US20200190095A1 - Pyrimido-pyridazinone compounds and methods of use thereof - Google Patents

Pyrimido-pyridazinone compounds and methods of use thereof Download PDF

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US20200190095A1
US20200190095A1 US16/800,111 US202016800111A US2020190095A1 US 20200190095 A1 US20200190095 A1 US 20200190095A1 US 202016800111 A US202016800111 A US 202016800111A US 2020190095 A1 US2020190095 A1 US 2020190095A1
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pyridazin
amino
phenyl
oxo
dihydropyrimido
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Aranapakam Venkatesan
Roger Smith
Subramanya Hosahalli
Vijay Potluri
Sunil Kumar Panigrahi
Vishnu Basetti
Karunasree Kunta
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Abs Development 1 Inc
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Asana Biosciences LLC
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Definitions

  • Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within cells. Almost all kinases contain a similar 250 to 300 amino acid catalytic domain. The kinases can be categorized into families by the substrates they phosphorylate.
  • JAK2 (Janus kinase 2) is a family of intracellular non-receptor tyrosine kinases. JAK2 is expressed ubiquitously in hematopoietic cells and abundantly in primary leukemic cells from children with acute lymphoblastic leukemia.
  • the downstream substrates of JAK include the signal tranducer activator of transcription (STAT) proteins. STAT proteins function both as signaling molecules and transcription factors and ultimately bind to specific DNA sequences present in the promoters of cytokine-responsive genes.
  • STAT signal tranducer activator of transcription
  • JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses such as allergies, asthma, autoimmune diseases such as transplant (allograft) rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, as well as in solid and hematologic malignancies such as leukemia and lymphomas.
  • Spleen tyrosine kinase is a member of the syk family of protein tyrosine kinases and plays a crucial role in inflammatory and allergic responses. Syk triggers IgE and IgG receptor mediated signaling in mast cells, basophils, and macrophages leading to degranulation and cytokine release.
  • ITAM-mediated signaling has emerged as a primary event in signaling pathways responsible for human pathologies.
  • ITAM-mediated signaling is responsible for relaying activation signals initiated at classical immune receptors such as T-cell receptors, B-cell receptors, and Fc receptors in immune cells and at GPVI and Fc ⁇ RIIa in platelets to downstream intracellular molecules such as Syk.
  • the binding of a ligand to an ITAM-containing receptor triggers signaling events which allows for the recruitment of proteins from a family of nonreceptor tyrosine kinases called the Src family. These kinases phosphorylate tyrosine residues within the ITAM sequence, a region with which the tandem SH2 domains on either Syk or ZAP-70 interact. The interaction of Syk with diphosphorylated ITAM sequences induces a conformation change in the kinases that allows for tyrosine phosphorylation of the kinase itself.
  • kinases not only do these kinases contribute to normal host defense, they also play roles in the pathogenesis of diseases. Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, Alzheimer's disease and hormone-related diseases. As a consequence, there have been substantial efforts in medicinal chemistry to find inhibitors of protein kinases for use as therapeutic agents.
  • the present invention provides a compound of Formula (I), wherein R 1 and R 2 are defined herein.
  • the invention provides a pharmaceutical composition containing a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • the invention provides a method for co-regulating JAK-2 and Syk by administering a therapeutically effective amount of a compound of Formula (I) to a patient in need thereof.
  • methods for treating inflammation include administering a compound of Formula (I) to a patient in need thereof.
  • FIGS. 1A, 1B, 2A and 2B provide comparative data illustrating the anti-inflammatory effects of methotrexate, a known anti-inflammatory, and a compound described herein which is encompassed by the compound of Formula (I), using the Collagen Induced Arthritis (CIA) model of human rheumatoid arthritis (RA) in female lewis rats.
  • CIA Collagen Induced Arthritis
  • RA rheumatoid arthritis
  • FIG. 1A illustrates anti-inflammatory effects as a function of the amount of edema (mL) vs. time (days).
  • the black diamonds ( ⁇ ) represent results for the control.
  • the triangles ( ⁇ ) represent results for the compound of Example 19.
  • the crosses (x) represent results for methotrexate.
  • FIG. 1B illustrates anti-inflammatory effects as a function of the amount of edema (mL) vs. time (days).
  • the circles ( ⁇ ) represent results for the control.
  • the inverted triangles ( ⁇ ) represent results for the compound of Example 62.
  • the astericks (*) represent results for the compound of Example 108.
  • the squares ( ⁇ ) represent results for the compound of Example 189.
  • the diamonds ( ⁇ ) represent results for the compound of Example 191.
  • FIG. 2A illustrates anti-inflammatory effects as a function of arhtritic score (per rat) vs. time (days).
  • the black diamonds ( ⁇ ) represent results for the control.
  • the triangles ( ⁇ ) represent results for the compound of Example 19.
  • the crosses (x) represent results for methotrexate.
  • FIG. 2B illustrates anti-inflammatory effects as a function of arhtritic score (per rat) vs. time (days).
  • the circles ( ⁇ ) represent results for the control.
  • the triangles ( ⁇ ) represent results for the compound of Example 62.
  • the astericks (*) represent results for the compound of Example 108.
  • the squares ( ⁇ ) represent results for the compound of Example 189.
  • the diamonds ( ⁇ ) represent results for the compound of Example 191.
  • the invention provides compounds and pharmaceutical composition thereof, which are capable of reducing or eliminating inflammation caused by tissue insult, injury, or pathology.
  • the invention further provides compounds and compositions which function through a protein kinase inhibitory mechanism.
  • the present invention provides a compound of Formula (I):
  • R 1 is NR 4 R 5 , optionally substituted C 1 to C 6 alkoxy, optionally substituted C 6 to C 14 aryl, optionally substituted heteroaryl, optionally substituted 3-10 membered monocyclic or bicyclic cycloalkyl, or optionally substituted 3-10 membered monocyclic or bicyclic heterocyclyl.
  • the 3-4 membered cycloalkyl and heterocyclyl are saturated.
  • the hydrogen atoms on the same carbon atom of the cycloalkyl or heterocyclyl are optionally replaced with an optionally substituted 3-6 membered cycloalkyl or heterocyclyl to form a spirocycloalkyl or spiroheterocyclyl.
  • the hydrogen atoms on the same atom of the cycloalkyl or heterocyclyl are optionally replaced with O to form an oxo substituent.
  • a compound of Formula (I) wherein R 1 is NR 4 R 5 , optionally substituted C 1 to C 6 alkoxy, optionally substituted C 6 to C 14 aryl, optionally substituted heteroaryl, optionally substituted 3-10 membered monocyclic or bicyclic cycloalkyl, or optionally substituted 3-10 membered monocyclic or bicyclic heterocyclyl.
  • R 1 is NR 4 R 5 , optionally substituted C 1 to C 6 alkoxy, optionally substituted C 6 to C 14 aryl, optionally substituted heteroaryl, optionally substituted 3-10 membered monocyclic or bicyclic cycloalkyl, or optionally substituted 3-10 membered monocyclic or bicyclic heterocyclyl.
  • the 3-4 membered cycloalkyl and heterocyclyl rings are saturated.
  • Hydrogen atoms on the same carbon atom of the cycloalkyl or heterocyclyl are optionally replaced with an optionally substituted 3-6 membered cycloalkyl or heterocyclyl to form a spirocycloalkyl or spiroheterocyclyl.
  • hydrogen atoms on the same atom of the cycloalkyl or heterocyclyl are optionally replaced with O to form an oxo substituent.
  • R 2 is phenyl or 5-6 membered heteroaryl containing at least one N or NH in the backbone, wherein R 2 is optionally substituted with one or more R 19 and when R 2 is 4-pyridyl, the 4-pyridyl lacks a carbonyl substituent at the 2 nd position.
  • R 19 is NR 4 R 5 , (C 1 to C 6 alkyl)NR 4 R 5 , C 1 to C 6 alkyl, C(O)NR 4 R 5 , C 3 to C 8 cycloalkyl substituted with one or more R 21 , or heterocyclyl substituted with one or more R 21 .
  • R 21 is (C 1 to C 6 alkyl)CN, (C 1 to C 6 alkyl)C(O)OH, (C 1 to C 6 alkyl)C(O)NH 2 , (C 1 to C 6 alkyl)C(O)NHCH 2 CH 2 OH, or (C 1 to C 6 alkyl)C(O)N(CH 2 CH 2 OH) 2 .
  • R 4 and R 5 are independently selected from among H, C 1 to C 6 alkyl, C 1 to C 6 hydroxyalkyl, and (C 1 to C 6 alkyl)N(C 1 to C 6 alkyl)(C 1 to C 6 alkyl).
  • R 4 and R 5 are joined to form an optionally substituted 3-8 membered heterocyclyl optionally further containing one or more O, S(O) n , or NR 9 .
  • R 9 is H, OH, (C 1 to C 6 alkyl)C(O)OH, (C 1 to C 6 alkyl)C(O)NH 2 , (C 1 to C 6 alkyl)C(O)NHCH 2 CH 2 OH, (C 1 to C 6 alkyl)C(O)N(CH 2 CH 2 OH) 2 , C(O)(C 1 to C 6 alkyl)NH 2 , C(O)(C 1 to C 6 alkyl)OH, C 1 to C 6 hydroxyalkyl, or C 1 to C 6 alkyl and n is 0 to 2.
  • R 9 is CH 2 CH 2 OH.
  • Hydrogen atoms on the same carbon atom of the heterocyclyl are optionally replaced with a 3-6 membered cycloalkyl or heterocyclyl optionally substituted with one or more R 20 to form a spirocycloalkyl or spiroheterocyclyl.
  • R 20 is C(O)O(C 1 to C 6 alkyl), C(O)OH, (C 1 to C 6 alkyl)C(O)OH, (C 1 to C 6 alkyl)C(O)NH 2 , (C 1 to C 6 alkyl)C(O)NHCH 2 CH 2 OH, or (C 1 to C 6 alkyl)C(O)N(CH 2 CH 2 OH) 2 .
  • hydrogen atoms on the same atom of any of the heterocyclyls or cycloalkyls of R 9 are optionally replaced with O to form an oxo substituent; or a pharmaceutically acceptable salt or ester thereof.
  • a compound of Formula (I) wherein R 1 is NR 4 R 5 , C 1 to C 6 alkoxy, optionally substituted phenyl, heteroaryl, optionally substituted 3-10 membered cycloalkyl, or optionally substituted 3-10 membered monocyclic or bicyclic heterocyclyl. Hydrogen atoms on the same carbon atom of the cycloalkyl or heterocyclyl are optionally replaced with an optionally substituted 3-6 membered cycloalkyl or heterocyclyl to form a spirocycloalkyl or spiroheterocyclyl.
  • R 2 is phenyl or pyrazole, wherein R 2 is optionally substituted with one or more R 19 .
  • R 19 is NR 4 R 5 , (C 1 to C 6 alkyl)NR 4 R 5 , C 1 to C 6 alkyl, C(O)NR 4 R 5 , C 3 to C 8 cycloalkyl substituted with one or more R 21 , or heterocyclyl substituted with one or more R 21 .
  • R 21 is (C 1 to C 6 alkyl)CN, (C 1 to C 6 alkyl)C(O)OH, (C 1 to C 6 alkyl)C(O)NH 2 , (C 1 to C 6 alkyl)C(O)NHCH 2 CH 2 OH, (C 1 to C 6 alkyl)C(O)N(CH 2 CH 2 OH) 2 .
  • R 4 and R 5 are (a) independently selected from among H, C 1 to C 6 alkyl, C 1 to C 6 hydroxyalkyl, and (C 1 to C 6 alkyl)N(C 1 to C 6 alkyl)(C 1 to C 6 alkyl) or (b) joined to form an optionally substituted 3-8 membered heterocyclyl optionally further containing one or more O, S(O) n , or NR 9 .
  • R 9 is H, OH, C 1 to C 6 hydroxyalkyl, (C 1 to C 6 alkyl)C(O)OH, (C 1 to C 6 alkyl)C(O)NH 2 , (C 1 to C 6 alkyl)C(O)NHCH 2 CH 2 OH, (C 1 to C 6 alkyl)C(O)N(CH 2 CH 2 OH) 2 , C(O)(C 1 to C 6 alkyl)NH 2 , C(O)(C 1 to C 6 alkyl)OH, or C 1 to C 6 alkyl and n is 0 to 2.
  • R 9 is CH 2 CH 2 OH.
  • R 20 is C(O)O(C 1 to C 6 alkyl), C(O)OH, (C 1 to C 6 alkyl)C(O)OH, (C 1 to C 6 alkyl)C(O)NH 2 , (C 1 to C 6 alkyl)C(O)NHCH 2 CH 2 OH, or (C 1 to C 6 alkyl)C(O)N(CH 2 CH 2 OH) 2 .
  • hydrogen atoms on the same atom of the heterocyclyl (b) or cycloalkyl are optionally replaced with O to form an oxo substituent; or a pharmaceutically acceptable salt or ester thereof.
  • a compound of Formula (I) wherein R 1 is NR 4 R 5 , C 1 to C 6 alkoxy, phenyl optionally substituted with C(O)O(C 1 to C 6 alkyl), C(O)OH, O(C 1 to C 3 perfluoroalkyl), C 1 to C 6 alkoxy, halogen, CH 2 -heterocyclyl, or CH 2 CN, 5-8 membered cycloalkyl, heteroaryl, or 3-10 membered monocyclic or bicyclic heterocyclyl optionally substituted with (C 1 to C 6 alkyl)C(O)OH, C 1 to C 6 alkyl, CN, C(O)OH, or (C 1 to C 6 alkyl)CN.
  • Hydrogen atoms on the same carbon atom of the cycloalkyl or heterocyclyl are optionally replaced with an optionally substituted 3-6 membered cycloalkyl or heterocyclyl to form a spirocycloalkyl or spiroheterocyclyl.
  • hydrogen atoms on the same atom of the cycloalkyl or heterocyclyl are optionally replaced with O to form an oxo substituent.
  • R 2 is phenyl or pyrazole, wherein R 2 is optionally substituted with one R 19 .
  • R 19 is NR 4 R 5 , (C 1 to C 6 alkyl)NR 4 R 5 , C 1 to C 6 alkyl, C(O)NR 4 R 5 , C 3 to C 8 cycloalkyl substituted with one or more R 21 , or heterocyclyl substituted with one or more R 21 .
  • R 21 is (C 1 to C 6 alkyl)CN, (C 1 to C 6 alkyl)C(O)OH, (C 1 to C 6 alkyl)C(O)NH 2 , (C 1 to C 6 alkyl)C(O)NHCH 2 CH 2 OH, or (C 1 to C 6 alkyl)C(O)N(CH 2 CH 2 OH) 2 .
  • R 4 and R 5 are (a) independently selected from among H, C 1 to C 6 alkyl, C 1 to C 6 hydroxyalkyl, and (C 1 to C 6 alkyl)N(C 1 to C 6 alkyl)(C 1 to C 6 alkyl).
  • R 4 and R 5 may also be (b) joined to form a 5-8 membered heterocyclyl optionally further containing one or two O, S(O) n , or NR 9 .
  • R 9 is H, OH, C 1 to C 6 hydroxyalkyl (C 1 to C 6 alkyl)C(O)OH, C(O)(C 1 to C 6 alkyl)NH 2 , C(O)(C 1 to C 6 alkyl)OH, (C 1 to C 6 alkyl)C(O)NH 2 , (C 1 to C 6 alkyl)C(O)NHCH 2 CH 2 OH, (C 1 to C 6 alkyl)C(O)N(CH 2 CH 2 OH) 2 , or C 1 to C 6 alkyl and n is 0 to 2.
  • R 9 is CH 2 CH 2 OH.
  • Hydrogen atoms on the same carbon atom of the heterocyclyl are optionally replaced with a 3-5 membered cycloalkyl optionally substituted with one or more R 20 to form a spirocycloalkyl.
  • R 20 is C(O)O(C 1 to C 6 alkyl), C(O)OH, (C 1 to C 6 alkyl)C(O)OH, (C 1 to C 6 alkyl)C(O)NH 2 , (C 1 to C 6 alkyl)C(O)C(O)C(O)NHCH 2 CH 2 OH, or (C 1 to C 6 alkyl)C(O)N(CH 2 CH 2 OH) 2 .
  • hydrogen atoms on the same atom of the heterocyclyl (b) or cycloalkyl (b) are optionally replaced with O to form an oxo substituent; or a pharmaceutically acceptable salt or ester thereof.
  • Some compounds within the present invention possess one or more chiral centers, and the present invention includes each separate enantiomer of such compounds as well as mixtures of the enantiomers. Where multiple chiral centers exist in compounds of the present invention, the invention includes each possible combination of chiral centers within a compound, as well as all possible enantiomeric and diastereomeric mixtures thereof. All chiral, diastereomeric, and racemic forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials.
  • the number of carbon atoms present in a given group is designated “C x -C y ”, where x and y are the lower and upper limits, respectively.
  • a group designated as “C 1 -C 6 ” contains from 1 to 6 carbon atoms.
  • the carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.
  • the nomenclature of substituents that are not explicitly defined herein are arrived at by naming from left to right the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
  • arylalkyloxycabonyl refers to the group (C 6 -C 14 aryl)-(C 1 -C 6 alkyl)-O—C(O)—.
  • Terms not defined herein have the meaning commonly attributed to them by those skilled in the art.
  • Alkyl refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms, for example, a C 1 -C 12 alkyl group may have from 1 to 12 (inclusive) carbon atoms in it.
  • Examples of C 1 -C 6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
  • C 1 -C 8 alkyl groups include, but are not limited to, methyl, propyl, pentyl, hexyl, heptyl, 3-methylhex-1-yl, 2,3-dimethylpent-2-yl, 3-ethylpent-1-yl, octyl, 2-methylhept-2-yl, 2,3-dimethylhex-1-yl, and 2,3,3-trimethylpent-1-yl.
  • An alkyl group can be unsubstituted or substituted with one or more of halogen, NH 2 , (alkyl)NH, (alkyl)(alkyl)N—, —N(alkyl)C(O)(alkyl), —NHC(O)(alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), CN, OH, alkoxy, alkyl, C(O)OH, —C(O)O(alkyl), —C(O)(alkyl), aryl, heteroaryl, heterocyclyl, cycloalkyl, haloalkyl, aminoalkyl-, —OC(O)(alkyl), carboxyamidoalkyl-, and NO 2 .
  • halogen NH 2 , (alkyl)NH, (alkyl)(alky
  • Alkoxy refers to the group R—O— where R is an alkyl group, as defined above.
  • Exemplary C 1 -C 6 alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy.
  • An alkoxy group can be unsubstituted or substituted with one or more of halogen, OH, alkoxy, NH 2 , (alkyl)amino-, di(alkyl)amino-, (alkyl)C(O)N(C 1 -C 3 alkyl)-, (alkyl)carboxyamido-, HC(O)NH—, H 2 NC(O)—, (alkyl)NHC(O)—, di(alkyl)NC(O)—, CN, C(O)OH, (alkoxy)carbonyl-, (alkyl)C(O)—, aryl, heteroaryl, cycloalkyl, haloalkyl, amino(C 1 -C 6 alkyl)-, (alkyl)carboxyl-, carboxyamidoalkyl-, or NO 2 .
  • Aryl refers to an aromatic 6 to 14 membered hydrocarbon group.
  • Examples of a C 6 -C 14 aryl group include, but are not limited to, phenyl, ⁇ -naphthyl, ⁇ -naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenanaphthyl.
  • Examples of a C 6 -C 10 aryl group include, but are not limited to, phenyl, ⁇ -naphthyl, ⁇ -naphthyl, biphenyl, and tetrahydronaphthyl.
  • An aryl group can be unsubstituted or substituted with one or more of alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, OH, hydroxyalkyl, —O-(hydroxyalkyl), —O-(alkyl)-C(O)OH, -(alkyl)-(alkoxy)-halogen, NH 2 , aminoalkyl-, dialkylamino-, C(O)OH, —C(O)O-(alkyl), —OC(O)(alkyl), —O-(alkyl)-N(alkyl)(alkyl), N-alkylamido-, —C(O)NH 2 , (alkyl)amido-, NO 2 , (aryl)alkyl, alkoxy, aryloxy, heteroaryloxy, (aryl)amino, (alkoxy)carbonyl-, (alkyl)amido-, (alky
  • bicycle or “bicyclic” as used herein refers to a molecule that features two fused rings, which rings are a cycloalkyl, heterocyclyl, or heteroaryl.
  • the rings are fused across a bond between two atoms.
  • the bicyclic moiety formed therefrom shares a bond between the rings.
  • the bicyclic moiety is formed by the fusion of two rings across a sequence of atoms of the rings to form a bridgehead.
  • a “bridge” is an unbranched chain of one or more atoms connecting two bridgeheads in a polycyclic compound.
  • the bicyclic molecule is a “spiro” or “spirocyclic” moiety.
  • the spirocyclic group is a carbocyclic or heterocyclic ring which bound through a single carbon atom of the spirocyclic moiety to a single carbon atom of a carbocyclic or heterocyclic moiety.
  • the spirocyclic group is a cycloalkyl and is bound to another cycloalkyl.
  • the spirocyclic group is a cycloalkyl and is bound to a heterocyclyl.
  • the spirocyclic group is a heterocyclyl and is bound to another heterocyclyl.
  • the spirocyclic group is a heterocyclyl and is bound to a cycloalkyl.
  • (Aryl)alkyl refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with an aryl group as defined above.
  • (C 6 -C 14 aryl)alkyl-moieties include benzyl, benzhydryl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl and the like.
  • An (aryl)alkyl group can be unsubstituted or substituted with one or more of halogen, CN, NH 2 , OH, (alkyl)amino-, di(alkyl)amino-, (alkyl)C(O)N(alkyl)-, (alkyl)carboxyamido-, HC(O)NH—, H 2 NC(O)—, (alkyl)NHC(O)—, di(alkyl)NC(O)—, CN, OH, alkoxy, alkyl, C(O)OH, (alkoxy)carbonyl-, (alkyl)C(O)—, aryl, heteroaryl, cycloalkyl, haloalkyl, amino(alkyl)-, (alkyl)carboxyl-, carboxyamidoalkyl-, or NO 2 .
  • (Alkoxy)carbonyl- refers to the group alkyl-O—C(O)—.
  • Exemplary (C 1 -C 6 alkoxy)carbonyl-groups include but are not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy.
  • An (alkoxy)carbonyl group can be unsubstituted or substituted with one or more of halogen, OH, NH 2 , (alkyl)amino-, di(alkyl)amino-, (alkyl)C(O)N(alkyl)-, (alkyl)carboxyamido-, HC(O)NH—, H 2 NC(O)—, (alkyl)NHC(O)—, di(alkyl)NC(O)—, CN, alkoxy, C(O)OH, (alkoxy)carbonyl-, (alkyl)C(O)—, aryl, heteroaryl, cycloalkyl, haloalkyl, amino(alkyl)-, (alkyl)carboxyl-, carboxyamidoalkyl-, or NO 2 .
  • (Alkyl)amido- refers to a —C(O)NH— group in which the nitrogen atom of said group is attached to a C 1 -C 6 alkyl group, as defined above.
  • Representative examples of a (C 1 -C 6 alkyl)amido-group include, but are not limited to, —C(O)NHCH 3 , —C(O)NHCH 2 CH 3 , —C(O)NHCH 2 CH 2 CH 3 , —C(O)NHCH 2 CH 2 CH 2 CH 3 , —C(O)NHCH 2 CH 2 CH 2 CH 2 CH 3 , —C(O)NHCH(CH 3 ) 2 , —C(O)NHCH 2 CH(CH 3 ) 2 , —C(O)NHCH(CH 3 )CH 2 CH 3 , —C(O)NH—C(CH 3 ) 3 and —C(O)NHCH 2 C(CH 3 ) 3 .
  • (Alkyl)amino- refers to an —NH group, the nitrogen atom of said group being attached to a alkyl group, as defined above.
  • Representative examples of an (C 1 -C 6 alkyl)amino-group include, but are not limited to CH 3 NH—, CH 3 CH 2 NH—, CH 3 CH 2 CH 2 NH—, CH 3 CH 2 CH 2 CH 2 NH—, (CH 3 ) 2 CHNH—, (CH 3 ) 2 CHCH 2 NH—, CH 3 CH 2 CH(CH 3 )NH— and (CH 3 ) 3 CNH—.
  • An (alkyl)amino group can be unsubstituted or substituted on the alkyl moiety with one or more of halogen, NH 2 , (alkyl)amino-, di(alkyl)amino-, (alkyl)C(O)N(alkyl)-, (alkyl)carboxyamido-, HC(O)NH—, H 2 NC(O)—, (alkyl)NHC(O)—, di(alkyl)NC(O)—, CN, OH, alkoxy, alkyl, C(O)OH, (alkoxy)carbonyl-, (alkyl)C(O)—, aryl, heteroaryl, cycloalkyl, haloalkyl, amino(alkyl)-, (alkyl)carboxyl-, carboxyamidoalkyl-, or NO 2 .
  • halogen NH 2 , (alkyl)amino-, di(alky
  • Aminoalkyl- refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with —NH 2 ; one or both H of the NH 2 may be replaced by a substituent.
  • Alkylcarboxyl- refers to an alkyl group, defined above that is attached to the parent structure through the oxygen atom of a carboxyl (C(O)—O—) functionality.
  • (Alkyl)carboxyamido- refers to a —NHC(O)— group in which the carbonyl carbon atom of said group is attached to a C 1 -C 6 alkyl group, as defined above.
  • Representative examples of a (C 1 -C 6 alkyl)carboxyamido-group include, but are not limited to, —NHC(O)CH 3 , —NHC(O)CH 2 CH 3 , —NHC(O)CH 2 CH 2 CH 3 , —NHC(O)CH 2 CH 2 CH 2 CH 3 , —NHC(O)CH 2 CH 2 CH 2 CH 2 CH 3 , —NHC(O)CH(CH 3 ) 2 , —NHC(O)CH 2 CH(CH 3 ) 2 , —NHC(O)CH(CH 3 )CH 2 CH 3 , —NHC(O)—C(CH 3 ) 3 and —NHC(O)CH 2 C(CH 3 ) 3
  • (Aryl)amino refers to a radical of formula (aryl)-NH—, wherein aryl is as defined above.
  • (Aryl)oxy refers to the group Ar—O— where Ar is an aryl group, as defined above.
  • Cycloalkyl refers to a non-aromatic, saturated, partially saturated, monocyclic, bicyclic or polycyclic hydrocarbon 3 to 12 membered ring system.
  • Representative examples of a C 3 -C 12 cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl, decahydronaphthalen-1-yl, octahydro-1H-inden-2-yl, decahydro-1H-benzo[7]annulen-2-yl, and dodecahydros-indacen-4-yl.
  • C 3 -C 10 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decahydronaphthalen-1-yl, and octahydro-1H-inden-2-yl.
  • Representative examples of a C 3 -C 8 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and octahydropentalen-2-yl.
  • a cycloalkyl can be unsubstituted or substituted with one or more of halogen, NH 2 , (alkyl)NH, (alkyl)(alkyl)N—, —N(alkyl)C(O)(alkyl), —NHC(O)(alkyl), —NHC(O)H, —C(O)NH 2 , —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), CN, OH, alkoxy, alkyl, C(O)OH, —C(O)O(alkyl), —C(O) alkyl), aryl, heteroaryl, cycloalkyl, haloalkyl, aminoalkyl-, —OC(O)(alkyl), carboxyamidoalkyl-, and NO 2 . Additionally, each of any two hydrogen atoms on the same carbon atom of the carbocyclic ring can be replaced by an
  • Halo or “halogen” refers to —F, —Cl, —Br and —I.
  • C 1 -C 6 haloalkyl refers to a C 1 -C 6 alkyl group, as defined above, wherein one or more of the C 1 -C 6 alkyl group's hydrogen atoms has been replaced with F, Cl, Br, or I. Each substitution can be independently selected from F, C 1 , Br, or I.
  • C 1 -C 6 haloalkyl-group include, but are not limited to, —CH 2 F, —CCl 3 , —CF 3 , CH 2 CF 3 , —CH 2 Cl, —CH 2 CH 2 Br, —CH 2 CH 2 I, —CH 2 CH 2 CH 2 F, —CH 2 CH 2 CH 2 Cl, —CH 2 CH 2 CH 2 CH 2 Br, —CH 2 CH 2 CH 2 CH 2 I, —CH 2 CH 2 CH 2 CH 2 CH 2 Br, —CH 2 CH 2 CH 2 CH 2 CH 2 I, —CH 2 CH(Br)CH 3 , —CH 2 CH(C 1 )CH 2 CH 3 , —CH(F)CH 2 CH 3 and —C(CH 3 ) 2 (CH 2 Cl).
  • Heteroaryl refers to a monocyclic, bicyclic, or polycyclic aromatic ring system containing at least one ring atom selected from the heteroatoms oxygen, sulfur and nitrogen.
  • Examples of C 1 -C 9 heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, in
  • Bicyclic C 1 -C 9 hetroaryl groups include those where a phenyl, pyridine, pyrimidine or pyridazine ring is fused to a 5 or 6-membered monocyclic heteroaryl ring having one or two nitrogen atoms in the ring, one nitrogen atom together with either one oxygen or one sulfur atom in the ring, or one O or S ring atom.
  • monocyclic C 1 -C 4 heteroaryl groups include 2H-tetrazole, 3H-1,2,4-triazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, imidazole, and pyrrole.
