Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
  • C07F5/02—Boron compounds
  • C07F5/025—Boronic and borinic acid compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
  • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
  • C07F5/02—Boron compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
  • C07F9/6509—Six-membered rings
  • C07F9/650905—Six-membered rings having the nitrogen atoms in the positions 1 and 2
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
  • C07F9/02—Phosphorus compounds
  • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
  • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
  • C07F9/6509—Six-membered rings
  • C07F9/650905—Six-membered rings having the nitrogen atoms in the positions 1 and 2
  • C07F9/650947—Six-membered rings having the nitrogen atoms in the positions 1 and 2 condensed with carbocyclic rings or carbocyclic ring systems

Definitions

• C1q is a large multimeric protein of 460 kDa consisting of 18 polypeptide chains (6 C1q A chains, 6 C1q B chains, and 6 C1q C chains). These chains form a large symmetric protein composed of three sections: the tail, arms and globular head regions.
• the single tail section divides into six symmetric arms, each of which terminates in a globular head.
• Most of the C1q circulating in blood carries a heteroterameric complex of the complement proteins C1r and C1s, two serine proteases that bind to C1q initially as inactive zymogens. This large multichain assembly is known as C1-complex. Binding of the C1-complex to the surface of a cell or to the appropriate complement-binding epitope of a recruiting protein, such as that found in an antibody Fc region induces a conformational change that leads to a sequence of activation and amplification events. In response to binding. C1r is activated first, subsequently cleaving and activating C1s.
• Complement C4 is then recruited to the complex where it is incorporated and cleaved to C4b by C1s. This cleavage results in exposure of a moiety which can attach C4b to the cell surface covalently. This new complex subsequently recruits complement C2 where, in association with C4b, it is cleaved to C2a by C1s.
• the surface linked complex of C4b and C2a forms the C3-convertase, which drives the subsequent cleavage and surface linking of complement C3 and activates downstream steps of the complement cascade.
• a single C1-complex is capable of building multiple C3-convertase modules on the surface, resulting in a powerful amplification of the original targeting event.
• C1r and/or C1s expression may also be elevated through local induction as part of a biological response and the actions of these proteases may further contribute to the progression of disease pathology (see, for example Xavier et al Am. J.
• the complement system is a central component of innate immunity and bridges the innate to the adaptive immune response. However, it can also turn its destructive capabilities against host cells. Aberrant activation or insufficient regulation of the complement cascade is involved in numerous diseases and pathological conditions. As a consequence, many neurodegenerative, inflammatory and autoimmune diseases are thought to be caused, or at least substantially driven, by unleashed complement factor activity. For example, the cognitive abilities of humans, and especially of patients suffering from neurodegenerative diseases, are highly dependent on synapse formation. The formation of precise neuronal circuits during development is a highly regulated and dynamic process.
• synapse loss often occurs long before the pathology and clinical symptoms in many neurodegenerative diseases.
• Timely therapeutic intervention to prevent or reduce synapse loss may slow down or prevent progression of clinical symptoms of neurodegenerative diseases. Therefore, inhibition or modulation of classical complement activity has been recognized as a promising therapeutic strategy.
• R 1 is hydrogen, halogen, amino, hydroxyl, alkoxy, or alkylthio
• V and W are each independently CR a or N
• each R a independently is hydrogen, halogen, nitro, cyano, amino, hydroxyl, alkoxy, alkylthio, or alkyl
• X is CR b or N
• R b is hydrogen, halogen, nitro, cyano, amino, hydroxyl, alkoxy, alkylthio, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl
• each U independently is N or CR c
• each R c independently is hydrogen, halogen, alkoxy, or alkyl
• ring Z 1 is a five- or six-membered ary
• the present disclosure provides pharmaceutical compositions comprising a compound provided herein and a pharmaceutically acceptable excipient.
• the present disclosure provides methods of making a compound provided herein.
• the present disclosure provides methods of treating diseases associated with complement activation in an individual in need thereof, comprising administering a therapeutically effective amount of a compound provided herein.
• the present disclosure provides methods of inhibiting C1s, comprising contacting the C1s with a compound disclosed herein.
• the present disclosure provides methods of inhibiting activated C1s, comprising contacting the C1s with a compound disclosed herein.
• the current disclosure provides compounds of formula I or II: 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; each R a independently is hydrogen, halogen, nitro, cyano, amino, hydroxyl, alkoxy, alkylthio, or alkyl; X is CR b or N; R b is hydrogen, halogen, nitro, cyano, amino, hydroxyl, alkoxy, alkylthio, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; each U independently is N or CR c ; each R c independently is hydrogen, halogen, alkyl, or alkoxy; ring Z 1 is a five- or six-member
• Z 1 is an aromatic moiety
• the shared bond between rings Z 1 and Z 2 has aromatic character.
• the compound is represented by formula I-a or II-a:
• R 1 is hydrogen, amino, hydroxyl, alkoxy, or alkylthio.
• R 1 is hydroxyl or C 1-3 alkoxy.
• R 1 is amino, preferably -NH2 or -NHCH3, such as NH2.
• each R 2 independently is halogen, nitro, cyano, amino, acylamino, amido, hydroxyl, alkoxy, alkylthio, phosphonate, dialkylphosphine oxide, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or two vicinal R 2 , together with the intervening carbon atoms to which they attach, combine to form a 5- or 6-membered carbocycle, 5- or 6-membered heterocycle, 5- or 6-membered aryl, or 5- or 6-membered heteroaryl.
• each R 2 independently is halogen, cyano, amino, acylamino, amido, hydroxyl, alkoxy, dialkylphosphine oxide, haloalkyl, sulfonyl, alkyl, carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaralkyl or heteroaryl.
• two vicinal R 2 together with the intervening carbon atoms to which they attach, combine to form a 5- or 6-membered carbocycle, 5- or 6-membered heterocycle, 5- or 6-membered aryl, or 5- or 6-membered heteroaryl.
• two vicinal R 2 together with the intervening carbon atoms to which they attach, combine to form a 5- or 6-membered heteroaryl.
• two vicinal R 2 together with the intervening carbon atoms to which they attach, combine to form a 5- or 6-membered heteroaryl ring.
• the 5- or 6-membered heteroaryl ring is furan, pyrazole, indazole or oxazole.
• two vicinal R 2 together with the intervening carbon atoms to which they attach, combine to form a 5- or 6-membered heterocycle.
• the 5- or 6-membered heterocycle is tetrahydrofuran or tetrahydropyran,
• each R a independently is hydrogen, halogen, amino, hydroxyl, alkoxy, or alkyl, preferably hydrogen.
• R b is hydrogen, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, preferably hydrogen, C 1 -C 3 alkyl, or cyclopropyl. In preferred embodiments, R b is methyl. In certain embodiments, R c is hydrogen, halogen, or alkyl. In certain embodiments, one of V, W, and X is N. In certain embodiments, two of V, W, and X are N. In certain embodiments, W and X are N and V is CR a . In certain such embodiments, R a is hydrogen. In certain embodiments, V and W are N and X is CR b .
• R b is hydrogen or methyl. In certain preferred embodiments, R b is methyl. In certain embodiments, U is CR c . In certain embodiments, R c is hydrogen, F, methyl, methoxy or Cl. In some preferred embodiments U is CH. In certain embodiments, ring Z 1 is phenyl or a five- or six-membered heteroaryl. In certain preferred embodiments, ring Z 1 is phenyl. In such embodiments, for example, the compound may be represented by formula I-b or II-b: In certain embodiments, ring Z 1 is a five- or six-membered heteroaryl. In certain embodiments, ring Z 1 is a pyrazolyl.
• ring Z 1 is a pyridinyl.
• the compound may be represented by formula I-c or II-c:
• the compound is represented by formula I, for example by formula I-a, I-b or I-c.
• the compound is represented by formula I-c- 1: wherein n is 0, 1, or 2, and R 2a is alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.
• the compound is represented by formula I-c-2: (I-c-2), wherein n is 0, 1, or 2, and R 2a is alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.
• R 2a is alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.
• R 2a is alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.
• R 2a is alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.
• R 2a is methyl, difluoromethyl, -
• R 3 is . In other embodiments, R 3 is . In certain embodiments, R 3 is . In certain embodiments, R 3a and R 3b independently are hydrogen, alkyl, acyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain preferred embodiments, R 3a and R 3b are hydrogen. In certain embodiments, R 3a and R 3b , together with the boron atom and the two intervening oxygen atoms that separate them, combine such that R 3 is a heterocyclyl, such as a five- or six-membered heterocyclyl.
• R 3 may be represented as wherein: each R 5 independently is halogen, nitro, cyano, amino, acylamino, amido, hydroxyl, oxo, carboxy, alkoxy, alkylthio, alkyl (e.g.
• R 3 is In certain such embodiments, R 3 is and R 3a , R 3b and M, together with the boron atom and the intervening atoms, combine such that R 3 is a polycyclic heterocycle.
• R 3 may be wherein R d is H or C1-C4 alkyl, preferably H or methyl, and more preferably H.
• R d is H or C1-C4 alkyl, preferably H or methyl, and more preferably H.
• dative bonds may form in compounds comprising an atom with a lone electron pair (such as a Nitrogen atom) and a Boron atom. That is, the lone pair of electrons may coordinate with the empty orbital of boron. This may be indicated with an arrow from the donor atom to the boron, as shown below: .
• Such compounds may be represented with or without the dative bond; both representations refer to the same compound.
• the compound is represented by formula II, for example formula II-a, II-b or II-c.
• the compound is represented by formula II- b-1, II-b-2, or II-b-3:
• each R 6 independently is halogen, alkyl, or oxo.
• ring Z 2 is , In certain embodiments, ring Z 2 is In certain preferred embodiments, R 3a is hydrogen. In certain embodiments, R 3a is methyl. In certain embodiments, the compound is selected from: ,
• the pharmaceutically acceptable salt of any of the above- described compounds is a formic acid salt, methanesulfonic acid salt, ethane sulfonic acid salt, or maleic acid salt.
• the present disclosure provides pharmaceutical compositions, comprising the compound of any one of the preceding claims and a pharmaceutically acceptable excipient. Definitions Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art.
• agent is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues.
• a chemical compound such as an organic or inorganic compound, a mixture of chemical compounds
• a biological macromolecule such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate
• an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues.
• Agents include, for example, agents whose structure is known, and those whose structure is not known. The ability of such agents to inhibit complement factors may render them suitable as “therapeutic agents” in the methods and compositions of this disclosure.
• a “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats). “Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
• 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, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
• Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
• preventing is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.
• a condition such as a local recurrence (e.g., pain)
• a disease such as cancer
• a syndrome complex such as heart failure or any other medical condition
• prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount.
• administering or “administration of” a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art.
• a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct).
• a compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent.
• Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
• a compound or an agent is administered orally, e.g., to a subject by ingestion.
• the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.
• the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents).
• the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially.
• a “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect.
