21: 1-[4-chloro-2-[4-[(2,4-dimethoxyphenyl)methylamino]cinnolin-7-yl]phenyl]-N-methylpyrazole-3-carboxamide [ka] A mixture of 1-(2-bromo-4-chlorophenyl)-N-methylpyrazole-3-carboxamide (205.0 mg, 0.650 mmol), N-[(2,4-dimethoxyphenyl)methyl]-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cinnolin-4-amine (356.92 mg, 0.850 mmol), and 2N aqueous sodium carbonate (0.65 mL, 1.3 mmol) in 1,2-dimethoxyethane (6 mL) was degassed under N for 10 minutes. Next, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (42.6 mg, 0.070 mmol) was added, and the resulting reaction mixture was stirred at 80 °C for 7 hours. The mixture was filtered through a pad of Celite and washed with MeOH. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (KP-NH silica gel, SNAP 12) eluting with a gradient of 0% to 10% MeOH in DCM to give 1-[4-chloro-2-[4-[(2,4-dimethoxyphenyl)methylamino]cinnolin-7-yl]phenyl]-N-methylpyrazole-3-carboxamide (285 mg, 0.539 mmol, 82.67% yield) as a brown powder. 1 H NMR(400MHz,DMSO-d6)δ2.72(d,J=4.70Hz,3H),3.74(s,3H),3.86(s,3H),4.48(d,J=5.73Hz, 2H),6.47(dd,J=8.40,2.37Hz,1H),6.58-6.65(m,2H),7.14(d,J=8.36Hz,1H),7.17(dd,J=8. 80,1.98Hz,1H),7.62(d,J=2.45Hz,1H),7.70-7.76(m,2H),7.84-7.87(m,1H),7.95(d,J=1.8 1Hz,1H), 7.98(t,J=5.91Hz,1H),8.17(q,J=4.59Hz,1H),8.21(d,J=8.80Hz,1H),8.48(s,1H). LC-MS (method A): room temperature 0.71 min, MS (ESI) m / z=529.23[M+H] + .

[0324] Intermediate 22: 3-(2-bromo-4-chlorophenyl)-1H-pyrazole [ka] A mixture of 2-bromo-4-chloroiodobenzene (1.0 g, 3.15 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (672.58 mg, 3.47 mmol) in 1,4-dioxane (10 mL) and 2 M aqueous sodium carbonate (4.73 mL, 9.45 mmol) was degassed with N for 10 minutes. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (231.2 mg, 0.320 mmol) was then added, and the resulting reaction mixture was stirred at 90 °C overnight. The mixture was cooled to room temperature, filtered through Celite, and washed with EtOAc. The filtrate was evaporated, and the residue was purified by column chromatography (KP-NH silica gel, SNAP 55) eluting with a gradient of 5% to 50% EtOAc in cyclohexane to give 3-(2-bromo-4-chlorophenyl)-1H-pyrazole (500 mg, 1.942 mmol, 61.62% yield) as a colorless oil. 1 H NMR (400MHz, chloroform-d) δ6.75(d,J=2.29Hz,1H),7.36(dd,J=8.36,2.11Hz,1H),7. 59(d,J=8.35Hz,1H),7.66(d,J=2.28Hz,1H),7.70(d,J=2.10Hz,1H),10.46(s,1H). LC-MS (Method A): 1.05 min at room temperature, MS (ESI) m / z=257.2 and 259.2 [M+H] + .

[0325] Intermediate 23: 3-(2-bromo-4-chlorophenyl)-1-(oxan-2-yl)pyrazole [ka] 3,4-Dihydro-2H-pyran (147.0 mg, 1.75 mmol) was added to a solution of 3-(2-bromo-4-chlorophenyl)-1H-pyrazole (300.0 mg, 1.17 mmol) and trifluoroacetic acid (0.100 mL) in toluene (2 mL). The resulting mixture was stirred at room temperature for 3 h and then evaporated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO and brine, dried over NaSO, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (KP-Sil silica gel, SNAP 25) eluting with a 5% to 50% gradient of dichloromethane in cyclohexane to give 3-(2-bromo-4-chlorophenyl)-1-(oxan-2-yl)pyrazole (250 mg, 0.732 mmol, 62.81% yield) as a white solid. 1 H NMR (400MHz, chloroform-d) δ1.55-1.79(m,3H),2.01-2.24(m,3H),3.74(td,J=11.11,2.94Hz,1H),4.05-4.18(m,1H),5.45(d d,J=9.00,3.30Hz,1H),6.82(d,J=2.45Hz,1H),7.33(dd,J=8.36,2.14Hz,1H),7.65-7.68(m,2H),7.71(d,J=8.36Hz,1H). LC-MS (Method A): 1.35 minutes at room temperature, MS (ESI) m / z=341.1 and 343.1 [M+H] + .