  • a heteroaryl group can be unsubstituted or substituted with one or more of C 1 -C 6 alkyl, halogen, haloalkyl, OH, CN, hydroxyalkyl, NH 2 , aminoalkyl-, dialkylamino-, C(O)OH, —C(O)O-(alkyl), —OC(O)(alkyl), N-alkylamido-, —C(O)NH 2 , (alkyl)amido-, —NO 2 , (aryl)alkyl, alkoxy, aryloxy, heteroaryloxy, (aryl)amino, (alkoxy)carbonyl-, (alkyl)amido-, (alkyl)amino, aminoalkyl-, alkylcarboxyl-, (alkyl)carboxyamido-, (aryl)alkyl-, (aryl)amino-, cycloalkenyl, di(alky
  • Heterocycle refers to monocyclic, bicyclic, polycyclic, or bridged head molecules in which at least one ring atom is a heteroatom.
  • a heterocycle may be saturated or partially saturated.
  • Exemplary C 1 -C 9 heterocyclyl groups include but are not limited to aziridine, oxirane, oxirene, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6-tetrahydropyridine-1-yl, tetrahydropyran, pyran, thiane, thiine, piperazine, azepane, diazepane, oxazine, 5,6-dihydro-4H-1,3-oxazin-2-yl, 2,5-diazabicyclo[2.2.1]heptane, 2,
  • C 1 heterocyclyl radicals would include but are not limited to oxaziranyl, diaziridinyl, and diazirinyl
  • C 2 heterocyclyl radicals include but are not limited to aziridinyl, oxiranyl, and diazetidinyl
  • C 9 heterocyclyl radicals include but are not limited to azecanyl, tetrahydroquinolinyl, and perhydroisoquinolinyl.
  • a heterocyclyl group can be unsubstituted or substituted with one or more of alkyl, halogen, alkoxy, haloalkyl, OH, hydroxyalkyl, —C(O)-(hydroxyalkyl), NH 2 , aminoalkyl-, dialkylamino-, C(O)OH, —C(O)O-(alkyl), —OC(O)(alkyl), N-alkylamido-, —C(O)NH 2 , (alkyl)amido-, —C(O)-(alkyl)-CN, (alkyl)-CN, or NO 2 .
  • Heterocyclyl(alkyl)- refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a heterocycle group as defined above.
  • Heterocyclyl(C 1 -C 6 alkyl)-moieties include 1-piperazinylethyl, 4-morpholinylpropyl, 6-piperazinylhexyl, and the like.
  • a heterocyclyl(alkyl) group can be unsubstituted or substituted with one or more of halogen, NH 2 , (alkyl)amino-, di(alkyl)amino-, (alkyl)C(O)N(alkyl)-, (alkyl)carboxyamido-, HC(O)NH—, H 2 NC(O)—, (alkyl)NHC(O)—, di(alkyl)NC(O)—, CN, OH, alkoxy, alkyl, C(O)OH, (alkoxy)carbonyl-, (alkyl)C(O)—, 4- to 7-membered monocyclic heterocycle, aryl, heteroaryl, or cycloalkyl.
  • Heteroaryl(alkyl) refers to a heteroaryl which is attached to an alkyl group and the heteroaryl is defined above.
  • “Hydroxyalkyl” refers to a alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with OH groups.
  • Examples of C 1 -C 6 hydroxyalkyl moieties include, for example, —CH 2 OH, —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 CH(OH)CH 2 OH, —CH 2 CH(OH)CH 3 , —CH(CH 3 )CH 2 OH and higher homologs.
  • Perfluoroalkyl- refers to alkyl group, defined above, having two or more fluorine atoms. Examples of a C 1 -C 6 perfluoroalkyl-group include CF 3 , CH 2 CF 3 , CF 2 CF 3 and CH(CF 3 ) 2 .
  • a “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or gorilla.
  • salts include but are not limited to, e.g., water-soluble and water-insoluble salts, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, bromide, butyrate, calcium, chloride, choline, citrate, edisylate (camphorsulfonate), fumarate, gluconate, glucuronate, glutamate, hydrobromide, hydrochloride, lauryl sulfate, malate, maleate, mandelate, mesylate, palmitate, pantothenate, phosphate, potassium, propionate, p-toluenesulfonate, salicylate, sodium, stearate, succinate, and sulfate salts.
  • water-soluble and water-insoluble salts such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, bromide,
  • ACN is acetonitrile
  • DMSO dimethylsulfoxide
  • DMF is N,N-dimethylformamide
  • DMF.DMA dimethylformamide dimethylacetal
  • TFA is trifluroroacetic acid
  • mCPBA meta-chloroperbenzoic acid
  • RT room temperature
  • THF is tetrahydrofuran
  • NMP is N-methyl pyrrolidinone.
  • Scheme 1 provides the synthesis of compounds of Formula (I).
  • Ethyl acetoacetate 1 is converted to the corresponding bis(methylthio)methylene derivative 2 using carbon disulfide, an organic or inorganic base such as K 2 CO 3 and a alkylating agent.
  • the alkylating agent is an alkyl iodide, alkyl triflate, or alkyl sulfonate.
  • the alkylating agent is a methylating agent.
  • the alkylating agent is methyl iodide. Reaction of 2 with an R 1 -optionally substituted amidine hydrochloride in the presence of a base results in pyrimidine 3.
  • the base utilized to form pyrimidine 3 is Et 3 N or Hünig's base.
  • the alkyl group on the pyrimidine group of compound 3 is then oxidized using an oxidizing agent. In one embodiment, the oxidation is performed using SeO 2 .
  • the resulting pyrimidine aldehyde 4 is converted to pyrimido-pyridazinone 5 using hydrazine hydrate or hydrazine hydrochloride.
  • the methyl thio group in compound 5 is oxidized to a methane sulfonyl using meta-chloroperoxybenzoic acid (mCPBA) or hydrogen peroxide/acetic acid.
  • mCPBA meta-chloroperoxybenzoic acid
  • the methane sulfonyl group of compound 6 is replaced with an R 2 -substituted aniline to provide compound (I).
  • the R 2 -substituted aniline is an aryl or heteroaryl substituted aniline.
  • Scheme 2 provides the synthesis of compound IB which are encompassed by the structure of Formula (I).
  • ethyl acetoacetate 1 is converted to the corresponding bis(methylthio)methylene derivative 2 using carbon disulfide, K 2 CO 3 and methyl iodide.
  • Reaction of 2 with an R′-substituted benzamidine hydrochloride in the presence of Et 3 N results in pyrimidine 3a.
  • the methyl group bound to the C-atom of pyrimidine 3a is then oxidized using SeO 2 .
  • the resulting pyrimidine aldehyde 4a is converted to pyrimido-pyridazinone 5a using hydrazine hydrate or hydrazine hydrochloride.
  • Scheme 3 provides the synthesis of compounds IC which are encompassed by the structure of Formula (I).
  • Treatment of ethyl chloroformate 7 with ammonium thiocyanate results in the production of ethyl thiocyanato formate 8 which upon treatment with ethyl 3-amino crotanoate results in compound 9.
  • Compound 9 is cyclized to compound 10 by treatment with an organic or inorganic base.
  • the organic or inorganic base is a strong base.
  • the strong base is a tertiary organic base.
  • the strong base is aqueous Et 3 N.
  • the dichloro pyrimidine 11 is obtained by treating compound 10 with a chlorinating agent.
  • the chlorinating agent is POCl 3 .
  • this transformation can also be carried out by using other chlorinating agents such as PCl 5 , SOCl 2 in the presence of an organic base such as TEA, tributyl amine, and N,N-dimethylaniline.
  • the 4-position of dichloropyrimidine 11 is then substituted by reaction with an optionally substituted (R 2 ) aniline to afford compound 12.
  • the 2-position of pyrimidine 12 is then R 1 -substituted using coupling agents such as boronic acids or boronic ester reagents to provide compound 13.
  • the methyl group at position 4 of pyrimidine 13 is then oxidized using an oxidizing agent such as SeO 2 to provide compound 14.
  • the resulting pyrimidine aldehyde 14 is converted to pyrimido-pyridazinone 1C using hydrazine hydrate.
  • Scheme 4 provides the synthesis of compounds ID which are encompassed by the structure of Formula (I).
  • Treatment of ethyl chloroformate 7 with ammonium thiocyanate results in ethyl thiocyanato formate 8 which upon treatment with ethyl 3-amino crotanoate results in compound 9.
  • Compound 9 is cyclized to compound 10 as described in Scheme 3, i.e., by treatment with aqueous Et 3 N.
  • the dichloro pyrimidine compound 11 is obtained by treating compound 10 with POCl 3 .
  • the 4-position of dichloropyrimidine 11 is then substituted by reaction with an optionally R-substituted aniline to afford compound 12a.
  • the 2-position of pyrimidine compound 12a is then substituted with an R′-substituted aryl or heteroaryl group using a boronic acid or an boronic ester reagent to provide compound 13a.
  • the boronic acid is (R′-aryl)-B(OH) 2 or (R′-heteroaryl)-B(OH) 2 .
  • the methyl at position-4 on pyrimidine 13a is then oxidized using SeO 2 .
  • the resulting pyrimidine aldehyde 14a is converted to pyrimido-pyridazinone 1D using hydrazine hydrate.
  • Scheme 5 provides the synthesis of compound IE which are encompassed by the structure of Formula (I).
  • Compound 12 is reacted with an optionally substituted amine (NHR 4 R 5 ) to provide compound 15.
  • the methyl group at the 4-position of compound 15 is reacted with DMF.DMA to provide compound 16.
  • Compound 17 is obtained by oxidative cleavage of the olefin of compound 16. In one embodiment, oxidative cleavage is performed using NaIO 4 .
  • pyrimido-pyridazinone IE is obtained by cyclizing the aldehyde 17. In one embodiment, the cyclizaton is performed using hydrazine, hydrazine hydrate or hydrazine hydrochloride, as described previously.
  • Scheme 6 provides the synthesis of compounds 1F which are encompassed by the structure of Formula (I).
  • Compound 12a is reacted with optionally substituted amines to result in 15a.
  • the methyl group of 15a is reacted with DMF.DMA to give compound 16a.
  • the aldehyde 17a is obtained by the oxidative cleavage of the olefin in 16a. In one embodiment, the oxidative cleavage is performed with NaIO 4 .
  • the pyrimido-pyridazinone 1F is obtained by cyclizing aldehyde 17a. In one embodiment, cyclization is performed using with hydrazine.
  • Scheme 7 provides the synthesis of compound 1G which are encompassed by the structure of Formula (I).
  • Compound 10 is reacted with an alkylating agent to the S-methyl compound 18.
  • the reacted is performed under basic conditions.
  • the alkylating agent is methyl iodide, ethyl iodide, propyl iodide, dimethylsulfate, among others.
  • Compound 19 is obtained by chlorinating compound 18.
  • compound 18 is chlorinated using POCl 3 .
  • Compound 19 is then NR 4 R 5 substituted with an optionally substituted amine to provide compound 20 [using NHR 4 R 5 ?].
  • the methyl group of compound 20 is reacted with DMF.DMA to give compound 21.
  • the aldehyde 22 is obtained by the oxidative cleavage of the olefin group in compound 21.
  • the oxidative cleavage is performed with NaIO 4 .
  • compound 20 may directly converted to the pyrimidine aldehyde 22 by oxidizing the methyl group using SeO 2 or a combination of CO 2 , t-butyl hydroperoxide, and an alcohol such as C 1 to C 6 alkyl)H 2 OH.
  • the resulting pyrimidine aldehyde 22 is converted to pyrimido-pyridazinone 23 using hydrazine hydrate or hydrazine hydrochloride.
  • the methyl thio group in compound 23 is oxidized to a methane sulfonyl group.
  • compound 23 is reacted with meta-chloroperoxybenzoic acid (mCPBA) or hydrogen peroxide/acetic acid.
  • mCPBA meta-chloroperoxybenzoic acid
  • the methane sulfonyl group of compound 24 is replaced with suitably substituted aniline to provide compound 1G.
  • Scheme 8 provides the synthesis of compound 1H which is encompassed by the structure of Formula (I).
  • compound 19 is coupled with an optionally substituted boronic acid or boronic ester to give compound 25.
  • the coupling is performed in the presence of a coupling agent such as Pd(PPh 3 ) 4 or PdCl 2 (PPh 3 ) 2 .
  • the methyl group in compound 25 is then oxidized to the corresponding aldehyde.
  • the oxidation is performed using SeO 2 or a combination of CO 2 , t-butyl hydroperoxide, and an alcohol such as C 1 to C 6 alkyl)H 2 OH to give compound 26.
  • Compound 26 is converted to pyrimido-pyridazinone 27 using hydrazine hydrate or hydrazine hydrochloride.
  • the methyl thio group in compound 27 is then oxidized to a methane sulfonyl group.
  • the oxidation is performed using mCPBA or hydrogen peroxide/acetic acid.
  • the methane sulfonyl group of compound 28 is replaced with suitably substituted aniline to provide compound 1H.
  • compositions of the invention comprise a compound of Formula (I) optionally with other pharmaceutically inert or inactive ingredients.
  • the pharmaceutically inert or inactive ingredient is one or more pharmaceutically acceptable carrier or excipient.
  • the present invention also contemplates combining the compound of Formula (I) with one or more therapeutic agents, i.e., active ingredients, as described below.
  • a compound of Formula (I) is combined with one or more inert/inactive ingredients and one or more therapeutic agents.
  • compositions of the invention contain an amount of a compound of Formula (I) that is effective for treating inflammation in a subject.
  • dosage of the compound of Formula (I) to achieve a therapeutic effect will depend on factors such as the formulation, pharmacological potency of the drug, age, weight and sex of the patient, condition being treated, severity of the patient's symptoms, specific compound of Formula (I), route of delivery, and response pattern of the patient. It is also contemplated that the treatment and dosage of the compound of Formula (I) may be administered in unit dosage form and that one skilled in the art would adjust the unit dosage form accordingly to reflect the relative level of activity. The decision as to the particular dosage to be employed (and the number of times to be administered per day) is within the discretion of the ordinarily-skilled physician, and may be varied by titration of the dosage to the particular circumstances to produce the desired therapeutic effect.
  • the therapeutically effective amount is about 0.0001% to about 25% w/w. In another embodiment, the therapeutically effective amount is less than about 20% w/w, about 15% w/w, about 10% w/w, about 5% w/w, or about 1% w/w. In another embodiment, the therapeutically effective amount is about 0.0001% to about 10% w/w. In a further embodiment, the therapeutically effective amount is about 0.005 to about 5% w/w. In yet another embodiment, the therapeutically effective amount is about 0.01 to about 5% w/w.
  • the therapeutically effective amount is about 0.01% w/w, about 0.05% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, or about 5% w/w.
  • the therapeutically effective amounts may be provided on regular schedule, i.e., on a less than daily, weekly, monthly, or yearly basis or on an irregular schedule with varying administration days, weeks, months, etc.
  • the therapeutically effective amount to be administered may vary.
  • the therapeutically effective amount for the first dose is higher than the therapeutically effective amount for one or more of the subsequent doses.
  • the therapeutically effective amount for the first dose is lower than the therapeutically effective amount for one or more of the subsequent doses.
  • Equivalent dosages may be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every 2 weeks, about every 3 weeks, about every month, about every 2 months, about every 3 months and about every 6 months.
  • the number and frequency of dosages corresponding to a completed course of therapy will be determined according to the judgment of a health-care practitioner.
  • the therapeutically effective amounts described herein refer to total amounts administered for a given time period; that is, if more than one compound of Formula (I) is administered, the therapeutically effective amounts correspond to the total amount administered.
  • the compound of Formula (I) may be administered by any route, taking into consideration the specific condition for which it has been selected.
  • the compounds of Formula (I) may be delivered orally, by injection (including intravascularly, e.g, intravenously or intra-arterially), inhalation (intranasally and intratracheally), ocularly, transdermally (via simple passive diffusion formulations or via facilitated delivery using, for example, iontophoresis, microporation with microneedles, radio-frequency ablation or the like), intravascularly, subcutaneously, intramuscularly, sublingually, intracranially, epidurally, rectally, and vaginally, among others.
  • the compound of Formula (I) may be administered by injection, transdermally or topically.
  • the compound of Formula (I) may be administered topically to the eye, e.g., as solutions, suspensions or ointments.
  • ophthalmically compatible carriers which may be used include, without limitation, an aqueous solution, such as saline solution, oil solution or ointments containing ophthalmically compatible preservatives, surfactants, buffers, and viscosity regulators.
  • aqueous solution such as saline solution
  • These compositions may also contain stabilizing agents, antibacterial agents, and may be manufactured in different dosage units, suitable for ocular administration.
  • Drug inserts either soluble or insoluble, may also be used.
  • the compound of Formula (I) may be administered by injection.
  • Solutions for injection or infusion may be prepared as aqueous solutions.
  • the compound of Formula (I) is present in a concentration of about 0.001 ⁇ g/mL to 1 mg/mL, or this amount may be adjusted higher or lower as needed.
  • These solutions may also contain stabilizing agents, antibacterial agents, buffers and may be manufactured in different dosage unit ampoules or bottles.
  • the compound of Formula (I) may be administered rectally.
  • Dosage units for rectal administration may be prepared in the form of ointments or suppositories, which contain the compound of Formula (I) in a mixture with a neutral fat base, or they may be prepared in the form of gelatin-rectal capsules that contain the compound of Formula (I) in a mixture with, e.g., a vegetable oil or paraffin oil.
  • Ointments, suppositories or creams containing at least one compound of Formula (I) are useful for the treatment of hemorrhoids.
  • the compound of Formula (I) may be administered orally.
  • Dosage units for oral administration include, without limitation, tablets, caplets, capsules, powders, suspensions, microcapsules, dispersible powder, granules, suspensions, syrups, elixirs, and aerosols, which contain the compound of Formula (I) optionally with one or more excipient.
  • the compositions are compressed into a tablet or caplet.
  • the tablet or caplet may be administered to the subject.
  • the tablet or caplet may be added to a capsule.
  • the composition containing the compound of Formula (I) is added directly to a capsule.
  • the capsule includes hydroxypropyl methylcellulose, hypromellose capsule, or a hard shell gelatin capsule.
  • the tablets or caplets are optionally film-coated using film-coatings known to those of skill in the art.
  • the film-coating is selected from among polymers such as, without limitation, hydroxypropylmethylcellulose, ethyl cellulose, polyvinyl alcohols, and combinations thereof.
  • the compound of Formula (I) may be administered alone, i.e., neat, it may also be administered in the presence of one or more pharmaceutical carriers that are physiologically compatible.
  • the amount of the pharmaceutical carrier(s) is determined by the solubility and chemical nature of the compound of Formula (I), chosen route of administration, and standard pharmacological practice.
  • the carriers may be in dry (solid) or liquid form and must be pharmaceutically acceptable.
  • Liquid pharmaceutical compositions are typically sterile solutions or suspensions. When liquid carriers are utilized for parenteral administration, they are desirably sterile liquids. Liquid carriers are typically utilized in preparing solutions, suspensions, emulsions, syrups and elixirs. A variety of suitable liquid carriers is known and may be readily selected by one of skill in the art.
  • Such carriers may include, e.g., dimethylsulfoxide (DMSO), saline, buffered saline, cyclodextrin, hydroxypropylcyclodextrin (HPP ⁇ CD), n-dodecyl- ⁇ -D-maltoside (DDM) and mixtures thereof.
  • DMSO dimethylsulfoxide
  • saline buffered saline
  • cyclodextrin hydroxypropylcyclodextrin
  • HPP ⁇ CD hydroxypropylcyclodextrin
  • DDM n-dodecyl- ⁇ -D-maltoside
  • the compound of Formula (I) is dissolved a liquid carrier.
  • the compound of Formula (I) is suspended in a liquid carrier.
  • One of skill in the art of formulations would be able to select a suitable liquid carrier, depending on the route of administration.
  • the compound of Formula (I) may alternatively be formulated in a solid carrier of which
  • the composition may be compacted into a unit dose form, i.e., tablet or caplet.
  • the composition may be added to unit dose form, i.e., a capsule.
  • the composition may be formulated for administration as a powder.
  • the solid carrier may perform a variety of functions, i.e., may perform the functions of two or more of the excipients described below.
  • a solid carrier may also act as a flavoring agent, lubricant, solubilizer, suspending agent, filler, glidant, compression aid, binder, disintegrant, or encapsulating material.
  • compositions may also be sub-divided to contain appropriate quantities of the compound of Formula (I).
  • the unit dosage can be packaged compositions, e.g., packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • excipients which may be combined with one or more compound of Formula (I) include, without limitation, adjuvants, antioxidants, binders, buffers, coatings, coloring agents, compression aids, diluents, disintegrants, emulsifiers (e.g., polyoxyethylene fatty acid esters), emollients, encapsulating materials, fillers, flavoring agents, glidants, granulating agents, lubricants, metal chelators, osmo-regulators, pH adjustors (e.g., sodium hydroxide), preservatives, solubilizers, sorbents, stabilizing agents, sweeteners (such as saccharin), surfactants, suspending agents, syrups, thickening agents (e.g., carboxypolymethylene or hydroxypropylmethylcellulose), penetration enhancers (e.g., hydroxypolyethoxydodecane, DMSO, DMAC, DDM, etc) or viscosity regulator
  • compositions may be utilized as inhalants.
  • compositions may be prepared as fluid unit doses using a compound of Formula (I) and a vehicle for delivery by an atomizing spray pump or by dry powder for insufflation.
  • compositions may be utilized as aerosols, i.e., oral or intranasal.
  • the compositions are formulated for use in a pressurized aerosol container together with a gaseous or liquefied propellant, e.g., dichlorodifluoromethane, carbon dioxide, nitrogen, propane, and the like.
  • a gaseous or liquefied propellant e.g., dichlorodifluoromethane, carbon dioxide, nitrogen, propane, and the like.
  • a metered dose in one or more actuations.
  • compositions may be administered by a modified-release delivery device.
  • Modified-release refers to delivery of a compound of Formula (I) which is controlled, for example over a period of at least about 8 hours (e.g., extended delivery) to at least about 12 hours (e.g., sustained delivery). Such devices may also permit immediate release (e.g., therapeutic levels achieved in under about 1 hour, or in less than about 2 hours).
  • suitable modified-release delivery devices For use in such modified-release delivery devices, the compound of Formula (I) is formulated as described herein.
  • the compounds of Formula (I) are combined with other medications or therapeutic agents in a single composition.
  • the present invention is not so limited.
  • the compounds of Formula (I) may be administered in one or more separate formulations from other compounds of Formula (I), or other medications or therapeutic agents as described below.
  • agents typically used to treat inflammation may be used in conjunction with a combination of the invention in the methods, compositions, and kits described herein.
  • agents include, but are not limited to, non-steroidal anti-inflammatory drugs.
  • the compound of Formula (I) may be combined with glucose or dextrose when utilized for infusion or as a regional analgesic or anti-pruritic.
  • the compound of Formula (I) may be combined with thickening agents to form a jelly, or may also contain penetration enhancers, for use in topical or dermal applications such as for urogenital topical procedures.
  • the compound of Formula (I) may be formulated as an ointment for administration to accessible mucous membranes.
  • kits or packages of pharmaceutical formulations containing the compounds of Formula (I) or compositions described herein may be organized to indicate a single formulation or combination of formulations to be taken at each desired time.
  • the kit contains packaging or a container with the compound of Formula (I) formulated for the desired delivery route.
  • the kit contains instructions on dosing and an insert regarding the compound of Formula (I).
  • the kit may further contain instructions for monitoring local or circulating levels of product and materials for performing such assays including, e.g., reagents, well plates, containers, markers or labels, and the like.
  • Such kits are readily packaged in a manner suitable for treatment of a desired indication.
  • the kit may also contain instructions for use of an oral dosage form such as a pill, capsule, patch, spray pump or other delivery device.
  • suitable components to include in such kits will be readily apparent to one of skill in the art, taking into consideration the desired indication and the delivery route.
  • a package or kit can include the compound of Formula (I) in each dosage unit (e.g., solution, lotion, tablet, pill, drug-eluting patch or other unit described above or utilized in drug delivery), and optionally instructions for administering the doses less-than-daily, daily, weekly, or monthly, for a predetermined length of time or as prescribed.
  • a package or kit can include placebos during periods when the compound of Formula (I) is not delivered.
  • a package or kit may contain a sequence of dosage units which provide the desired variability.
  • the package has indicators for each period.
  • the package is a foil or blister package, labeled ampoule, vial or bottle.
  • the packaging means of a kit may itself be geared for administration, such as an inhalant, syringe, pipette, eye dropper, or other such apparatus, from which the formulation may be applied to an affected area of the body, such as the lungs, injected into a subject, or even applied to and mixed with the other components of the kit.
  • kits also may be provided in dried or lyophilized forms.
  • reagents or components are provided as a dried form, reconstitution generally is by the addition of a suitable solvent. It is envisioned that the solvent also may be provided in another package.
  • kits of the present invention also will typically include a means for containing the vials or other suitable packaging means in close confinement for commercial sale such as, e.g., injection or blow-molded plastic containers into which the desired vials are retained.
  • a means for containing the vials or other suitable packaging means in close confinement for commercial sale such as, e.g., injection or blow-molded plastic containers into which the desired vials are retained.
  • the kits also may include, or be packaged with a separate instrument for assisting with the injection/administration or placement of the composition within the body of an animal.
  • a separate instrument for assisting with the injection/administration or placement of the composition within the body of an animal.
  • Such an instrument may be an inhalant, syringe, pipette, forceps, measuring spoon, eye dropper or any such medically approved delivery means.
  • a kit in one embodiment, contains a compound of Formula (I).
  • the compound of Formula (I) may be in the presence or absence of one or more of the carriers or excipients described above.
  • the kit may optionally contain instructions for administering the compound of Formula (I) to a subject having inflammation.
  • a kit in a further embodiment, contains a compound of Formula (I) in a second dosage unit, and one or more of the carriers or excipients described above in a third dosage unit.
  • the kit may optionally contain instructions for administering the compound of Formula (I) to a subject having inflammation.
  • the methods, compositions, and kits of the invention can be used to treat inflammation resulting from a number of conditions.
  • the term “inflammation” as used herein includes all types of inflammation.
  • the inflammation may be acute or chronic.
  • the inflammation may be nociceptive, dysfunctional, idiopathic, neuropathic, somatic, visceral, and/or procedural.
  • the inflammation may be from a migraine, gynecological condition, pre-labor or labor, stroke, surgery, neuralgia, sickle cell, interstitial cystitis, urological condition (such as urethritis), dental work/injury, or headache, among other.
  • Inflammation may also occur in patients with cancer, which may be due to multiple causes, such as nerve compression and mechanical forces resulting from tissue distension as a consequence of invasion by a tumor and tumor metastasis into bone or other tissues.
  • inflammation results from neuropathy, such as post-herpetic neuralgia.
  • the inflammation results from a surgery or procedure.
  • the inflammation results from an infection, cancer, colitis, cystitis, irritable bowel syndrome, or idiopathic neuropathy.
  • Somatic inflammation includes inflammation in bone, joint, muscle, skin, or connective tissue.
  • Central inflammation includes inflammation arising as a consequence of brain trauma, stroke, or spinal cord injury.
  • Viceral inflammation includes inflammation in visceral organs, such as the respiratory or gastrointestinal tract and pancreas, the urinary tract and reproductive organs. In one embodiment, visceral inflammation results from tumor involvement of the organ capsule. In another embodiment, visceral inflammation from obstruction of hollow viscus.
  • Idiopathic inflammation refers to inflammation which has no underlying cause or refers to inflammation caused by condition which remains undiagnosed.
  • Disfunctional inflammation refers to inflammation which occurs in the absence of a noxious stimulus, tissue damage or a lesion to the nervous system.
  • dysfunctional inflammation results from rheumatologic conditions such as arthritis and fibromyalgia, tension type headache, irritable bowel disorders and erythermalgia.
  • Nociceptive inflammation includes inflammation caused by noxious stimuli that threaten to or actually injure body tissues.
  • nociceptive inflammation results from a cut, bruise, bone fracture, crush injury, burn, trauma, surgery, labor, sprain, bump, injection, dental procedure, skin biopsy, or obstruction.
  • nociceptive inflammation is located in the skin, musculoskeletal system, or internal organs.
  • Neurotoxic inflammation is inflammation due to abnormal processing of sensory input by the peripheral or central nervous system consequent on a lesion to these systems.
  • neuropathic inflammation is chronic and non-malignant.
  • neuropathic inflammation is due to trauma, surgery, herniation of an intervertebral disk, spinal cord injury, diabetes, infection with herpes zoster (shingles), HIV/AIDS, late-stage cancer, amputation (such as mastectomy), carpal tunnel syndrome, chronic alcohol use, exposure to radiation, and as an unintended side-effect of neurotoxic treatment agents, such as certain anti-HIV and chemotherapeutic drugs.
  • “Procedural inflammation” includes refers to inflammation arising from a medical procedure.
  • the medical procedure may include any type of medical, dental or surgical procedure.
  • the procedural inflammation is postoperative.
  • the inflammation is associated with an injection, draining an abscess, surgery, dermatological, dental procedure, ophthalmic procedure, arthroscopy and use of other medical instrumentation, and/or cosmetic surgery.
  • a “migraine” is a type of headache, typically defined clinically as being caused by activation of sensory fibers innervating the meninges of the brain.
  • treat is meant to include therapy utilized to remedy a health problem or condition in a patient or subject.
  • the health problem or condition may be eliminated permanently or for a short period of time.
  • the health problem or condition may be prevented.
  • the severity of the health problem or condition, or of one or more symptoms characteristic of the health problem or condition may be lessened permanently, or for a short period of time.
  • the effectiveness of a treatment of inflammation can be determined using any standard inflammation index, such as those described herein, or can be determined based on the patient's subjective inflammation assessment. A patient is considered “treated” if there is a reported reduction in inflammation, or a reduced reaction to stimuli that should cause inflammation.
  • the treatment methods described herein include administering a compound of Formula (I) to a patient. Additional, optional agents, such as those described above for use in the combination, may be administered to the patient prior to, concurrently with, or subsequent to the compound of Formula (I).