• a therapeutically effective amount may be administered in one or more administrations.
• the precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.
• the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not.
• optionally substituted alkyl refers to the alkyl may be substituted as well as where the alkyl is not substituted. It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
• 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 2 -O-alkyl, -OP(O)(O-alkyl) 2 or –CH 2 -OP(O)(O-alkyl) 2 .
• “optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted.
• the term “alkyl” refers to saturated aliphatic groups, including but not limited to C1-C10 straight-chain alkyl groups or C1-C10 branched-chain alkyl groups.
• the “alkyl” group refers to C 1 -C 6 straight-chain alkyl groups or C 1 -C 6 branched- chain alkyl groups.
• alkyl group refers to C 1 -C 4 straight-chain alkyl groups or C1-C4 branched-chain alkyl groups.
• 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 and the like.
• 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, etc.
• acyl is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
• 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-.
• acyloxy is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.
• alkoxy refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
• alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
• C x-y or “C x -C y ”, when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain.
• C0alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.
• a C 1-6 alkyl group for example, contains from one to six carbon atoms in the chain.
• alkylamino refers to an amino group substituted with at least one alkyl group.
• alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.
• amide refers to a group wherein R 9 , R 10 , and R 11 , each independently represent a hydrogen or hydrocarbyl group, or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure, or R 10 and R 11 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
• amino refers to a group , wherein R 9 , R 10 , and R 11 , each independently represent a hydrogen or hydrocarbyl group, or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure, or R 10 and R 11 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
• amino refers to a group , wherein R 10 represents a hydrogen or hydrocarbyl group.
• amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by , wherein R 9 , R 10 , and R 10 ’ each independently represent a hydrogen or a hydrocarbyl group, or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
• aminoalkyl refers to an alkyl group substituted with an amino group.
• aralkyl refers to an alkyl group substituted with an aryl group.
• aryl as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
• the ring is a 5- to 7-membered ring, more preferably a 6-membered ring.
• aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
• Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
• the term”azido” is art-recognized and refers to the group –N 3.
• the term “carbamate” is art-recognized and refers to a group , wherein R 9 and R 10 independently represent hydrogen or a hydrocarbyl group.
• the term “carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings.
• Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
• the term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring.
• Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings.
• an aromatic ring e.g., phenyl
• an aromatic ring e.g., phenyl
• a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic.
• 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.
• Carbocycles may be substituted at any one or more positions capable of bearing a hydrogen atom.
• the term “carbonate” is art-recognized and refers to a group -OCO 2 -.
• esteer refers to a group -C(O)OR 9 wherein R 9 represents a hydrocarbyl group.
• ether refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group.
• an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-.
• Ethers may be either symmetrical or unsymmetrical.
• 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.
• halo and halogen as used herein means halogen and includes chloro, fluoro, bromo, and iodo.
• haloalkyl refers to an alkyl group wherein one or more hydrogens is replaced with a halogen.
• haloalkoxy refers to an alkoxy group in which one or more hydrogen atoms is replaced with a halogen atom.
• heteroalkyl and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.
• heteroaryl and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
• heteroaryl and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
• Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
• heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
• heterocyclylalkyl refers to an alkyl group substituted with a heterocycle group.
• heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
• heterocyclyl and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
• Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
• Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.
• hydroxyalkyl refers to an alkyl group substituted with a hydroxy group.
• mine is art-recognized and refers to a group wherein R 9 is a hydrogen or a hydrocarbyl group, and R 10 represents a hydrocarbyl group, or R 9 and R 10 taken together with the N atom to which R 9 is attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
• lower when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer.
• acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).
• oxime is art regognized and refers to the group wherein R 9 represents hydrogen or a hydrocarbyl group.
• polycyclyl refers to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted.
• each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
• the term “sulfate” is art-recognized and refers to the group –OSO 3 H, or a pharmaceutically acceptable salt thereof.
• the term “sulfonamide” is art-recognized and refers to the group represented by the general formulae , wherein R 9 and R 10 independently represents hydrogen or hydrocarbyl.
• the term “sulfoxide” is art-recognized and refers to the group–S(O)-.
• the term “sulfonate” is art-recognized and refers to the group SO 3 H, or a pharmaceutically acceptable salt thereof.
• substitution refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
• the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
• the permissible substituents can be one or more and the same or different for appropriate organic compounds.
• the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
• Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic mo
• thioalkyl refers to an alkyl group substituted with a thiol group.
• thioester refers to a group -C(O)SR 9 or –SC(O)R 9 wherein R 9 represents a hydrocarbyl.
• thioether is equivalent to an ether, wherein the oxygen is replaced with a sulfur.
• urea is art-recognized and may be represented by the general formula , wherein R 9 and R 10 independently represent hydrogen or a hydrocarbyl.
• a compound disclosed herein inhibits a complement factor.
• Complement factor inhibition may be measured according to techniques known to those skilled in the art, such as an enzyme assay.
• C1s inhibition can be determined according to the enzyme assay disclosed herein in Example 174.
• a compound inhibits C1s when the PIC50 determined according to the procedure described in Example 174 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.
• compositions, excipients, adjuvants, polymers and other materials and/or dosage forms which 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.
• “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients.
• pharmaceutically acceptable acid addition salt as used herein means any non-toxic organic or inorganic salt of any base compounds represented by Formula I or II.
• Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
• Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids.
• Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form.
• the acid addition salts of compounds of Formula I or II are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
• the selection of the appropriate salt will be known to one skilled in the art.
• Other non-pharmaceutically acceptable salts e.g., oxalates, may be used, for example, in the isolation of compounds of Formula I or II for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
• pharmaceutically acceptable basic addition salt means any non-toxic organic or inorganic base addition salt of any acid compounds represented by Formula I or II or any of their intermediates.
• Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide.
• Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art. Many of the compounds useful in the methods and compositions of this disclosure have at least one stereogenic center in their structure.
• This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30.
• the disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01/062726.
• certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (enthafen) isomers. In each instance, the disclosure includes both mixture and separate individual isomers. Some of the compounds may also exist in tautomeric forms.
• Prodrug or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the compound of the present disclosure (e.g., compounds of Formula I, II or II).
• Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety 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 produce the active compound.
• Examples of prodrugs using ester or phosphoramidate as biologically labile or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference.
• the prodrugs of this disclosure are metabolized to produce a compound of Formula I or Formula II.
• the present disclosure includes within its scope, prodrugs of the compounds described herein.
• 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 for formulating a drug for medicinal or therapeutic use.
• Log of solubility means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter, diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use.
• Log of solubility “LogS” or “logS” as used herein is used in the art to quantify the aqueous solubility of a compound.
• the aqueous solubility of a compound significantly affects its absorption and distribution characteristics. A low solubility often goes along with a poor absorption.
• compositions and methods of the present invention may be utilized to treat an individual in need thereof.
• the individual is a mammal such as a human, or a non-human mammal.
• the composition or the compound When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier.
• Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
• the aqueous solution is pyrogen-free, or substantially pyrogen-free.
• the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
• the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
• the composition can also be present in a transdermal delivery system, e.g., a skin patch.
• composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.
• a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention.
• physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
• the choice of a 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 selfemulsifying drug delivery system or a selfmicroemulsifying drug delivery system.
• the pharmaceutical composition also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
• the pharmaceutical composition may be a solid dispersion.
• solid dispersion refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components.
• the solid dispersion can be an amorphous solid dispersion.
• amorphous solid dispersion refers to stable solid dispersions comprising an amorphous drug substance and a polymer.
• amorphous drug substance it is meant that the amorphous solid dispersion contains drug substance in a substantially amorphous solid state form.
• pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which 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.
• pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as 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 injurious to the patient.
• materials which 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 carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
• a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin).
• the compound may also be formulated for inhalation.
• a compound may be simply dissolved or suspended in sterile water.
• compositions suitable for same can be found in, for example, 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 in patents cited therein.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
• the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, 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 that amount of the compound which produces a therapeutic effect.
• compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients.
• active compound such as a compound of the invention
• 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.
• Formulations of the 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 basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a 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 pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