[0326] Intermediate 24: 7-[5-chloro-2-[1-(oxan-2-yl)pyrazol-3-yl]phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine [ka] A mixture of 3-(2-bromo-4-chlorophenyl)-1-(oxan-2-yl)pyrazole (250.0 mg, 0.730 mmol) and N-[(2,4-dimethoxyphenyl)methyl]-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cinnolin-4-amine (462.45 mg, 1.1 mmol) in 1,2-dimethoxyethane (9.074 mL) and 2 M aqueous sodium carbonate (0.91 mL, 1.83 mmol) was degassed with N for 10 min. Next, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (47.84 mg, 0.070 mmol) was added, and the resulting reaction mixture was stirred at 75 °C for 4 h. The mixture was cooled to room temperature, filtered through Celite, and washed with EtOAc. The filtrate was evaporated, and the residue was purified by column chromatography (KP-NH silica gel, SNAP 28) eluting with a gradient of 5% to 95% EtOAc in cyclohexane to give 7-[5-chloro-2-[1-(oxan-2-yl)pyrazol-3-yl]phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (150 mg, 0.270 mmol, 36.86% yield) as a yellow powder. LC-MS (Method A): RT 1.14 min, MS (ESI) m / z = 557.1 [M+H] + .

[0327] Intermediate 25: 1-(2-bromo-4-chloro-5-methylphenyl)pyrazole [ka] A mixture of 1-bromo-5-chloro-2-fluoro-4-methylbenzene (750.0 mg, 3.36 mmol), pyrazole (274.14 mg, 4.03 mmol), and dicesium carbonate (1858.95 mg, 5.71 mmol) in DMA (7.5 mL) was stirred at 100 °C for 2 h and then cooled to room temperature. EtOAc and water were added. The phases were separated, and the organic phase was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (Sfar D, 2 × 25 g in succession) eluting with a gradient of 0% to 30% EtOAc in cyclohexane to give 1-(2-bromo-4-chloro-5-methylphenyl)pyrazole (451 mg, 1.661 mmol, 49.49% yield) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ2.36(s,3H),6.53(dd,J=2.42,1.76Hz,1H),7.58(d,J=0.66 Hz,1H),7.75(dd,J=1.87,0.55Hz,1H),7.94(s,1H),8.08(dd,J=2.42,0.66Hz,1H). LC-MS (Method A): 1.19 min at room temperature, MS (ESI) m / z=272.9 and 274.9 [M+H] + .

[0328] Intermediate 26: 7-(5-chloro-4-methyl-2-pyrazol-1-ylphenyl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine [ka] A mixture of N-[(2,4-dimethoxyphenyl)methyl]-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cinnolin-4-amine (418.91 mg, 0.990 mmol), 1-(2-bromo-4-chloro-5-methylphenyl)pyrazole (180.0 mg, 0.660 mmol), and 2N aqueous sodium carbonate (0.66 mL, 1.33 mmol) in 1,2-dimethoxyethane (15 mL) was degassed for 10 minutes. [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (43.34 mg, 0.070 mmol) was added, and the mixture was degassed for an additional 10 minutes before stirring at 85 °C for 28 hours. The mixture was cooled to room temperature, diluted with EtOAc, and filtered through a pad of Celite, washing with EtOAc. The volatiles were removed and the residue was purified by column chromatography (KP-NH silica gel, 2 × 28 g in succession) eluting with a gradient of 20% to 100% EtOAc in cyclohexane to give 7-(5-chloro-4-methyl-2-pyrazol-1-ylphenyl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (73 mg, 0.150 mmol, 22.66% yield) as a brownish solid. 1 H NMR(400MHz,DMSO-d6)δ2.48(s,3H),3.74(s,3H),3.87(s,3H),4.48(d,J=5.72H z,2H),6.30-6.33(m,1H),6.47(dd,J=8.36,2.42Hz,1H),6.62(d,J=2.42Hz,1H) ,7.12-7.16(m,2H),7.59(d,J=1.76Hz,1H),7.64-7.67(m,2H),7.78(s,1H),7.8 5(d,J=1.98Hz,1H),7.95(t,J=5.83Hz,1H),8.18(d,J=8.80Hz,1H),8.46(s,1H). LC-MS (Method A): Room temperature 0.82 min, MS (ESI) m / z=486.18[M+H] + .