  • Ethyl 2-hydroxy-4-mercapto-6-methylpyrimidine-5-carboxylate (1.4 g, 6.54 mmol) was taken up in POCl 3 (13.67 mL) at 0° C., tri-n-butylamine was added and the mixture heated to 90° C. for 5 hours. The mixture was cooled, poured slowly on to crushed ice and extracted with dichloromethane. The organic layer was washed with water, dried over Na 2 SO 4 and concentrated under vacuum. The pure product was obtained by column purification over silica gel using 3% EtOAc/hexane as eluent.
  • the objective of this assay was to examine by radiometric method the ability of compounds to inhibit Syk kinase enzyme.
  • Spleen tyrosine kinase is a cytosolic protein tyrosine kinase that plays a crucial role in inflammatory and allergic responses. Syk triggers IgE and IgG receptor mediated signaling in mast cells, basophils, and macrophages leading to degranulation and cytokine release. Abnormal function of Syk has also been implicated in several instances of hematopoietic malignancies.
  • Syk is capable of phosphorylating substrates such as VAV, LAT, SLP-76, which in turn activate MAPK, PLCy signaling pathways. Crystallization studies of the Syk catalytic domain (360-635) showed more activity compared to the full length Syk enzyme.
  • This in vitro assay tests the ability of syk to phosphorylate a substrate peptide in the presence of ATP. By using a radio-labeled form of ATP, it is possible to measure the amount of phosphorylation of the substrate.
  • the enzyme transfers a radio-labeled phosphate group from ⁇ 32 P labeled ATP to pG4T. Briefly the enzyme was incubated with substrate, radio-labeled & cold ATP and substrate in buffer with or without compounds.
  • the reaction mixture was transferred on to a Multiscreen filter plate and unreacted ⁇ 32 P ATP was washed off.
  • the filter plate was dried and the radioactivity was measured on a scintillation counter to estimate the incorporated radioactivity on the substrate.
  • the percent inhibition of activity of the enzyme was calculated by comparing counts in the presence and absence of compounds.
  • Tris Buffer composition Reagent Supplier 50 mM tris-hydrochloride (Tris) Sigma, Cat #T5941 10 mM magnesium chloride (MgCl 2 ) Sigma, Cat #M9272 2.5 mM Di thiotretol (DTT) Sigma, Cat #D-0632 500 ⁇ M sodium orthovanadate Sigma, Cat. #S6508 500 ⁇ M ethylene glycol tetra acetic acid Sigma, Cat#E3889 (EGTA) 0.001% Triton ® X-100 reagent Loba Chemie, CAS #9002-93-1 (surfactant with molecule formula of C 14 H 22 O(C 2 H 4 O) n (n 9-10)
  • the assay squares were washed 3 times for 5 minutes each in ortho-phosphoric acid (0.5%) and once in acetone. Assay squares were dried for 15 minutes in a 30° C. oven and transferred to 96 well optiplate. Microscint-O® reagent (100 ⁇ L, Perkin Elmer) was added to each well, the plate was sealed with Topseal®-A microplates and incubated for 10 minutes at room temperature at very low speed on rocker and the plate was read in the Topcount® NXL instrument.
  • % ⁇ ⁇ inhibition 100 - ⁇ CPM ⁇ ⁇ for ⁇ ⁇ reaction ⁇ ⁇ containing ⁇ ⁇ compound * 100 ⁇ ( CPM ⁇ ⁇ for ⁇ ⁇ positive ⁇ ⁇ control )
  • the % inhibitions of the compound vs. concentrations of NCE were plotted using Graphpad® Prism software to calculate the IC 50 of the active NCE.
  • the objective of this assay was to screen compounds in a Time-resolved fluorescence resonance energy transfer (TR-FRET) Enzymatic assay method for their potential to inhibit JAK2 (Janus kinase) activity.
  • TR-FRET Time-resolved fluorescence resonance energy transfer
  • JAK 2 (Janus kinase 2) is a family of intracellular non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. These kinases have apparent molecular weight of about 130 Kda. They were initially named “just another kinase” 1 & 2 (since they were just two of a large number of discoveries in a PCR-based screen of kinases), but were ultimately published as “Janus kinase”. JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity while the other negatively regulates the kinase activity of the first. They are crucial signal transducers for a variety of cytokines, growth factors and interferons.
  • TR-FRET assays are homogeneous proximity assays where Eu-labeled antiphosphotyrosine antibody binds to the phosphorylated substrates labeled with Ulight fluorescence acceptor. Eu can transfer energy to Ulight accepter in the complex and the interaction of two dye-labeled binding partners is detected by the energy transfer between a donor and an acceptor dye, and the subsequent light emission by the acceptor dye. The intensity of the light emission is proportional to the level of Ulight peptide phosphorylation.
  • the objective of this assay was to examine by Fluorescence method the effect of compounds on ⁇ -hexosaminidase release during immune complex mediated degranulation in RBL2H3 cells.
  • ICs immune complexes
  • ICs immune complexes
  • IgE immunoglobulin E
  • Fc ⁇ RI immunoglobulin E
  • the mast cell release a variety of potent biologically active molecules, including cytokines, lipid-derived mediators, amines, protease, and proteoglycans.
  • Protocol A 24 Well Format
  • RBL2H3 cells were maintained in MEM complete media containing 10% FBS at 70%-80% confluence in a mammalian cell culture CO 2 incubator with 5% CO 2 at 37° C. 2 ⁇ 10 5 cells/well were plated in 1 mL of complete media and incubated for 5 hours for cell attachment. Complete media was replaced with 1 mL of serum free MEM media containing 1.2 ⁇ g/mL of anti-DNP rat IgE as sensitizing agent and further incubated overnight with 5% CO 2 at 37° C. The following day, cells were washed with serum free media and further treated with various concentrations of test compounds (in 0.1% DMSO) for 45 minutes at 37° C. and 5% CO 2 .
  • test compounds in 0.1% DMSO
  • % release of ⁇ -Hexosaminidase for the test compound was calculated using the following formula:
  • Protocol B 96 Well Format
  • RBL2H 3 cells were maintained in MEM complete media containing 10% FBS at 70-80% confluence in a mammalian cell culture CO 2 incubator with 5% CO 2 at 37° C. 5 ⁇ 10 4 cells/well were plated in 200 ⁇ L of complete media containing 0.3 ⁇ g/mL of anti-DNP rat IgE as sensitizing agent for 24 hours at 37° C. & 5% CO 2 . The following day, cells were washed twice with PIPES buffer for 10 minutes at 37° C. and replenished with serum free MEM media. Cells were treated with various concentrations of test compounds (in 0.5% DMSO) for 15 minutes at 37° C. and 5% CO 2 .
  • the cells were further stimulated with 0.1 ⁇ g/mL of DNP-BSA for 45 minutes.
  • the plates were spun for 5 minutes at 2000 rpm and 25 ⁇ L of culture supernatant was then transferred from each assay well into a 96 well black coated plate.
  • Fifth ⁇ L P-NAG substrate was added and incubated at RT for 30 minutes. After incubation with substrate, 150 ⁇ L of stop solution was added and fluorescence was monitored. (Excitation 355 nm; Emission 460 nm). See, Yamamoto, JPET, 306(3):1174-1181 (2003) and Taylor, MCB, 15(8): 4149-4157 (1995), which are herein incorporated by reference.
  • CIA Collagen Induced Arthritis
  • RA rheumatoid arthritis
  • cII type II collagen
  • CIA exhibits several features of human RA such as severe swelling/inflammation of joints, synovial hyperplasia, cartilage destruction and bone erosion.
  • Pathophysiology of CIA consists of T cell component, as evidenced by increased infiltration of T-cells in joint synovium and also, by attenuation of CIA in T-cell deficient mice.
  • CIA development involves B cell component too, as is evidenced by circulating cII antibody in disease animals and also, failure to develop the disease in xid mice/B cell deficient mice/CXCR5 null mice. Recently, a significant role of macrophages has also been suggested in the pathogenesis of CIA as well as human RA. See, Pine, “Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor”, Clin. Immunol., 2007, 124(3):244-57; Xiong cha, “Suppression of the onset and progression of collagen-induced arthritis in rats by QFGJS, a preparation from an anti-arthritic Chinese herbal formula”, J.
  • mice Female Lewis rats (8 per group, 6-8 weeks old) were immunized on day 1 with type II collagen (Immunization grade Bovine type II; Chondrex; Cat #20021) emulsified with Complete Freund's Adjuvant (Sigma; Cat # F5881) at a final concentration of 1.2 mg/mL).
  • type II collagen Immunization grade Bovine type II; Chondrex; Cat #20021
  • Complete Freund's Adjuvant Sigma; Cat # F5881
  • a booster injection of the same type II collagen emulsified with Incomplete Freund's Adjuvant (Sigma, Cat # F5506) (0.25 mL/rat) was given to the animals on day 8 at the base of the tail (100 ⁇ g).
  • the final cII concentration in the booster was 0.4 ⁇ g/mL.
  • Animals with an arthritic score of ⁇ 1 were grouped and dosing with test compound (30 mg/kg bid) or methotrexate (0.5 mg/kg) started between about day 12 to day 14, with daily dosing of their respective compounds continuing for 10 days.
  • Edema Paw volumes are measured by Plethysmometry for the animals before induction of CIA (Basal readings) and on Day 1, 3, 6 and 9 of dosing period. Both hind paw volumes were measured and edema was calculated by subtracting from the basal mean.
  • % ⁇ ⁇ inhibition ⁇ ⁇ of ⁇ ⁇ Edema ( 1 - ⁇ Mean ⁇ ⁇ Edema ⁇ ⁇ in ⁇ ⁇ treated ⁇ ⁇ animals ⁇ ⁇ on ⁇ ⁇ day ⁇ ⁇ n ′ ′ _ ( Mean ⁇ ⁇ Edema ⁇ ⁇ in ⁇ ⁇ treated ⁇ ⁇ animals ⁇ ⁇ on ⁇ ⁇ day ⁇ ⁇ 0 ′ ′ ) ( Mean ⁇ ⁇ Edema ⁇ ⁇ in ⁇ ⁇ control ⁇ ⁇ animals ⁇ ⁇ on ⁇ ⁇ day ⁇ n ′ ) ( Mean ⁇ ⁇ Edema ⁇ ⁇ in ⁇ ⁇ control ⁇ ⁇ animals ⁇ ⁇ on ⁇ ⁇ day ⁇ 0 ′ ) ⁇ ) ⁇ 100
  • This example illustrates that the compounds may be utilized for treating inflammation. See FIGS. 1-2 .
  • Type III hypersensitivity reactions are immune complex-mediated, and involve the deposition of antigen/antibody complexes mainly in the vascular walls, serosa (pleura, pericardium, synovium), and glomeruli. This involves formation of antigen/antibody complexes after the intradermal injection of an antibody. If the animal was previously injected with antigen and dye (has circulating antigen), an Arthus reaction occurs. This manifests as local vasculitis due to deposition of immune complexes in dermal blood vessels. Activation of complement and recruitment of PMNs ensue, resulting in an inflammatory response and extravasation of dye to the skin.
  • mice Female c57BL/6 mice were given an antigen injection in which the antigen was 0.1% Ovalbumin (OVA) in PBS containing 1% Evans blue (EB) at the concentration of 10 mL/kg intravenously under Isoflurane anesthesia [2.5 mg/mouse with a body weight of 25 g].
  • Ovalbumin Ovalbumin
  • EB Evans blue
  • PBS phosphate buffered saline
  • mice were euthanized by cervical dislocation 4 hours after antigen (Ovalbumin) challenge. Skin tissue was assessed for edema by tracing the edema area on to a transparent plastic sheet. Punch biopsies of the injection sites were collected.
  • Edema area was measured manually by scale. Two diameters were taken and averaged for each animal.
  • Percent ⁇ ⁇ inhibition ⁇ ⁇ of ⁇ ⁇ OD ⁇ 1 - [ Mean ⁇ ⁇ OD ⁇ ⁇ in ⁇ ⁇ treated ⁇ ⁇ animals Mean ⁇ ⁇ OD ⁇ ⁇ in ⁇ ⁇ control ⁇ ⁇ animals ] ⁇ ⁇ 100
  • Percent ⁇ ⁇ inhibition ⁇ ⁇ of ⁇ ⁇ edema ⁇ ⁇ area ⁇ 1 - [ Mean ⁇ ⁇ edema ⁇ ⁇ area ⁇ ⁇ ⁇ in ⁇ ⁇ treated ⁇ ⁇ animals Mean ⁇ ⁇ edema ⁇ ⁇ area ⁇ ⁇ ⁇ in ⁇ ⁇ control ⁇ ⁇ animals ] ⁇ ⁇ 100
  • This example illustrates that the compounds described herein may be utilized in treating inflammation.

Abstract

The present application provides novel pyrimido-pyridazinone compounds and methods for preparing and using these compounds. These compounds are useful in treating inflammation in patients by administering one or more of the compounds to a patient. In one embodiment, the novel pyrimido-pyridazinone compound is of Formula (I) and R1 and R2 are defined herein.
Figure US20200190095A1-20200618-C00001

Description

    BACKGROUND
  • Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within cells. Almost all kinases contain a similar 250 to 300 amino acid catalytic domain. The kinases can be categorized into families by the substrates they phosphorylate.
  • JAK2 (Janus kinase 2) is a family of intracellular non-receptor tyrosine kinases. JAK2 is expressed ubiquitously in hematopoietic cells and abundantly in primary leukemic cells from children with acute lymphoblastic leukemia. The downstream substrates of JAK include the signal tranducer activator of transcription (STAT) proteins. STAT proteins function both as signaling molecules and transcription factors and ultimately bind to specific DNA sequences present in the promoters of cytokine-responsive genes. JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses such as allergies, asthma, autoimmune diseases such as transplant (allograft) rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, as well as in solid and hematologic malignancies such as leukemia and lymphomas.
  • Spleen tyrosine kinase (syk) is a member of the syk family of protein tyrosine kinases and plays a crucial role in inflammatory and allergic responses. Syk triggers IgE and IgG receptor mediated signaling in mast cells, basophils, and macrophages leading to degranulation and cytokine release.
  • Immunoreceptor tyrosine activation motif (ITAM)-mediated signaling has emerged as a primary event in signaling pathways responsible for human pathologies. ITAM-mediated signaling is responsible for relaying activation signals initiated at classical immune receptors such as T-cell receptors, B-cell receptors, and Fc receptors in immune cells and at GPVI and FcγRIIa in platelets to downstream intracellular molecules such as Syk.
  • The binding of a ligand to an ITAM-containing receptor triggers signaling events which allows for the recruitment of proteins from a family of nonreceptor tyrosine kinases called the Src family. These kinases phosphorylate tyrosine residues within the ITAM sequence, a region with which the tandem SH2 domains on either Syk or ZAP-70 interact. The interaction of Syk with diphosphorylated ITAM sequences induces a conformation change in the kinases that allows for tyrosine phosphorylation of the kinase itself.
  • Not only do these kinases contribute to normal host defense, they also play roles in the pathogenesis of diseases. Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, Alzheimer's disease and hormone-related diseases. As a consequence, there have been substantial efforts in medicinal chemistry to find inhibitors of protein kinases for use as therapeutic agents.
  • There is a need in the art for compounds that are dual inhibitors of Syk/JAK2, as well as for methods for treating conditions that can benefit from such inhibition.
    • SUMMARY OF THE INVENTION
  • In one aspect, the present invention provides a compound of Formula (I), wherein R1 and R2 are defined herein.
  • Figure US20200190095A1-20200618-C00002
  • In another aspect, the invention provides a pharmaceutical composition containing a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • In a further aspect, the invention provides a method for co-regulating JAK-2 and Syk by administering a therapeutically effective amount of a compound of Formula (I) to a patient in need thereof.
  • In yet another aspect, methods for treating inflammation are provided and include administering a compound of Formula (I) to a patient in need thereof.
  • Other aspects and advantages of the invention will be readily apparent from the following detailed description of the invention.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIGS. 1A, 1B, 2A and 2B provide comparative data illustrating the anti-inflammatory effects of methotrexate, a known anti-inflammatory, and a compound described herein which is encompassed by the compound of Formula (I), using the Collagen Induced Arthritis (CIA) model of human rheumatoid arthritis (RA) in female lewis rats. After type II collagen (cII) induced CIA, the compound of Example 19 (2×30 mg/kg) and methotrexate (0.5 mg/kg) were administered daily or twice daily, respectively, to separate rats.
  • FIG. 1A illustrates anti-inflammatory effects as a function of the amount of edema (mL) vs. time (days). The black diamonds (♦) represent results for the control. The triangles (▴) represent results for the compound of Example 19. The crosses (x) represent results for methotrexate.
  • FIG. 1B illustrates anti-inflammatory effects as a function of the amount of edema (mL) vs. time (days). The circles (●) represent results for the control. The inverted triangles (▾) represent results for the compound of Example 62. The astericks (*) represent results for the compound of Example 108. The squares (▪) represent results for the compound of Example 189. The diamonds (♦) represent results for the compound of Example 191.
  • FIG. 2A illustrates anti-inflammatory effects as a function of arhtritic score (per rat) vs. time (days). The black diamonds (♦) represent results for the control. The triangles (▴) represent results for the compound of Example 19. The crosses (x) represent results for methotrexate.
  • FIG. 2B illustrates anti-inflammatory effects as a function of arhtritic score (per rat) vs. time (days). The circles (●) represent results for the control. The triangles (▴) represent results for the compound of Example 62. The astericks (*) represent results for the compound of Example 108. The squares (▪) represent results for the compound of Example 189. The diamonds (♦) represent results for the compound of Example 191.
    •  DETAILED DESCRIPTION OF THE INVENTION
  • The invention provides compounds and pharmaceutical composition thereof, which are capable of reducing or eliminating inflammation caused by tissue insult, injury, or pathology. The invention further provides compounds and compositions which function through a protein kinase inhibitory mechanism.
  • In one aspect, the present invention provides a compound of Formula (I):
  • Figure US20200190095A1-20200618-C00003
  • In this formula, R1 is NR4R5, optionally substituted C1 to C6 alkoxy, optionally substituted C6 to C14 aryl, optionally substituted heteroaryl, optionally substituted 3-10 membered monocyclic or bicyclic cycloalkyl, or optionally substituted 3-10 membered monocyclic or bicyclic heterocyclyl. In one aspect, the 3-4 membered cycloalkyl and heterocyclyl are saturated. In another aspect, the hydrogen atoms on the same carbon atom of the cycloalkyl or heterocyclyl are optionally replaced with an optionally substituted 3-6 membered cycloalkyl or heterocyclyl to form a spirocycloalkyl or spiroheterocyclyl. In a further aspect, the hydrogen atoms on the same atom of the cycloalkyl or heterocyclyl are optionally replaced with O to form an oxo substituent.
      • i. In another embodiment, R1 is N(C1 to C6 alkyl)(C1 to C6 alkyl) or C1 to C6 alkoxy.
      • ii. In still a further embodiment, R1 is N(CH(CH3)2)2, N(CH3)2, OCH2CH3, or OCH3.
      • iii. In another embodiment, R1 is optionally substituted phenyl.
      • iv. In still another embodiment, R1 is of the structure:
  • Figure US20200190095A1-20200618-C00004
        • wherein, R22, R23, R24, R25, and R26 are, independently, H, C(O)(C1 to C6 alkoxy), C(O)OH, O(C1 to C3 perfluoroalkyl), O(C1 to C6 perfluoroalkoxy), C1 to C6 alkoxy, halogen, (C1 to C6 alkyl)heterocyclyl, or (C1 to C6 alkyl)CN.
      • v. In a further embodiment, R1 is:
  • Figure US20200190095A1-20200618-C00005
      • vi. In yet another embodiment, R1 is optionally substituted 5-9 membered saturated heterocyclyl.
      • vii. In still a further embodiment, R1 is of the structure:
  • Figure US20200190095A1-20200618-C00006
        • wherein, R34, R35, R36, and R37 are, independently, H, C1 to C6 alkyl, or CN; Y is (C(R8)2)x, NR7(C(R8)2)x, O, (S═O), SO2, or NR7; R7 and R8 are, independently, H, C1 to C6 alkyl, C(O)OH, (C1 to C6 alkyl)CN, (C1 to C6 alkyl)C(O)OH, C(O)(C1 to C6 alkyl)CN, or CN; and x is 0 to 2.
      • viii. In another embodiment, R1 is:
  • Figure US20200190095A1-20200618-C00007
      • ix. In still a further embodiment, R1 is of the structure:
  • Figure US20200190095A1-20200618-C00008
        • wherein, f, g, h, j, and m are, independently, absent, (CH2), CH(R3), Z, or C═O; R3 is H, C(O)OH, or C(O)O(C1 to C6 alkyl); R45, R46, R47, and R48 are, independently, H or C1 to C6 alkyl; and Z is O, S, SO, SO2, or NH.
      • x. In yet another embodiment, R1 is:
  • Figure US20200190095A1-20200618-C00009
      • xi. In a further embodiment, R1 is a heteroaryl.
      • xii. In yet another embodiment, R1 is thiophene, benzooxole, or pyridine.
      • xiii. In still another embodiment, R1 is a monocyclic C3 to C8 cycloalkyl.
      • xiv. In yet a further embodiment, R1 is cycloheptyl or cyclohexyl, both optionally substituted with —N(C1 to C6 alkyl)(C1 to C6 alkyl).
      • xv. In another embodiment, R1 is piperidine substituted with C(O)(C1 to C6 alkyl)CN.
      • xvi. In still a further embodiment, R1 is:
  • Figure US20200190095A1-20200618-C00010
      • a. In one embodiment, R2 is phenyl substituted with C(O)NR4R5.
      • b. In another embodiment, R2 is phenyl substituted with
  • Figure US20200190095A1-20200618-C00011
      • c. In a further embodiment, R2 is phenyl substituted with NR4R5.
      • d. In yet another embodiment, R2 is phenyl substituted with (C1 to C6 alkyl)NR4R5.
      • e. In another embodiment, R2 is phenyl substituted with NR4R5 or (C1 to C6 alkyl)NR4R5 and R4 and R5 are taken together with the nitrogen atom to which they are attached to form a 6-membered ring.
      • f. In still a further embodiment, R2 is phenyl substituted with NR4R5 or (C1 to C6 alkyl)NR4R5 and R4 and R5 are joined to form a heterocyclyl of the structure:
  • Figure US20200190095A1-20200618-C00012
        • wherein, R10, R1, R12, and R13 are, independently, H or C1 to C6 alkyl; R14 is halogen, OH, C(O)OH, C1 to C6 alkoxy, (C1 to C6 alkyl)halogen, (C1 to C6 alkyl)C(O)OH, C1 to C6 hydroxyalkyl, C3 to C8 cycloalkyl, (C1 to C6 alkyl)C(O)NH2, (C1 to C6 alkyl)C(O)NH(C1 to C6 hydroxyalkyl), (C1 to C6 alkyl)C(O)N(C1 to C6 hydroxyalkyl)2, (C1 to C6 alkyl)CN, (C1 to C6 alkyl)heteroaryl, or heteroaryl; and R18 is C1 to C6 hydroxyalkyl or (C1 to C6 alkyl)C(O)OH.
      • g. In yet a further embodiment, R2 is phenyl substituted with NR4R5 or (C1 to C6 alkyl)NR4R5 and wherein R4 and R5 are joined to form an optionally substituted piperidine or diazepane.
      • h. In another embodiment, R2 is phenyl substituted with NR4R5 or (C1 to C6 alkyl)NR4R5 and R4 and R5 are joined to form:
  • Figure US20200190095A1-20200618-C00013
      • i. In still a further embodiment, R2 is phenyl substituted with NR4R5 or (C1 to C6 alkyl)NR4R5 and R4 and R5 are joined to form a heterocyclyl of the structure:
  • Figure US20200190095A1-20200618-C00014
        • wherein, a, b, c, d, and e are, independently, absent, (CH2), CH(R3), Z, or C═O; R3 is H, C(O)OH, C1 to C6 hydroxyalkyl, or C(O)O(C1 to C6 alkyl); R10, R11, R12, and R13 are, independently, H or C1 to C6 alkyl; and Z is O, S, or NH.
      • j. In yet another embodiment, R2 is phenyl substituted with NR4R5 or (C1 to C6 alkyl)NR4R5 and R4 and R5 are joined to form:
  • Figure US20200190095A1-20200618-C00015
      • k. In a further embodiment, R2 is phenyl substituted with NR4R5 or (C1 to C6 alkyl)NR4R5 and R4 and R5 are taken together to form a heterocyclyl of the structure:
  • Figure US20200190095A1-20200618-C00016
        • wherein, R10, R11, R12, and R13 are, independently, H or C1 to C6 alkyl; Y is O or NR9; and R9 is H, C1 to C6 alkyl, OH, C(O)OH, C1 to C6 hydroxyalkyl, (C1 to C6 alkyl)NH2, (C1 to C6 alkyl)N(C1 to C6 alkyl)(C1 to C6 alkyl), (C1 to C6 alkyl)(C1 to C6 alkoxy), C(O)(C1 to C6 alkyl)NH2, (C1 to C6 alkyl)C(O)OH, C(O)(C1 to C6 hydroxyalkyl), C(O)(C1 to C6 alkyl)CN, (C1 to C6 alkyl)CN, (C1 to C6 alkyl)halogen, or (C1 to C6 alkyl)O(C1 to C6 alkyl)C(O)(C1 to C6 alkyl)NH2; wherein 2 hydrogen atoms attached to the same carbon atom are optionally replaced with ═O.
      • l. In yet another embodiment, R2 is phenyl substituted with NR4R5 or (C1 to C6 alkyl)NR4R5 and R4 and R5 are taken together to form an optionally substituted morpholine or piperazine.
      • m. In still a further embodiment, R2 is phenyl substituted with NR4R5 or (C1 to C6 alkyl)NR4R5 and R4 and R5 are taken together to form:
  • Figure US20200190095A1-20200618-C00017
      • n. In another embodiment, R2 is phenyl substituted with (C1 to C6 alkyl)NR4R5.
      • o. In yet a further embodiment, R2 is phenyl substituted with (C1 to C6 alkyl)NR4R5 and R4 and R5 are (C1 to C6 hydroxyalkyl).
      • p. In still another embodiment, R2 is phenyl substituted with (C1 to C6 alkyl)NR4R5 and NR4R5 is:
  • Figure US20200190095A1-20200618-C00018
      • q. In a further embodiment, R2 is phenyl substituted with (C1 to C6 alkyl)NR4R5 and R4 and R5 are joined to form an optionally substituted 6-membered ring.
      • r. In yet another embodiment, R2 is phenyl substituted with (C1 to C6 alkyl)NR4R5 and NR4R5 are joined to form the 6-membered ring:
  • Figure US20200190095A1-20200618-C00019
        • wherein, R14 is H, OH, C(O)OH, C1 to C6 alkyl, or (C1 to C6 alkyl)CN.
      • s. In another embodiment, R2 is phenyl substituted with (C1 to C6 alkyl)NR4R5 and NR4R5 are joined to form the 6-membered ring:
  • Figure US20200190095A1-20200618-C00020
        • wherein, Y is O or NR9; and R9 is H, C1 to C6 alkyl, OH, C1 to C6 hydroxyalkyl, C(O)(C1 to C6 hydroxyalkyl), C(O)(C1 to C6 alkyl)CN, (C1 to C6 alkyl)CN, (C1 to C6 alkyl)NH2, (C1 to C6 alkyl)halogen, C(O)(C1 to C6 alkyl)CN or (C1 to C6 alkyl)O(C1 to C6 alkyl)C(O)(C1 to C6 alkyl)NH2.
      • t. In still a further embodiment, R2 is phenyl substituted with (C1 to C6 alkyl)NR4R5 and NR4R5 are joined to form the 6-membered ring
  • Figure US20200190095A1-20200618-C00021
        • wherein, a, b, c, d, and e are, independently, absent, (CH2), CH(R3), or O; and R3 is H or C(O)OH.
      • u. In yet another embodiment, R2 is a heteroaryl substituted with (C1 to C6 alkyl)NR4R5.
      • v. In still another embodiment, R2 is:
  • Figure US20200190095A1-20200618-C00022
      • w. In a further embodiment, R2 is a heteroaryl substituted with NR4R5.
      • x. In still another embodiment, R2 is a heteroaryl substituted with NR4R5 and the heteroaryl is pyridine.
      • y. In yet a further embodiment, R2 is of the structure:
  • Figure US20200190095A1-20200618-C00023
      • z. In another embodiment, R2 is of the structure:
  • Figure US20200190095A1-20200618-C00024
        • wherein, R80 is OH, —(C1 to C6 alkyl)CN, C1 to C6 hydroxyalkyl, (C1 to C6 alkyl)C(O)NH2, (C1 to C6 alkyl)heterocycle or —(C1 to C6 alkyl) C(O)OH.
      • aa. In still a further embodiment, R2 is of the structure:
  • Figure US20200190095A1-20200618-C00025
        • wherein, p is 1 to 6; and R81 is H or C(O)OH.
      • bb. In another embodiment, R2 is of the structure:
  • Figure US20200190095A1-20200618-C00026
        • wherein, R90 is H, C1 to C6 alkyl, C(O)(C1 to C6 alkyl)CN, (C1 to C6 alkyl)C(O)OH, or C(O)C1 to C6 hydroxyalkyl.
      • cc. In yet another embodiment, wherein R2 is phenyl substituted with one or more C1 to C6 alkoxy, (C1 to C6 alkyl)halogen, C1 to C6 trifluoroalkoxy, (C1 to C6 alkyl)C(O)OH, halogen, optionally substituted C3 to C8 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —O—(C1 to C6 alkyl)C(O)OH, —O—(C1 to C6 alkyl)NR4R5, —O(optionally substituted heterocycle), —O(C1 to C6 alkyl)N(C1 to C6 alkyl)(C1 to C6 alkyl), —O(C1 to C6 alkyl)NH2, C1 to C6 hydroxyalkyl, —O(C1 to C6 hydroxyalkyl), —O(C1 to C6 alkyl)C(O)OH, —C1 to C6 alkoxy-C1 to C6 alkoxy, —O(heterocycle)(C1 to C6 hydroxyalkyl), —SO2(C1 to C6 alkyl), or —(C1 to C6 alkyl)(C1 to C6 alkoxy)halogen.