• capsules including sprinkle capsules and gelatin capsules
• cachets pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth)
• lyophile powders,
• compositions or compounds may also be administered as a bolus, electuary or paste.
• solid dosage forms for oral administration capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like)
• the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6)
• the pharmaceutical compositions may also comprise buffering agents.
• Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
• a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent.
• Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets, and other solid dosage forms of the 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-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
• compositions may be sterilized by, for example, 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 they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
• embedding compositions that can be used include polymeric substances and waxes.
• the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
• Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• inert diluents commonly used in the art, such
• the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
• Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
• Dosage forms for the 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.
• the ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
• Powders and sprays can contain, in addition to an 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.
• Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
• parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
• compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
• aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
• polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
• vegetable oils such as olive oil
• 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.
• These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
• microorganisms Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions.
• isotonic agents such as sugars, sodium chloride, and the like into the compositions.
• prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
• the rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form.
• delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
• injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
• Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
• active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
• Methods of introduction may also be provided by rechargeable or biodegradable devices.
• Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals.
• biocompatible polymers including hydrogels
• biodegradable and non-degradable polymers can be used to form an implant for the sustained release of a compound at a particular target site.
• Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as 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.
• the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
• a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
• terapéuticaally effective amount is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence 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, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine 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, herein incorporated by reference).
• 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.
• the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
• the active compound may be administered two or three times daily.
• the active compound will be administered once daily.
• the patient receiving this treatment is any animal in need, including primates, in particular humans; and other mammals such as equines, cattle, swine, sheep, cats, and dogs; poultry; and pets in general.
• compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.
• the present disclosure includes the use of pharmaceutically acceptable salts (see Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci.66: 1-19.) of compounds of the invention in the compositions and methods of the present invention.
• contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts.
• contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, 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.
• contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.
• contemplated salts of the invention include, but are not limited to, 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,
• the pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared.
• the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
• Wetting agents, emulsifiers and lubricants, 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 compositions.
• antioxidants examples 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 Methods of Treatment
• the present disclosure provides methods of treating a disease or condition associated with complement activation in an individual in need thereof, comprising administering a therapeutically effective amount of the compounds provided herein.
• the compounds disclosed herein act as C1s inhibitors and can therefore prevent complement activation, in turn treating diseases that associated with complement activation.
• the disease or condition is selected from a neurodegenerative disorder, an inflammatory disease, an autoimmune disease, an ophthalmic disease, and a metabolic disorder.
• diseases or conditions can fall into more than one of the aforementioned categories of diseases.
• conditions can be both neurological and autoimmune, autoimmune and inflammatory, ophthalmic and neurologic, and so on.
• Diseases or conditions associated with complement activation that may be treated in accordance with the present methods include without limitation: Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, progressive multiple schlerosis, glaucoma, myotonic dystrophy, Guillain-Barre ⁇ syndrome, Myasthenia Gravis, spinal muscular atrophy, Down syndrome, Parkinson’s disease, Huntington’s disease, traumatic brain injury, epilepsy, frontotemporal dementia, diabetes, obesity, atherosclerosis, rheumatoid arthritis, acute respiratory distress syndrome,pemphigus, pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, immune-mediated necrotizing myopathy, vitiligo, paraneoplastic syndromes, a vasculitis disease, hypocomplementemic urticarial vasculitis, chronic spontaneous urticaria, remote tissue injury after ischemia and reperfusion, complement activation during cardiopulmonary bypass surgery, dermatomy
• the disease or condition associated with complement activation that may be treated in accordance with the present methods includes Guillain- Barre ⁇ syndrome, amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), geographic atrophy, cold agglutinin disease, warm autoimmune hemoltyic anemia, lupus nephritis, and multifocal motor neuropathy.
• the disease or condition associated with complement activation that may be treated in accordance with the present methods is Guillain-Barre ⁇ syndrome.
• the disease or condition associated with complement activation that may be treated in accordance with the present methods is ALS.
• the disease or condition associated with complement activation that may be treated in accordance with the present methods is HD. In certain embodiments, the disease or condition associated with complement activation that may be treated in accordance with the present methods is geographic atrophy. In certain embodiments, the disease or condition associated with complement activation that may be treated in accordance with the present methods is cold agglutinin disease. In certain embodiments, the disease or condition associated with complement activation that may be treated in accordance with the present methods is warm autoimmune hemoltyic anemia. In certain embodiments, the disease or condition associated with complement activation that may be treated in accordance with the present methods is lupus nephritis.
• the disease or condition associated with complement activation that may be treated in accordance with the present methods is multifocal motor neuropathy.
• the disease or condition is a neurodegenerative disorder, for example one associated with loss of synapses or loss of nerve connections, with synapse loss dependent on C1q, C1 complex, CR1, C3, CR3, C4, or CR4, with pathological activity- dependent synaptic loss, or with synapse phagocytosis by microglia.
• the neurodegenerative disorder is associated with dysregulation of C1s.
• the neurodegenerative disorder is associated with activation or dysregulation of C1s.
• the neurodegenerative disorder is associated with activation of C1s.
• the neurodegenerative disorder is selected from Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, progressive multiple schlerosis, glaucoma, myotonic dystrophy, Guillain-Barre ⁇ syndrome (GBS), Myasthenia Gravis, spinal muscular atrophy, Down syndrome, Parkinson’s disease, Huntington’s disease (HD), traumatic brain injury, epilepsy, age-related macular degeneration, immune-mediated necrotizing myopathy (IMNM) and frontotemporal dementia.
• ALS amyotrophic lateral sclerosis
• GBS Guillain-Barre ⁇ syndrome
• HD Huntington’s disease
• traumatic brain injury epilepsy
• age-related macular degeneration age-related macular degeneration
• IMNM immune-mediated necrotizing myopathy
• the neurodegenerative disorder is selected from Guillain- Barre ⁇ syndrome, Huntington’s disease, amyotrophic lateral sclerosis, and geographic atrophy.Age-related macular degeneration (AMD) diseases include wet AMD and dry AMD. Furthermore, dry AMD involves early, intermediate and late stages, with the late stage being referred to as geographic atrophy, which refers to a progressive loss of cells in the retina.
• the disease or condition is an inflammatory disease, an autoimmune disease, metabolic disorder, or an ophthalmic disease. In certain embodiments, the inflammatory disease, autoimmune disease, a metabolic disorder, or ophthalmic diesease is associated with activation or dysregulation of C1s.
• the inflammatory disease, autoimmune disease, metabolic disorder, or ophthalmic disease is is selected from diabetes, obesity, atherosclerosis, rheumatoid arthritis, acute respiratory distress syndrome, pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, remote tissue injury after ischemia and reperfusion, complement activation during cardiopulmonary bypass surgery, dermatomyositis, pemphigus, lupus nephritis and resultant glomerulonephritis and vasculitis, kidney fibrosis, systemic lupus erythematosus, Hashimoto’s thyroiditis, Addison’s disease, Celiac disease, Crohn’s disease, pernicious anaemia, immune-mediated necrotizing myopathy, vitiligo, paraneoplastic syndromes, a vasculitis disease, hypocomplementemic urticarial vasculitis, chronic spontaneous urticaria, chronic idiopathic demy
• the disease is cold agglutinin disease, warm autoimmune hemolytic anemia, geographic atrophy, lupus nephritis or multifocal motor neuropathy.
• the disease is an autoimmune hemolytic anemia, such as cold agglutinin disease or warm autoimmune hemolytic anemia.
• the present disclosure provides methods of inhibiting C1s, comprising contacting the C1s with a compound disclosed herein.
• the present disclosure provides methods of inhibiting activated C1s, comprising contacting the C1s with a compound disclosed herein.
• contacting the C1s with the compound comprises administering the compound to an individual.
• LC-MS Method B Total ion current (TIC) and DAD UV chromatographic traces together with MS and UV spectra associated with the peaks were taken on a UPLC/MS Acquity TM system equipped with PDA detector and coupled to a Waters single quadrupole mass spectrometer operating in alternated positive and negative electrospray ionization mode.
• Nuclear magnetic resonance (NMR) spectroscopy was carried out using one of the following instruments: a Bruker Avance 400 instrument equipped with probe DUAL 400MHz S1, a Bruker Avance 400 instrument equipped with probe 6 S1400 MHz 5mm 1 H- 13 C ID, a Bruker Avance III 400 instrument with nanobay equipped with probe Broadband BBFO 5 mm direct, a 400 MHz Agilent Direct Drive instrument with ID AUTO-X PFG probe, all operating at 400 MHz, or an Agilent VNMRS500 Direct Drive instrument equipped with a 5 mm Triple Resonance 1 H ⁇ 13 C/ 15 N ⁇ cryoprobe operating at 500 MHz. The spectra were acquired in the stated solvent at around room temperature unless otherwise stated.
• reaction time the reaction time, number of equivalents of reagents and temperature can be modified for each specific reaction and that it may be necessary or desirable to employ different work-up or purification techniques.
• microwave irradiation the microwave used is a Biotage Initiator. The actual power supplied varies during the course of the reaction in order to maintain a constant temperature.