[0329] Intermediate 27: 1-(2-bromo-4-chlorophenyl)pyrazole-4-carbaldehyde [ka] A mixture of 2-bromo-4-chloro-1-fluorobenzene (1.0 g, 4.77 mmol), 1H-pyrazole-4-carbaldehyde (550.46 mg, 5.73 mmol), and dicesium carbonate (2.64 g, 8.12 mmol) in DMA (10 mL) was stirred at 100 °C for 2.5 h and then cooled to room temperature. EtOAc and water were added, the two phases were separated, and the organic phase was washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (KP-Sil silica gel, SNAP 50) eluting with a gradient of 0% to 50% EtOAc in cyclohexane to give 1-(2-bromo-4-chlorophenyl)pyrazole-4-carbaldehyde (520 mg, 1.821 mmol, 38.14% yield) as a white powder. 1 H NMR (400MHz, DMSO-d6) δ7.64-7.70 (m, 2H), 8.06 (dd, J = 1.89, 0.68Hz, 1H), 8.28 (s, 1H), 8.88 (s, 1H), 9.93 (s, 1H). LC-MS (method A): room temperature 0.99 min, MS (ESI) m / z=284.87 and 286.93 [M+H] + .

[0330] Intermediate 28: 1-(2-bromo-4-chlorophenyl)-4-(difluoromethyl)pyrazole [ka] DAST (0.41 mL, 3.1 mmol) was added dropwise to a solution of 1-(2-bromo-4-chlorophenyl)pyrazole-4-carbaldehyde (520.0 mg, 1.82 mmol) in DCM (12 mL) at 0 °C. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 24 h. The mixture was quenched with saturated aqueous NaHCO3 and extracted three times with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (KP-Sil silica gel, SNAP 25) eluting with a gradient of 1% to 40% EtOAc in cyclohexane to give 1-(2-bromo-4-chlorophenyl)-4-(difluoromethyl)pyrazole (285 mg, 0.927 mmol, 50.89% yield) as a white powder. 1 H NMR (400 MHz, chloroform-d) δ 7.13 (t, J = 55.82 Hz, 1H), 7.59-7.70 (m, 2H), 8.02 (s, 1H), 8.04 (d, J = 2.20 Hz, 1H), 8.49 (t, J = 1.86 Hz, 1H). 19 F NMR (377MHz, DMSO-d6) δ-105.69. LC-MS (Method A): 1.15 minutes at room temperature, MS (ESI) m / z=307.02 and 308.95 [M+H] + .

[0331] Interm...

Claims

1. Formula III-a or III-b: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein: R １ is hydrogen, halogen, amino, hydroxyl, alkoxy, or alkylthio; V and W are each independently CR ａ or N; R ａ is hydrogen, halogen, nitro, cyano, amino, hydroxyl, alkoxy, alkylthio, or alkyl; X is CR ｂ or N; with the proviso that two of V, W, and X are N; R ｂ is hydrogen, halogen, nitro, cyano, amino, hydroxyl, alkoxy, alkylthio, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; Each U is independently N or CR ｃ and Each R ｃ are independently hydrogen, halogen, or alkyl; Ring Z ２ is a 5-, 6-, or 7-membered heterocycle; Each R ２ are independently halogen, nitro, cyano, amino, acylamino, amido, hydroxyl, alkylthio, phosphonate, dialkylphosphine oxide, sulfonyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or OR 2a , where R 2a is selected from hydrogen, alkyl, haloalkyl, aryl, and cycloalkyl; or two adjacent R ２ are joined together 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 a 5- or 6-membered heteroaryl; or R ２ and Ar, together with the intervening atoms to which they are attached, combine to form a 5- to 7-membered carbocyclic or 5- to 7-membered heterocyclic ring; n is 0 or an integer selected from 1 to 3, as long as the valence permits; Each R ６ are independently halogen, nitro, cyano, amino, acylamino, amido, hydroxyl, oxo, carboxyl, alkoxy, alkylthio, acyl, amidino, azide, carbamoyl, carboxyl, carboxyester, guanidine, haloalkyl, 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 R ６ any two of together with the intervening carbon atom(s) to which they are attached are linked to form a carbocyclic or heterocyclic ring; q is 0 or an integer selected from 1 to 6, as long as the valence allows; R ３ teeth 【Chemistry 2】 and M is N(R ８ ) ３ , N(R ８ ) ２ , OR ８ or SR ８ and Each R ８ are independently hydrogen, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R ３ａ and R ３ｂ is independently hydrogen, alkyl, acyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R ３ａ and R ３ｂ is bonded together with the boron atom and the two intervening oxygen atoms separating them to form a monocyclic or polycyclic heterocyclyl; or R ３ａ , R ３ｂ and M, together with the boron atom and the intervening oxygen atoms, are bonded to form a polycyclic heterocycle; The compound wherein Ar is aryl or heteroaryl.