      • dd. In a further embodiment, wherein R2 is of the structure:
  • Figure US20200190095A1-20200618-C00027
        • wherein, R6 is H, (C1 to C6 alkyl)C(O)OH, or (C1 to C6 alkyl)CN.
      • ee. In still another embodiment, R2 is of the structure:
  • Figure US20200190095A1-20200618-C00028
        • wherein, z is 1, 2, 3, 4, 5, or 6.
      • ff. In another embodiment, R2 is of the structure:
  • Figure US20200190095A1-20200618-C00029
        • wherein, R6 is H or (C1 to C6 alkyl)C(O)OH.
      • gg. In yet a further embodiment, R2 is —O(C1 to C6 alkyl)NR4R5.
      • hh. In still another embodiment, R2 is of the structure:
  • Figure US20200190095A1-20200618-C00030
        • wherein, y is 2 to 6; and R50 is H, OH, C1 to C6 alkyl, C1 to C6 hydroxyalkyl, or —(C1 to C6 alkyl)C(O)OH.
      • ii. In further embodiment, R2 is of the structure:
  • Figure US20200190095A1-20200618-C00031
        • wherein, m is 2 to 6; y is 0 or 1; Z is O or NR60; and R60 is H, C1 to C6 alkyl, C1 to C6 hydroxyalkyl, —(C1 to C6 alkyl)CN, —(C1 to C6 alkyl)C(O)OH, —(C1 to C6 alkyl)CONH2, or —C(O)(C1 to C6 alkyl)OH; wherein 2 hydrogen atoms attached to one carbon atom of the nitrogen-ring are replaced with an oxo or optionally substituted 3-8 membered spirocyclic ring.
      • jj. In yet another embodiment, R2 is of the structure:
  • Figure US20200190095A1-20200618-C00032
        • wherein, r is 2 to 6; and R70 is H, C(O)OH or C1 to C6 hydroxyalkyl.
      • kk. In still a further embodiment, R2 is:
  • Figure US20200190095A1-20200618-C00033
      • ll. In another embodiment, R2 is aryl substituted with —O—(C1 to C6 alkyl)-heterocycle.
      • mm. In a further embodiment, R2 is:
  • Figure US20200190095A1-20200618-C00034
  • In one aspect, a compound of Formula (I) is provided, wherein R1 is NR4R5, optionally substituted C1 to C6 alkoxy, optionally substituted C6 to C14 aryl, optionally substituted heteroaryl, optionally substituted 3-10 membered monocyclic or bicyclic cycloalkyl, or optionally substituted 3-10 membered monocyclic or bicyclic heterocyclyl. The 3-4 membered cycloalkyl and heterocyclyl rings are saturated. Hydrogen atoms on the same carbon atom of the cycloalkyl or heterocyclyl are optionally replaced with an optionally substituted 3-6 membered cycloalkyl or heterocyclyl to form a spirocycloalkyl or spiroheterocyclyl. In addition or alternatively, hydrogen atoms on the same atom of the cycloalkyl or heterocyclyl are optionally replaced with O to form an oxo substituent. R2 is phenyl or 5-6 membered heteroaryl containing at least one N or NH in the backbone, wherein R2 is optionally substituted with one or more R19 and when R2 is 4-pyridyl, the 4-pyridyl lacks a carbonyl substituent at the 2nd position. R19 is NR4R5, (C1 to C6 alkyl)NR4R5, C1 to C6 alkyl, C(O)NR4R5, C3 to C8 cycloalkyl substituted with one or more R21, or heterocyclyl substituted with one or more R21. R21 is (C1 to C6 alkyl)CN, (C1 to C6 alkyl)C(O)OH, (C1 to C6 alkyl)C(O)NH2, (C1 to C6 alkyl)C(O)NHCH2CH2OH, or (C1 to C6 alkyl)C(O)N(CH2CH2OH)2. R4 and R5 are independently selected from among H, C1 to C6 alkyl, C1 to C6 hydroxyalkyl, and (C1 to C6 alkyl)N(C1 to C6 alkyl)(C1 to C6 alkyl). Alternatively, R4 and R5 are joined to form an optionally substituted 3-8 membered heterocyclyl optionally further containing one or more O, S(O)n, or NR9. R9 is H, OH, (C1 to C6 alkyl)C(O)OH, (C1 to C6 alkyl)C(O)NH2, (C1 to C6 alkyl)C(O)NHCH2CH2OH, (C1 to C6 alkyl)C(O)N(CH2CH2OH)2, C(O)(C1 to C6 alkyl)NH2, C(O)(C1 to C6 alkyl)OH, C1 to C6 hydroxyalkyl, or C1 to C6 alkyl and n is 0 to 2. In one embodiment, R9 is CH2CH2OH. Hydrogen atoms on the same carbon atom of the heterocyclyl are optionally replaced with a 3-6 membered cycloalkyl or heterocyclyl optionally substituted with one or more R20 to form a spirocycloalkyl or spiroheterocyclyl. R20 is C(O)O(C1 to C6 alkyl), C(O)OH, (C1 to C6 alkyl)C(O)OH, (C1 to C6 alkyl)C(O)NH2, (C1 to C6 alkyl)C(O)NHCH2CH2OH, or (C1 to C6 alkyl)C(O)N(CH2CH2OH)2. Alternatively, or in addition, hydrogen atoms on the same atom of any of the heterocyclyls or cycloalkyls of R9 are optionally replaced with O to form an oxo substituent; or a pharmaceutically acceptable salt or ester thereof.
  • In another aspect, a compound of Formula (I) is provided, wherein R1 is NR4R5, C1 to C6 alkoxy, optionally substituted phenyl, heteroaryl, optionally substituted 3-10 membered cycloalkyl, or optionally substituted 3-10 membered monocyclic or bicyclic heterocyclyl. Hydrogen atoms on the same carbon atom of the cycloalkyl or heterocyclyl are optionally replaced with an optionally substituted 3-6 membered cycloalkyl or heterocyclyl to form a spirocycloalkyl or spiroheterocyclyl. In addition or alternatively, hydrogen atoms on the same atom of the cycloalkyl or heterocyclyl are optionally replaced with O to form an oxo substituent. R2 is phenyl or pyrazole, wherein R2 is optionally substituted with one or more R19. R19 is NR4R5, (C1 to C6 alkyl)NR4R5, C1 to C6 alkyl, C(O)NR4R5, C3 to C8 cycloalkyl substituted with one or more R21, or heterocyclyl substituted with one or more R21. R21 is (C1 to C6 alkyl)CN, (C1 to C6 alkyl)C(O)OH, (C1 to C6 alkyl)C(O)NH2, (C1 to C6 alkyl)C(O)NHCH2CH2OH, (C1 to C6 alkyl)C(O)N(CH2CH2OH)2. R4 and R5 are (a) independently selected from among H, C1 to C6 alkyl, C1 to C6 hydroxyalkyl, and (C1 to C6 alkyl)N(C1 to C6 alkyl)(C1 to C6 alkyl) or (b) joined to form an optionally substituted 3-8 membered heterocyclyl optionally further containing one or more O, S(O)n, or NR9. R9 is H, OH, C1 to C6 hydroxyalkyl, (C1 to C6 alkyl)C(O)OH, (C1 to C6 alkyl)C(O)NH2, (C1 to C6 alkyl)C(O)NHCH2CH2OH, (C1 to C6 alkyl)C(O)N(CH2CH2OH)2, C(O)(C1 to C6 alkyl)NH2, C(O)(C1 to C6 alkyl)OH, or C1 to C6 alkyl and n is 0 to 2. In one embodiment, R9 is CH2CH2OH. Hydrogen atoms on the same carbon atom of the heterocyclyl are optionally replaced with a 3-6 membered cycloalkyl or heterocyclyl to form a spirocycloalkyl or spiroheterocyclyl optionally substituted with one or more R20. R20 is C(O)O(C1 to C6 alkyl), C(O)OH, (C1 to C6 alkyl)C(O)OH, (C1 to C6 alkyl)C(O)NH2, (C1 to C6 alkyl)C(O)NHCH2CH2OH, or (C1 to C6 alkyl)C(O)N(CH2CH2OH)2. Alternatively, or in addition, hydrogen atoms on the same atom of the heterocyclyl (b) or cycloalkyl are optionally replaced with O to form an oxo substituent; or a pharmaceutically acceptable salt or ester thereof.
  • In a further aspect, a compound of Formula (I) is provided, wherein R1 is NR4R5, C1 to C6 alkoxy, phenyl optionally substituted with C(O)O(C1 to C6 alkyl), C(O)OH, O(C1 to C3 perfluoroalkyl), C1 to C6 alkoxy, halogen, CH2-heterocyclyl, or CH2CN, 5-8 membered cycloalkyl, heteroaryl, or 3-10 membered monocyclic or bicyclic heterocyclyl optionally substituted with (C1 to C6 alkyl)C(O)OH, C1 to C6 alkyl, CN, C(O)OH, or (C1 to C6 alkyl)CN. Hydrogen atoms on the same carbon atom of the cycloalkyl or heterocyclyl are optionally replaced with an optionally substituted 3-6 membered cycloalkyl or heterocyclyl to form a spirocycloalkyl or spiroheterocyclyl. In addition or alternatively, hydrogen atoms on the same atom of the cycloalkyl or heterocyclyl are optionally replaced with O to form an oxo substituent. R2 is phenyl or pyrazole, wherein R2 is optionally substituted with one R19. R19 is NR4R5, (C1 to C6 alkyl)NR4R5, C1 to C6 alkyl, C(O)NR4R5, C3 to C8 cycloalkyl substituted with one or more R21, or heterocyclyl substituted with one or more R21. R21 is (C1 to C6 alkyl)CN, (C1 to C6 alkyl)C(O)OH, (C1 to C6 alkyl)C(O)NH2, (C1 to C6 alkyl)C(O)NHCH2CH2OH, or (C1 to C6 alkyl)C(O)N(CH2CH2OH)2. R4 and R5 are (a) independently selected from among H, C1 to C6 alkyl, C1 to C6 hydroxyalkyl, and (C1 to C6 alkyl)N(C1 to C6 alkyl)(C1 to C6 alkyl). R4 and R5 may also be (b) joined to form a 5-8 membered heterocyclyl optionally further containing one or two O, S(O)n, or NR9. R9 is H, OH, C1 to C6 hydroxyalkyl (C1 to C6 alkyl)C(O)OH, C(O)(C1 to C6 alkyl)NH2, C(O)(C1 to C6 alkyl)OH, (C1 to C6 alkyl)C(O)NH2, (C1 to C6 alkyl)C(O)NHCH2CH2OH, (C1 to C6 alkyl)C(O)N(CH2CH2OH)2, or C1 to C6 alkyl and n is 0 to 2. In one embodiment, R9 is CH2CH2OH. Hydrogen atoms on the same carbon atom of the heterocyclyl are optionally replaced with a 3-5 membered cycloalkyl optionally substituted with one or more R20 to form a spirocycloalkyl. R20 is C(O)O(C1 to C6 alkyl), C(O)OH, (C1 to C6 alkyl)C(O)OH, (C1 to C6 alkyl)C(O)NH2, (C1 to C6 alkyl)C(O)NHCH2CH2OH, or (C1 to C6 alkyl)C(O)N(CH2CH2OH)2. Alternatively, or in addition, hydrogen atoms on the same atom of the heterocyclyl (b) or cycloalkyl (b) are optionally replaced with O to form an oxo substituent; or a pharmaceutically acceptable salt or ester thereof.
  • Some compounds within the present invention possess one or more chiral centers, and the present invention includes each separate enantiomer of such compounds as well as mixtures of the enantiomers. Where multiple chiral centers exist in compounds of the present invention, the invention includes each possible combination of chiral centers within a compound, as well as all possible enantiomeric and diastereomeric mixtures thereof. All chiral, diastereomeric, and racemic forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials.
  • The following definitions are used in connection with the compounds of the present invention unless the context indicates otherwise. In general, the number of carbon atoms present in a given group is designated “Cx-Cy”, where x and y are the lower and upper limits, respectively. For example, a group designated as “C1-C6” contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like. Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming from left to right the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent “arylalkyloxycabonyl” refers to the group (C6-C14 aryl)-(C1-C6 alkyl)-O—C(O)—. Terms not defined herein have the meaning commonly attributed to them by those skilled in the art.
  • “Alkyl” refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms, for example, a C1-C12 alkyl group may have from 1 to 12 (inclusive) carbon atoms in it. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. Examples of C1-C8 alkyl groups include, but are not limited to, methyl, propyl, pentyl, hexyl, heptyl, 3-methylhex-1-yl, 2,3-dimethylpent-2-yl, 3-ethylpent-1-yl, octyl, 2-methylhept-2-yl, 2,3-dimethylhex-1-yl, and 2,3,3-trimethylpent-1-yl. An alkyl group can be unsubstituted or substituted with one or more of halogen, NH2, (alkyl)NH, (alkyl)(alkyl)N—, —N(alkyl)C(O)(alkyl), —NHC(O)(alkyl), —NHC(O)H, —C(O)NH2, —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), CN, OH, alkoxy, alkyl, C(O)OH, —C(O)O(alkyl), —C(O)(alkyl), aryl, heteroaryl, heterocyclyl, cycloalkyl, haloalkyl, aminoalkyl-, —OC(O)(alkyl), carboxyamidoalkyl-, and NO2.
  • “Alkoxy” refers to the group R—O— where R is an alkyl group, as defined above. Exemplary C1-C6 alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy. An alkoxy group can be unsubstituted or substituted with one or more of halogen, OH, alkoxy, NH2, (alkyl)amino-, di(alkyl)amino-, (alkyl)C(O)N(C1-C3 alkyl)-, (alkyl)carboxyamido-, HC(O)NH—, H2NC(O)—, (alkyl)NHC(O)—, di(alkyl)NC(O)—, CN, C(O)OH, (alkoxy)carbonyl-, (alkyl)C(O)—, aryl, heteroaryl, cycloalkyl, haloalkyl, amino(C1-C6 alkyl)-, (alkyl)carboxyl-, carboxyamidoalkyl-, or NO2.
  • Aryl refers to an aromatic 6 to 14 membered hydrocarbon group. Examples of a C6-C14 aryl group include, but are not limited to, phenyl, α-naphthyl, β-naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenanaphthyl. Examples of a C6-C10 aryl group include, but are not limited to, phenyl, α-naphthyl, β-naphthyl, biphenyl, and tetrahydronaphthyl. An aryl group can be unsubstituted or substituted with one or more of alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, OH, hydroxyalkyl, —O-(hydroxyalkyl), —O-(alkyl)-C(O)OH, -(alkyl)-(alkoxy)-halogen, NH2, aminoalkyl-, dialkylamino-, C(O)OH, —C(O)O-(alkyl), —OC(O)(alkyl), —O-(alkyl)-N(alkyl)(alkyl), N-alkylamido-, —C(O)NH2, (alkyl)amido-, NO2, (aryl)alkyl, alkoxy, aryloxy, heteroaryloxy, (aryl)amino, (alkoxy)carbonyl-, (alkyl)amido-, (alkyl)amino, aminoalkyl-, alkylcarboxyl-, (alkyl)carboxyamido-, (aryl)alkyl-, (aryl)amino-, cycloalkenyl, di(alkyl)amino-, heteroaryl, (heteroaryl)alkyl-, heterocyclyl, —O-(heterocyclyl), heterocyclyl(alkyl)-, (hydroxyalkyl)NH—, (hydroxyalkyl)2N, —SO2(alkyl) or a spiro substituent.
  • The term “bicycle” or “bicyclic” as used herein refers to a molecule that features two fused rings, which rings are a cycloalkyl, heterocyclyl, or heteroaryl. In one embodiment, the rings are fused across a bond between two atoms. The bicyclic moiety formed therefrom shares a bond between the rings. In another embodiment, the bicyclic moiety is formed by the fusion of two rings across a sequence of atoms of the rings to form a bridgehead. Similarly, a “bridge” is an unbranched chain of one or more atoms connecting two bridgeheads in a polycyclic compound. In another embodiment, the bicyclic molecule is a “spiro” or “spirocyclic” moiety. The spirocyclic group is a carbocyclic or heterocyclic ring which bound through a single carbon atom of the spirocyclic moiety to a single carbon atom of a carbocyclic or heterocyclic moiety. In one embodiment, the spirocyclic group is a cycloalkyl and is bound to another cycloalkyl. In another embodiment, the spirocyclic group is a cycloalkyl and is bound to a heterocyclyl. In a further embodiment, the spirocyclic group is a heterocyclyl and is bound to another heterocyclyl. In still another embodiment, the spirocyclic group is a heterocyclyl and is bound to a cycloalkyl.
  • “(Aryl)alkyl” refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with an aryl group as defined above. (C6-C14 aryl)alkyl-moieties include benzyl, benzhydryl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl and the like. An (aryl)alkyl group can be unsubstituted or substituted with one or more of halogen, CN, NH2, OH, (alkyl)amino-, di(alkyl)amino-, (alkyl)C(O)N(alkyl)-, (alkyl)carboxyamido-, HC(O)NH—, H2NC(O)—, (alkyl)NHC(O)—, di(alkyl)NC(O)—, CN, OH, alkoxy, alkyl, C(O)OH, (alkoxy)carbonyl-, (alkyl)C(O)—, aryl, heteroaryl, cycloalkyl, haloalkyl, amino(alkyl)-, (alkyl)carboxyl-, carboxyamidoalkyl-, or NO2.
  • “(Alkoxy)carbonyl-” refers to the group alkyl-O—C(O)—. Exemplary (C1-C6 alkoxy)carbonyl-groups include but are not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy. An (alkoxy)carbonyl group can be unsubstituted or substituted with one or more of halogen, OH, NH2, (alkyl)amino-, di(alkyl)amino-, (alkyl)C(O)N(alkyl)-, (alkyl)carboxyamido-, HC(O)NH—, H2NC(O)—, (alkyl)NHC(O)—, di(alkyl)NC(O)—, CN, alkoxy, C(O)OH, (alkoxy)carbonyl-, (alkyl)C(O)—, aryl, heteroaryl, cycloalkyl, haloalkyl, amino(alkyl)-, (alkyl)carboxyl-, carboxyamidoalkyl-, or NO2.
  • “(Alkyl)amido-” refers to a —C(O)NH— group in which the nitrogen atom of said group is attached to a C1-C6 alkyl group, as defined above. Representative examples of a (C1-C6 alkyl)amido-group include, but are not limited to, —C(O)NHCH3, —C(O)NHCH2CH3, —C(O)NHCH2CH2CH3, —C(O)NHCH2CH2CH2CH3, —C(O)NHCH2CH2CH2CH2CH3, —C(O)NHCH(CH3)2, —C(O)NHCH2CH(CH3)2, —C(O)NHCH(CH3)CH2CH3, —C(O)NH—C(CH3)3 and —C(O)NHCH2C(CH3)3.
  • “(Alkyl)amino-” refers to an —NH group, the nitrogen atom of said group being attached to a alkyl group, as defined above. Representative examples of an (C1-C6 alkyl)amino-group include, but are not limited to CH3NH—, CH3CH2NH—, CH3CH2CH2NH—, CH3CH2CH2CH2NH—, (CH3)2CHNH—, (CH3)2CHCH2NH—, CH3CH2CH(CH3)NH— and (CH3)3CNH—. An (alkyl)amino group can be unsubstituted or substituted on the alkyl moiety with one or more of halogen, NH2, (alkyl)amino-, di(alkyl)amino-, (alkyl)C(O)N(alkyl)-, (alkyl)carboxyamido-, HC(O)NH—, H2NC(O)—, (alkyl)NHC(O)—, di(alkyl)NC(O)—, CN, OH, alkoxy, alkyl, C(O)OH, (alkoxy)carbonyl-, (alkyl)C(O)—, aryl, heteroaryl, cycloalkyl, haloalkyl, amino(alkyl)-, (alkyl)carboxyl-, carboxyamidoalkyl-, or NO2.
  • “Aminoalkyl-” refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with —NH2; one or both H of the NH2 may be replaced by a substituent.
  • “Alkylcarboxyl-” refers to an alkyl group, defined above that is attached to the parent structure through the oxygen atom of a carboxyl (C(O)—O—) functionality. Examples of (C1-C6 alkyl)carboxyl-include acetoxy, propionoxy, propylcarboxyl, and isopentylcarboxyl.
  • “(Alkyl)carboxyamido-” refers to a —NHC(O)— group in which the carbonyl carbon atom of said group is attached to a C1-C6 alkyl group, as defined above. Representative examples of a (C1-C6 alkyl)carboxyamido-group include, but are not limited to, —NHC(O)CH3, —NHC(O)CH2CH3, —NHC(O)CH2CH2CH3, —NHC(O)CH2CH2CH2CH3, —NHC(O)CH2CH2CH2CH2CH3, —NHC(O)CH(CH3)2, —NHC(O)CH2CH(CH3)2, —NHC(O)CH(CH3)CH2CH3, —NHC(O)—C(CH3)3 and —NHC(O)CH2C(CH3)3.
  • “(Aryl)amino” refers to a radical of formula (aryl)-NH—, wherein aryl is as defined above. “(Aryl)oxy” refers to the group Ar—O— where Ar is an aryl group, as defined above.
  • “Cycloalkyl” refers to a non-aromatic, saturated, partially saturated, monocyclic, bicyclic or polycyclic hydrocarbon 3 to 12 membered ring system. Representative examples of a C3-C12 cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl, decahydronaphthalen-1-yl, octahydro-1H-inden-2-yl, decahydro-1H-benzo[7]annulen-2-yl, and dodecahydros-indacen-4-yl. Representative examples of a C3-C10 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decahydronaphthalen-1-yl, and octahydro-1H-inden-2-yl. Representative examples of a C3-C8 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and octahydropentalen-2-yl. A cycloalkyl can be unsubstituted or substituted with one or more of halogen, NH2, (alkyl)NH, (alkyl)(alkyl)N—, —N(alkyl)C(O)(alkyl), —NHC(O)(alkyl), —NHC(O)H, —C(O)NH2, —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), CN, OH, alkoxy, alkyl, C(O)OH, —C(O)O(alkyl), —C(O) alkyl), aryl, heteroaryl, cycloalkyl, haloalkyl, aminoalkyl-, —OC(O)(alkyl), carboxyamidoalkyl-, and NO2. Additionally, each of any two hydrogen atoms on the same carbon atom of the carbocyclic ring can be replaced by an oxygen atom to form an oxo (═O) substituent.
  • “Halo” or “halogen” refers to —F, —Cl, —Br and —I.
  • “C1-C6 haloalkyl” refers to a C1-C6 alkyl group, as defined above, wherein one or more of the C1-C6 alkyl group's hydrogen atoms has been replaced with F, Cl, Br, or I. Each substitution can be independently selected from F, C1, Br, or I. Representative examples of an C1-C6 haloalkyl-group include, but are not limited to, —CH2F, —CCl3, —CF3, CH2CF3, —CH2Cl, —CH2CH2Br, —CH2CH2I, —CH2CH2CH2F, —CH2CH2CH2Cl, —CH2CH2CH2CH2Br, —CH2CH2CH2CH2I, —CH2CH2CH2CH2CH2Br, —CH2CH2CH2CH2CH2I, —CH2CH(Br)CH3, —CH2CH(C1)CH2CH3, —CH(F)CH2CH3 and —C(CH3)2(CH2Cl).
  • “Heteroaryl” refers to a monocyclic, bicyclic, or polycyclic aromatic ring system containing at least one ring atom selected from the heteroatoms oxygen, sulfur and nitrogen. Examples of C1-C9 heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Bicyclic C1-C9 hetroaryl groups include those where a phenyl, pyridine, pyrimidine or pyridazine ring is fused to a 5 or 6-membered monocyclic heteroaryl ring having one or two nitrogen atoms in the ring, one nitrogen atom together with either one oxygen or one sulfur atom in the ring, or one O or S ring atom. Examples of monocyclic C1-C4 heteroaryl groups include 2H-tetrazole, 3H-1,2,4-triazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, imidazole, and pyrrole. A heteroaryl group can be unsubstituted or substituted with one or more of C1-C6 alkyl, halogen, haloalkyl, OH, CN, hydroxyalkyl, NH2, aminoalkyl-, dialkylamino-, C(O)OH, —C(O)O-(alkyl), —OC(O)(alkyl), N-alkylamido-, —C(O)NH2, (alkyl)amido-, —NO2, (aryl)alkyl, alkoxy, aryloxy, heteroaryloxy, (aryl)amino, (alkoxy)carbonyl-, (alkyl)amido-, (alkyl)amino, aminoalkyl-, alkylcarboxyl-, (alkyl)carboxyamido-, (aryl)alkyl-, (aryl)amino-, cycloalkenyl, di(alkyl)amino-, heteroaryl, (heteroaryl)alkyl-, heterocyclyl, hetyerocyclyl(alkyl)-, (hydroxyalkyl)NH—, (hydroxyalkyl)2N or a spiro substituent.
  • “Heterocycle” or “heterocyclyl” refers to monocyclic, bicyclic, polycyclic, or bridged head molecules in which at least one ring atom is a heteroatom. A heterocycle may be saturated or partially saturated. Exemplary C1-C9 heterocyclyl groups include but are not limited to aziridine, oxirane, oxirene, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6-tetrahydropyridine-1-yl, tetrahydropyran, pyran, thiane, thiine, piperazine, azepane, diazepane, oxazine, 5,6-dihydro-4H-1,3-oxazin-2-yl, 2,5-diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane, 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 6-oxa-3,8-diazabicyclo[3.2.1]octane, 7-oxa-2,5-diazabicyclo[2.2.2]octane, 2,7-dioxa-5-azabicyclo[2.2.2]octane, 2-oxa-5-azabicyclo[2.2.1]heptane-5-yl, 2-oxa-5-azabicyclo[2.2.2]octane, 3,6-dioxa-8-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.1.1]heptane, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 5,7-dioxa-2-azabicyclo[2.2.2]octane, 6,8-dioxa-3-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.1.1]heptane, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, 2-methyl-2,5-diazabicyclo[2.2.1]heptane-5-yl, 1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl, 3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl-, 7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl, 9-oxa-3-azabicyclo[3.3.1]nonan-3-yl, 3-oxa-9-azabicyclo[3.3.1]nonan-9-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl, 4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl, thiazine, dithiane, and dioxane. The contemplated heterocycle rings or ring systems have a minimum of 3 members. Therefore, for example, C1 heterocyclyl radicals would include but are not limited to oxaziranyl, diaziridinyl, and diazirinyl, C2 heterocyclyl radicals include but are not limited to aziridinyl, oxiranyl, and diazetidinyl, C9 heterocyclyl radicals include but are not limited to azecanyl, tetrahydroquinolinyl, and perhydroisoquinolinyl. A heterocyclyl group can be unsubstituted or substituted with one or more of alkyl, halogen, alkoxy, haloalkyl, OH, hydroxyalkyl, —C(O)-(hydroxyalkyl), NH2, aminoalkyl-, dialkylamino-, C(O)OH, —C(O)O-(alkyl), —OC(O)(alkyl), N-alkylamido-, —C(O)NH2, (alkyl)amido-, —C(O)-(alkyl)-CN, (alkyl)-CN, or NO2.
  • “Heterocyclyl(alkyl)-” refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a heterocycle group as defined above. Heterocyclyl(C1-C6 alkyl)-moieties include 1-piperazinylethyl, 4-morpholinylpropyl, 6-piperazinylhexyl, and the like. A heterocyclyl(alkyl) group can be unsubstituted or substituted with one or more of halogen, NH2, (alkyl)amino-, di(alkyl)amino-, (alkyl)C(O)N(alkyl)-, (alkyl)carboxyamido-, HC(O)NH—, H2NC(O)—, (alkyl)NHC(O)—, di(alkyl)NC(O)—, CN, OH, alkoxy, alkyl, C(O)OH, (alkoxy)carbonyl-, (alkyl)C(O)—, 4- to 7-membered monocyclic heterocycle, aryl, heteroaryl, or cycloalkyl.
  • “Heteroaryl(alkyl)” refers to a heteroaryl which is attached to an alkyl group and the heteroaryl is defined above.
  • “Hydroxyalkyl” refers to a alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with OH groups. Examples of C1-C6 hydroxyalkyl moieties include, for example, —CH2OH, —CH2CH2OH, —CH2CH2CH2OH, —CH2CH(OH)CH2OH, —CH2CH(OH)CH3, —CH(CH3)CH2OH and higher homologs.
  • “Perfluoroalkyl-” refers to alkyl group, defined above, having two or more fluorine atoms. Examples of a C1-C6 perfluoroalkyl-group include CF3, CH2CF3, CF2CF3 and CH(CF3)2.
  • A “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or gorilla.
  • With the proviso that when R2 is 4-pyridyl, then there cannot be a carbonyl substituent at the 2-position of the 4-pyridyl moiety;
  • Representative “pharmaceutically acceptable salts” include but are not limited to, e.g., water-soluble and water-insoluble salts, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, bromide, butyrate, calcium, chloride, choline, citrate, edisylate (camphorsulfonate), fumarate, gluconate, glucuronate, glutamate, hydrobromide, hydrochloride, lauryl sulfate, malate, maleate, mandelate, mesylate, palmitate, pantothenate, phosphate, potassium, propionate, p-toluenesulfonate, salicylate, sodium, stearate, succinate, and sulfate salts.