• Examples 1-171 Preparation of Exemplary Compounds EXAMPLE 1: [3-(1-AMINOPHTHALAZIN-6-YL)PHENYL]BORONIC ACID (1) To a solution of 6-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]phthalazin-1-amine trifluoroacetic acid salt (89.0 mg, 0.190 mmol) in THF (2 mL), 1M hydrochloric acid solution (1.0 mL, 1 mmol) and sodium periodate (20.64 mg, 0.100 mmol) were added. The mixture was stirred at room temperature for 16h and the volatiles were removed by evaporation.
• EXAMPLE 2 [3-(1-AMINOPHTHALAZIN-6-YL)-4-METHOXYPHENYL]BORONIC ACID FORMIC ACID SALT (2) 6-[2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phthalazin-1- amine trifluoroacetic acid salt (360.0 mg, 0.730 mmol) was dissolved in THF (21.6 mL) and 1M hydrochloric acid solution (10.26 mL, 10.26 mmol) was added. The mixture was stirred vigorously for 3 hours, then evaporated.
• EXAMPLE 3 6-[2-METHOXY-5-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2- YL)PHENYL]PHTHALAZIN-1-AMINE TRIFLUOROACETIC ACID SALT (3)
• N-[(2,4-dimethoxyphenyl)methyl]-6-[2-methoxy-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phthalazin-1-amine 350.0 mg, 0.660 mmol
• DCM 4.71 mL
• trifluoroacetic acid 4.71 mL
• EXAMPLE 5 [3-(4-AMINOCINNOLIN-7-YL)-4-METHOXYPHENYL]BORONIC ACID (5) 7-[2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cinnolin-4- amine trifluoroacetic acid (450.0 mg, 0.920 mmol) was dissolved in Et 2 O (12 mL) and 2M hydrochloric acid solution (13.34 mL, 26.69 mmol) was added. The mixture was stirred vigorously for 1.5 hours. CH 3 CN (10 mL) was added and the two phases (Et 2 O/Water + CH3CN) were separated.
• EXAMPLE 7 [3-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-4-METHOXYPHENYL]BORONIC ACID FORMIC ACID SALT (7) 6-[2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4- methylphthalazin-1-amine trifluoroacetic acid salt (28.0 mg, 0.060 mmol) was suspended in Et 2 O (2 mL) and 2M hydrochloric acid solution (0.83 mL, 0.830 mmol) was added. The mixture was stirred vigorously for 45 min and water (5 mL) and Et2O (5 mL) were added.
• EXAMPLE 11 [3-(1-AMINO-4-CYCLOPROPYLPHTHALAZIN-6-YL)PHENYL]BORONIC ACID FORMIC ACID SALT (11)
• a solution of [3-[4-cyclopropyl-1-[(2,4-dimethoxyphenyl)methylamino]phthalazin- 6-yl]phenyl]boronic acid (50.0 mg, 0.110 mmol) in DCM (0.200 mL) and trifluoroacetic acid (0.200 mL) was stirred at room temperature for 1 hour then it was concentrated under reduced pressure.
• EXAMPLE 14 6-(1-HYDROXY-3H-2,1-BENZOXABOROL-6-YL)-4-METHYLPHTHALAZIN-1- AMINE FORMIC ACID SALT (14)
• N-[(2,4-dimethoxyphenyl)methyl]-4-methyl-6-[4-(oxan-2- yloxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phthalazin-1-amine (78.0 mg, 0.120 mmol) in DCM (2 mL), trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 1.5h and then the volatiles were removed.
• EXAMPLE 15 [3-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-4- (TRIFLUOROMETHOXY)P
• EXAMPLE 16 [3-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-4-[2-[2-[2-[2-(2- METHOXYETHOXY)ETHOXY]ETHOXY]ETHOXY]ETHOXY]PHENYL]BORONIC ACID (16) 6-[2-[2-[2-[2-[2-[2-(2-Methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-methylphthalazin-1-amine trifluoroacetic acid salt (45.0 mg, 0.070 mmol) was suspended in Et 2 O (2 mL) and 2M hydrochloric acid solution (1.0 mL, 2 mmol) was added.
• EXAMPLE 18 [3-(1-AMINOPHTHALAZIN-6-YL)-4-[(2- CHLOROBENZOYL)AMINO]PHENYL]BORONIC ACID FORMIC ACID SALT (18) A solution of [4-benzamido-3-[1-[(2,4-dimethoxyphenyl)methylamino]phthalazin- 6-yl]phenyl]boronic acid (46.97 mg, 0.090 mmol) in DCM (0.250 mL) and trifluoroacetic acid (0.250 mL) was stirred at room temperature for 1 hour then it was concentrated under reduced pressure.
• EXAMPLE 19 [3-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-4-ETHYLPHENYL]BORONIC ACID FORMIC ACID SALT (19) A solution of [3-[1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalazin-6- yl]-4-fluorophenyl]boronic acid (56.0 mg, 0.110 mmol) in DCM (3 mL) and trifluoroacetic acid (0.5 mL) was stirred for 2 hours at room temperature then it was concentrated under reduced pressure.
• EXAMPLE 20 6-(1-HYDROXY-5-METHOXY-3H-2,1-BENZOXABOROL-6-YL)-4- METHYLPHTHALAZIN-1-AMINE (20) Trifluoroacetic acid (2 mL) was added to a solution of N-[(2,4- dimethoxyphenyl)methyl]-6-[2-methoxy-4-(oxan-2-yloxymethyl)-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl]-4-methylphthalazin-1-amine (133.0 mg, 0.200 mmol) in DCM (2 mL).
• EXAMPLE 21 6-[2-METHOXY-5-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2- YL)PHENYL]-3-METHYLISOQUINOLIN-1-AMINE TRIFLUOROACETIC ACID SALT (21)
• EXAMPLE 23 [1-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)PYRAZOL-4-YL]BORONIC ACID (23)
• a solution of [1-[1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalazin-6- yl]pyrazol-4-yl]boronic acid (56.0 mg, 0.130 mmol) in DCM (3 mL) and trifluoroacetic acid (1 mL) was stirred for 2 hours at room temperature then it was concentrated under reduced pressure.
• EXAMPLE 26 6-(1-HYDROXY-3,4-DIHYDRO-2,1-BENZOXABORININ-7-YL)-4- METHYLPHTHALAZIN-1-AMINE FORMIC ACID SALT (26) Trifluoroacetic acid (2.5 mL) was added to a solution of N-[(2,4- dimethoxyphenyl)methyl]-4-methyl-6-[4-[2-(oxan-2-yloxy)ethyl]-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl]phthalazin-1-amine (50.0 mg, 0.080 mmol) in DCM (2.5 mL) and the mixture was stirred at room temperature for 1h.
• EXAMPLE 29 [3-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-4-CYANOPHENYL]BORONIC ACID (29) Trifluoroacetic acid (1 mL) was added to a suspension of [4-cyano-3-[1-[(2,4- dimethoxyphenyl)methylamino]-4-methylphthalazin-6-yl]phenyl]boronic acid (35.0 mg, 0.080 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 2h, then the volatiles were removed.
• EXAMPLE 30 [5-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-6-METHOXYPYRIDIN-3- YL]BORONIC ACID (30) A suspension of [5-[1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalazin-6- yl]-6-methoxypyridin-3-yl]boronic acid (54.0 mg, 0.120 mmol) in DCM (1 mL) and trifluoroacetic acid (1 mL) was stirred at room temperature for 1h, then it was concentrated. Et2O (1 mL) was added to the residue and the mixture was stirred for 1h, then it was filtered and washed with Et 2 O.
• EXAMPLE 31 [3-(4-AMINO-5-FLUOROCINNOLIN-7-YL)-4-METHOXYPHENYL]BORONIC ACID (31)
• a solution of N-[(2,4-dimethoxyphenyl)methyl]-5-fluoro-7-[2-methoxy-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cinnolin-4-amine (90.0 mg, 0.130 mmol) in DCM (2 mL) and trifluoroacetic acid (2 mL) was stirred at room temperature for 2 days then it was concentrated under reduced pressure.
• EXAMPLE 32 6-(1-HYDROXY-6-METHOXY-3,4-DIHYDRO-2,1-BENZOXABORININ-7-YL)-4- METHYLPHTHALAZIN-1-AMINE FORMIC ACID SALT (32) Trifluoroacetic acid (1 mL) was added to a suspension of N-[(2,4- dimethoxyphenyl)methyl]-6-[2-methoxy-4-[2-(oxan-2-yloxy)ethyl]-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl]-4-methylphthalazin-1-amine (11.0 mg, 0.020 mmol) in DCM (1 mL).
• Step 2 The material obtained in Step 1 was dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 1h and the volatiles were evaporated. The residue was dissolved in MeOH (20 mL) and filtered over a short pad of Celite. The filtrate was evaporated and the obtained solid was triturated with Et2O.
• the solid residue was purified by column chromatography (KP-C18-HS, SNAP 12g) eluting with a gradient of CH 3 CN (+0.1% of HCOOH) in water (+0.1% of HCOOH) from 1% to 40% to give [3-(1-amino-4-methylphthalazin-6-yl)-2-fluoro-4-methoxyphenyl]boronic acid formic acid salt (29 mg, 0.078 mmol, 15.6% yield over two steps) as a white solid.
• EXAMPLE 35 [5-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-2-(DIFLUOROMETHYL)-4- METHOXYPHENYL]BORONIC ACID (35) Palladium(II) diacetate (1.347 mg, 0.006 mmol), 6-[5-chloro-4-(difluoromethyl)-2- methoxyphenyl]-N-[(2,4-dimethoxyphenyl)methyl]-4-methylphthalazin-1-amine (60 mg, 0.120 mmol), potassium acetate (35.33 mg, 0.360 mmol), dicyclohexyl-[2-[2,4,6-tri(propan- 2- yl)phenyl]phenyl]phosphine (5.721 mg, 0.012 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-d
• EXAMPLE 37 [5-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-4-METHOXY-2- (TRIFLUOROMETHYL)PHENYL]BORONIC ACID FORMIC ACID SALT (37)
• Step1 Palladium(II) diacetate (5.14 mg, 0.020 mmol), 6-[5-chloro-2-methoxy-4- (trifluoromethyl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]-4-methylphthalazin-1-amine (237.0 mg, 0.460 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (17.45 mg, 0.040 mmol), potassium acetate (134.72 mg, 1.37 mmol) and 4,4,5,5-tetramethyl- 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y
• Step 2 The mixture obtained in Step 1 was dissolved in DCM (1 mL) and trifluoroacetic acid (1 mL) was added. The mixture stirred at room temperature for 1h and the volatiles were evaporated to give crude 6-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-4-(trifluoromethyl)phenyl]-4-methylphthalazin-1-amine trifluoroacetic salt.
• Step 3 The crude material obtained in Step 2 was suspended in 2M hydrochloric acid solution (1.0 mL, 2 mmol) and Et2O (2 mL), and the mixture was stirred at room temperature for 20min. Water (20 mL) was added and the layers were separated.
• EXAMPLE 38 3-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-5- (TRIFLUOROMETHYL)PHENYL]BORONIC ACID (38) Trifluoroacetic acid (2 mL) was added to a solution of [3-[1-[(2,4- dimethoxyphenyl)methylamino]-4-methylphthalazin-6-yl]-5-(trifluoromethyl)phenyl]boronic acid (90.0 mg, 0.180 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 1h and the volatiles were evaporated. The residue was dissolved in MeOH and the precipitate was filtered over a short pad of Celite.
• EXAMPLE 39 [3-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-4- (TRIFLUOROMETHYL)PHENYL]BORONIC ACID FORMIC ACID SALT (39)
• a solution of [3-[1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalazin-6- yl]-4-(trifluoromethyl)phenyl]boronic acid (93.0 mg, 0.190 mmol) in DCM (0.500 mL) and trifluoroacetic acid (0.500 mL) was stirred at room temperature for 2 hours then it was concentrated under reduced pressure.
• EXAMPLE 40 [3-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-5- DIMETHYLPHOSPHORYLPHENYL]BORONIC ACID FORMIC ACID SALT (40) A solution of [3-[1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalazin-6- yl]-5-dimethylphosphorylphenyl]boronic acid (94.0 mg, 0.190 mmol) in DCM (0.500 mL) and trifluoroacetic acid (0.500 mL) was stirred at room temperature for 2 hours then it was concentrated under reduced pressure.
• EXAMPLE 41 [5-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-4-CYANO-2- METHYLPHENYL]BORONIC ACID (41)
• Step 1 Trifluoroacetic acid (2 mL) was added to a solution of 2-[1-[(2,4- dimethoxyphenyl)methylamino]-4-methylphthalazin-6-yl]-5-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzonitrile (123.42 mg, 0.220 mmol) in DCM (2 mL) and the mixture was stirred at room temperature for 1h.
• Step 2 The material obtained in Step 1 was suspended in Et2O (2 mL) and 2M hydrochloric acid solution (2.0 mL, 0.300 mmol) and the mixture was stirred at room temperature for 30 min. The mixture was diluted with water (10 mL) and washed with Et 2 O (3 x 10 mL).
• EXAMPLE 42 [3-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-4-METHOXY-5- METHYLPHENYL]BORONIC ACID FORMIC ACID SALT (42) 6-[2-Methoxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4- methylphthalazin-1-amine trifluoroacetic acid salt (94.0 mg, 0.230 mmol) was suspended in Et 2 O (5 mL) and 2M hydrochloric acid solution (3.0 mL, 6 mmol) was added. To aid solubility DCM (50 uL) was added.
• EXAMPLE 43 [5-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-2-CYCLOPROPYL-4- METHOXYPHENYL]BORONIC ACID (43) Palladium(II) diacetate (3.21 mg, 0.010 mmol), 6-(5-chloro-4-cyclopropyl-2- methoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]-4-methylphthalazin-1-amine (140.0 mg, 0.290 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (13.62 mg, 0.030 mmol), potassium acetate (84.12 mg, 0.860 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxa
• EXAMPLE 45 [5-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-2-METHOXY-3- METHYLPHENYL]BORONIC ACID (45) Trifluoroacetic acid (2 mL) was added to a solution of [5-[1-[(2,4- dimethoxyphenyl)methylamino]-4-methylphthalazin-6-yl]-2-methoxy-3- methylphenyl]boronic acid (41.0 mg, 0.090 mmol) in DCM (2 mL) and the mixture was stirred at room temperature for 1h. The volatiles were evaporated and the residue was dissolved in MeOH.
• Step 2 The crude product obtained in Step 1 was suspended in DCM (4 mL) and trifluoroacetic acid (4 mL) was added. The mixture was stirred at room temperature for 4h and the volatiles were evaporated. The residue was purified by column chromatography (KP- C18-HS, SNAP 30g) eluting with a gradient of CH 3 CN (+0.1% of HCOOH) in water (+0.1% of HCOOH) from 1% to 15%.
• the partially purified product obtained was submitted to semi- preparative HPLC purification (Column: Chiralcel OD-H (25 x 2.0 cm), 5 ⁇ m. Mobile phase: n-Hexane/(Ethanol + 0.1% isopropylamine) 80/20 % v/v. Flow rate: 17 ml/min). Fractions containing the desired compound were collected and evaporated. The residue was dissolved in MeOH (+ 5% of TFA) (5 mL) and water (5 mL) was added.