2. W and X are N and V is CR ａ 2. The compound of claim 1, wherein:

3. R ａ The compound of claim 2 wherein is hydrogen.

4. V and W are N and X is CR ｂ 2. The compound of claim 1, wherein:

5. R ｂ is hydrogen, C １ -C ３ 5. The compound of claim 4, wherein the aryl group is alkyl, or cyclopropyl, preferably methyl.

6. Each U is CR ｃ 2. The compound of claim 1, wherein:

7. The compound has formula IV-a or IV-b: 【Transformation 3】 or a pharmaceutically acceptable salt thereof.

8. The compound has formula V: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

9. The compound has formula VI: 【Transformation 5】 or a pharmaceutically acceptable salt thereof, wherein: Y is O, NH, or CH ２ and Y is NH, or CH ２ If ６ 8. The compound of claim 7 , substituted by:

10. The compound has formula VI: 【Transformation 6】 or a pharmaceutically acceptable salt thereof.

11. R ６ 2. The compound of claim 1, wherein is methyl and q is 1 or 2.

12. The compound has formula VI-a: 【Transformation 7】 or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , wherein Ar is a 5- or 6-membered heteroaryl.

14. 2. The compound of claim 1, wherein Ar is selected from furanyl, thienyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrrolyl, imidazolyl, diazolyl, tetrazolyl, thiazolyl, isothiazolyl, triazolyl, thiadiazolyl, isoxazolyl, oxazolyl, and pyrimidinyl.

15. 10. The compound of claim 1, wherein Ar is substituted with at least one alkyl, halogen, haloalkyl, alkoxy (e.g., haloalkoxy), cyano, heterocyclyl, amide, ester, or sulfonamide.

16. R １ The compound of claim 1 , wherein is amino.

17. Each R ２ is independently halogen, cyano, amino, acylamino, amido, hydroxyl, alkoxy, dialkylphosphine oxide, haloalkyl, sulfonyl, alkyl, carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaralkyl, or heteroaryl.

18. R ２ is OR ２ａ and R ２ａ The compound of claim 1 , wherein is selected from alkyl, haloalkyl, aryl, and cycloalkyl.

19. R ２ａ is methyl, difluoromethyl, -CF ２ CHF ２ , -CHFCF ３ , -CH ２ CF ３ , -(CH ２ CH ２ O) ２ CH ３ , 【Transformation 8】 or cyclopropyl.

20. R ２ａ 19. The compound of claim 18, wherein is methyl.

21. R ３ but 【Chemistry 9】 2. The compound of claim 1, wherein:

22. R ３ａ and R ３ｂ 22. The compound of claim 21, wherein is hydrogen.

23. R ３ａ and R ３ｂ together with the boron atom and the two intervening oxygen atoms separating them, form R ３ is attached so as to be heterocyclyl.

24. R ３ but, 【Chemistry 10】 and During the ceremony, Each R ５ are independently halogen, nitro, cyano, amino, acylamino, amido, hydroxyl, oxo, carboxy, alkoxy, alkylthio, alkyl (e.g., carboxymethyl), aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or any two R ５ independently, together with the intervening carbon atom(s) to which they are attached, are joined to form a carbocyclic or heterocyclic ring; 24. The compound of claim 23, wherein p is 0 or an integer selected from 1 to 6, as long as the valence permits.

25. R ３ but, 【Chemistry 11】 25. The compound of claim 24, wherein:

26. R ３ but, 【Chemistry 12】 and R ３ａ , R ３ｂ and M together with the boron atom and any intervening atoms form R ３ The compound of claim 1 , wherein

27. R ３ but, 【Chemistry 13】 27. The compound of claim 26, wherein:

28. The compound is 【Chemistry 14-1】 【Chemistry 14-2】 【Chemistry 14-3】 【Chemistry 14-4】 【Chemistry 14-5】 【Chemistry 14-6】 or a pharmaceutically acceptable salt thereof.