  • The following abbreviations are used and have the indicated definitions: ACN is acetonitrile; DMSO is dimethylsulfoxide; DMF is N,N-dimethylformamide; DMF.DMA is dimethylformamide dimethylacetal; TFA is trifluroroacetic acid; mCPBA is meta-chloroperbenzoic acid; RT is room temperature; THF is tetrahydrofuran; and NMP is N-methyl pyrrolidinone.
  • Methods useful for making the compounds of Formula (I) are set forth in the Examples below and generalized in Schemes I-III. One of skill in the art will recognize that Schemes 1-III can be adapted to produce the compounds of Formula (I) and pharmaceutically accepted salts of compounds of Formula (I) according to the present invention. In the reactions described, reactive functional groups, such as hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, may be protected to avoid unwanted reactions. Conventional protecting groups may be used in accordance with standard practice.
  • Figure US20200190095A1-20200618-C00035
  • Scheme 1 provides the synthesis of compounds of Formula (I). Ethyl acetoacetate 1 is converted to the corresponding bis(methylthio)methylene derivative 2 using carbon disulfide, an organic or inorganic base such as K2CO3 and a alkylating agent. In one embodiment, the alkylating agent is an alkyl iodide, alkyl triflate, or alkyl sulfonate. In another embodiment, the alkylating agent is a methylating agent. In a further embodiment, the alkylating agent is methyl iodide. Reaction of 2 with an R1-optionally substituted amidine hydrochloride in the presence of a base results in pyrimidine 3. In one embodiment, the base utilized to form pyrimidine 3 is Et3N or Hünig's base. The alkyl group on the pyrimidine group of compound 3 is then oxidized using an oxidizing agent. In one embodiment, the oxidation is performed using SeO2. The resulting pyrimidine aldehyde 4 is converted to pyrimido-pyridazinone 5 using hydrazine hydrate or hydrazine hydrochloride. The methyl thio group in compound 5 is oxidized to a methane sulfonyl using meta-chloroperoxybenzoic acid (mCPBA) or hydrogen peroxide/acetic acid. Finally, the methane sulfonyl group of compound 6 is replaced with an R2-substituted aniline to provide compound (I). In one embodiment, the R2-substituted aniline is an aryl or heteroaryl substituted aniline.
  • Figure US20200190095A1-20200618-C00036
  • Scheme 2 provides the synthesis of compound IB which are encompassed by the structure of Formula (I). In this embodiment, ethyl acetoacetate 1 is converted to the corresponding bis(methylthio)methylene derivative 2 using carbon disulfide, K2CO3 and methyl iodide. Reaction of 2 with an R′-substituted benzamidine hydrochloride in the presence of Et3N results in pyrimidine 3a. The methyl group bound to the C-atom of pyrimidine 3a is then oxidized using SeO2. The resulting pyrimidine aldehyde 4a is converted to pyrimido-pyridazinone 5a using hydrazine hydrate or hydrazine hydrochloride. The methyl thio group in compound 5a is oxidized to a methane sulfonyl group using mCPBA. Finally, the methane sulfonyl group is replaced with an R″-substituted aniline to give compound 1B.
  • Figure US20200190095A1-20200618-C00037
  • Scheme 3 provides the synthesis of compounds IC which are encompassed by the structure of Formula (I). Treatment of ethyl chloroformate 7 with ammonium thiocyanate results in the production of ethyl thiocyanato formate 8 which upon treatment with ethyl 3-amino crotanoate results in compound 9. Compound 9 is cyclized to compound 10 by treatment with an organic or inorganic base. In one embodiment the organic or inorganic base is a strong base. In one embodiment, the strong base is a tertiary organic base. In another embodiment, the strong base is aqueous Et3N. The dichloro pyrimidine 11 is obtained by treating compound 10 with a chlorinating agent. In one embodiment, the chlorinating agent is POCl3. In another embodiment, this transformation can also be carried out by using other chlorinating agents such as PCl5, SOCl2 in the presence of an organic base such as TEA, tributyl amine, and N,N-dimethylaniline. The 4-position of dichloropyrimidine 11 is then substituted by reaction with an optionally substituted (R2) aniline to afford compound 12. The 2-position of pyrimidine 12 is then R1-substituted using coupling agents such as boronic acids or boronic ester reagents to provide compound 13. The methyl group at position 4 of pyrimidine 13 is then oxidized using an oxidizing agent such as SeO2 to provide compound 14. The resulting pyrimidine aldehyde 14 is converted to pyrimido-pyridazinone 1C using hydrazine hydrate.
  • Figure US20200190095A1-20200618-C00038
  • Scheme 4 provides the synthesis of compounds ID which are encompassed by the structure of Formula (I). Treatment of ethyl chloroformate 7 with ammonium thiocyanate results in ethyl thiocyanato formate 8 which upon treatment with ethyl 3-amino crotanoate results in compound 9. Compound 9 is cyclized to compound 10 as described in Scheme 3, i.e., by treatment with aqueous Et3N. The dichloro pyrimidine compound 11 is obtained by treating compound 10 with POCl3. The 4-position of dichloropyrimidine 11 is then substituted by reaction with an optionally R-substituted aniline to afford compound 12a. The 2-position of pyrimidine compound 12a is then substituted with an R′-substituted aryl or heteroaryl group using a boronic acid or an boronic ester reagent to provide compound 13a. In one embodiment, the boronic acid is (R′-aryl)-B(OH)2 or (R′-heteroaryl)-B(OH)2. The methyl at position-4 on pyrimidine 13a is then oxidized using SeO2. The resulting pyrimidine aldehyde 14a is converted to pyrimido-pyridazinone 1D using hydrazine hydrate.
  • Figure US20200190095A1-20200618-C00039
  • Scheme 5 provides the synthesis of compound IE which are encompassed by the structure of Formula (I). Compound 12 is reacted with an optionally substituted amine (NHR4R5) to provide compound 15. The methyl group at the 4-position of compound 15 is reacted with DMF.DMA to provide compound 16. Compound 17 is obtained by oxidative cleavage of the olefin of compound 16. In one embodiment, oxidative cleavage is performed using NaIO4. Finally, pyrimido-pyridazinone IE is obtained by cyclizing the aldehyde 17. In one embodiment, the cyclizaton is performed using hydrazine, hydrazine hydrate or hydrazine hydrochloride, as described previously.
  • Figure US20200190095A1-20200618-C00040
  • Scheme 6 provides the synthesis of compounds 1F which are encompassed by the structure of Formula (I). Compound 12a is reacted with optionally substituted amines to result in 15a. The methyl group of 15a is reacted with DMF.DMA to give compound 16a. The aldehyde 17a is obtained by the oxidative cleavage of the olefin in 16a. In one embodiment, the oxidative cleavage is performed with NaIO4. Finally, the pyrimido-pyridazinone 1F is obtained by cyclizing aldehyde 17a. In one embodiment, cyclization is performed using with hydrazine.
  • Figure US20200190095A1-20200618-C00041
  • Scheme 7 provides the synthesis of compound 1G which are encompassed by the structure of Formula (I). Compound 10 is reacted with an alkylating agent to the S-methyl compound 18. In one embodiment, the reacted is performed under basic conditions. In another embodiment, the alkylating agent is methyl iodide, ethyl iodide, propyl iodide, dimethylsulfate, among others. Compound 19 is obtained by chlorinating compound 18. In one embodiment, compound 18 is chlorinated using POCl3. Compound 19 is then NR4R5 substituted with an optionally substituted amine to provide compound 20 [using NHR4R5?]. The methyl group of compound 20 is reacted with DMF.DMA to give compound 21. The aldehyde 22 is obtained by the oxidative cleavage of the olefin group in compound 21. In one embodiment, the oxidative cleavage is performed with NaIO4. Alternatively, compound 20 may directly converted to the pyrimidine aldehyde 22 by oxidizing the methyl group using SeO2 or a combination of CO2, t-butyl hydroperoxide, and an alcohol such as C1 to C6 alkyl)H2OH. The resulting pyrimidine aldehyde 22 is converted to pyrimido-pyridazinone 23 using hydrazine hydrate or hydrazine hydrochloride. The methyl thio group in compound 23 is oxidized to a methane sulfonyl group. In one embodiment compound 23 is reacted with meta-chloroperoxybenzoic acid (mCPBA) or hydrogen peroxide/acetic acid. Finally, the methane sulfonyl group of compound 24 is replaced with suitably substituted aniline to provide compound 1G.
  • Figure US20200190095A1-20200618-C00042
  • Scheme 8 provides the synthesis of compound 1H which is encompassed by the structure of Formula (I). In this scheme, compound 19 is coupled with an optionally substituted boronic acid or boronic ester to give compound 25. In one embodiment, the coupling is performed in the presence of a coupling agent such as Pd(PPh3)4 or PdCl2(PPh3)2. The methyl group in compound 25 is then oxidized to the corresponding aldehyde. In one embodiment, the oxidation is performed using SeO2 or a combination of CO2, t-butyl hydroperoxide, and an alcohol such as C1 to C6 alkyl)H2OH to give compound 26. Compound 26 is converted to pyrimido-pyridazinone 27 using hydrazine hydrate or hydrazine hydrochloride. The methyl thio group in compound 27 is then oxidized to a methane sulfonyl group. In one embodiment, the oxidation is performed using mCPBA or hydrogen peroxide/acetic acid. Finally, the methane sulfonyl group of compound 28 is replaced with suitably substituted aniline to provide compound 1H.
  • Pharmaceutical compositions of the invention comprise a compound of Formula (I) optionally with other pharmaceutically inert or inactive ingredients. In one embodiment, the pharmaceutically inert or inactive ingredient is one or more pharmaceutically acceptable carrier or excipient. The present invention also contemplates combining the compound of Formula (I) with one or more therapeutic agents, i.e., active ingredients, as described below. In a further embodiment, a compound of Formula (I) is combined with one or more inert/inactive ingredients and one or more therapeutic agents.
  • The pharmaceutical compositions of the invention contain an amount of a compound of Formula (I) that is effective for treating inflammation in a subject. Specifically, the dosage of the compound of Formula (I) to achieve a therapeutic effect will depend on factors such as the formulation, pharmacological potency of the drug, age, weight and sex of the patient, condition being treated, severity of the patient's symptoms, specific compound of Formula (I), route of delivery, and response pattern of the patient. It is also contemplated that the treatment and dosage of the compound of Formula (I) may be administered in unit dosage form and that one skilled in the art would adjust the unit dosage form accordingly to reflect the relative level of activity. The decision as to the particular dosage to be employed (and the number of times to be administered per day) is within the discretion of the ordinarily-skilled physician, and may be varied by titration of the dosage to the particular circumstances to produce the desired therapeutic effect.
  • In one embodiment, the therapeutically effective amount is about 0.0001% to about 25% w/w. In another embodiment, the therapeutically effective amount is less than about 20% w/w, about 15% w/w, about 10% w/w, about 5% w/w, or about 1% w/w. In another embodiment, the therapeutically effective amount is about 0.0001% to about 10% w/w. In a further embodiment, the therapeutically effective amount is about 0.005 to about 5% w/w. In yet another embodiment, the therapeutically effective amount is about 0.01 to about 5% w/w. In still a further embodiment, the therapeutically effective amount is about 0.01% w/w, about 0.05% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, or about 5% w/w.
  • The therapeutically effective amounts may be provided on regular schedule, i.e., on a less than daily, weekly, monthly, or yearly basis or on an irregular schedule with varying administration days, weeks, months, etc. Alternatively, the therapeutically effective amount to be administered may vary. In one embodiment, the therapeutically effective amount for the first dose is higher than the therapeutically effective amount for one or more of the subsequent doses. In another embodiment, the therapeutically effective amount for the first dose is lower than the therapeutically effective amount for one or more of the subsequent doses. Equivalent dosages may be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every 2 weeks, about every 3 weeks, about every month, about every 2 months, about every 3 months and about every 6 months. The number and frequency of dosages corresponding to a completed course of therapy will be determined according to the judgment of a health-care practitioner. The therapeutically effective amounts described herein refer to total amounts administered for a given time period; that is, if more than one compound of Formula (I) is administered, the therapeutically effective amounts correspond to the total amount administered.
  • The compound of Formula (I) may be administered by any route, taking into consideration the specific condition for which it has been selected. The compounds of Formula (I) may be delivered orally, by injection (including intravascularly, e.g, intravenously or intra-arterially), inhalation (intranasally and intratracheally), ocularly, transdermally (via simple passive diffusion formulations or via facilitated delivery using, for example, iontophoresis, microporation with microneedles, radio-frequency ablation or the like), intravascularly, subcutaneously, intramuscularly, sublingually, intracranially, epidurally, rectally, and vaginally, among others. Desirably, the compound of Formula (I) may be administered by injection, transdermally or topically.
  • In one embodiment, the compound of Formula (I) may be administered topically to the eye, e.g., as solutions, suspensions or ointments. Examples of ophthalmically compatible carriers which may be used include, without limitation, an aqueous solution, such as saline solution, oil solution or ointments containing ophthalmically compatible preservatives, surfactants, buffers, and viscosity regulators. These compositions may also contain stabilizing agents, antibacterial agents, and may be manufactured in different dosage units, suitable for ocular administration. Drug inserts, either soluble or insoluble, may also be used.
  • In another embodiment, the compound of Formula (I) may be administered by injection. Solutions for injection or infusion may be prepared as aqueous solutions. Desirably, the compound of Formula (I) is present in a concentration of about 0.001 μg/mL to 1 mg/mL, or this amount may be adjusted higher or lower as needed. These solutions may also contain stabilizing agents, antibacterial agents, buffers and may be manufactured in different dosage unit ampoules or bottles.
  • In a further embodiment, the compound of Formula (I) may be administered rectally. Dosage units for rectal administration may be prepared in the form of ointments or suppositories, which contain the compound of Formula (I) in a mixture with a neutral fat base, or they may be prepared in the form of gelatin-rectal capsules that contain the compound of Formula (I) in a mixture with, e.g., a vegetable oil or paraffin oil. Ointments, suppositories or creams containing at least one compound of Formula (I) are useful for the treatment of hemorrhoids.
  • In yet another embodiment, the compound of Formula (I) may be administered orally. Dosage units for oral administration include, without limitation, tablets, caplets, capsules, powders, suspensions, microcapsules, dispersible powder, granules, suspensions, syrups, elixirs, and aerosols, which contain the compound of Formula (I) optionally with one or more excipient. In one embodiment, the compositions are compressed into a tablet or caplet. In another embodiment, the tablet or caplet may be administered to the subject. In another embodiment, the tablet or caplet may be added to a capsule. In a further embodiment, the composition containing the compound of Formula (I) is added directly to a capsule. In one embodiment, the capsule includes hydroxypropyl methylcellulose, hypromellose capsule, or a hard shell gelatin capsule. In yet another embodiment the tablets or caplets are optionally film-coated using film-coatings known to those of skill in the art. In one embodiment, the film-coating is selected from among polymers such as, without limitation, hydroxypropylmethylcellulose, ethyl cellulose, polyvinyl alcohols, and combinations thereof.
  • Although the compound of Formula (I) may be administered alone, i.e., neat, it may also be administered in the presence of one or more pharmaceutical carriers that are physiologically compatible. The amount of the pharmaceutical carrier(s) is determined by the solubility and chemical nature of the compound of Formula (I), chosen route of administration, and standard pharmacological practice. The carriers may be in dry (solid) or liquid form and must be pharmaceutically acceptable. Liquid pharmaceutical compositions are typically sterile solutions or suspensions. When liquid carriers are utilized for parenteral administration, they are desirably sterile liquids. Liquid carriers are typically utilized in preparing solutions, suspensions, emulsions, syrups and elixirs. A variety of suitable liquid carriers is known and may be readily selected by one of skill in the art. Such carriers may include, e.g., dimethylsulfoxide (DMSO), saline, buffered saline, cyclodextrin, hydroxypropylcyclodextrin (HPPβCD), n-dodecyl-β-D-maltoside (DDM) and mixtures thereof. In one embodiment, the compound of Formula (I) is dissolved a liquid carrier. In another embodiment, the compound of Formula (I) is suspended in a liquid carrier. One of skill in the art of formulations would be able to select a suitable liquid carrier, depending on the route of administration. The compound of Formula (I) may alternatively be formulated in a solid carrier of which a variety of solid carriers and excipients are known to those of skill in the art. In one embodiment, the composition may be compacted into a unit dose form, i.e., tablet or caplet. In another embodiment, the composition may be added to unit dose form, i.e., a capsule. In a further embodiment, the composition may be formulated for administration as a powder. The solid carrier may perform a variety of functions, i.e., may perform the functions of two or more of the excipients described below. For example, a solid carrier may also act as a flavoring agent, lubricant, solubilizer, suspending agent, filler, glidant, compression aid, binder, disintegrant, or encapsulating material.
  • The composition may also be sub-divided to contain appropriate quantities of the compound of Formula (I). For example, the unit dosage can be packaged compositions, e.g., packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • Examples of excipients which may be combined with one or more compound of Formula (I) include, without limitation, adjuvants, antioxidants, binders, buffers, coatings, coloring agents, compression aids, diluents, disintegrants, emulsifiers (e.g., polyoxyethylene fatty acid esters), emollients, encapsulating materials, fillers, flavoring agents, glidants, granulating agents, lubricants, metal chelators, osmo-regulators, pH adjustors (e.g., sodium hydroxide), preservatives, solubilizers, sorbents, stabilizing agents, sweeteners (such as saccharin), surfactants, suspending agents, syrups, thickening agents (e.g., carboxypolymethylene or hydroxypropylmethylcellulose), penetration enhancers (e.g., hydroxypolyethoxydodecane, DMSO, DMAC, DDM, etc) or viscosity regulators (such as polymers to increase viscosity). See, for example, the excipients described in the “Handbook of Pharmaceutical Excipients”, 5th Edition, Eds.: Rowe, Sheskey, and Owen, APhA Publications (Washington, D.C.), Dec. 14, 2005, which is incorporated herein by reference.
  • In one embodiment, the compositions may be utilized as inhalants. For this route of administration, compositions may be prepared as fluid unit doses using a compound of Formula (I) and a vehicle for delivery by an atomizing spray pump or by dry powder for insufflation.
  • In another embodiment, the compositions may be utilized as aerosols, i.e., oral or intranasal. For this route of administration, the compositions are formulated for use in a pressurized aerosol container together with a gaseous or liquefied propellant, e.g., dichlorodifluoromethane, carbon dioxide, nitrogen, propane, and the like. Also provided is the delivery of a metered dose in one or more actuations.
  • In another embodiment, the compositions may be administered by a modified-release delivery device. “Modified-release” as used herein refers to delivery of a compound of Formula (I) which is controlled, for example over a period of at least about 8 hours (e.g., extended delivery) to at least about 12 hours (e.g., sustained delivery). Such devices may also permit immediate release (e.g., therapeutic levels achieved in under about 1 hour, or in less than about 2 hours). Those of skill in the art know suitable modified-release delivery devices. For use in such modified-release delivery devices, the compound of Formula (I) is formulated as described herein.
  • Also contemplated is the administration of the compounds of Formula (I) with other medication(s) or therapeutic agent(s). In one embodiment, the compounds of Formula (I) are combined with other medications or therapeutic agents in a single composition. However, the present invention is not so limited. In other embodiments, the compounds of Formula (I) may be administered in one or more separate formulations from other compounds of Formula (I), or other medications or therapeutic agents as described below.
  • Additionally, one or more agents typically used to treat inflammation may be used in conjunction with a combination of the invention in the methods, compositions, and kits described herein. Such agents include, but are not limited to, non-steroidal anti-inflammatory drugs.
  • The compound of Formula (I) may be combined with glucose or dextrose when utilized for infusion or as a regional analgesic or anti-pruritic.
  • Further, the compound of Formula (I) may be combined with thickening agents to form a jelly, or may also contain penetration enhancers, for use in topical or dermal applications such as for urogenital topical procedures.
  • Finally, the compound of Formula (I) may be formulated as an ointment for administration to accessible mucous membranes.
  • Also provided herein are kits or packages of pharmaceutical formulations containing the compounds of Formula (I) or compositions described herein. The kits may be organized to indicate a single formulation or combination of formulations to be taken at each desired time.
  • Suitably, the kit contains packaging or a container with the compound of Formula (I) formulated for the desired delivery route. Suitably, the kit contains instructions on dosing and an insert regarding the compound of Formula (I).
  • Optionally, the kit may further contain instructions for monitoring local or circulating levels of product and materials for performing such assays including, e.g., reagents, well plates, containers, markers or labels, and the like. Such kits are readily packaged in a manner suitable for treatment of a desired indication. For example, the kit may also contain instructions for use of an oral dosage form such as a pill, capsule, patch, spray pump or other delivery device. Other suitable components to include in such kits will be readily apparent to one of skill in the art, taking into consideration the desired indication and the delivery route.
  • The compounds of Formula (I) or compositions described herein can be a single dose or for continuous or periodic discontinuous administration. For continuous administration, a package or kit can include the compound of Formula (I) in each dosage unit (e.g., solution, lotion, tablet, pill, drug-eluting patch or other unit described above or utilized in drug delivery), and optionally instructions for administering the doses less-than-daily, daily, weekly, or monthly, for a predetermined length of time or as prescribed. When the compound of Formula (I) is to be delivered periodically in a discontinuous fashion, a package or kit can include placebos during periods when the compound of Formula (I) is not delivered. When varying concentrations of a composition, of the components of the composition, or the relative ratios of the compounds of Formula (I) or agents within a composition over time is desired, a package or kit may contain a sequence of dosage units which provide the desired variability.
  • A number of packages or kits are known in the art for dispensing pharmaceutical agents for periodic oral use. In one embodiment, the package has indicators for each period. In another embodiment, the package is a foil or blister package, labeled ampoule, vial or bottle.
  • The packaging means of a kit may itself be geared for administration, such as an inhalant, syringe, pipette, eye dropper, or other such apparatus, from which the formulation may be applied to an affected area of the body, such as the lungs, injected into a subject, or even applied to and mixed with the other components of the kit.
  • One or more components of these kits also may be provided in dried or lyophilized forms. When reagents or components are provided as a dried form, reconstitution generally is by the addition of a suitable solvent. It is envisioned that the solvent also may be provided in another package.
  • The kits of the present invention also will typically include a means for containing the vials or other suitable packaging means in close confinement for commercial sale such as, e.g., injection or blow-molded plastic containers into which the desired vials are retained. Irrespective of the number or type of packages and as discussed above, the kits also may include, or be packaged with a separate instrument for assisting with the injection/administration or placement of the composition within the body of an animal. Such an instrument may be an inhalant, syringe, pipette, forceps, measuring spoon, eye dropper or any such medically approved delivery means.
  • In one embodiment, a kit is provided and contains a compound of Formula (I). The compound of Formula (I) may be in the presence or absence of one or more of the carriers or excipients described above. The kit may optionally contain instructions for administering the compound of Formula (I) to a subject having inflammation.
  • In a further embodiment, a kit is provided and contains a compound of Formula (I) in a second dosage unit, and one or more of the carriers or excipients described above in a third dosage unit. The kit may optionally contain instructions for administering the compound of Formula (I) to a subject having inflammation.
  • As discussed above, the methods, compositions, and kits of the invention can be used to treat inflammation resulting from a number of conditions. The term “inflammation” as used herein includes all types of inflammation. In one embodiment, the inflammation may be acute or chronic. In another embodiment, the inflammation may be nociceptive, dysfunctional, idiopathic, neuropathic, somatic, visceral, and/or procedural. For example, the inflammation may be from a migraine, gynecological condition, pre-labor or labor, stroke, surgery, neuralgia, sickle cell, interstitial cystitis, urological condition (such as urethritis), dental work/injury, or headache, among other. Inflammation may also occur in patients with cancer, which may be due to multiple causes, such as nerve compression and mechanical forces resulting from tissue distension as a consequence of invasion by a tumor and tumor metastasis into bone or other tissues.
  • In one embodiment, inflammation results from neuropathy, such as post-herpetic neuralgia. In still another embodiment, the inflammation results from a surgery or procedure. In yet a further embodiment, the inflammation results from an infection, cancer, colitis, cystitis, irritable bowel syndrome, or idiopathic neuropathy.
  • “Somatic inflammation” includes inflammation in bone, joint, muscle, skin, or connective tissue.
  • “Central inflammation” includes inflammation arising as a consequence of brain trauma, stroke, or spinal cord injury.
  • “Visceral inflammation” includes inflammation in visceral organs, such as the respiratory or gastrointestinal tract and pancreas, the urinary tract and reproductive organs. In one embodiment, visceral inflammation results from tumor involvement of the organ capsule. In another embodiment, visceral inflammation from obstruction of hollow viscus.
  • “Idiopathic inflammation” refers to inflammation which has no underlying cause or refers to inflammation caused by condition which remains undiagnosed.
  • “Dysfunctional inflammation” refers to inflammation which occurs in the absence of a noxious stimulus, tissue damage or a lesion to the nervous system. In one embodiment, dysfunctional inflammation results from rheumatologic conditions such as arthritis and fibromyalgia, tension type headache, irritable bowel disorders and erythermalgia.
  • “Nociceptive inflammation” includes inflammation caused by noxious stimuli that threaten to or actually injure body tissues. In one embodiment, nociceptive inflammation results from a cut, bruise, bone fracture, crush injury, burn, trauma, surgery, labor, sprain, bump, injection, dental procedure, skin biopsy, or obstruction. In another embodiment, nociceptive inflammation is located in the skin, musculoskeletal system, or internal organs.
  • “Neuropathic inflammation” is inflammation due to abnormal processing of sensory input by the peripheral or central nervous system consequent on a lesion to these systems. In one embodiment, neuropathic inflammation is chronic and non-malignant. In one embodiment, neuropathic inflammation is due to trauma, surgery, herniation of an intervertebral disk, spinal cord injury, diabetes, infection with herpes zoster (shingles), HIV/AIDS, late-stage cancer, amputation (such as mastectomy), carpal tunnel syndrome, chronic alcohol use, exposure to radiation, and as an unintended side-effect of neurotoxic treatment agents, such as certain anti-HIV and chemotherapeutic drugs.
  • “Procedural inflammation” includes refers to inflammation arising from a medical procedure. The medical procedure may include any type of medical, dental or surgical procedure. In one embodiment, the procedural inflammation is postoperative. In another embodiment, the inflammation is associated with an injection, draining an abscess, surgery, dermatological, dental procedure, ophthalmic procedure, arthroscopy and use of other medical instrumentation, and/or cosmetic surgery.
  • A “migraine” is a type of headache, typically defined clinically as being caused by activation of sensory fibers innervating the meninges of the brain.
  • The term “treat”, “treating”, or any variation thereof is meant to include therapy utilized to remedy a health problem or condition in a patient or subject. In one embodiment, the health problem or condition may be eliminated permanently or for a short period of time. In a further embodiment, the health problem or condition may be prevented. In another embodiment, the severity of the health problem or condition, or of one or more symptoms characteristic of the health problem or condition, may be lessened permanently, or for a short period of time. The effectiveness of a treatment of inflammation can be determined using any standard inflammation index, such as those described herein, or can be determined based on the patient's subjective inflammation assessment. A patient is considered “treated” if there is a reported reduction in inflammation, or a reduced reaction to stimuli that should cause inflammation.
  • In one embodiment, the treatment methods described herein include administering a compound of Formula (I) to a patient. Additional, optional agents, such as those described above for use in the combination, may be administered to the patient prior to, concurrently with, or subsequent to the compound of Formula (I).
  • The present invention is further exemplified, but not limited, by the following examples that illustrate the preparation of compounds of Formula (I) according to the invention
    • EXAMPLES Example 1: 4-(4-morpholinophenylamino)-2-phenylpyrimido[5,4-d]pyridazin-5(6H)-one
  • Figure US20200190095A1-20200618-C00043
    • a: Ethyl 2-(bis(methylthio)methylene)-3-oxobutanoate
  • Figure US20200190095A1-20200618-C00044
  • To a solution of ethyl acetoacetate (10 g, 76.9 mmol) in DMF (40 mL) was added K2CO3 (10.6 g, 76.9 mmol) and the reaction mixture was stirred at RT for 2 hours. Carbon disulfide (8.8 g, 230 mmol) was added, stirring was continued. After 2 hours, methyl iodide was added and stirring was continued for additional 10 hours. The reaction mixture was partitioned between ethyl acetate and water, the organic layer washed with water and dried over Na2SO4 and the solvent evaporated in vacuum. The crude product was purified by column chromatography over silica gel using ethyl acetate and petroleum ether as eluent to give the desired product (8.8 g). 1H-NMR 400 Hz (CDCl3): δ 4.29 (q, J=7.2 Hz, 2H), 2.44 (s, 6H), 2.34 (s, 3H), 1.33 (t, J=7.2 Hz, 3H); MS m/z 235 (M+1).
    • b: Ethyl 4-methyl-6-(methylthio)-2-phenylpyrimidine-5-carboxylate
  • Figure US20200190095A1-20200618-C00045
  • To a solution of ethyl 2-(bis(methylthio)methylene)-3-oxobutanoate (500 mg, 2 mmol) in ethanol was added benzamidine acetate (732 mg, 6 mmol) and triethyl amine (1.41 mL) and the reaction mixture was refluxed overnight. The reaction mixture was concentrated and partitioned between ethyl acetate and water and the organic layer washed with water and dried over Na2SO4 and the solvent evaporated in vacuum. The crude product was purified by column chromatography over silica gel using 1% ethyl acetate in petroleum ether as eluent to give the desired product (350 mg). 1H-NMR 400 Hz (CDCl3): δ 8.50 (d, J=7.6 Hz, 2H), 7.50-7.46 (m, 3H), 4.45 (q, J=7.2 Hz, 2H), 2.67 (s, 3H), 2.65 (s, 3H), 1.44 (t, J=7.2 Hz, 3H); MS m/z 288.7 (M+1).