• EXAMPLE 47 [3-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-5-DIMETHYLPHOSPHORYL-2- FLUOROPHENYL]BORONIC ACID FORMIC ACID SALT (47) 6-(3-Chloro-5-dimethylphosphoryl-2-fluorophenyl)-N-[(2,4-dimethoxyphenyl) methyl]-4-methylphthalazin-1-amine (75.0 mg, 0.150 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (111.18 mg, 0.440 mmol) and potassium acetate (42.97 mg, 0.440 mmol) were solubilized in 1,4-dioxane (1.558 mL).
• the resulting solution was degassed for 10 minutes with N2 then palladium(II) diacetate (1.64 mg, 0.010 mmol) and dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (6.96 mg, 0.010 mmol) were added.
• the resulting reaction mixture was stirred at 75°C for 2 hours then it was cooled to room temperature and filtered over Celite, washing with EtOAc. The filtrate was evaporated under reduced pressure and the residue was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.8 mL). The resulting mixture was stirred for 2 hours at room temperature then it was concentrated under reduced pressure.
• EXAMPLE 48 [3-(4-AMINOCINNOLIN-7-YL)-2-FLUORO-4-METHOXYPHENYL]BORONIC ACID (48)
• Step 1 Palladium(II) diacetate (4.48 mg, 0.020 mmol), 7-(3-chloro-2-fluoro-6- methoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (181.0 mg, 0.400 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (15.21 mg, 0.030 mmol), potassium acetate (117.41 mg, 1.2 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (303.79 mg, 1.2 m
• Step 2 The crude material from Step 1 was dissolved in a mixture of DCM (2 mL) and trifluoroacetic acid (4 mL). The mixture was stirred at room temperature for 3h and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge (5g). The cartridge was washed with 4CV of MeOH, 2CV of MeOH/H2O (8:2) and 1CV with MeOH. The product was eluted from the SCX cartridge with 3CV of a 2M solution of NH3 in MeOH.
• EXAMPLE 49 [3-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-4-METHOXY-5- (TRIFLUOROMETHYL)PHENYL]BORONIC ACID (49)
• EXAMPLE 50 [5-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-2-CHLORO-4- METHOXYPHENYL]BORONIC ACID (50)
• Step 1 6-(5-Bromo-4-chloro-2-methoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]-4- methylphthalazin-1-amine (139.0 mg, 0.260 mmol), potassium acetate (77.39 mg, 0.790 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9.64 mg, 0.010 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (200.24 mg, 0.790 mmol) were dissolved in 1,4-dioxan
• Step 2 The crude material from Step 1 was combined with a similar crude material prepared by the same procedure described in Step 1 but starting with 41 mg of 6-(5-Bromo-4- chloro-2-methoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]-4-methylphthalazin-1-amine. The combined crude material was dissolved in a mixture of DCM (4 mL) and trifluoroacetic acid (4 mL).
• EXAMPLE 51 [3-(4-AMINOCINNOLIN-7-YL)-4-(OXAN-4-YLOXY)PHENYL]BORONIC ACID FORMIC ACID SALT (51)
• Step 1 Palladium(II) diacetate (3.08 mg, 0.010 mmol), 7-[5-chloro-2-(oxan-4- yloxy)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (134.0 mg, 0.270 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (10.48 mg, 0.020 mmol), potassium acetate (80.88 mg, 0.820 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaboro
• Step 2 The crude material from Step 1 was dissolved in a mixture of DCM (2 mL) and trifluoroacetic acid (4 mL). The mixture was stirred at room temperature for 3h and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge (5g). The cartridge was washed with 4CV of MeOH, 2CV of MeOH/H2O (8:2) and 1CV of MeOH. The product was eluted from the SCX cartridge with 3CV of a 2M solution of NH3 in MeOH.
• EXAMPLE 53 7-[2-METHOXY-5-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2- YL)PHENYL]CINNOLIN-4-AMINE TRIFLUOROACETIC ACID SALT (53)
• EXAMPLE 54 7- ⁇ 2-METHOXY-5-[(1S,2S,6R,8S)-2,9,9-TRIMETHYL-3,5-DIOXA-4- BORATRICYCLO[6.1.1.02 , 6]DECAN-4-YL]PHENYL ⁇ CINNOLIN-4-AMINE (54)
• EXAMPLE 56 7-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-1-HYDROXY-4H-2,1- BENZOXABORININ-3-ONE TRIFLUOROACETIC ACID SALT (56)
• a 1M aqueous solution of LiOH (1.34 mL, 1.34 mmol) was added to a solution of ethyl 2-[4-(1-amino-4-methylphthalazin-6-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]acetate (150.0 mg, 0.340 mmol) in methanol (2 mL) and the mixture stirred at room temperature for 3h.
• EXAMPLE 57 [3-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-5-FLUORO-4- METHOXYPHENYL]BORONIC ACID TRIFLUOROACETIC ACID SALT (57) A mixture of [3-[1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalazin-6-yl]-5- fluoro-4-methoxyphenyl]boronic acid (9 mg, 0.019 mmol) in DCM (0.50 mL) and trifluoroacetic acid (0.25 mL) was stirred at room temperature for 2h, then the volatiles were removed.
• EXAMPLE 58 [3-(4-AMINOCINNOLIN-7-YL)-4-METHOXY-5-(OXAN-4-YL)PHENYL]BORONIC ACID (58) Palladium(II) diacetate (1.62 mg, 0.010 mmol), 7-[5-chloro-2-methoxy-3-(oxan-4- yl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (75.0 mg, 0.140 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (6.88 mg, 0.010 mmol), potassium acetate (42.46 mg, 0.430 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (
• EXAMPLE 59 [3-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-4-(3- METHYLBUTANOYLAMINO)PHENYL]BORONIC ACID FORMIC ACID SALT (59) A mixture of N-[2-[1-[(2,4-dimethoxyphenyl)methylamino]-4-methylphthalazin-6- yl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methylbutanamide (47.0 mg, 0.080 mmol) in DCM (0.600 mL) and trifluoroacetic acid (0.600 mL) was stirred at room temperature for 1h, then the volatiles were removed.
• EXAMPLE 62 [3-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-4- DIMETHYLPHOSPHORYLPHENYL]BORONIC ACID FORMIC ACID SALT (62) Palladium(II) diacetate (4.28 mg, 0.020 mmol), 6-(5-chloro-2- dimethylphosphorylphenyl)-N-[(2,4-dimethoxyphenyl)methyl]-4-methylphthalazin-1-amine (210.0 mg, 0.380 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (14.53 mg, 0.030 mmol), potassium acetate (112.2 mg, 1.14 mmol) and 4,4,5,5-tetramethyl- 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (290.33 mg,
• EXAMPLE 64 [3-(4-AMINOCINNOLIN-7-YL)-4-(3-METHYLBUTANAMIDO)PHENYL]BORONIC ACID FORMIC ACID SALT (64)
• a mixture of N-[2-[4-[(2,4-dimethoxyphenyl)methylamino]cinnolin-7-yl]-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-methylbutanamide (54.0 mg, 0.090 mmol) in DCM (1.5 mL) and trifluoroacetic acid (1 mL) was stirred overnight at room temperature, then the volatiles were removed.
• EXAMPLE 65 [3-(4-AMINOCINNOLIN-7-YL)-4-(4-METHYLPENTANAMIDO)PHENYL]BORONIC ACID FORMIC ACID SALT (65) A mixture of N-[2-[4-[(2,4-dimethoxyphenyl)methylamino]cinnolin-7-yl]-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-methylpentanamide (61.0 mg, 0.100 mmol) and trifluoroacetic acid (1 mL) in DCM (1.5 mL) was stirred overnight at room temperature, then the volatiles were removed.
• EXAMPLE 66 6-(4,4-DIFLUORO-1-HYDROXY-3H-2,1-BENZOXABORININ-7-YL)-4- METHYLPHTHALAZIN-1-AMINE (66) A mixture of 6-[4-[2-[tert-butyl(dimethyl)silyl]oxy-1,1-difluoroethyl]-3- chlorophenyl]-N-[(2,4-dimethoxyphenyl)methyl]-4-methylphthalazin-1-amine (66.0 mg, 0.110 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (54.58 mg, 0.210 mmol), cesium fluoride (32.65 mg, 0.210 mmol), trimethyl(2,2,2-trifluoroethoxy)silane (38.86 mg, 0.230 mmol) and dichlor
• the mixture was heated to 100°C under microwave irradiation for 3 hours in a microwave reactor.
• the mixture was then cooled to room temperature and filtered over a pad of Celite, washing with MeOH.
• the filtrate was evaporated and the residue was dissolved in DCM (4 mL) and trifluoroacetic acid (4 mL) and stirred for 2 hours at room temperature, then concentrated under reduced pressure.
• the residue was purified by column chromatography (KP-C18-HS, 30g) eluting with a gradient of CH 3 CN in water (+0.1% of HCOOH) from 2% to 95%. Fractions containing the partially purified product were collected and evaporated.
• EXAMPLE 70 [5-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-2-BENZAMIDOPHENYL]BORONIC ACID (70) A mixture of N-[2-chloro-4-[1-[(2,4-dimethoxyphenyl)methylamino]-4- methylphthalazin-6-yl]phenyl]benzamide (640.0 mg, 1.15 mmol), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (643.43 mg, 2.53 mmol), cesium fluoride (349.89 mg, 2.3 mmol), trimethyl(2,2,2-trifluoroethoxy)silane (416.53 mg, 2.42 mmol) and dichlorobis(trimethylphosphine)nickel (6.49 mg, 0.020 mmol) were dissolved in THF (11 mL
• EXAMPLE 74 [5-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-2- (TRIFLUOROMETHYL)PHENYL]BORONIC ACID FORMIC ACID SALT (74)
• EXAMPLE 75 [4-METHOXY-3-[4-(METHYLAMINO)CINNOLIN-7-YL]PHENYL]BORONIC ACID FORMIC ACID SALT (75) A mixture of 7-(5-chloro-2-methoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]-N- methylcinnolin-4-amine (200.0 mg, 0.440 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (338.64 mg, 1.33 mmol), dicyclohexyl-[2- [2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (16.95 mg, 0.040 mmol), potassium acetate (130.87 mg, 1.33 mmol) and palladium(II) diacetate (4.99 mg, 0.020
• EXAMPLE 82 [3-(4-AMINOCINNOLIN-7-YL)-4-(OXOLAN-2-YLMETHOXY)PHENYL]BORONIC ACID FORMIC ACID SALT (82) Palladium(II) diacetate (4.44 mg, 0.020 mmol), 7-[5-chloro-2-(oxolan-2- ylmethoxy)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (200.0 mg, 0.400 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (18.84 mg, 0.040 mmol), potassium acetate (116.37 mg, 1.19 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxa
• EXAMPLE 83 [5-(4-AMINOCINNOLIN-7-YL)-4-METHOXY-2- (TRIFLUOROMETHYL)PHENYL]BORONIC ACID FORMIC ACID SALT (83)
• EXAMPLE 84 [5-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-6-(TRIFLUOROMETHYL)PYRIDIN- 3-YL]BORONIC ACID (84) A mixture of 6-[5-chloro-2-(trifluoromethyl)pyridin-3-yl]-N-[(2,4- dimethoxyphenyl)methyl]-4-methylphthalazin-1-amine formic acid salt (182.66 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 (260.15 mg, 1.02 mmol), potassium acetate (100.54 mg, 1.02 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (13.02 mg, 0.030 mmol), and pal
• EXAMPLE 86 7-[4-(TRIFLUOROMETHYL)-3-[(1S,2S,6R,8S)-2,9,9-TRIMETHYL-3,5-DIOXA-4- BORATRICYCLO[6.1.1.02 , 6]DECAN-4-YL]PHENYL]CINNOLIN-4-AMINE (86) Bis[(+)-pinanediolato]diboron (259.35 mg, 0.720 mmol), 7-[3-chloro-4- (trifluoromethyl)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (130.0 mg, 0.240 mmol) and potassium acetate (71.08 mg, 0.720 mmol) were dissolved 1,4-dioxane (2.5 mL) in a microwave vial and the mixture was deoxygenated under N 2 for 10 min.
• EXAMPLE 88 [5-(4-AMINOCINNOLIN-7-YL)-2-(TRIFLUOROMETHYL)PHENYL]BORONIC ACID FORMIC ACID SALT (88) 7 ⁇ [4 ⁇ (Trifluoromethyl) ⁇ 3 ⁇ [(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 (56.0 mg, 0.020 mmol) was dissolved in water (1 mL), MeCN (1 mL) and MeOH (1 mL) and formic acid (0.05 uL, 0.001 mmol) was added.
• EXAMPLE 89 [5-(1-AMINO-4-METHYLPHTHALAZIN-6-YL)-2-(2- METHYLPROPANAMIDO)PHENYL]BORONIC ACID (89) [5-[1-[(2,4-Dimethoxyphenyl)methylamino]-4-methylphthalazin-6-yl]-2-(2- methylpropanoylamino)phenyl]boronic acid (56.0 mg, 0.110 mmol) was dissolved in DCM (1.371 mL) and trifluoroacetic acid (1.371 mL) was added. The mixture was stirred for 2 hours.
• EXAMPLE 90 7- ⁇ 2-FLUORO-6-METHOXY-3-[(1R,2R,6S,8R)-2,6,9,9-TETRAMETHYL-3,5- DIOXA-4-BORATRICYCLO[6.1.1.02 , 6]DECAN-4-YL]PHENYL ⁇ CINNOLIN-4-AMINE (90) A suspension of [3-(4-aminocinnolin-7-yl)-2-fluoro-4-methoxyphenyl]boronic acid (26.0 mg, 0.080 mmol) and (1R,3S,4R,5R)-3,4,6,6-tetramethylbicyclo[3.1.1]heptane-3,4-diol (15.3 mg, 0.080 mmol) in THF (0.830 mL) was stirred at 45°C for three hours then it was evaporated in vacuo.
• EXAMPLE 92 [3-(4-AMINO-6-FLUOROCINNOLIN-7-YL)-4-METHOXYPHENYL]BORONIC ACID FORMIC ACID SALT (92) Palladium(II) diacetate (5.44 mg, 0.020 mmol), 7-(5-chloro-2-methoxyphenyl)-N- [(2,4-dimethoxyphenyl)methyl]-6-fluorocinnolin-4-amine (220.0 mg, 0.480 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (23.11 mg, 0.050 mmol), potassium acetate (142.71 mg, 1.45 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (0.37 g, 1.45
• EXAMPLE 96 7 ⁇ 2 ⁇ METHOXY ⁇ 5 ⁇ [(1S,2R,6S,8S) ⁇ 2,6 ⁇ DIMETHYL ⁇ 3,5 ⁇ DIOXA ⁇ 4 ⁇ BORATRICYCLO[6.1.1.0 2,6 ]DECAN ⁇ 4 ⁇ YL]PHENYL ⁇ CINNOLIN ⁇ 4 ⁇ AMINE (96)
• a suspension of [3-(4-aminocinnolin-7-yl)-4-methoxyphenyl]boronic acid (50.0 mg, 0.160 mmol) and (1R,3S,4R,5R)-3,4,6,6-tetramethylbicyclo[3.1.1]heptane-3,4-diol (29.35 mg, 0.160 mmol) in THF (1.5 mL) was stirred at 50°C overnight then it was evaporated in vacuo.
• Step 2 The crude material from Step 1 was dissolved in DCM (1.76 mL) and trifluoroacetic acid (1.06 mL) and the mixture was stirred overnight at room temperature then it was concentrated under reduced pressure. The residue was dissolved in MeOH/H 2 O (9:1) and loaded onto an SCX cartridge (5 g).
• 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 (5g). The cartridge was washed with MeOH/H2O (9:1) then the product was eluted from the SCX cartridge with a 2M solution of NH 3 in MeOH.
• Step 2 The crude material from Step 1 was dissolved in a mixture of DCM (6 mL) and trifluoroacetic acid (6 mL). The mixture was stirred at room temperature for 6 hours and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge (10g). The cartridge was washed with MeOH then the product was eluted from the SCX cartridge with a 2M solution of NH 3 in MeOH.