29. 2. The compound of claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride, formate, methanesulfonate, ethanesulfonate, or maleate salt.

30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 29 and a pharmaceutically acceptable excipient.

31. Use of the composition of claim 30 in the manufacture of a medicament for treating a disease or condition associated with complement activation.

32. 32. The use of claim 31 , wherein the disease or condition is selected from a neurodegenerative disorder, an inflammatory disease, an autoimmune disease, an ocular disease, and a metabolic disease.

33. The disease or condition is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, progressive multiple sclerosis, glaucoma, myotonic dystrophy, Guillain-Barré syndrome, myasthenia gravis, spinal muscular atrophy, Down's 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, vitiligo, paraneoplastic syndromes, vasculitic diseases, hypocomplementemic urticarial vasculitis, chronic spontaneous urticaria, ischemia, and Remote tissue damage after glaucoma 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, cardioplegia-induced coronary endothelial dysfunction, type II membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure, cryoglobulinemia, antiphospholipid syndrome, chronic open-angle glaucoma, acute angle-closure glaucoma Disorders, macular degeneration, wet age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, choroidal neovascularization, 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, ischemic optic neuropathy, retinal vasculitis, ANCA vasculitis, Wegener's granulomatosis, Purtscher's retinopathy, Sjogren's dry eye disease, sarcoidosis, temporal artery inflammation, polyarteritis nodosa, allografts, hyperacute rejection, hemodialysis, chronic obstructive pulmonary distress syndrome, asthma, aspiration pneumonia, immune thrombocytopenia, autoimmune hemolytic anemia, cold agglutinin disease, thermal autoimmune hemolytic anemia, coronary artery disease, Becker muscular dystrophy, limb girdle muscular dystrophies (LGMD) (e.g., sarcoglycanopathy, dystroglycanopathy, dysferlinopathy), type VI collagen-related disorders (e.g., Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD)), congenital muscular dystrophies (CMD) and congenital myopathies,and distal muscular dystrophy / myopathy (e.g., Miyoshi myopathy).

34. Use of a compound according to any one of claims 1 to 29 in the manufacture of a medicament for inhibiting activated C1s.

35. The pharmaceutical composition of claim 30 for use in treating a disease or condition associated with complement activation in an individual in need thereof.

36. The pharmaceutical composition of claim 35, wherein the disease or condition is selected from a neurodegenerative disorder, an inflammatory disease, an autoimmune disease, an ocular disease, and a metabolic disease.

37. The disease or condition is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, progressive multiple sclerosis, glaucoma, myotonic dystrophy, Guillain-Barré syndrome, myasthenia gravis, spinal muscular atrophy, Down's 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, vitiligo, paraneoplastic syndromes, vasculitic diseases, hypocomplementemic urticarial vasculitis, chronic spontaneous urticaria, ischemia, and Remote tissue damage after glaucoma 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, cardioplegia-induced coronary endothelial dysfunction, type II membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure, cryoglobulinemia, antiphospholipid syndrome, chronic open-angle glaucoma, acute angle-closure glaucoma Disorders, macular degeneration, wet age-related macular degeneration, dry age-related macular degeneration, geographic atrophy, choroidal neovascularization, 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, ischemic optic neuropathy, retinal vasculitis, ANCA vasculitis, Wegener's granulomatosis, Purtscher's retinopathy, Sjogren's dry eye disease, sarcoidosis, temporal artery inflammation, polyarteritis nodosa, allografts, hyperacute rejection, hemodialysis, chronic obstructive pulmonary distress syndrome, asthma, aspiration pneumonia, immune thrombocytopenia, autoimmune hemolytic anemia, cold agglutinin disease, thermal autoimmune hemolytic anemia, coronary artery disease, Becker muscular dystrophy, limb girdle muscular dystrophies (LGMD) (e.g., sarcoglycanopathy, dystroglycanopathy, dysferlinopathy), type VI collagen-related disorders (e.g., Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD)), congenital muscular dystrophies (CMD) and congenital myopathies,and distal muscular dystrophy / myopathy (e.g., Miyoshi myopathy).

38. The pharmaceutical composition of claim 30 for use in an individual in need thereof in inhibiting activated C1s.

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