    • c: Ethyl 4-formyl-6-(methylthio)-2-phenylpyrimidine-5-carboxylate
  • Figure US20200190095A1-20200618-C00046
  • To a solution of ethyl 4-methyl-6-(methylthio)-2-phenylpyrimidine-5-carboxylate (5 g 17.4 mmol) in 1,4-dioxane (50 mL) was added selenium dioxide (9.6 g, 86.5 mmol) and water (1.5 mL) and the reaction mixture was refluxed for 12 hours. Dioxane was removed in a vacuum and the crude solid suspended in ethyl acetate and filtered. The filtrate was concentrated and purified by column chromatography over silica gel using 10% ethyl acetate in petroleum ether as eluent to give the desired product (3.1 g). 1H-NMR (400 Hz, CDCl3): δ 10.10 (s, 1H), 8.54 (d, J=7.2 Hz, 2H), 7.56-7.43 (m, 3H), 4.47 (q, J=7.2 Hz, 2H), 2.67 (s, 3H), 2.64 (s, 3H), 1.42 (t, J=7.2 Hz, 3H); MS m/z 303.1 (M+1).
    • d: 4-(methylthio)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one
  • Figure US20200190095A1-20200618-C00047
  • To a solution of ethyl 4-formyl-6-(methylthio)-2-phenylpyrimidine-5-carboxylate (600 mg, 1.98 mmol) in ethanol (15 mL) was added hydrazine dihydrochloride (0.2 g, 1.98 mmol) and the mixture refluxed for 1 hour. The precipitated solid was filtered and dried in vacuum. The desired product (520 mg) was obtained by column chromatography over silica gel using methanol/dichloromethane as eluent. 1H-NMR (400 Hz, DMSO-d6): δ 13.19 (s, 1H), 8.54 (d, J=8.0 Hz, 2H), 8.36 (s, 1H), 7.64-7.58 (m, 3H), 2.67 (s, 3H); MS m/z 271.1 (M+1).
    • e: 4-(4-Morpholinophenylamino)-2-phenylpyrimido[5,4-d]pyridazin-5(6H)-one
  • 4-(Methylthio)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one (0.1 g, 0.37 mmol) was dissolved in dichloromethane, m-chloro perbenzoic acid (0.19 g) was added and the reaction mixture was stirred room temperature for 10-12 hours. The solid precipitate was filtered and dried under vacuum. The crude product was dissolved in NMP, 4-(morpholinomethyl)aniline (45 mg, 0.25 mmol) was added and the reaction mixture was heated to 60° C. for 30 minutes. The reaction mixture was cooled and ice water was added. The solid precipitate was filtered and dried under vacuum to yield the desired product (38 mg).
    • Example 2: Methyl 4-(5-oxo-4-(4-(piperazin-1-ylmethyl)phenylamino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)benzoate hydrochloride
  • Figure US20200190095A1-20200618-C00048
    • a: (Z)-Ethyl 3-amino-2-(ethoxycarbonylcarbamothioyl)but-2-enoate
  • Figure US20200190095A1-20200618-C00049
  • To a solution of ethyl chloroformate (1 g, 9.2 mmol) in 1,4-dioxane cooled to 0° C. was added ammonium thiocyanate (0.771 g, 10 mmol) and pyridine (0.726 g, 9.2 mmol) and the mixture was stirred at 0° C. for 2 hours. The reaction mixture was extracted with diethyl ether, dried over Na2SO4 and concentrated in vacuum to give crude ethyl isothiocyanatoformate. This crude product was added dropwise over a period of 2-3 hours to a solution of ethyl 3-aminocrotanoate (1.19 g, 9.2 mmol) in dioxane at 0-10° C. The reaction mixture was quenched with ice water and the resulting solid filtered and dried to get the desired crude product, which is used without further purification. 1H NMR (400 MHz, CDCl3): δ 10.52 (s, 1H), 9.51 (s, 1H), 5.25 (s, 1H), 4.21-4.12 (m, 4H), 2.26 (s, 3H), 1.29-1.21 (m, 6H); MS m/z 261.1 (M+1).
    • b: Ethyl 2-hydroxy-4-mercapto-6-methylpyrimidine-5-carboxylate
  • Figure US20200190095A1-20200618-C00050
  • (Z)-ethyl 3-amino-2-(ethoxycarbonylcarbamothioyl)but-2-enoate was dissolved in 30% aqueous triethyl amine and the reaction mixture stirred at 70° C. After 2 hours, the reaction mixture was cooled and neutralized with glacial acetic acid and the aqueous mixture extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4 and concentrated under vacuum to give the desired product. 1H NMR (400 MHz, DMSO-d6): δ 12.54 (s, 1H), 11.85 (s, 1H), 4.21 (q, J=7.6 Hz, 2H), 2.03 (s, 3H), 1.24 (t. J=7.6 Hz, 3H); MS m/z 213.1 (M−1).
    • c: Ethyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate
  • Figure US20200190095A1-20200618-C00051
  • Ethyl 2-hydroxy-4-mercapto-6-methylpyrimidine-5-carboxylate (1.4 g, 6.54 mmol) was taken up in POCl3 (13.67 mL) at 0° C., tri-n-butylamine was added and the mixture heated to 90° C. for 5 hours. The mixture was cooled, poured slowly on to crushed ice and extracted with dichloromethane. The organic layer was washed with water, dried over Na2SO4 and concentrated under vacuum. The pure product was obtained by column purification over silica gel using 3% EtOAc/hexane as eluent. 1H NMR (400 MHz, CDCl3): δ 4.47 (q, J=6.8 Hz, 2H), 2.57 (s, 3H), 1.42 (t. J=6.8 Hz, 3H); MS m/z 235.1 (M+1).
    • d: Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-2-chloro-6-methylpyrimidine-5-carboxylate
  • Figure US20200190095A1-20200618-C00052
  • Ethyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate (0.5 g, 2.1 mmol) and tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate (0.6 g, 2.06 mmol) were dissolved in NMP and stirred at 0° C. for 2 hour. The reaction mixture was poured onto water and extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4 and evaporated under vacuum to get the desired compound (0.62 g). 1H NMR (400 MHz, CDCl3): δ 10.58 (s, 1H), 7.58 (d, J=6.4 Hz, 2H), 7.31 (d, J=6.4 Hz, 2H), 4.45 (q, J=6.8 Hz, 2H), 3.56 (s, 2H), 3.41 (m, 4H), 2.69 (s, 3H), 2.47 (m, 4H), 1.45 (s, 9H), 1.43 (t, J=6.8 Hz, 3H); MS m/z 490.0 (M+1).
    • e: Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-2-(4-(methoxycarbonyl)phenyl)-6-methylpyrimidine-5-carboxylate
  • Figure US20200190095A1-20200618-C00053
  • Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-2-chloro-6-methylpyrimidine-5-carboxylate (0.8 g, 1.63 mmol), K2CO3 (0.56 g, 4 mmol), Pd(PPh3)4(0.28 g, 0.24 mmol) were dissolved in dioxane/water (20:1), 4-(methoxycarbonyl)phenylboronic acid (0.38 g, 2.1 mmol) was added the mixture was heated to 100° C. for 3 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated and purified by column chromatography over silica gel using 30% EtOAc/hexanes as eluent to give the desired product (0.7 g). 1H NMR (400 MHz, DMSO-d6): δ 9.88 (s, 1H), 8.43 (d, J=8.0 Hz, 2H), 8.10 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 4.39 (q, J=6.8 Hz, 2H), 3.89 (s, 3H), 3.49 (s, 2H), 2.68 (m, 4H), 2.50 (s, 3H), 2.33 (m, 4H), 1.91 (t, J=6.8 Hz, 3H), 1.39 (s, 9H); MS m/z 590.2 (M+1).
    • f: Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-formyl-2-(4-(methoxycarbonyl)phenyl)pyrimidine-5-carboxylate
  • Figure US20200190095A1-20200618-C00054
  • Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-2-(4-(methoxycarbonyl)phenyl)-6-methylpyrimidine-5-carboxylate (0.63 g, 1.06 mmol) was dissolved in dioxane (10 mL), SeO2 (0.6 g, 5.4 mmol) and water (0.096 mL) were added and the reaction mixture heated at 100° C. for 3.5 hours. The reaction mixture was concentrated in vacuum and the mixture loaded on to a column of silica gel and eluted with MeOH, dichloromethane as eluent, to give the desired compound (0.52 g). 1H NMR (400 MHz, DMSO-d6): δ 10.18 (s, 1H), 9.53 (s, 1H), 8.56 (d, J=8.4 Hz, 2H), 8.08 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 4.39 (q, J=6.8 Hz, 2H), 3.89 (s, 3H), 3.41 (s, 2H), 3.26 (m, 4H), 2.35 (m, 4H)), 1.39 (s, 9H), 1.36 (t, J=6.8 Hz, 3H); MS m/z 636.5 (M+1).
    • g: tert-butyl 4-(4-(2-(4-(methoxycarbonyl)phenyl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)benzyl)piperazine-1-carboxylate
  • Figure US20200190095A1-20200618-C00055
  • Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-formyl-2-(4-(methoxycarbonyl)phenyl)pyrimidine-5-carboxylate (0.5 g, 0.82 mmol) was dissolved in ethanol (5 mL), hydrazine hydrate (60 μL, 1.24 mmol) was added and the mixture is refluxed for 2.5 hours. The reaction mixture was cooled to obtain a solid precipitate. The precipitate was filtered and the solid dried under vacuum (0.4 g). 1H NMR (400 MHz, DMSO-d6): δ 13.41 (s, 1H), 11.52 (s, 1H), 8.52 (d, J=8.4 Hz, 2H), 8.34 (s, 1H), 8.13 (d, J=8.8 Hz, 2H), 7.86 (d, J=8.8 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 3.90 (s, 3H), 3.51 (s, 2H), 3.29 (t, J=4.4 Hz, 4H), 2.34 (t, J=4.4 Hz, 4H), 1.39 (s, 9H); MS m/z 572.3 (M+1).
    • h: Methyl 4-(5-oxo-4-(4-(piperazin-1-ylmethyl)phenylamino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)benzoate hydrochloride
  • Tert-butyl 4-(4-(2-(4-(methoxycarbonyl)phenyl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)benzyl)piperazine-1-carboxylate (0.1 g, 0.175 mmol) was dissolved in dioxane.HCl (5 mL) and stirred at room temperature for 1.5 hours. The solid obtained was filtered and the residue washed with EtOAc and dried to give the desired product (40 mg).
    • Example 3: 2-morpholino-4-(4-(piperazin-1-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride
  • Figure US20200190095A1-20200618-C00056
    • a: Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-methyl-2-morpholinopyrimidine-5-carboxylate
  • Figure US20200190095A1-20200618-C00057
  • Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-2-chloro-6-methylpyrimidine-5-carboxylate (0.6 g, 1.23 mmol) was dissolved in NMP (5 mL), morpholine (0.14 mL) was added and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4 and evaporated to give the desired product (0.53 g). 1H NMR (400 MHz, DMSO-d6): δ 10.48 (s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 4.30 (q, J=6.8 Hz, 2H), 3.75 (s, 2H), 3.64 (m, 4H), 3.46-3.21 (m, 8H), 2.69 (s, 3H), 2.41 (m, 4H), 1.38 (s, 9H), 1.33 (t, J=6.8 Hz, 3H); MS m/z 541.1 (M+1).
    • b: (E)-ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-(2-(dimethylamino)vinyl)-2-morpholinopyrimidine-5-carboxylate
  • Figure US20200190095A1-20200618-C00058
  • Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-methyl-2-morpholinopyrimidine-5-carboxylate (350 mg, 0.64 mmol) was dissolved in DMF (5 mL), dimethyl formamide dimethyl acetal (0.26 mL) was added and the mixture was heated to 130° C. for 12 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4 and evaporated to give the desired product (0.23 g). 1H NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 7.94 (d, J=12.2 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.8 Hz, 2H), 5.89 (d, J=12.2 Hz, 1H), 4.30 (q, J=6.8 Hz, 2H), 3.80 (s, 2H), 3.75-3.65 (m, 8H), 3.33 (m, 4H), 3.32 (m, 6H), 2.41 (m, 4H), 1.38 (s, 9H), 1.32 (t, J=6.8 Hz, 3H); MS m/z 596.4 (M+1).
    • c: Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-formyl-2-morpholinopyrimidine-5-carboxylate
  • Figure US20200190095A1-20200618-C00059
  • (E)-ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-(2-(dimethylamino)vinyl)-2-morpholinopyrimidine-5-carboxylate (0.2 g, 0.336 mmol) was dissolved in methanol (4 mL) and to this mixture at room temperature was added a solution of sodium periodate (0.21 g, 1 mmol) in methanol (4 mL). The mixture was stirred at room temperature for 3 hours and the precipitate filtered. The filtrate was evaporated, diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and evaporated in vacuum. The crude product was purified by column chromatography over silica gel using acetone/dichloromethane as eluent. (0.11 g). 1H NMR (400 MHz, DMSO-d6): δ 10.07 (s, 1H), 10.02 (s, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 4.31 (q, J=6.8 Hz, 2H), 3.83 (s, 2H), 3.75-3.65 (m, 8H), 3.33 (m, 4H), 2.32 (m, 4H), 1.38 (s, 9H), 1.31 (t, J=6.8 Hz, 3H); MS m/z 555.5 (M+1).
    • d: 2-morpholino-4-(4-(piperazin-1-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride
  • Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-formyl-2-morpholinopyrimidine-5-carboxylate (100 mg, 0.18 mmol) was dissolved in ethanol, hydrazine dihydrochloride (28 mg, 26 mmol) was added and the mixture was refluxed for 3 hours. The solid precipitated was filtered and dried in vacuum to give the desired product (49 mg).
  • By repeating the procedures described in the above examples, using appropriate starting materials, the following compounds of Formula I, as identified in Table 1, are obtained, together with their spectroscopic data in Table 2.
  • TABLE 1
    Synthetic
    Ex Structure IUPAC Name Scheme
    1
    Figure US20200190095A1-20200618-C00060
         		4-(4- morpholinophenylamino)-2- phenylpyrimido[4,5- d]pyridazin-5(6H)-one 1
    2
    Figure US20200190095A1-20200618-C00061
         		methyl 4-(5-oxo-4-(4- (piperazin-1- ylmethyl)phenylamino)-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)benzoate hydrochloride 3
    3
    Figure US20200190095A1-20200618-C00062
         		2-morpholino-4-(4-(piperazin- 1- ylmethyl)phenylamino)pyrimido [4,5-d]pyridazin-5(6H)-one hydrochloride 5
    4
    Figure US20200190095A1-20200618-C00063
         		4-(4- (morpholinomethyl)phenyl- amino)-2-phenylpyrimido[4,5- d]pyridazin-5(6H)-one 1
    5
    Figure US20200190095A1-20200618-C00064
         		4-(4-(4-ethylpiperazin-1- yl)phenylamino)-2- phenylpyrimido[4,5- d]pyridazin-5(6H)-one 1
    6
    Figure US20200190095A1-20200618-C00065
         		4-(4-((4-ethylpiperazin-1- yl)methyl)phenylamino)-2- phenylpyrimido[4,5- d]pyridazin-5(6H)-one 1
    7
    Figure US20200190095A1-20200618-C00066
         		2-phenyl-4-(4-(piperazin-1- ylmethyl)phenylamino)pyrimido [4,5-d]pyridazin-5(6H)-one hydrochloride 1
    8
    Figure US20200190095A1-20200618-C00067
         		2-phenyl-4-(4-(piperazin-1- yl)phenylamino)pyrimido[4,5- d]pyridazin-5(6H)-one 1
    9
    Figure US20200190095A1-20200618-C00068
         		4-(4-(morpholine-4- carbonyl)phenylamino)-2- phenylpyrimido[4,5- d]pyridazin-5(6H)-one 1
    10
    Figure US20200190095A1-20200618-C00069
         		4-(4-(bis(2- hydroxyethyl)amino)phenyl- amino)-2-phenylpyrimido[4,5- d]pyridazin-5(6H)-one 1
    11
    Figure US20200190095A1-20200618-C00070
         		4-(4-(4-(2- aminoacetyl)piperazin-1- yl)phenylamino)-2- phenylpyrimido[4,5- d]pyridazin-5(6H)-one hydrochloride 1
    12
    Figure US20200190095A1-20200618-C00071
         		2-(4-(4-(5-oxo-2-phenyl-5,6- dihydropyrimido[4,5- d]pyridazin-4- ylamino)phenyl)piperazin-1- yl)acetic acid 1
    13
    Figure US20200190095A1-20200618-C00072
         		1-(4-(5-oxo-2-phenyl-5,6- dihydropyrimido[4,5- d]pyridazin-4- ylamino)phenyl)piperidine-4- carboxylic acid 1
    14
    Figure US20200190095A1-20200618-C00073
         		4-(4-(4-(2- aminoacetyl)piperazin-1- yl)phenylamino)-2- phenylpyrimido[4,5- d]pyridazin-5(6H)-one 1
    15
    Figure US20200190095A1-20200618-C00074
         		N-(2-(dimethylamino)ethyl)- N-methyl-4-(5-oxo-2-phenyl- 5,6-dihydropyrimido[4,5- d]pyridazin-4- ylamino)benzamide 1
    16
    Figure US20200190095A1-20200618-C00075
         		4-(4-(2-oxo-1,7- diazaspiro[3.5]nonan-7- yl)phenylamino)-2- phenylpyrimido[4,5- d]pyridazin-5(6H)-one 1
    17
    Figure US20200190095A1-20200618-C00076
         		4-(4-(2-oxa-7- azaspiro[3.5]nonan-7- yl)phenylamino)-2- phenylpyrimido[4,5- d]pyridazin-5(6H)-one 1
    18
    Figure US20200190095A1-20200618-C00077
         		4-(4- morpholinophenylamino)-2- (6-azaspiro[2.5]octan-6- yl)pyrimido[4,5-d]pyridazin- 5(6H)-one 5
    19
    Figure US20200190095A1-20200618-C00078
         		6-(4-(5-oxo-2-phenyl-5,6- dihydropyrimido[4,5- d]pyridazin-4- ylamino)phenyl)-6- azaspiro[2.5]octane-1- carboxylic acid 1
    20
    Figure US20200190095A1-20200618-C00079
         		ethyl 6-(4-(5-oxo-2-phenyl- 5,6-dihydropyrimido[4,5- d]pyridazin-4- ylamino)phenyl)-6- azaspiro[2.5]octane-1- carboxylate 1
    21
    Figure US20200190095A1-20200618-C00080
         		6-(4-(5-oxo-2-phenyl-5,6- dihydropyrimido[4,5- d]pyridazin-4- ylamino)benzyl)-6- azaspiro[2.5]octane-1- carboxylic acid 1
    22
    Figure US20200190095A1-20200618-C00081
         		sodium 6-(4-(5-oxo-2-phenyl- 5,6-dihydropyrimido[4,5- d]pyridazin-4- ylamino)phenyl)-6- azaspiro[2.5]octane-1- carboxylate 1
    23
    Figure US20200190095A1-20200618-C00082
         		4-(4-(2-oxa-7- azaspiro[3.5]nonan-7- ylmethyl)phenylamino)-2- phenylpyrimido[4,5- d]pyridazin-5(6H)-one 1
    24
    Figure US20200190095A1-20200618-C00083
         		4-(4-(piperazin-1- ylmethyl)phenylamino)-2- (thiophen-3-yl)pyrimido[4,5- d]pyridazin-5(6H)-one hydrochloride 3
    25
    Figure US20200190095A1-20200618-C00084
         		6-(5-oxo-4-(4-(piperazin-1- ylmethyl)phenylamino)-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)-6- azaspiro[2.5]octane-1- carboxylic acid hydrochloride 5
    26
    Figure US20200190095A1-20200618-C00085
         		4-(4-(4-ethylpiperazin-1- yl)phenylamino)-2- morpholinopyrimido[4,5- d]pyridazin-5(6H)-one 5
    27
    Figure US20200190095A1-20200618-C00086
         		4-(5-oxo-4-(4-(piperazin-1- ylmethyl)phenylamino)-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)benzoic acid hydrochloride 3
    28
    Figure US20200190095A1-20200618-C00087
         		4-(4-(4-ethylpiperazin-1- yl)phenylamino)-2-(4- (trifluoromethoxy)phenyl)pyrimido [4,5-d]pyridazin-5(6H)- one 3
    29
    Figure US20200190095A1-20200618-C00088
         		methyl 4-(4-(4- morpholinophenylamino)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)benzoate 3
    30
    Figure US20200190095A1-20200618-C00089
         		4-(4-(piperazin-1- ylmethyl)phenylamino)-2- (piperidin-1-yl)pyrimido[4,5- d]pyridazin-5(6H)-one hydrochloride 5
    31
    Figure US20200190095A1-20200618-C00090
         		2-(3-methoxyphenyl)-4-(4- (piperazin-1- ylmethyl)phenylamino)pyrimido [4,5-d]pyridazin-5(6H)-one hydrochloride 3
    32
    Figure US20200190095A1-20200618-C00091
         		2-(piperazin-1-yl)-4-(4- (piperazin-1- ylmethyl)phenylamino)pyrimido [4,5-d]pyridazin-5(6H)-one dihydrochloride 5
    33
    Figure US20200190095A1-20200618-C00092
         		2-(benzo[d][1,3]dioxol-5-yl)- 4-(4-(piperazin-1- ylmethyl)phenylamino)pyrimido [4,5-d]pyridazin-5(6H)-one hydrochloride 3
    34
    Figure US20200190095A1-20200618-C00093
         		2-(1-(4-(5-oxo-2-phenyl-5,6- dihydropyrimido[4,5- d]pyridazin-4- ylamino)phenyl)piperidin-4- yl)acetic acid 1
    35
    Figure US20200190095A1-20200618-C00094
         		1-(4-(5-oxo-2-phenyl-5,6- dihydropyrimido[4,5- d]pyridazin-4- ylamino)benzyl)piperidine-4- carboxylic acid 1
    36
    Figure US20200190095A1-20200618-C00095
         		2-(2-methoxyphenyl)-4-(4- (piperazin-1- ylmethyl)phenylamino)pyrimido [4,5-d]pyridazin-5(6H)-one hydrochloride 3
    37
    Figure US20200190095A1-20200618-C00096
         		4-(4-(4-ethylpiperazin-1- yl)phenylamino)-2-(thiophen- 3-yl)pyrimido[4,5- d]pyridazin-5(6H)-one hydrochloride 3
    38
    Figure US20200190095A1-20200618-C00097
         		9-(5-oxo-4-(4-(piperazin-1- ylmethyl)phenylamino)-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)-3,9- diazaspiro[5.5]undecane-2,4- dione hydrochloride 5
    39
    Figure US20200190095A1-20200618-C00098
         		6-(4-(5-oxo-2-(thiophen-3- yl)-5,6-dihydropyrimido[4,5- d]pyridazin-4- ylamino)phenyl)-6- azaspiro[2.5]octane-1- carboxylic acid 3
    40
    Figure US20200190095A1-20200618-C00099
         		2-(4-chlorophenyl)-4-(4- (piperazin-1- ylmethyl)phenylamino)pyrimido [4,5-d]pyridazin-5(6H)-one hydrochloride 3
    41
    Figure US20200190095A1-20200618-C00100
         		2-(4-methoxyphenyl)-4-(4- (piperazin-1- ylmethyl)phenylamino)pyrimido [4,5-d]pyridazin-5(6H)-one hydrochloride 3
    42
    Figure US20200190095A1-20200618-C00101
         		6-(4-((2-morpholino-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)-6- azaspiro[2.5]octane-1- carboxylic acid 5
    43
    Figure US20200190095A1-20200618-C00102
         		2-(1-(5-oxo-4-((4-(piperazin- 1-ylmethyl)phenyl)amino)- 5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetic acid hydrochloride 5
    44
    Figure US20200190095A1-20200618-C00103
         		2-(1-oxidothiomorpholino)- 4-((4-(piperazin-1- ylmethyl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one hydrochloride 5
    45
    Figure US20200190095A1-20200618-C00104
         		2-(4-methylpiperazin-1-yl)-4- ((4-(piperazin-1- ylmethyl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one hydrochloride 5
    46
    Figure US20200190095A1-20200618-C00105
         		6-(4-((2-(4-methoxyphenyl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)-6- azaspiro[2.5]octane-1- carboxylic acid 3
    47
    Figure US20200190095A1-20200618-C00106
         		6-(4-((2-(3-methoxyphenyl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)-6- azaspiro[2.5]octane-1- carboxylic acid 3
    48
    Figure US20200190095A1-20200618-C00107
         		4-((4-(piperazin-1- ylmethyl)phenyl)amino)-2- (pyrrolidin-1-yl)pyrimido[4,5- d]pyridazin-5(6H)-one hydrochloride 5
    49
    Figure US20200190095A1-20200618-C00108
         		2-(dimethylamino)-4-((4- (piperazin-1- ylmethyl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one hydrochloride 5
    50
    Figure US20200190095A1-20200618-C00109
         		2-ethoxy-4-((4-(piperazin-1- ylmethyl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one hydrochloride 5
    51
    Figure US20200190095A1-20200618-C00110
         		1-(5-oxo-4-((4-(piperazin-1- ylmethyl)phenyl)amino)-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidine-4- carboxylic acid hydrochloride 5
    52
    Figure US20200190095A1-20200618-C00111
         		2-(azepan-1-yl)-4-((4- (piperazin-1- ylmethyl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one hydrochloride 5
    53
    Figure US20200190095A1-20200618-C00112
         		6-(4-((2-(2-methoxyphenyl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)-6- azaspiro[2.5]octane-1- carboxylic acid 3
    54
    Figure US20200190095A1-20200618-C00113
         		2-(diisopropylamino)-4-((4- (piperazin-1- ylmethyl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one hydrochloride 5
    55
    Figure US20200190095A1-20200618-C00114
         		2-(4- (morpholinomethyl)phenyl)- 4-((4-(piperazin-1- ylmethyl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one hydrochloride 3
    56
    Figure US20200190095A1-20200618-C00115
         		1-(5-oxo-4-((4-(piperazin-1- ylmethyl)phenyl)amino)-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidine-4- carbonitrile hydrochloride 5
    57
    Figure US20200190095A1-20200618-C00116
         		2-(4-ethylpiperazin-1-yl)-4- ((4-(piperazin-1- ylmethyl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one hydrochloride 5
    58
    Figure US20200190095A1-20200618-C00117
         		4-((1-(2-morpholinoethyl)- 1H-pyrazol-4-yl)amino)-2- phenylpyrimido[4,5- d]pyridazin-5(6H)-one 1
    59
    Figure US20200190095A1-20200618-C00118
         		2-(1,4-diazepan-1-yl)-4-((4- (piperazin-1- ylmethyl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one dihydrochloride 5
    60
    Figure US20200190095A1-20200618-C00119
         		2-(azepan-1-yl)-4-((4- morpholinophenyl)amino) pyrimido[4,5-d]pyridazin-5(6H)- one 5
    61
    Figure US20200190095A1-20200618-C00120
         		2-methoxy-4-((4-(piperazin-1- ylmethyl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one hydrochloride 5
    62
    Figure US20200190095A1-20200618-C00121
         		6-(4-((2-(azepan-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)-6- azaspiro[2.5]octane-1- carboxylic acid 5
    63
    Figure US20200190095A1-20200618-C00122
         		2-phenyl-4-((1-(2-(piperazin- 1-yl)ethyl)-1H-pyrazol-4- yl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one hydrochloride 1
    64
    Figure US20200190095A1-20200618-C00123
         		4-((1-(2-(4-methylpiperazin- 1-yl)ethyl)-1H-pyrazol-4- yl)amino)-2- phenylpyrimido[4,5- d]pyridazin-5(6H)-one 1
    65
    Figure US20200190095A1-20200618-C00124
         		4-((1-(2-(4-ethylpiperazin-1- yl)ethyl)-1H-pyrazol-4- yl)amino)-2- phenylpyrimido[4,5- d]pyridazin-5(6H)-one 1
    66
    Figure US20200190095A1-20200618-C00125
         		6-(4-((2-(4- (cyanomethyl)piperidin-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)-6- azaspiro[2.5]octane-1- carboxylic acid 5
    67
    Figure US20200190095A1-20200618-C00126
         		2-(azepan-1-yl)-4-((3,4,5- trimethoxyphenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 5
    68
    Figure US20200190095A1-20200618-C00127
         		2-(azepan-1-yl)-4-((4- (morpholine-4- carbonyl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 5
    69
    Figure US20200190095A1-20200618-C00128
         		2-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)acetic acid 5
    70
    Figure US20200190095A1-20200618-C00129
         		2-(1-(4-((2-(4- (cyanomethyl)piperazin-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)acetic acid 5
    71
    Figure US20200190095A1-20200618-C00130
         		2-(1-(4-((2-(4- (cyanomethyl)piperidin-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)acetic acid 5
    72
    Figure US20200190095A1-20200618-C00131
         		6-(4-((2-(1,4-diazepan-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)-6- azaspiro[2.5]octane-1- carboxylic acid hydrochloride 5
    73
    Figure US20200190095A1-20200618-C00132
         		6-(4-((2-(4- (cyanomethyl)piperazin-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)-6- azaspiro[2.5]octane-1- carboxylic acid 5
    74
    Figure US20200190095A1-20200618-C00133
         		6-(4-((2-(4-cyanopiperidin-1- yl)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)-6- azaspiro[2.5]octane-1- carboxylic acid 5
    75
    Figure US20200190095A1-20200618-C00134
         		2-(1-(4-((2-(4-cyanopiperidin- 1-yl)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)acetic acid 5
    76
    Figure US20200190095A1-20200618-C00135
         		1-(4-((2-(4-cyanopiperidin-1- yl)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)benzyl)piperidine-4- carboxylic acid 5
    77
    Figure US20200190095A1-20200618-C00136
         		2-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)benzyl)piperidin-4- yl)acetic acid 5
    78
    Figure US20200190095A1-20200618-C00137
         		1-(4-((2-(4- (cyanomethyl)piperidin-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)benzyl)piperidine-4- carboxylic acid 5
    79
    Figure US20200190095A1-20200618-C00138
         		6-(4-((2-cyclohexyl-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)-6- azaspiro[2.5]octane-1- carboxylic acid 3
    80
    Figure US20200190095A1-20200618-C00139
         		2-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)acetonitrile 5
    81
    Figure US20200190095A1-20200618-C00140
         		6-(4-((2-cycloheptyl-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)-6- azaspiro[2.5]octane-1- carboxylic acid 3
    82
    Figure US20200190095A1-20200618-C00141
         		2-(1-(4-((5-oxo-2-phenyl-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)acetonitrile 1
    83
    Figure US20200190095A1-20200618-C00142
         		4-((4-((4-(2-hydroxy-2- methylpropanoyl)piperazin-1- yl)methyl)phenyl)amino)-2- phenylpyrimido[4,5- d]pyridazin-5(6H)-one 1
    84
    Figure US20200190095A1-20200618-C00143
         		2-(azepan-1-yl)-4-((4-((4-(2- hydroxy-2- methylpropanoyl)piperazin-1- yl)methyl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 3
    85
    Figure US20200190095A1-20200618-C00144
         		2-(azepan-1-yl)-4-((4-((4- methylpiperazin-1- yl)methyl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 3
    86
    Figure US20200190095A1-20200618-C00145
         		2-(4-(4-((5-oxo-2-phenyl-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-1- yl)acetic acid 1
    87
    Figure US20200190095A1-20200618-C00146
         		2-(4-(4-((5-oxo-2-phenyl-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)cyclohexyl) acetic acid 3
    88
    Figure US20200190095A1-20200618-C00147
         		2-(1-(4-((2-(azocan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)acetic acid 5
    89
    Figure US20200190095A1-20200618-C00148
         		2-(azepan-1-yl)-4-((4-(2- (piperazin-1- yl)ethoxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one hydrochloride 5
    90
    Figure US20200190095A1-20200618-C00149
         		2-(1-(4-((2-cycloheptyl-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)acetic acid 3
    91
    Figure US20200190095A1-20200618-C00150
         		2-(4-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)cyclohexyl) acetic acid 5
    92
    Figure US20200190095A1-20200618-C00151
         		4-(4-((2-(azepan-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenoxy)butanoic acid 5
    93
    Figure US20200190095A1-20200618-C00152
         		2-(azepan-1-yl)-4-((4-(2- morpholinoethoxy)phenyl) amino)pyrimido[4,5-d]pyridazin- 5(6H)-one 5
    94
    Figure US20200190095A1-20200618-C00153
         		4-((4-(2- morpholinoethoxy)phenyl) amino)-2-phenylpyrimido[4,5- d]pyridazin-5(6H)-one 3
    95