• Step 2 The crude material from Step 1 was dissolved in DCM (2.5 mL) and trifluoroacetic acid (1.5 mL) and the mixture was stirred overnight at room temperature then it was concentrated under reduced pressure. The residue was dissolved in MeOH/H 2 O (9:1) and loaded onto an SCX cartridge (5 g).
• EXAMPLE 101 7-[2-(DIFLUOROMETHOXY)-5-[(1S,2S,6R,8S)-2,9,9-TRIMETHYL-3,5-DIOXA- 4-BORATRICYCLO[6.1.1.02,6]DECAN-4-YL]PHENYL]CINNOLIN-4-AMINE (101)
• a suspension of [3-(4-aminocinnolin-7-yl)-4-(difluoromethoxy)phenyl]boronic acid 700.0 mg, 2.11 mmol
• (1S,3R,4S,5S)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol (359.96 mg, 2.11 mmol) in THF (28 mL) was stirred at 45°C overnight, then the mixture was concentrated in vacuo.
• EXAMPLE 103 7- ⁇ 2-METHOXY-5-[(1S,2S,6R,8S)-2,6,9,9-TETRAMETHYL-3,5-DIOXA-4- BORATRICYCLO[6.1.1.02 , 6]DECAN-4-YL]PHENYL ⁇ CINNOLIN-4-AMINE (103)
• a suspension of [3-(4-aminocinnolin-7-yl)-4-methoxyphenyl]boronic acid (50.0 mg, 0.170 mmol) and (1S,3R,4S,5S)-3,4,6,6-tetramethylbicyclo[3.1.1]heptane-3,4-diol (31.22 mg, 0.170 mmol) in THF (1.597 mL) was stirred at 50 °C for 24 hours.
• Step 2 The crude material from Step 1 was dissolved in DCM (1.25 mL) and trifluoroacetic acid (0.75 mL) and the mixture was stirred overnight at room temperature then it was concentrated under reduced pressure. The residue was dissolved in MeOH/H2O (9:1) and loaded onto an SCX cartridge (2 g).
• Step 1 A mixture of 7-[5-chloro-2-(1,2,2,2-tetrafluoroethoxy)phenyl]-N-[(2,4- dimethoxyphenyl)methyl]cinnolin-4-amine (100.0 mg, 0.190 mmol), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (145.97 mg, 0.570 mmol) and potassium acetate (56.41 mg, 0.570 mmol) in 1,4-dioxane (2.8 mL) was degassed under argon for 10 minutes then dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (7.31 mg, 0.020 mmol) and palladium(II) diacetate (2.15 mg, 0.010 mmol) were added and the mixture stirred at 70
• Step 2 The crude material from Step 1 was combined with a similar crude isolated from an analogous reaction performed on 27 mg of 7-[5-chloro-2-(1,2,2,2- tetrafluoroethoxy)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine.
• Step 2 The crude material from Step 1 was dissolved in trifluoroacetic acid (2 mL) and DCM (2 mL) and the mixture stirred at room temperature for 6 hours.
• EXAMPLE 110 [3-(4-AMINOCINNOLIN-7-YL)-4-[2-(OXOLAN-2-YL)ETHOXY]PHENYL]BORONIC ACID (110) Palladium(II) diacetate (3.89 mg, 0.020 mmol), 7-[5-chloro-2-[2-(oxolan-2- yl)ethoxy]phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (180.0 mg, 0.346 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (16.5 mg, 0.030 mmol), potassium acetate (101.91 mg, 1.04 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaboro
• EXAMPLE 112 [3-(4-AMINOCINNOLIN-7-YL)-4-[2-(OXOLAN-3-YL)ETHOXY]PHENYL]BORONIC ACID FORMIC ACID SALT (112) Palladium(II) diacetate (3.24 mg, 0.010 mmol), 7-[5-chloro-2-[2-(oxolan-3- yl)ethoxy]phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (150.0 mg, 0.290 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (11.0 mg, 0.020 mmol), potassium acetate (84.93 mg, 0.870 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,
• Step 1 Palladium(II) diacetate (4.77 mg, 0.020 mmol), 7-[5-chloro-2-[(4,4- dimethyloxolan-2-yl)methoxy]phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (227.0 mg, 0.430 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (16.21 mg, 0.030 mmol), potassium acetate (125.14 mg, 1.28 mmol) and 4,4,5,5-tetramethyl- 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (323.81 mg, 1.28 mmol) were dissolved in 1,4-dioxane (5 mL).
• Step 2 The crude material from Step 1 was dissolved in a mixture of DCM (3.11 mL) and trifluoroacetic acid (3.11 mL). The mixture was stirred 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/H2O (9:1) then the product was eluted from the SCX cartridge with a 2M solution of NH 3 in MeOH.
• Step 1 A mixture of 7-[5-chloro-2-(2-cyclopropylethoxy)phenyl]-N-[(2,4- dimethoxyphenyl)methyl]cinnolin-4-amine (292.0 mg, 0.600 mmol), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (453.99 mg, 1.79 mmol) and potassium acetate (175.45 mg, 1.79 mmol) in 1,4-dioxane (6.5 mL) was degassed for 10 minutes under argon, then dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (22.73 mg, 0.050 mmol) and palladium(II) diacetate (6.69 mg, 0.030 mmol) were added and the mixture stirred at 80°C for 2
• Step 2 The crude material from Step 1 was dissolved in trifluoroacetic acid (4 mL) and DCM (6 mL) and the mixture was stirred at room temperature for 3 hours, then the volatiles were removed under reduced pressure.
• Step 2 The crude material from Step 1 was dissolved in trifluoroacetic acid (1.8 mL) and DCM (3 mL) and the mixture stirred at room temperature for 3 hours, then the volatiles were removed under reduced pressure.
• EXAMPLE 117 [3-(4-AMINOCINNOLIN-7-YL)-4-CYCLOBUTOXYPHENYL]BORONIC ACID (117) Palladium(II) diacetate (3.3 mg, 0.010 mmol), 7-(5-chloro-2-cyclobutyloxyphenyl)- N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (140.0 mg, 0.290 mmol), dicyclohexyl-[2- [2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (14.02 mg, 0.030 mmol), potassium acetate (86.6 mg, 0.880 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1,3,2-dioxaborolane (224.08 mg, 0.880 mmol) were dissolved in 1,
• EXAMPLE 119 [4-(4-AMINOCINNOLIN-7-YL)-2-METHYL-1,3-BENZOXAZOL-6-YL]BORONIC ACID FORMIC ACID SALT (119)
• Step 1 A mixture of 7-(6-chloro-2-methyl-1,3-benzoxazol-4-yl)-N-[(2,4- dimethoxyphenyl)methyl]cinnolin-4-amine (136.0 mg, 0.300 mmol), potassium acetate (86.87 mg, 0.890 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (224.79 mg, 0.890 mmol) were dissolved in 1,4-dioxane (8.435 mL) and the mixture was degassed with Ar for 10 minutes.
• EXAMPLE 120 [3-(4-AMINOCINNOLIN-7-YL)-4-(PROPAN-2-YLCARBAMOYL)PHENYL]BORONIC ACID FORMIC ACID SALT (120)
• Step 1 Palladium(II) diacetate (2.06 mg, 0.010 mmol), 4-chloro-2-[4-[(2,4- dimethoxyphenyl)methylamino]cinnolin-7-yl]-N-propan-2-ylbenzamide formic acid salt (90 mg, 0.169 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (6.99 mg, 0.010 mmol), potassium acetate (53.97 mg, 0.550 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-diox
• 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 (10g). The cartridge was washed with MeOH/H2O (9:1) then the product was eluted from the SCX cartridge with a 2M solution of NH 3 in MeOH.
• Step 2 The crude material from Step 1 was dissolved in DCM (3 mL) and trifluoroacetic acid (3 mL) was stirred for 10h at room temperature then it was concentrated under reduced pressure. The residue was dissolved in MeOH/H2O (9:1) and loaded onto an SCX cartridge (5 g).
• EXAMPLE 122 [7-(4-AMINOCINNOLIN-7-YL)-2-METHYL-1,3-BENZOXAZOL-5-YL]BORONIC ACID FORMIC ACID SALT (122)
• Step 1 Palladium(II) diacetate (0.66 mg, 0 mmol), 7-(5-chloro-2-methyl-1,3- benzoxazol-7-yl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (27.0 mg, 0.060 mmol), potassium acetate (17.25 mg, 0.180 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (44.63 mg, 0.180 mmol) were dissolved in 1,4- dioxane (1.6 mL) and the mixture was degassed with Ar for 10 minutes.
• Step 2 The crude material from Step 1 was dissolved in DCM (2 mL) and trifluoroacetic acid (1 mL) and stirred overnight at room temperature then it was concentrated under reduced pressure. The residue was dissolved in MeOH/H 2 O (9:1) and loaded onto an SCX cartridge (2 g).
• EXAMPLE 123 [3-(4-AMINOCINNOLIN-7-YL)-4- ⁇ [(2R,4R,6S)-2,6-DIMETHYLOXAN-4- Step 1: Palladium(II) diacetate (2.71 mg, 0.010 mmol), 7-(5-chloro-2- ⁇ [(2R,4r,6S)- 2,6-dimethyloxan-4-yl]oxy ⁇ phenyl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine formic acid salt (140.0 mg, 0.240 mmol), potassium acetate (71.06 mg, 0.720 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (183.87 mg, 0.720 mmol) were dissolved in 1,4-dioxane (8.7 mL
• Step 2 The crude material from Step 1 was dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL) and stirred overnight at room temperature then concentrated under reduced pressure. The residue was dissolved in MeOH/H 2 O (9:1) and loaded onto an SCX cartridge (5 g).
• 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 (10g). The cartridge was washed with MeOH/H 2 O (9:1) then the product was eluted from the SCX cartridge with a 2M solution of NH3 in MeOH.
• Step 2 The crude material from Step 1 was dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL) and stirred overnight at room temperature then concentrated under reduced pressure. The residue was dissolved in MeOH/H2O (9:1) and loaded onto an SCX cartridge (2 g).
• EXAMPLE 126 [3-(4-AMINOCINNOLIN-7-YL)-4-[(6-OXOPIPERIDIN-3- YL)OXY]PHENYL]BORONIC ACID (126) Palladium(II) diacetate (3.68 mg, 0.020 mmol), 5-[4-chloro-2-[4-[(2,4- dimethoxyphenyl)methylamino]cinnolin-7-yl]phenoxy]piperidin-2-one (170.0 mg, 0.330 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (15.62 mg, 0.030 mmol), potassium acetate (96.44 mg, 0.980 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2
• EXAMPLE 127 2-[4-(4-AMINOCINNOLIN-7-YL)-2-(DIHYDROXYBORANYL)PHENYL]ACETIC ACID (127) Step 1: A mixture of N-[(2,4-dimethoxyphenyl)methyl]-7-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)cinnolin-4-amine (0.93 g, 2.2 mmol), tert-butyl 2- ⁇ 4-chloro-2- [(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4- yl]phenyl ⁇ acetate (0.89 g, 2.2 mmol), potassium dihydrogen phosphate (299.4 mg, 2.2 mmol) and tripotassium phosphate (933.99 mg, 4.4 mmol) in 1,4-diox
• Step 2 The material from step 1 was dissolved in DCM (6 mL) and trifluoroacetic acid (3 mL) and the mixture stirred for 3 hours at room temperature.
• 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 (10g). The cartridge was washed with MeOH/H2O (9:1) then the product was eluted from the SCX cartridge with a 2M solution of NH 3 in MeOH.
• EXAMPLE 129 [3-(4-AMINOQUINOLIN-6-YL)-4-METHOXYPHENYL]BORONIC ACID FORMIC ACID SALT (129)
• Step 1 Palladium(II) diacetate (14.16 mg, 0.060 mmol), 6-(5-chloro-2- methoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]quinolin-4-amine (590.0 mg, 1.26 mmol), potassium acetate (371.45 mg, 3.78 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (961.14 mg, 3.78 mmol) were dissolved in 1,4-dioxane (34 mL) and the mixture was degassed with Ar for 10 minutes.
• Step 2 The crude material from Step 1 was dissolved in DCM (3 mL) and trifluoroacetic acid (3 mL) and stirred overnight at room temperature then it was concentrated under reduced pressure. The residue was dissolved in MeOH/H2O (9:1) and loaded onto an SCX cartridge (20 g). The cartridge was washed with MeOH/H 2 O (9:1) and the product was eluted from the SCX cartridge with a 2 M solution of NH3 in MeOH.
• EXAMPLE 130 [3-(8-AMINO-1,7-NAPHTHYRIDIN-3-YL)-4-METHOXYPHENYL]BORONIC ACID FORMIC ACID SALT (130) Palladium(II) diacetate (4.12 mg, 0.020 mmol), 3-(5-chloro-2-methoxyphenyl)-N- [(2,4-dimethoxyphenyl)methyl]-1,7-naphthyridin-8-amine (160.0 mg, 0.370 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (14.0 mg, 0.030 mmol), potassium acetate (108.07 mg, 1.1 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (279.63 mg,
• EXAMPLE 132 7-[2-(DIFLUOROMETHOXY)-5-[(1S,2S,6R,8S)-2,6,9,9-TETRAMETHYL-3,5- DIOXA-4-BORATRICYCLO[6.1.1.02 , 6]DECAN-4-YL]PHENYL]CINNOLIN-4-AMINE (132) A suspension of [3-(4-aminocinnolin-7-yl)-4-(difluoromethoxy)phenyl]boronic acid (60.0 mg, 0.180 mmol) and (1S,3R,4S,5S)-3,4,6,6-tetramethylbicyclo[3.1.1]heptane-3,4-diol (32.73 mg, 0.180 mmol) in THF (1.9 mL) was stirred overnight at 50°C, then the mixture was concentrated in vacuo.
• EXAMPLE 134 [5-(4-AMINOCINNOLIN-7-YL)-4-METHOXY-2-METHYLPHENYL]BORONIC ACID FORMIC ACID SALT (134)
• Step 1 Palladium(II) diacetate (8.36 mg, 0.040 mmol), 7-(5-chloro-2-methoxy-4- methylphenyl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (335.0 mg, 0.740 mmol), potassium acetate (219.21 mg, 2.23 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (567.22 mg, 2.23 mmol) were dissolved in 1,4-dioxane (12.5 mL) and the mixture was degassed with Ar for 10 minutes.
• Step 2 The crude material from Step 1 was dissolved in DCM (8 mL) and trifluoroacetic acid (6.5 mL) and stirred for seven hours at room temperature then it was concentrated under reduced pressure. The residue was dissolved in MeOH/H 2 O (9:1) and loaded onto an SCX cartridge (20 g).
• EXAMPLE 135 7-(5- ⁇ 2,4-DIOXA-3-BORATETRACYCLO[5.3.1.15 , 9.01 , 5]DODECAN-3-YL ⁇ -2- METHOXYPHENYL)CINNOLIN-4-AMINE (135)
• 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 (10g). The cartridge was washed with MeOH/H2O (9:1) then the product was eluted from the SCX cartridge with a 2M solution of NH 3 in MeOH.
• EXAMPLE 138 [7-(4-AMINOCINNOLIN-7-YL)-2,3-DIHYDRO-1-BENZOFURAN-5-YL]BORONIC ACID FORMIC ACID SALT (138)
• Step 1 Palladium(II) diacetate (3.63 mg, 0.020 mmol), 7-(5-chloro-2,3-dihydro-1- benzofuran-7-yl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (145.0 mg, 0.320 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (12.35 mg, 0.030 mmol), potassium acetate (95.31 mg, 0.970 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,
• 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 (10g). The cartridge was washed with MeOH/H2O (9:1) then the product was eluted from the SCX cartridge with a 2M solution of NH 3 in MeOH.