    Figure US20200190095A1-20200618-C00154
         		2-(azepan-1-yl)-4-((4-(2-(4- methylpiperazin-1- yl)ethoxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 5
    96
    Figure US20200190095A1-20200618-C00155
         		2-(1-(2-(4-((2-(azepan-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenoxy)ethyl) piperidin-4-yl)acetic acid 5
    97
    Figure US20200190095A1-20200618-C00156
         		2-(1-(5-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)pyridin-2- yl)piperidin-4-yl)acetonitrile 5
    98
    Figure US20200190095A1-20200618-C00157
         		1-(2-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenoxy)ethyl) piperidine-4-carboxylic acid 5
    99
    Figure US20200190095A1-20200618-C00158
         		2-(1-(5-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)pyridin-2- yl)piperidin-4-yl)acetamide 5
    100
    Figure US20200190095A1-20200618-C00159
         		2-(1-(4-((2-(4-(2- cyanopropan-2-yl)piperidin-1- yl)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)acetic acid 5
    101
    Figure US20200190095A1-20200618-C00160
         		2-(1-(5-((5-oxo-2-phenyl-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)pyridin-2- yl)piperidin-4-yl)acetonitrile 3
    102
    Figure US20200190095A1-20200618-C00161
         		2-(1-(5-((5-oxo-2-phenyl-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)pyridin-2- yl)piperidin-4-yl)acetamide 3
    103
    Figure US20200190095A1-20200618-C00162
         		2-(1-(5-((2-(4- (cyanomethyl)piperidin-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)pyridin-2- yl)piperidin-4-yl)acetonitrile 5
    104
    Figure US20200190095A1-20200618-C00163
         		2-(azepan-1-yl)-4-((4- (piperazine-1- carbonyl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one hydrochloride 5
    105
    Figure US20200190095A1-20200618-C00164
         		2-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)acetamide 5
    106
    Figure US20200190095A1-20200618-C00165
         		2-(4-(2-(4-((2-(azepan-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenoxy)ethyl) piperazin-1-yl)acetic acid 3
    107
    Figure US20200190095A1-20200618-C00166
         		2-(azepan-1-yl)-4-((4-(2- (piperazin-1- yl)ethoxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 5
    108
    Figure US20200190095A1-20200618-C00167
         		2-(1-(5-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)pyridin-2- yl)piperidin-4-yl)acetic acid 5
    109
    Figure US20200190095A1-20200618-C00168
         		2-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)-N-(2- hydroxyethyl)acetamide 5
    110
    Figure US20200190095A1-20200618-C00169
         		2-(azepan-1-yl)-4-((4- (((2S,5S)-5-(hydroxymethyl)- 1,4-dioxan-2- yl)methoxy)phenyl)amino) pyrimido[4,5-d]pyridazin-5(6H)- one 5
    111
    Figure US20200190095A1-20200618-C00170
         		2-(4-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperazin-1- yl)-2-methylpropanenitrile 5
    112
    Figure US20200190095A1-20200618-C00171
         		2-(4-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperazin-1- yl)-2-methylpropanamide 5
    113
    Figure US20200190095A1-20200618-C00172
         		2-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)acetonitrile 5
    114
    Figure US20200190095A1-20200618-C00173
         		2-(1-(5-((2-(4- (cyanomethyl)piperidin-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)pyridin-2- yl)piperidin-4-yl)acetonitrile 5
    115
    Figure US20200190095A1-20200618-C00174
         		2-(azepan-1-yl)-4-((4-(2-(4- (2-hydroxy-2- methylpropanoyl)piperazin-1- yl)ethoxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 5
    116
    Figure US20200190095A1-20200618-C00175
         		2-(1-(5-((2-(4- (cyanomethyl)piperidin-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)pyridin-2- yl)piperidin-4-yl)acetic acid 5
    117
    Figure US20200190095A1-20200618-C00176
         		2-(1-(4-((2-(3,5- dimethylpiperidin-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)acetic acid 5
    118
    Figure US20200190095A1-20200618-C00177
         		2-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)-N,N-bis(2- hydroxyethyl)acetamide 5
    119
    Figure US20200190095A1-20200618-C00178
         		2-methyl-2-(1-(4-((5-oxo-2- phenyl-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)propanenitrile 3
    120
    Figure US20200190095A1-20200618-C00179
         		2-(4-(2-(4-((2-(azepan-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenoxy)ethyl) piperazin-1-yl)-2- methylpropanenitrile 5
    121
    Figure US20200190095A1-20200618-C00180
         		2-(1-(4-((2-(2,6- dimethylmorpholino)-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)acetic acid 3
    122
    Figure US20200190095A1-20200618-C00181
         		4-((4-(((2S,5S)-5- (hydroxymethyl)-1,4-dioxan- 2-yl)methoxy)phenyl)amino)- 2-phenylpyrimido[4,5- d]pyridazin-5(6H)-one 3
    123
    Figure US20200190095A1-20200618-C00182
         		2-((1S,4S)-4-(4-((2-(azepan- 1-yl)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)cyclohexyl) acetic acid 5
    124
    Figure US20200190095A1-20200618-C00183
         		(2R,5S)-5-((4-((2-(azepan-1- yl)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenoxy)methyl)- 1,4-dioxane-2-carboxylic acid 5
    125
    Figure US20200190095A1-20200618-C00184
         		2-(4-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperazin-1- yl)acetic acid 5
    126
    Figure US20200190095A1-20200618-C00185
         		2-(1-(3-(4-((2-(azepan-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenoxy)propyl) piperidin-4-yl)acetic acid 5
    127
    Figure US20200190095A1-20200618-C00186
         		6-(4-((2-(cyclohexylamino)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)spiro[2.5] octane-1-carboxylic acid 5
    128
    Figure US20200190095A1-20200618-C00187
         		6-(4-((5-oxo-2-(piperidin-1- yl)-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)spiro[2.5] octane-1-carboxylic acid 5
    129
    Figure US20200190095A1-20200618-C00188
         		2-((1R,4R)-4-(4-((2-(azepan- 1-yl)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)cyclohexyl) acetic acid 5
    130
    Figure US20200190095A1-20200618-C00189
         		3-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)propanoic acid 5
    131
    Figure US20200190095A1-20200618-C00190
         		2-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)cyclopropanecarboxylic acid 5
    132
    Figure US20200190095A1-20200618-C00191
         		3-(1-(4-((5-oxo-2-phenyl-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)propanoic acid 3
    133
    Figure US20200190095A1-20200618-C00192
         		6-(4-((2-(4-fluorophenyl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)-6- azaspiro[2.5]octane-1- carboxylic acid 3
    134
    Figure US20200190095A1-20200618-C00193
         		6-(5-((2-(azepan-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)pyridin-2-yl)-6- azaspiro[2.5]octane-1- carboxylic acid 5
    135
    Figure US20200190095A1-20200618-C00194
         		6-(4-((2-(azepan-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-4-yl)amino)-2- fluorophenyl)-6- azaspiro[2.5]octane-1- carboxylic acid 5
    136
    Figure US20200190095A1-20200618-C00195
         		2-(azepan-1-yl)-4-((4-(3- (piperazin-1- yl)propoxy)phenyl)amino) pyrimido[4,5-d]pyridazin-5(6H)- one 5
    137
    Figure US20200190095A1-20200618-C00196
         		6-(5-((5-oxo-2-phenyl-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)pyridin-2-yl)-6- azaspiro[2.5]octane-1- carboxylic acid 3
    138
    Figure US20200190095A1-20200618-C00197
         		6-(4-((5-oxo-2-(pyridin-4-yl)- 5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)-6- azaspiro[2.5]octane-1- carboxylic acid 3
    139
    Figure US20200190095A1-20200618-C00198
         		2-(azepan-1-yl)-4-((4-(4-(2- hydroxypropan-2- yl)piperidin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 5
    140
    Figure US20200190095A1-20200618-C00199
         		2-(4-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperazin-1- yl)-2-methylpropanoic acid 5
    141
    Figure US20200190095A1-20200618-C00200
         		6-(4-((2-(azocan-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)-6- azaspiro[2.5]octane-1- carboxylic acid 5
    142
    Figure US20200190095A1-20200618-C00201
         		2-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)-2-methylpropanoic acid 5
    143
    Figure US20200190095A1-20200618-C00202
         		2-methyl-2-(1-(4-((5-oxo-2- phenyl-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)propanoic acid 2
    144
    Figure US20200190095A1-20200618-C00203
         		2-(4-(5-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)pyridin-2- yl)piperazin-1-yl)acetic acid 7
    145
    Figure US20200190095A1-20200618-C00204
         		2-(4-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)-1,4- diazepan-1-yl)acetic acid 7
    146
    Figure US20200190095A1-20200618-C00205
         		2-(1-(4-((4-(4-(2- hydroxypropan-2- yl)piperidin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    147
    Figure US20200190095A1-20200618-C00206
         		3-(1-(4-((2-(4- (cyanomethyl)piperidin-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)propanoic acid 7
    148
    Figure US20200190095A1-20200618-C00207
         		6-(5-((2-(4- (cyanomethyl)piperidin-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)pyridin-2-yl)-6- azaspiro[2.5]octane-1- carboxylic acid 7
    149
    Figure US20200190095A1-20200618-C00208
         		1-(5-oxo-4-((4-(2-(piperazin- 1-yl)ethoxy)phenyl)amino)- 5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidine-4- carbonitrile 7
    150
    Figure US20200190095A1-20200618-C00209
         		2-(1-(5-oxo-4-((4-(2- (piperazin-1- yl)ethoxy)phenyl)amino)-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    151
    Figure US20200190095A1-20200618-C00210
         		2-(azepan-1-yl)-4-((4-(2-(4- ethylpiperazin-1- yl)ethoxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 7
    152
    Figure US20200190095A1-20200618-C00211
         		2-phenyl-4-((4-(2-(piperazin- 1- yl)ethoxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 8
    153
    Figure US20200190095A1-20200618-C00212
         		4-((4-(2-(piperazin-1- yl)ethoxy)phenyl)amino)-2- (piperidin-1-yl)pyrimido[4,5- d]pyridazin-5(6H)-one 7
    154
    Figure US20200190095A1-20200618-C00213
         		2-(4-(4-((5-oxo-2-(piperidin- 1-yl)-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)-1,4- diazepan-1-yl)acetic acid 7
    155
    Figure US20200190095A1-20200618-C00214
         		6-(4-((2-(4-methylpiperidin-1- yl)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)-6- azaspiro[2.5]octane-1- carboxylic acid 7
    156
    Figure US20200190095A1-20200618-C00215
         		2-(4-methylpiperidin-1-yl)-4- ((4-(2-(piperazin-1- yl)ethoxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one hydrochloride 7
    157
    Figure US20200190095A1-20200618-C00216
         		2-(azepan-1-yl)-4-((4-(2-(3- oxopiperazin-1- yl)ethoxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 7
    158
    Figure US20200190095A1-20200618-C00217
         		6-(2-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenoxy)ethyl)-6- azaspiro[2.5]octane-1- carboxylic acid 7
    159
    Figure US20200190095A1-20200618-C00218
         		2-(azepan-1-yl)-4-((4-(2- (diethylamino)ethoxy)phenyl) amino)pyrimido[4,5- d]pyridazin-5(6H)-one 7
    160
    Figure US20200190095A1-20200618-C00219
         		2-(cyclohexyl(methyl)amino)- 4-((4-(2-(piperazin-1- yl)ethoxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 7
    161
    Figure US20200190095A1-20200618-C00220
         		2-(1-(4-((2- (cyclohexyl(methyl)amino)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)acetic acid 7
    162
    Figure US20200190095A1-20200618-C00221
         		2-(4-(4-((2-(4- (cyanomethyl)piperidin-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperazin-1- yl)acetic acid 7
    163
    Figure US20200190095A1-20200618-C00222
         		2-(1-(4-((2-(3- methoxyphenyl)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)acetonitrile 8
    164
    Figure US20200190095A1-20200618-C00223
         		4-((4-(2-(1,4-diazepan-1- yl)ethoxy)phenyl)amino)-2- (azepan-1-yl)pyrimido[4,5- d]pyridazin-5(6H)-one 7
    165
    Figure US20200190095A1-20200618-C00224
         		2-(azepan-1-yl)-4-((4-(3- oxopiperazin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    166
    Figure US20200190095A1-20200618-C00225
         		2-(3-methoxyphenyl)-4-((4- (2-(piperazin-1- yl)ethoxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 8
    167
    Figure US20200190095A1-20200618-C00226
         		2-(azepan-1-yl)-4-((4-(2- (dimethylamino)ethoxy)phenyl) amino)pyrimido[4,5- d]pyridazin-5(6H)-one 7
    168
    Figure US20200190095A1-20200618-C00227
         		2-(azepan-1-yl)-4-((4-(2- (piperidin-4- yl)ethoxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 7
    169
    Figure US20200190095A1-20200618-C00228
         		2-(1-(5-oxo-4-((4-(2- (piperidin-4- yl)ethoxy)phenyl)amino)-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    170
    Figure US20200190095A1-20200618-C00229
         		6-(4-((2- (cyclohexyl(methyl)amino)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)-6- azaspiro[2.5]octane-1- carboxylic acid 7
    171
    Figure US20200190095A1-20200618-C00230
         		4-((4-(2-(1,4-diazepan-1- yl)ethoxy)phenyl)amino)-2- (piperidin-1-yl)pyrimido[4,5- d]pyridazin-5(6H)-one 7
    172
    Figure US20200190095A1-20200618-C00231
         		2-(azepan-1-yl)-4-((4-(2-(4- hydroxypiperidin-1- yl)ethoxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 7
    173
    Figure US20200190095A1-20200618-C00232
         		2-(azepan-1-yl)-4-((4-(3- (piperazin-1- yl)propyl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 7
    174
    Figure US20200190095A1-20200618-C00233
         		2-(1-(5-oxo-4-((4-(3- (piperazin-1- yl)propyl)phenyl)amino)-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    175
    Figure US20200190095A1-20200618-C00234
         		2-(azepan-1-yl)-4-((4-(4- ethyl-3-oxopiperazin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    176
    Figure US20200190095A1-20200618-C00235
         		2-morpholino-4-((4-(2- (piperazin-1- yl)ethoxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 5
    177
    Figure US20200190095A1-20200618-C00236
         		2-(2,6-dimethylmorpholino)- 4-((4-(2-(piperazin-1- yl)ethoxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 5
    178
    Figure US20200190095A1-20200618-C00237
         		2-(1-(4-((4-(4-ethyl-3- oxopiperazin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    179
    Figure US20200190095A1-20200618-C00238
         		2-(azepan-1-yl)-4-((4-(3-(4- hydroxypiperidin-1- yl)propyl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 7
    180
    Figure US20200190095A1-20200618-C00239
         		2-(azepan-1-yl)-4-((4-(4- ethylpiperazin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    181
    Figure US20200190095A1-20200618-C00240
         		4-((6-(2-(piperazin-1- yl)ethoxy)pyridin-3- yl)amino)-2-(piperidin-1- yl)pyrimido[4,5-d]pyridazin- 5(6H)-one 7
    182
    Figure US20200190095A1-20200618-C00241
         		2-(azepan-1-yl)-4-((6-(2- (piperazin-1- yl)ethoxy)pyridin-3- yl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one 7
    183
    Figure US20200190095A1-20200618-C00242
         		4-((4-(2-(4-hydroxypiperidin- 1-yl)ethoxy)phenyl)amino)-2- (piperidin-1-yl)pyrimido[4,5- d]pyridazin-5(6H)-one 7
    184
    Figure US20200190095A1-20200618-C00243
         		2-(azepan-1-yl)-4-((4-(2-(4- hydroxy-4-methylpiperidin-1- yl)ethoxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 7
    185
    Figure US20200190095A1-20200618-C00244
         		2-(1-(4-((4-(2-(4-hydroxy-4- methylpiperidin-1- yl)ethoxy)phenyl)amino)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    186
    Figure US20200190095A1-20200618-C00245
         		2-(azepan-1-yl)-4-((4-(4- hydroxypiperidin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    187
    Figure US20200190095A1-20200618-C00246
         		2-(1-(4-((4-(4-ethylpiperazin- 1-yl)phenyl)amino)-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    188
    Figure US20200190095A1-20200618-C00247
         		2-(azepan-1-yl)-4-((4-(2- (diisopropylamino)ethoxy) phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one 7
    189
    Figure US20200190095A1-20200618-C00248
         		2-(1-(4-((4-(4- hydroxypiperidin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    190
    Figure US20200190095A1-20200618-C00249
         		2-(azepan-1-yl)-4-((4-(4-(2- hydroxyethyl)piperazin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    191
    Figure US20200190095A1-20200618-C00250
         		2-(1-(4-((4-(4-(2- hydroxyethyl)piperazin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    192
    Figure US20200190095A1-20200618-C00251
         		2-(azepan-1-yl)-4-((4- (piperazin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    193
    Figure US20200190095A1-20200618-C00252
         		2-(1-(5-oxo-4-((4-(piperazin- 1-yl)phenyl)amino)-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    194
    Figure US20200190095A1-20200618-C00253
         		2-(azepan-1-yl)-4-((4-(4-(3- hydroxypropyl)piperidin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    195
    Figure US20200190095A1-20200618-C00254
         		2-(azepan-1-yl)-4-((4-(4-(2- hydroxyethyl)piperidin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    196
    Figure US20200190095A1-20200618-C00255
         		2-(1-(4-((4-(4-(2- hydroxyethyl)piperidin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    197
    Figure US20200190095A1-20200618-C00256
         		2-(1-(4-((4-(2-(4- ethylpiperazin-1- yl)ethyl)phenyl)amino)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    198
    Figure US20200190095A1-20200618-C00257
         		2-(azepan-1-yl)-4-((4-(2- (piperazin-1- yl)ethyl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    199
    Figure US20200190095A1-20200618-C00258
         		4-((4-(2- aminoethoxy)phenyl)amino)- 2-(azepan-1-yl)pyrimido[4,5- d]pyridazin-5(6H)-one 7
    200
    Figure US20200190095A1-20200618-C00259
         		2-(1-(4-((4-(2- aminoethoxy)phenyl)amino)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    201
    Figure US20200190095A1-20200618-C00260
         		2-(azepan-1-yl)-4-((4-(2-(4- hydroxypiperidin-1- yl)ethyl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    202
    Figure US20200190095A1-20200618-C00261
         		2-(azepan-1-yl)-4-((4-(4- (hydroxymethyl)piperidin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    203
    Figure US20200190095A1-20200618-C00262
         		2-(azepan-1-yl)-4-((4-(2-(4- (hydroxymethyl)piperidin-1- yl)ethoxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 7
    204
    Figure US20200190095A1-20200618-C00263
         		2-(1-(2-(4-((2-(azepan-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)piperidin-1- yl)ethyl)piperidin-4- yl)acetonitrile 7
    205
    Figure US20200190095A1-20200618-C00264
         		2-(1-(4-((4-(4-(3- hydroxypropyl)piperidin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    206
    Figure US20200190095A1-20200618-C00265
         		2-(4-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperazin-1- yl)acetonitrile 7
    207
    Figure US20200190095A1-20200618-C00266
         		2-(1-(4-((4-(4- (cyanomethyl)piperazin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    208
    Figure US20200190095A1-20200618-C00267
         		3-(4-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperazin-1- yl)propanoic acid 7
    209
    Figure US20200190095A1-20200618-C00268
         		2-(azepan-1-yl)-4-((4-(2-(4- ethylpiperazin-1- yl)ethyl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    210
    Figure US20200190095A1-20200618-C00269
         		2-(azepan-1-yl)-4-((4-(2-(4- hydroxy-4-methylpiperidin-1- yl)ethyl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    211
    Figure US20200190095A1-20200618-C00270
         		2-(azepan-1-yl)-4-((4-(2-(4- (2-hydroxyethyl)piperazin-1- yl)ethyl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    212
    Figure US20200190095A1-20200618-C00271
         		2-(1-(4-((4-(2-(4-(2- hydroxyethyl)piperazin-1- yl)ethyl)phenyl)amino)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    213
    Figure US20200190095A1-20200618-C00272
         		2-(4-(4-((2-(4- (cyanomethyl)piperidin-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperazin-1- yl)-2-methylpropanoic acid 7
    214
    Figure US20200190095A1-20200618-C00273
         		2-(azepan-1-yl)-4-((4-(4-(2- hydroxy-2- methylpropanoyl)piperazin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    215
    Figure US20200190095A1-20200618-C00274
         		3-(4-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperazin-1- yl)-3-oxopropanenitrile 7
    216
    Figure US20200190095A1-20200618-C00275
         		2-(1-(4-((4-(4- (hydroxymethyl)piperidin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    217
    Figure US20200190095A1-20200618-C00276
         		2-(azepan-1-yl)-4-((6-(4- hydroxypiperidin-1- yl)pyridin-3- yl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one 7
    218
    Figure US20200190095A1-20200618-C00277
         		2-(1-(4-((4-(2-(4- (hydroxymethyl)piperidin-1- yl)ethoxy)phenyl)amino)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    219
    Figure US20200190095A1-20200618-C00278
         		(phosphonooxy)methyl 6-(4- ((2-(azepan-1-yl)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)-6- azaspiro[2.5]octane-1- carboxylate 7
    220
    Figure US20200190095A1-20200618-C00279
         		3-(4-(4-((2-(4- (cyanomethyl)piperidin-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperazin-1- yl)propanoic acid 7
    221
    Figure US20200190095A1-20200618-C00280
         		2-(azepan-1-yl)-4-((6- (piperazin-1-yl)pyridin-3- yl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one 7
    222
    Figure US20200190095A1-20200618-C00281
         		2-(azepan-1-yl)-4-((4-(2-(2- hydroxyethyl)-2H-tetrazol-5- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    223
    Figure US20200190095A1-20200618-C00282
         		2-(1-(4-((4-(4-(2-hydroxy-2- methylpropanoyl)piperazin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    224
    Figure US20200190095A1-20200618-C00283
         		2-(1-(4-((4-(2- (diethylamino)ethoxy)phenyl) amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    225
    Figure US20200190095A1-20200618-C00284
         		2-(azepan-1-yl)-4-((4-(2- ethyl-2H-tetrazol-5- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    226
    Figure US20200190095A1-20200618-C00285
         		2-(1-(4-((4-(2-ethyl-2H- tetrazol-5-yl)phenyl)amino)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    227
    Figure US20200190095A1-20200618-C00286
         		4-((4-(2H-tetrazol-5- yl)phenyl)amino)-2-(azepan- 1-yl)pyrimido[4,5- d]pyridazin-5(6H)-one 7
    228
    Figure US20200190095A1-20200618-C00287
         		2-(1-(4-((6-(4-ethylpiperazin- 1-yl)pyridin-3-yl)amino)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    229
    Figure US20200190095A1-20200618-C00288
         		2-(azepan-1-yl)-4-((6-(4- ethylpiperazin-1-yl)pyridin-3- yl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one 7
    230
    Figure US20200190095A1-20200618-C00289
         		2-(4-(5-oxo-4-((4-(2- (piperazin-1- yl)ethoxy)phenyl)amino)-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperazin-1- yl)acetonitrile 7
    231
    Figure US20200190095A1-20200618-C00290
         		2-(1-(5-oxo-4-((6-(piperazin- 1-yl)pyridin-3-yl)amino)-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    232
    Figure US20200190095A1-20200618-C00291
         		2-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-3- yl)acetic acid 7
    233
    Figure US20200190095A1-20200618-C00292
         		2-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-3- yl)acetic acid 7
    234
    Figure US20200190095A1-20200618-C00293
         		3-(4-(5-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)pyridin-2- yl)piperazin-1-yl)-3- oxopropanenitrile 7
    235
    Figure US20200190095A1-20200618-C00294
         		2-(5-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)-2H-tetrazol- 2-yl)acetic acid 7
    236
    Figure US20200190095A1-20200618-C00295
         		2-(azepan-1-yl)-4-((6-(4-(2- hydroxyethyl)piperidin-1- yl)pyridin-3- yl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one 7
    237
    Figure US20200190095A1-20200618-C00296
         		3-(4-(5-((2-(4- (cyanomethyl)piperidin-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)pyridin-2- yl)piperazin-1-yl)-3- oxopropanenitrile 7
    238
    Figure US20200190095A1-20200618-C00297
         		2-(azepan-1-yl)-4-((6-(4-(2- hydroxy-2- methylpropanoyl)piperazin-1- yl)pyridin-3- yl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one 7
    239
    Figure US20200190095A1-20200618-C00298
         		2-(azepan-1-yl)-4-((4-(2-(4- (2-hydroxyethyl)piperazin-1- yl)ethoxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 7
    240
    Figure US20200190095A1-20200618-C00299
         		3-(4-(4-((2-(4- (cyanomethyl)piperidin-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperazin-1- yl)-3-oxopropanenitrile 7
    241
    Figure US20200190095A1-20200618-C00300
         		2-(5-(4-((2-(4- (cyanomethyl)piperidin-1-yl)- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)-2H-tetrazol- 2-yl)acetic acid 7
    242
    Figure US20200190095A1-20200618-C00301
         		2-(azepan-1-yl)-4-((6-(4- methylpiperazin-1-yl)pyridin- 3-yl)amino)primido[4,5- d]pyridazin-5(6H)-one 7
    243
    Figure US20200190095A1-20200618-C00302
         		2-(1-(4-((6-(4- methylpiperazin-1-yl)pyridin- 3-yl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    244
    Figure US20200190095A1-20200618-C00303
         		4-((4-(4-((2H-tetrazol-5- yl)methyl)piperidin-1- yl)phenyl)amino)-2-(azepan- 1-yl)pyrimido[4,5- d]pyridazin-5(6H)-one 7
    245
    Figure US20200190095A1-20200618-C00304
         		2-(1-(4-((4-(2H-tetrazol-5- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    246
    Figure US20200190095A1-20200618-C00305
         		2-(1-(4-((4-(4-((2H-tetrazol-5- yl)methyl)piperidin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    247
    Figure US20200190095A1-20200618-C00306
         		2-(azepan-1-yl)-4-((4-(4- methylpiperazin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    248
    Figure US20200190095A1-20200618-C00307
         		2-(1-(4-((4-(4- methylpiperazin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    249
    Figure US20200190095A1-20200618-C00308
         		2-(1-(5-((2-(4- (cyanomethyl)piperidin-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)pyridin-2- yl)piperidin-3-yl)acetic acid 7
    250
    Figure US20200190095A1-20200618-C00309
         		2-(1-(4-((2-(4- (cyanomethyl)piperidin-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)piperidin-3- yl)acetic acid 7
    251
    Figure US20200190095A1-20200618-C00310
         		2-(1-(4-((6-(4-(2-hydroxy-2- methylpropanoyl)piperazin-1- yl)pyridin-3-yl)amino)-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    252
    Figure US20200190095A1-20200618-C00311
         		4-((6-(4-((2H-tetrazol-5- yl)methyl)piperidin-1- yl)pyridin-3-yl)amino)-2- (azepan-1-yl)pyrimido[4,5- d]pyridazin-5(6H)-one 7
    253
    Figure US20200190095A1-20200618-C00312
         		2-(1-(4-((6-(4-((2H-tetrazol-5- yl)methyl)piperidin-1- yl)pyridin-3-yl)amino)-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    254
    Figure US20200190095A1-20200618-C00313
         		2-(4-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenoxy)piperidin- 1-yl)acetic acid 7
    255
    Figure US20200190095A1-20200618-C00314
         		2-(azepan-1-yl)-4-((4-(4-(2- methoxyethyl)piperazin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    256
    Figure US20200190095A1-20200618-C00315
         		2-(1-(4-((4-(4-(2- methoxyethyl)piperazin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    257
    Figure US20200190095A1-20200618-C00316
         		2-(1-(4-((4-(4-(2- aminoethyl)piperazin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    258
    Figure US20200190095A1-20200618-C00317
         		2-(azepan-1-yl)-4-((4-(1- (hydroxymethyl)-6- azaspiro[2.5]octan-6- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    259
    Figure US20200190095A1-20200618-C00318
         		2-(1-(4-((4-(1- (hydroxymethyl)-6- azaspiro[2.5]octan-6- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    260