• EXAMPLE 140 7-[2-(DIFLUOROMETHOXY)-4-METHYL-5-[(1S,2S,6R,8S)-2,9,9-TRIMETHYL- 3,5-DIOXA-4-BORATRICYCLO[6.1.1.02 , 6]DECAN-4-YL]PHENYL]CINNOLIN-4-AMINE (140) 7-[2-(Difluoromethoxy)-4-methyl-5-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.0 2,6 ]decan-4-yl]phenyl]-N- [(2,4-dimethoxyphenyl)methyl]cinnolin-4- amine (850.0 mg, 1.35 mmol) was dissolved in DCM (5 mL) and trifluoroacetic acid (4 mL) and the mixture stirred at room temperature for 4 hours.
• Step 2 The crude material from Step 1 was dissolved in DCM (6 mL) and trifluoroacetic acid (6 mL) was stirred overnight at room temperature. The volatiles were removed and the residue was dissolved in MeOH, then loaded onto an SCX cartridge (20 g). The cartridge was washed with MeOH and eluted with 2M solution of ammonia in MeOH.
• Step 2 The crude material from Step 1 was dissolved in DCM (5 mL) and trifluoroacetic acid (4 mL) and stirred for four hours at room temperature then concentrated under reduced pressure. The residue was dissolved in MeOH/H 2 O (9:1) and loaded onto an SCX cartridge (10 g).
• Step 2 The crude material from Step 1 was dissolved in a mixture of DCM (3 mL) and trifluoroacetic acid (3 mL). The mixture was stirred overnight at room temperature and the volatiles were evaporated. The residue was dissolved in MeOH and loaded onto an SCX cartridge (10g). The cartridge was washed with MeOH/H 2 O (9:1) then the product was eluted from the SCX cartridge with a 2M solution of NH3 in MeOH.
• EXAMPLE 144 (3- ⁇ 4-AMINOPYRIDO[3,2-C]PYRIDAZIN-7-YL ⁇ -4-METHOXYPHENYL)BORONIC ACID (144)
• Step 1 A mixture of 7-(5-chloro-2-methoxyphenyl)-N-[(2,4- dimethoxyphenyl)methyl]pyrido[3,2-c]pyridazin-4-amine (54.0 mg, 0.110 mmol), 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (86.63 mg, 0.340 mmol) and potassium acetate (33.48 mg, 0.340 mmol) in 1,4-dioxane (1.5 mL) was degassed for 10 minutes under argon, then dicyclohexyl-[2-[2,4,6-tri(propan-2- yl)phen
• Step 2 The crude material from Step 1 was dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL) and the mixture was stirred for 2 hours at room temperature, then further trifluoroacetic acid (1 mL) was added and the mixture was stirred for an additional 3 hours. The volatiles were removed under reduced pressure. The residue was dissolved in MeOH/H 2 O (9:1), then loaded onto an SCX cartridge (5 g), which was washed with MeOH/H2O (9:1) and then eluted with a 7 M solution of ammonia in MeOH.
• EXAMPLE 145 [8-(4-AMINOCINNOLIN-7-YL)-3,4-DIHYDRO-2H-CHROMEN-6-YL]BORONIC ACID FORMIC ACID SALT (145)
• Step 1 Palladium(II) diacetate (2.19 mg, 0.010 mmol), 7-(6-chloro-3,4-dihydro-2H- chromen-8-yl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (90.0 mg, 0.190 mmol), potassium acetate (57.36 mg, 0.580 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2- yl)phenyl]phenyl]phosphine (7.43 mg, 0.020 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-d
• Step 2 The crude material from Step 1 was dissolved in DCM (3 mL) and trifluoroacetic acid (2 mL) and stirred for seven hours at room temperature then it was concentrated under reduced pressure. The residue was dissolved in MeOH/H 2 O (9:1) and loaded onto an SCX cartridge (5 g).
• the resulting reaction mixture was stirred at 80°C for 4 hours then it was cooled to room temperature and filtered over Celite, washing with MeOH. The filtrate was evaporated under reduced pressure and the residue was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (3 mL). The resulting mixture was stirred overnight at room temperature then concentrated under reduced pressure. The residue was dissolved in MeOH/H2O (9:1), loaded onto an SCX cartridge and the cartridge was left to stand for 20 min. The cartridge was then washed with MeOH/H2O (9:1) and eluted with 7 M methanolic ammonia solution. The basic fractions were collected and evaporated under reduced pressure.
• Step 2 The crude material from Step 1 was dissolved in trifluoroacetic acid (2.5 mL) and DCM (3 mL) and stirred at room temperature for 17 hours, then it was evaporated in vacuo. The residue was taken up in MeOH and loaded onto an SCX cartridge (5 g) which was washed with MeOH and then eluted with a 7M solution of ammonia in MeOH. The basic fractions were collected and evaporated under reduced pressure. The residue was purified by flash chromatography (Sfar C18 D, 30 g), eluting with a gradient of MeCN (+0.1% of HCOOH) in water (+0.1% of HCOOH) from 1% to 35%.
• Step 2 The crude material from Step 1 was dissolved in DCM (3 mL) and trifluoroacetic acid (2 mL) was stirred overnight at room temperature then it was concentrated under reduced pressure. The residue was dissolved in MeOH/H 2 O (9:1) and loaded onto an SCX cartridge (5 g).
• EXAMPLE 150 [3-(4-AMINOCINNOLIN-7-YL)-4-(PYRROLIDIN-1-YL)PHENYL]BORONIC ACID FORMIC ACID SALT (150)
• Step 1 A mixture of 7 ⁇ [5 ⁇ chloro ⁇ 2 ⁇ (pyrrolidin ⁇ 1 ⁇ yl)phenyl] ⁇ N ⁇ [(2,4 ⁇ dimethoxyphenyl)methyl]cinnolin ⁇ 4 ⁇ amine (79.0 mg, 0.170 mmol), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (126.71 mg, 0.500 mmol) and potassium acetate (48.97 mg, 0.500 mmol) in 1,4-dioxane (3 mL) was degassed for 10 minutes under argon, then dicyclohexyl-[2-[2,4,6-tri(propan-2-y
• Step 2 The crude material from Step 1 was dissolved in trifluoroacetic acid (2 mL) and DCM (3 mL). The resulting mixture was stirred at room temperature for 7 hours, then additional trifluoroacetic acid (2 mL) was added and the mixture was stirred for a further 24 hours. The volatiles were removed under reduced pressure.
• Step 1 A solution of tert ⁇ butyl[(1 ⁇ 4 ⁇ chloro ⁇ 2 ⁇ [(1S,2S,6R,8S) ⁇ 2,9,9 ⁇ trimethyl ⁇ 3,5 ⁇ dioxa ⁇ 4 ⁇ boratricyclo[6.1.1.0 2,6 ]decan ⁇ 4 ⁇ yl]phenyl ⁇ 3 ⁇ methylbutan ⁇ 2 ⁇ yl)oxy]dimethylsilane (131.11 mg, 0.270 mmol), N-[(2,4-dimethoxyphenyl)methyl]-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)cinnolin-4-amine (125.0 mg, 0.300 mmol) and aqueous 2N sodium carbonate solution (296.7 uL, 0.590 mmol) in 1,2-dimethoxyethane (3 mL) was degassed for 10 min with N 2 .
• 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 in vacuo.
• EXAMPLE 156 7-(4-AMINOCINNOLIN-7-YL)-1H-2,3,1-BENZOXAZABORININ-1-OL FORMIC ACID SALT (156) N-[(2,4-Dimethoxyphenyl)methyl]-7-(1-hydroxy-2,3,1-benzoxazaborinin-7- yl)cinnolin-4-amine (27.0 mg, 0.060 mmol) was dissolved in DCM (1.5 mL) and trifluoroacetic acid (1.5 mL) and the mixture was stirred at room temperature for 4 hours, then it was concentrated under reduced pressure.
• 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 overnight at room temperature then concentrated under reduced pressure. The residue was dissolved in MeOH/H2O (9:1) and loaded onto an SCX cartridge (5 g).
• EXAMPLE 158 [3-(4-HYDROXYCINNOLIN-7-YL)-4-METHOXYPHENYL]BORONIC ACID (158)
• the crude reaction mixture from a preparation of Intermediate 19 starting with 50g of 7-(5-chloro-2-methoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine following a similar procedure to that described above was cooled in an ice bath and H2O was added causing precipitation of Intermediate 19. The mixture was stirred for 10 minutes and filtered. The filtrate was concentrated, quenched with saturated aqueous NH 4 Cl solution and extracted three times with EtOAc.
• EXAMPLE 159 [3-(4-AMINOCINNOLIN-7-YL)-4-(2H3)METHOXYPHENYL]BORONIC ACID FORMIC ACID SALT (159)
• Step 1 A mixture of 7 ⁇ [5 ⁇ chloro ⁇ 2 ⁇ ( 2 H 3 )methoxyphenyl] ⁇ N ⁇ [(2,4 ⁇ dimethoxyphenyl)methyl]cinnolin ⁇ 4 ⁇ amine (690.0 mg, 1.57 mmol), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.2 g, 4.72 mmol) and potassium acetate (462.84 mg, 4.72 mmol) in 1,4-dioxane (20 mL) was degassed for 10 minutes under argon.
• Step 2 The crude material from Step 1 was dissolved in DCM (5 mL) and trifluoroacetic acid (5 mL) and the mixture was stirred for 24 hours, then the volatiles were removed under reduced pressure. The residue was dissolved in MeOH/water (9:1) and loaded onto 2 SCX cartridges (10 g each) each of which was washed with MeOH and then eluted with a 7M solution of ammonia in MeOH. The basic fractions from both cartridges were collected and evaporated under reduced pressure. The residue was purified by flash chromatography (Sfar C18 D, 60 g) eluting with a gradient of MeCN (+0.1% of HCOOH) in water (+0.1% of HCOOH) from 1% to 35%.
• EXAMPLE 163 [3-(4-AMINOCINNOLIN-7-YL)-4-(1,1-DIFLUOROETHOXY)PHENYL]BORONIC ACID FORMIC ACID SALT (163)
• Step 1 Palladium(II) diacetate (3.47 mg, 0.020 mmol), 7-[5-chloro-2-(1,1- difluoroethoxy)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (150.0 mg, 0.310 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (11.77 mg, 0.020 mmol), potassium acetate (90.89 mg, 0.930 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-di
• 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/H 2 O (9:1) and then the product was eluted from the SCX cartridge with a 2M solution of NH3 in MeOH.
• EXAMPLE 164 [3-(4-AMINOCINNOLIN-7-YL)-4-METHANESULFONYLPHENYL]BORONIC ACID FORMIC ACID SALT (164) O O S O N OH N B HO OH NH 2 Palladium(II) diacetate (6.61 mg, 0.030 mmol), 7-(5-chloro-2-methylsulfonylphenyl)- N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (285.0 mg, 0.590 mmol), dicyclohexyl-[2- [2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (28.07 mg, 0.060 mmol), potassium acetate (173.38 mg, 1.77 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1,3,2-di
• EXAMPLE 165 [3-(4-AMINOCINNOLIN-7-YL)-4-(1,1-DIOXO-1,2,5-THIADIAZOLIDIN-2- YL)PHENYL]BORONIC ACID (165) Palladium(II) diacetate (3.51 mg, 0.020 mmol), tert-butyl 5-[4-chloro-2-[4-[(2,4- dimethoxyphenyl)methylamino]cinnolin-7-yl]phenyl]-1,1-dioxo-1,2,5-thiadiazolidine-2- carboxylate (196.0 mg, 0.310 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2- yl)phenyl]phenyl]phosphine (14.92 mg, 0.031 mmol), potassium acetate (92.16 mg, 0.940 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5-t
• EXAMPLE 166 7-[2-(3,3-DIFLUOROCYCLOBUTOXY)-5-[(1R,2R,6S,8R)-2,9,9-TRIMETHYL- 3,5-DIOXA-4-BORATRICYCLO[6.1.1.02 , 6]DECAN-4-YL]PHENYL]CINNOLIN-4-AMINE; FORMIC ACID (166) A mixture of [3-(4-aminocinnolin-7-yl)-4-(3,3-difluorocyclobutyl)oxyphenyl]boronic acid formic acid salt (38.0 mg, 0.090 mmol) and (1R,3S,4R,5R)-4,6,6- trimethylbicyclo[3.1.1]heptane-3,4-diol (15.51 mg, 0.090 mmol) in THF (0.997 mL) was stirred overnight at 50°C.
• Step 1 Palladium(II) diacetate (4.79 mg, 0.020 mmol), 7-[5-chloro-2-(4- fluorophenoxy)phenyl]-N-[(2,4-dimethoxyphenyl)methyl]cinnolin-4-amine (220 mg, 0.430 mmol), dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphine (20.33 mg, 0.040 mmol), potassium acetate (125.54 mg, 1.28 mmol), and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (324.83 mg, 1.28 mmol) were dissolved in 1,4-dioxane (5 mL).
• 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/H2O (9:1) and then the product was eluted from the SCX cartridge with a 2M solution of NH 3 in MeOH.
• 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/H2O (9:1) and then the product was eluted from the SCX cartridge with a 2M solution of NH 3 in MeOH.
• EXAMPLE 171 [3-(4-AMINOCINNOLIN-7-YL)-4-(2-METHYLTHIAZOL-5-YL)OXY- PHENYL]BORONIC ACID FORMIC ACID SALT (171) Palladium(II) diacetate (2.7 mg, 0.010 mmol), 7-[5-chloro-2-(2-methylthiazol-5- yl)oxy-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 (11.48 mg, 0.020 mmol), potassium acetate (70.91 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-diox
• Example 172 Preparation of Exemplary Intermediates.
• INTERMEDIATE 1 6-BROMO-1-CHLOROPHTHALAZINE A solution of 6-bromophthalazin-1(2H)-one (3.2 g, 14.22 mmol) in phosphorus oxychloride (20.8 mL, 222.47 mmol) was stirred at 100°C for 1 h. Then the phosphorus oxychloride was removed under reduced pressure. The residue was cooled in an ice bath and then quenched with 2N aqueous NaOH solution until the pH was basic.
• reaction was stirred for 30 min at -5°C, then for 30 min at room temperature and then the temperature was slowly raised to 60°C.
• the reaction mixture was heated at 60°C for 2 h, then it was cooled to room temperature and the resulting precipitate was filtered, washed with water, dried in the oven at 50°C overnight to give 7-bromocinnolin-1-ium-4-ol hydrochloride (7.463 g, 28.54 mmol, 61.09% yield) as a brownish powder.
• Step 2 To a solution of the mixture from Step 1 (50.0 mg, 0.110 mmol) in DCM (2 mL), trifluoroacetic acid (2 mL) was added and mixture was stirred at room temperature for 2h.
• INTERMEDIATE 58 6-(5-CHLOROPYRIDIN-3-YL)-N-[(2,4-DIMETHOXYPHENYL)METHYL]-4- METHYLPHTHALAZIN-1-AMINE
• the reaction vessel was degassed for 10 minutes with N2 and then stirred at room temperature for 1 hour. 3,4,7,8-Tetramethyl-1,10- phenanthroline (8.09 mg, 0.030 mmol) and (1Z,5Z)-cycloocta-1,5-diene iridium methyloxonium (11.41 mg, 0.020 mmol) were added and the reaction vessel was sealed and heated at 80°C for 16 h. The reaction mixture was allowed to return to room temperature and then it was exposed to air, diluted with methanol and concentrated under reduced pressure.
• INTERMEDIATE 68 6-[5-CHLORO-2-METHOXY-4-(OXAN-2-YLOXYMETHYL)PHENYL]-N- [(2,4-DIMETHOXYPHENYL)METHYL]-4-METHYLPHTHALAZIN-1-AMINE O O O N Cl N HN O O

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• General Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Immunology (AREA)
• Neurology (AREA)
• Ophthalmology & Optometry (AREA)
• Neurosurgery (AREA)
• Biomedical Technology (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Transplantation (AREA)
• Psychiatry (AREA)
• Hospice & Palliative Care (AREA)
• Diabetes (AREA)
• Obesity (AREA)
• Hematology (AREA)
• Biochemistry (AREA)
• Molecular Biology (AREA)
• Pulmonology (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Physical Education & Sports Medicine (AREA)
• Urology & Nephrology (AREA)
• Vascular Medicine (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Psychology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

Priority Applications (13)

Applications Claiming Priority (2)

Publications (1)

Family

ID=79729495

Family Applications (1)

Country Status (18)

Cited By (5)

Citations (7)

Family Cites Families (20)

• 2021
  • 2021-07-19 WO PCT/US2021/042198 patent/WO2022020244A1/en not_active Ceased
  • 2021-07-19 CN CN202310870524.5A patent/CN116947903A/zh active Pending
  • 2021-07-19 EP EP21845924.6A patent/EP4185592A4/en active Pending
  • 2021-07-19 AU AU2021311455A patent/AU2021311455A1/en active Pending
  • 2021-07-19 KR KR1020237005805A patent/KR20230041758A/ko active Pending
  • 2021-07-19 PE PE2023000109A patent/PE20231435A1/es unknown
  • 2021-07-19 JP JP2023503413A patent/JP7793595B2/ja active Active
  • 2021-07-19 CN CN202180059041.6A patent/CN116261564A/zh active Pending
  • 2021-07-19 AR ARP210102028A patent/AR123011A1/es unknown
  • 2021-07-19 IL IL299840A patent/IL299840A/en unknown
  • 2021-07-19 CA CA3186022A patent/CA3186022A1/en active Pending
  • 2021-07-19 MX MX2023000919A patent/MX2023000919A/es unknown
  • 2021-07-19 US US17/379,334 patent/US11814404B2/en active Active
  • 2021-07-19 PH PH1/2023/550153A patent/PH12023550153A1/en unknown
  • 2021-07-19 BR BR112023001007A patent/BR112023001007A2/pt unknown
  • 2021-07-20 UY UY0001039331A patent/UY39331A/es unknown
  • 2021-07-20 TW TW110126637A patent/TW202216168A/zh unknown
• 2023
  • 2023-01-19 CL CL2023000191A patent/CL2023000191A1/es unknown
  • 2023-01-20 CO CONC2023/0000683A patent/CO2023000683A2/es unknown
  • 2023-10-04 US US18/376,526 patent/US12509474B2/en active Active
• 2025
  • 2025-11-20 US US19/395,200 patent/US20260070932A1/en active Pending

Patent Citations (7)

Non-Patent Citations (12)

Also Published As

Similar Documents

Legal Events