    Figure US20200190095A1-20200618-C00319
         		2-(azepan-1-yl)-4-((4-(4-(3- hydroxypropyl)piperazin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    261
    Figure US20200190095A1-20200618-C00320
         		2-(1-(4-((4-(4-(3- hydroxypropyl)piperazin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    262
    Figure US20200190095A1-20200618-C00321
         		2-(4-(4-((2-(4- (cyanomethyl)piperidin-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenoxy)piperidin- 1-yl)acetic acid 7
    263
    Figure US20200190095A1-20200618-C00322
         		2-(azepan-1-yl)-4-((4-(4-(2- hydroxyethyl)-1,4-diazepan- 1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    264
    Figure US20200190095A1-20200618-C00323
         		2-(1-(4-((4-(4-(2- hydroxyethyl)-1,4-diazepan- 1-yl)phenyl)amino)-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    265
    Figure US20200190095A1-20200618-C00324
         		2-(azepan-1-yl)-4-((4-(4-(1- hydroxy-2-methylpropan-2- yl)piperazin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    266
    Figure US20200190095A1-20200618-C00325
         		2-(1-(4-((4-(4-(1-hydroxy-2- methylpropan-2-yl)piperazin- 1-yl)phenyl)amino)-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    267
    Figure US20200190095A1-20200618-C00326
         		2-(azepan-1-yl)-4-((4-(4-(2- (dimethylamino)ethyl)piperazin- 1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    268
    Figure US20200190095A1-20200618-C00327
         		2-(1-(4-((4-(4-(2- (dimethylamino)ethyl)piperazin- 1-yl)phenyl)amino)-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    269
    Figure US20200190095A1-20200618-C00328
         		2-(azepan-1-yl)-4-((4-(2-(4- ethylpiperazin-1-yl)-2- oxoethoxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 7
    270
    Figure US20200190095A1-20200618-C00329
         		2-(1-(4-((4-(2-(4- ethylpiperazin-1-yl)-2- oxoethoxy)phenyl)amino)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    271
    Figure US20200190095A1-20200618-C00330
         		2-(1-(4-((4-(2-(4- methylpiperazin-1-yl)-2- oxoethoxy)phenyl)amino)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    272
    Figure US20200190095A1-20200618-C00331
         		2-(azepan-1-yl)-4-((4-(3-(2- hydroxyethyl)piperidin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    273
    Figure US20200190095A1-20200618-C00332
         		2-(azepan-1-yl)-4-((4-(4-(2,3- dihydroxypropyl)piperazin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    274
    Figure US20200190095A1-20200618-C00333
         		2-(1-(4-((4-(4-(2,3- dihydroxypropyl)piperazin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    275
    Figure US20200190095A1-20200618-C00334
         		2-(azepan-1-yl)-4-((4-(4-(2- fluoroethyl)piperazin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    276
    Figure US20200190095A1-20200618-C00335
         		2-(1-(4-((4-(4-(2- fluoroethyl)piperazin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    277
    Figure US20200190095A1-20200618-C00336
         		2-(azepan-1-yl)-4-((6-(3- hydroxypiperidin-1- yl)pyridin-3- yl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one 7
    278
    Figure US20200190095A1-20200618-C00337
         		2-(1-(4-((6-(3- hydroxypiperidin-1- yl)pyridin-3-yl)amino)-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    279
    Figure US20200190095A1-20200618-C00338
         		2-(azepan-1-yl)-4-((4-(4,4- difluoropiperidin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    280
    Figure US20200190095A1-20200618-C00339
         		2-(1-(4-((4-(4,4- difluoropiperidin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    281
    Figure US20200190095A1-20200618-C00340
         		2-(azepan-1-yl)-4-((4-(3- hydroxypiperidin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    282
    Figure US20200190095A1-20200618-C00341
         		2-(1-(4-((4-(3- hydroxypiperidin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    283
    Figure US20200190095A1-20200618-C00342
         		2-(azepan-1-yl)-4-((4-(2-(4- methylpiperazin-1-yl)-2- oxoethoxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 7
    284
    Figure US20200190095A1-20200618-C00343
         		2-(1-(4-((4-(3- (hydroxymethyl)piperidin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    285
    Figure US20200190095A1-20200618-C00344
         		2-(azepan-1-yl)-4-((4-(3- (hydroxymethyl)piperidin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    286
    Figure US20200190095A1-20200618-C00345
         		2-(1-(4-((4-(3-(2- hydroxyethyl)piperidin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    287
    Figure US20200190095A1-20200618-C00346
         		2-(1-(4-((4-(4- methoxypiperidin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    288
    Figure US20200190095A1-20200618-C00347
         		2-(azepan-1-yl)-4-((4-(4- methoxypiperidin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    289
    Figure US20200190095A1-20200618-C00348
         		2-(azepan-1-yl)-4-((4-(4- fluoropiperidin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    290
    Figure US20200190095A1-20200618-C00349
         		2-(1-(4-((4-(4-fluoropiperidin- 1-yl)phenyl)amino)-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    291
    Figure US20200190095A1-20200618-C00350
         		2-(1-(4-((4-((1-(2- hydroxyethyl)piperidin-4- yl)oxy)phenyl)amino)-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    292
    Figure US20200190095A1-20200618-C00351
         		2-(azepan-1-yl)-4-((4- (piperidin-4- yloxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one hydrochloride 7
    293
    Figure US20200190095A1-20200618-C00352
         		2-(1-(4-((4-(2- hydroxyethoxy)phenyl)amino)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    294
    Figure US20200190095A1-20200618-C00353
         		2-(azepan-1-yl)-4-((4-(2- hydroxyethoxy)phenyl)amino) pyrimido[4,5-d]pyridazin- 5(6H)-one 7
    295
    Figure US20200190095A1-20200618-C00354
         		2-(1-(4-((4-(3- hydroxypropoxy)phenyl)amino)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    296
    Figure US20200190095A1-20200618-C00355
         		2-(azepan-1-yl)-4-((4-(3- hydroxypropoxy)phenyl)amino) pyrimido[4,5-d]pyridazin- 5(6H)-one 7
    297
    Figure US20200190095A1-20200618-C00356
         		2-(1-(4-((4-(4-(1-hydroxy-2- methylpropan-2-yl)-1,4- diazepan-1-yl)phenyl)amino)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    298
    Figure US20200190095A1-20200618-C00357
         		2-(azepan-1-yl)-4-((4-(4-(2- fluoroethyl)piperidin-1- yl)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    299
    Figure US20200190095A1-20200618-C00358
         		2-(1-(4-((4-(4-(2- fluoroethyl)piperidin-1- yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    300
    Figure US20200190095A1-20200618-C00359
         		2-(1-(4-((3,5- dimethoxyphenyl)amino)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    301
    Figure US20200190095A1-20200618-C00360
         		2-(1-(5-oxo-4-((4- (trifluoromethoxy)phenyl)amino)- 5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    302
    Figure US20200190095A1-20200618-C00361
         		2-(azepan-1-yl)-4-((3,5- dimethoxyphenyl)amino) pyrimido[4,5-d]pyridazin-5(6H)- one 7
    303
    Figure US20200190095A1-20200618-C00362
         		2-(azepan-1-yl)-4-((4- (trifluoromethoxy)phenyl)amino) pyrimido[4,5-d]pyridazin- 5(6H)-one 7
    304
    Figure US20200190095A1-20200618-C00363
         		3-(4-((2-(azepan-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)propanoic acid 7
    305
    Figure US20200190095A1-20200618-C00364
         		3-(4-((2-(4- (cyanomethyl)piperidin-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenyl)propanoic acid 7
    306
    Figure US20200190095A1-20200618-C00365
         		2-(azepan-1-yl)-4-((4-(bis(2- hydroxyethyl)amino)phenyl) amino)pyrimido[4,5- d]pyridazin-5(6H)-one 7
    307
    Figure US20200190095A1-20200618-C00366
         		2-(1-(4-((4-(bis(2- hydroxyethyl)amino)phenyl) amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    308
    Figure US20200190095A1-20200618-C00367
         		2-(azepan-1-yl)-4-((4-(3- hydroxypropyl)phenyl)amino) pyrimido[4,5-d]pyridazin- 5(6H)-one 7
    309
    Figure US20200190095A1-20200618-C00368
         		2-(1-(4-((4-(3- hydroxypropyl)phenyl)amino)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    310
    Figure US20200190095A1-20200618-C00369
         		2-(azepan-1-yl)-4-((3- (hydroxymethyl)phenyl)amino) pyrimido[4,5-d]pyridazin- 5(6H)-one 7
    311
    Figure US20200190095A1-20200618-C00370
         		2-(1-(4-((3- (hydroxymethyl)phenyl)amino)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    312
    Figure US20200190095A1-20200618-C00371
         		2-(1-(4-((4- fluorophenyl)amino)-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    313
    Figure US20200190095A1-20200618-C00372
         		2-(azepan-1-yl)-4-((4- fluorophenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    314
    Figure US20200190095A1-20200618-C00373
         		2-(azepan-1-yl)-4-((4-((1- hydroxy-2-methylpropan-2- yl)oxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    315
    Figure US20200190095A1-20200618-C00374
         		2-(1-(4-((4-((1-hydroxy-2- methylpropan-2- yl)oxy)phenyl)amino)-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    316
    Figure US20200190095A1-20200618-C00375
         		2-(4-((2-(azepan-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenoxy)-2- methylpropanoic acid 7
    317
    Figure US20200190095A1-20200618-C00376
         		2-(4-((2-(4- (cyanomethyl)piperidin-1-yl)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-4- yl)amino)phenoxy)-2- methylpropanoic acid 7
    318
    Figure US20200190095A1-20200618-C00377
         		2-(azepan-1-yl)-4-((3,4- dimethoxyphenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)- one 7
    319
    Figure US20200190095A1-20200618-C00378
         		2-(1-(4-((3,4- dimethoxyphenyl)amino)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    320
    Figure US20200190095A1-20200618-C00379
         		2-(azepan-1-yl)-4-((3- methoxyphenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    321
    Figure US20200190095A1-20200618-C00380
         		2-(1-(4-((3- methoxyphenyl)amino)-5- oxo-5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    322
    Figure US20200190095A1-20200618-C00381
         		2-(azepan-1-yl)-4-((4-(2- hydroxyethyl)phenyl)amino) pyrimido[4,5-d]pyridazin- 5(6H)-one 7
    323
    Figure US20200190095A1-20200618-C00382
         		2-(1-(4-((4-(2- hydroxyethyl)phenyl)amino)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    324
    Figure US20200190095A1-20200618-C00383
         		2-(azepan-1-yl)-4-((4-(2- methoxyethoxy)phenyl)amino) pyrimido[4,5-d]pyridazin- 5(6H)-one 7
    325
    Figure US20200190095A1-20200618-C00384
         		2-(1-(4-((4-(2- methoxyethoxy)phenyl)amino)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    326
    Figure US20200190095A1-20200618-C00385
         		2-(1-(5-oxo-4-((3,4,5- trimethoxyphenyl)amino)-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    327
    Figure US20200190095A1-20200618-C00386
         		2-(azepan-1-yl)-4- (benzo[d][1,3]dioxol-5- ylamino)pyrimido[4,5- d]pyridazin-5(6H)-one 7
    328
    Figure US20200190095A1-20200618-C00387
         		2-(1-(4-(benzo[d][1,3]dioxol- 5-ylamino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    329
    Figure US20200190095A1-20200618-C00388
         		2-(azepan-1-yl)-4-((4-((1-(2- hydroxyethyl)piperidin-4- yl)oxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5(6H)-one 7
    330
    Figure US20200190095A1-20200618-C00389
         		sodium (2-(4- (cyanomethyl)piperidin-1-yl)- 4-((4-(4-hydroxypiperidin-1- yl)phenyl)amino)-5- oxopyrimido[4,5-d]pyridazin- 6(5H)-yl)methyl phosphate 7
    331
    Figure US20200190095A1-20200618-C00390
         		2-(azepan-1-yl)-4-((4- (hydroxymethyl)phenyl)amino) pyrimido[4,5-d]pyridazin- 5(6H)-one 7
    332
    Figure US20200190095A1-20200618-C00391
         		2-(1-(4-((4- (hydroxymethyl)phenyl)amino)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    333
    Figure US20200190095A1-20200618-C00392
         		2-(1-(4-((4- (methylsulfonyl)phenyl)amino)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    334
    Figure US20200190095A1-20200618-C00393
         		2-(azepan-1-yl)-4-((4- (methylsulfonyl)phenyl)amino) pyrimido[4,5-d]pyridazin- 5(6H)-one 7
    335
    Figure US20200190095A1-20200618-C00394
         		2-(1-(4-((1H- benzo[d][1,2,3]triazol-5- yl)amino)-5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    336
    Figure US20200190095A1-20200618-C00395
         		2-(1-(5-oxo-4-((2-oxo-2,3- dihydro-1H- benzo[d]imidazol-5- yl)amino)-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    337
    Figure US20200190095A1-20200618-C00396
         		2-(1-(4-((4-(3- fluoropropyl)phenyl)amino)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    338
    Figure US20200190095A1-20200618-C00397
         		2-(1-(4-((4- (difluoromethoxy)phenyl)amino)- 5-oxo-5,6- dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4- yl)acetonitrile 7
    339
    Figure US20200190095A1-20200618-C00398
         		4-((1H-benzo[d][1,2,3]triazol- 5-yl)amino)-2-(azepan-1- yl)pyrimido[4,5-d]pyridazin- 5(6H)-one 7
  • The following compounds in Table A are prepared by one of skill in the art using the above-noted Schemes, descriptions, and Examples 1-339.
  • TABLE A
    Structure IUPAC Name
    Figure US20200190095A1-20200618-C00399
         		2-(2,6-dimethylpiperidin-1-yl)-4-((4- (piperazin-1- ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one
    Figure US20200190095A1-20200618-C00400
         		2-(1-(4-((2-(2,6-dimethylpiperidin-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)phenyl)piperidin-4-yl)acetic acid
    Figure US20200190095A1-20200618-C00401
         		6-(4-((2-(2,6-dimethylpiperidin-1-yl)-5- oxo-5,6-dihydropyrimido [4,5-d]pyridazin-4-yl)amino)phenyl)- 6-azaspiro[2.5]octane-1-carboxylic acid
    Figure US20200190095A1-20200618-C00402
         		2-(1-(4-((2-(2,6-dimethylpiperidin-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)phenyl)piperidin-4- yl)acetonitrile
    Figure US20200190095A1-20200618-C00403
         		2-(2,6-dimethylpiperidin-1-yl)-4-((4-(4-(2- hydroxy-2-methylpropanoyl)piperazin-1- yl)phenyl)amino)pyrimido[4,5-d]pyridazin- 5(6H)-one
    Figure US20200190095A1-20200618-C00404
         		2-(1-(5-((2-(2,6-dimethylpiperidin-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)pyridin-2-yl)piperidin-4- yl)acetic acid
    Figure US20200190095A1-20200618-C00405
         		2-(3,5-dimethylpiperidin-1-yl)-4-((4- (piperaizn-1- ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one
    Figure US20200190095A1-20200618-C00406
         		2-(1-(4-((2-(3,5-dimethylpiperidin-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)phenyl)piperidin-4-yl)acetic acid
    Figure US20200190095A1-20200618-C00407
         		6-(4-((2-(3,5-dimethylpiperidin-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)phenyl)-6-azaspiro[2.5]octane- 1-carboxylic acid
    Figure US20200190095A1-20200618-C00408
         		2-(1-(4-((2-(3,5-dimethylpiperidin-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)phenyl)piperidin-4- yl)acetonitrile
    Figure US20200190095A1-20200618-C00409
         		2-(3,5-dimethylpiperidin-1-yl)-4-((4-(4-(2- hydroxy-2-methylpropanoyl)piperidin-1- yl)phenyl)amino)pyrimido[4,5-d]pyridazin- 5(6H)-one
    Figure US20200190095A1-20200618-C00410
         		2-(1-(5-((2-(3,5-dimethylpiperidin-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)pyridin-2-yl)piperidin-4- yl)acetic acid
    Figure US20200190095A1-20200618-C00411
         		2-(2,6-dimethylmorpholino)-4-((4- (piperazin-1- ylmethyl)phenyl)amino)pyrimido[4,5-d] pyridazin-5(6H)-one
    Figure US20200190095A1-20200618-C00412
         		2-(1-(4-((2-(2,6-dimethylmorpholino)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)phenyl)piperidin-4-yl)acetic acid
    Figure US20200190095A1-20200618-C00413
         		6-(4-((2-(2,6-dimethylmorpholino)-5-oxo- 5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid
    Figure US20200190095A1-20200618-C00414
         		2-(1-(4-((2-(2,6-dimethylmorpholino)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)phenyl)piperidin-4- yl)acetonitrile
    Figure US20200190095A1-20200618-C00415
         		2-(2,6-dimethylmorpholino)-4-((4-(4-(2- hydroxy-2-methylpropanoyl)piperidin-1- yl)phenyl)amino)pyrimido[4,5-d]pyridazin- 5(6H)-one
    Figure US20200190095A1-20200618-C00416
         		2-(1-(5-((2-(2,6-dimethylmorpholino)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)pyridin-2-yl)piperidin-4- yl)acetic acid
    Figure US20200190095A1-20200618-C00417
         		2-(diisopropylamino)-4-((4-(piperazin-1- ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one
    Figure US20200190095A1-20200618-C00418
         		2-(1-(4-((2-(diisopropylamino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetic acid
    Figure US20200190095A1-20200618-C00419
         		6-(4-((2-(diisopropylamino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-6-azaspiro[2,5]octane-1- carboxylic acid
    Figure US20200190095A1-20200618-C00420
         		2-(1-(4-((2-(diisopropylamino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetonitrile
    Figure US20200190095A1-20200618-C00421
         		2-(diisopropylamino)-4-((4-(4-(2-hydroxy- 2-methylpropanoyl)piperidin-1- yl)phenyl)amino)pyrimido[4,5-d]pyridazin- 5(6H)-one
    Figure US20200190095A1-20200618-C00422
         		2-(1-(5-((2-(diisopropylamino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid
    Figure US20200190095A1-20200618-C00423
         		2-(2-methylpiperidin-1-yl)-4-((4- (piperazin-1- ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one
    Figure US20200190095A1-20200618-C00424
         		2-(1-(4-((2-(2-methylpiperidin-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetic acid
    Figure US20200190095A1-20200618-C00425
         		6-(4-((2-(2-methylpiperidin-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid
    Figure US20200190095A1-20200618-C00426
         		2-(1-(4-((2-(2-methylpiperidin-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetonitrile
    Figure US20200190095A1-20200618-C00427
         		4-((4-(4-(2-hydroxy-2- methylpropanoyl)piperidin-1- yl)phenyl)amino)-2-(2-methylpiperidin-1- yl)pyrimido[4,5-d]pyridazin-5(6H)-one
    Figure US20200190095A1-20200618-C00428
         		2-(1-(5-((2-(2-methylpiperidin-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid
    Figure US20200190095A1-20200618-C00429
         		1-(4-((2-(azepan-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidine-4-carboxylic acid
    Figure US20200190095A1-20200618-C00430
         		1-(4-((2-(azepan-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)benzyl)piperidine-4-carboxylic acid
    Figure US20200190095A1-20200618-C00431
         		4-((4-((4-(2H-tetrazol-5-yl)piperidin-1- yl)methyl)phenyl)amino)-2-(azepan-1- yl)pyrimido[4,5-d]pyridazin-5(6H)-one
    Figure US20200190095A1-20200618-C00432
         		4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1- yl)methyl)phenyl)amino)-2-(azepan-1- yl)pyrimido[4,5-d]pyridazin-5(6H)-one
    Figure US20200190095A1-20200618-C00433
         		2-(1-(4-((2-cycloheptyl-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetic acid
    Figure US20200190095A1-20200618-C00434
         		1-(4-((2-cycloheptyl-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidine-4-carboxylic acid
    Figure US20200190095A1-20200618-C00435
         		6-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid
    Figure US20200190095A1-20200618-C00436
         		2-(1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetic acid
    Figure US20200190095A1-20200618-C00437
         		1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidine-4-carboxylic acid
    Figure US20200190095A1-20200618-C00438
         		1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)benzyl)piperidine-4-carboxylic acid
    Figure US20200190095A1-20200618-C00439
         		1-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1- yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2- yl)piperidine-3-carbonitrile
    Figure US20200190095A1-20200618-C00440
         		2-(1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)benzyl)piperidin-4-yl)acetic acid
    Figure US20200190095A1-20200618-C00441
         		1-(4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1- yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2- yl)piperidine-3-carbonitrile
    Figure US20200190095A1-20200618-C00442
         		1-(4-((2-cycloheptyl-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)benzyl)piperidine-4-carboxylic acid
    Figure US20200190095A1-20200618-C00443
         		4-((4-((4-(2H-tetrazol-5-yl)piperidin-1- yl)methyl)phenyl)amino)-2- cycloheptylpyrimido[4,5-d]pyridazin- 5(6H)-one
    Figure US20200190095A1-20200618-C00444
         		2-(1-(4-((2-cycloheptyl-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)benzyl)piperidin-4-yl)acetic acid
    Figure US20200190095A1-20200618-C00445
         		4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1- yl)methyl)phenyl)amino)-2- cycloheptylpyrimido[4,5-d]pyridazin- 5(6H)-one
    Figure US20200190095A1-20200618-C00446
         		1-(4-((2-(4-cyanopiperidin-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidine-4-carboxylic acid
    Figure US20200190095A1-20200618-C00447
         		1-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1- yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2- yl)piperidine-4-carbonitrile
    Figure US20200190095A1-20200618-C00448
         		1-(4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1- yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2- yl)piperidine-4-carbonitrile
    Figure US20200190095A1-20200618-C00449
         		1-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)benzyl)piperidine-4-carboxylic acid
    Figure US20200190095A1-20200618-C00450
         		2-(1-(4-((4-((4-(2H-tetrazol-5-yl)piperidin- 1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2- yl)piperidin-4-yl)acetonitrile
    Figure US20200190095A1-20200618-C00451
         		2-(1-(4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1- yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2- yl)piperidin-4-yl)acetonitrile
    Figure US20200190095A1-20200618-C00452
         		1-(4-((2-(4-(cyanomethyl)piperazin-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)phenyl)piperidine-4-carboxylic acid
    Figure US20200190095A1-20200618-C00453
         		1-(4-((2-(4-(cyanomethyl)piperazin-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)benzyl)piperidine-4-carboxylic acid
    Figure US20200190095A1-20200618-C00454
         		2-(4-(4-((4-((4-(2H-tetrazol-5-yl)piperidin- 1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2- yl)piperazin-1-yl)acetonitrile
    Figure US20200190095A1-20200618-C00455
         		2-(1-(4-((2-(4-(cyanomethyl)piperazin-1- yl)-5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4-yl)amino)benzyl)piperidin-4- yl)acetic acid
    Figure US20200190095A1-20200618-C00456
         		2-(4-(4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1- yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2- yl)piperazin-1-yl)acetonitrile
    Figure US20200190095A1-20200618-C00457
         		6-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid
    Figure US20200190095A1-20200618-C00458
         		2-(1-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetic acid
    Figure US20200190095A1-20200618-C00459
         		1-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidine-4-carboxylic acid
    Figure US20200190095A1-20200618-C00460
         		1-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)benzyl)piperidine-4-carboxylic acid
    Figure US20200190095A1-20200618-C00461
         		6-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)- 5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4-yl)amino)phenyl)-6- azaspiro[2.5]octane-1-carboxylic acid
    Figure US20200190095A1-20200618-C00462
         		2-(1-(4-((2-(4-(2-cyanoacetyl)piperazin-1- yl)-5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4-yl)amino)phenyl)piperidin-4- yl)acetic acid
    Figure US20200190095A1-20200618-C00463
         		1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)- 5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4-yl)amino)phenyl)piperidine- 4-carboxylic acid
    Figure US20200190095A1-20200618-C00464
         		1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)- 5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4-yl)amino)benzyl)piperidine- 4-carboxylic acid
    Figure US20200190095A1-20200618-C00465
         		3-(4-(4-((4-((4-(2H-tetrazol-5-yl)piperidin- 1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2- yl)piperazin-1-yl)-3-oxopropanenitrile
    Figure US20200190095A1-20200618-C00466
         		2-(1-(4-((2-(4-(2-cyanoacetyl)piperazin-1- yl)-5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4-yl)amino)benzyl)piperidin-4- yl)acetic acid
    Figure US20200190095A1-20200618-C00467
         		4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1- yl)methyl)phenyl)amino)-2-(4-(2- isocyanoacetyl)piperazin-1- yl)pyrimido[4,5-d]pyridazin-5(6H)-one
    Figure US20200190095A1-20200618-C00468
         		6-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)- 5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4-yl)amino)phenyl)-6- azaspiro[2.5]octane-1-carboxylic acid
    Figure US20200190095A1-20200618-C00469
         		2-(1-(4-((2-(1-(2-cyanoacetyl)piperidin-4- yl)-5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4-yl)amino)phenyl)piperidin-4- yl)acetic acid
    Figure US20200190095A1-20200618-C00470
         		1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)- 5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4-yl)amino)phenyl)piperidine- 4-carboxylic acid
    Figure US20200190095A1-20200618-C00471
         		1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)- 5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4-yl)amino)benzyl)piperidine- 4-carboxylic acid
    Figure US20200190095A1-20200618-C00472
         		3-(4-(4-((4-((4-(2H-tetrazol-5-yl)piperidin- 1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2- yl)piperidin-1-yl)-3-oxopropanenitrile
    Figure US20200190095A1-20200618-C00473
         		2-(1-(4-((2-(1-(2-cyanoacetyl)piperidin-4- yl)-5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4-yl)amino)benzyl)piperidin-4- yl)acetic acid
    Figure US20200190095A1-20200618-C00474
         		4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1- yl)methyl)phenyl)amino)-2-(1-(2- isocyanoacetyl)piperridin-4- yl)pyrimido[4,5-d]pyridazin-5(6H)-one
  • TABLE 2
    Physical Data
    1H-NMR in DMSO-d6 at 400 Hz
    Ex # Structure (δ) MS m/z
    1
    Figure US20200190095A1-20200618-C00475
         		13.32 (s, 1H), 11.32 (s, 1H), 8.42 (d, J = 6.7 Hz, 2H), 8.29 (s, 1H), 7.76 (d, J = 8.6 Hz, 2H), 7.6-7.55 (m, 3H), 7.07 (d, J = 9.2 Hz, 2H), 3.77 (t, J = 4.9 Hz, 4H), 3.15 (t, J = 4.6 Hz, 4H) 401.3 (M + 1)
    2
    Figure US20200190095A1-20200618-C00476
         		13.47 (s, 1H), 11.62 (s, 1H), 9.75 (br, 2H), 8.51 (d, J = 8.3 Hz, 2H), 8.37 (s, 1H), 8.13 (d, J = 8.3 Hz, 2H), 8.0 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.3 HZ, 2H), 4.4 (s, 2H), 3.91 (s, 3H), 3.57-3.51 (m, 8H) 472.1 (M + 1)
    3
    Figure US20200190095A1-20200618-C00477
         		12.9 (s, 1H), 11.52 (s, 1H), 9.4 (s, 2H), 7.94 (s, 1H), 7.81 (d, J = 7.0 Hz, 2H), 7.61 (br, 2H), 4.3 (br, 2H), 3.84 (m, 4H), 3.7 (m, 4H), 3.47 (m, 8H) 423.0 (M + 1)
    4
    Figure US20200190095A1-20200618-C00478
         		13.37 (s, 1H), 11.51 (s, 1H), 8.45 (d, J = 5.9 Hz, 2H), 8.39 (s, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.6 (d, J = 7.0 Hz, 3H), 7.44 (d, J = 8.6 Hz, 2H), 4.03 (s, 4H), 3.59-3.58 (m, 4H), 3.5 (s, 2H) 415.4 (M + 1)
    5
    Figure US20200190095A1-20200618-C00479
         		13.31 (s, 1H), 11.33 (s, 1H), 8.42 (d, J = 6.7 Hz, 2H), 8.3 (s, 1H), 7.75 (d, J = 8.9 Hz, 2H), 7.62-7.56 (m, 3H), 7.06 (d, J = 8.9 Hz, 2H), 3.18 (t, J = 4.4 Hz, 4H), 2.39 (q, J = 7.2 Hz, 2), 1.24 (m, 4H), 1.05 (t, J = 7.2 Hz, 3H) 428.2 (M + 1)
    6
    Figure US20200190095A1-20200618-C00480
         		13.37 (s, 2H), 11.5 (s, 1H), 8.44 (d, J = 5.9 Hz, 2H), 8.34 (s, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 7.0 Hz, 3H), 7.41 (d, J = 8.3 Hz, 2H), 3.48 (s, 2H), 2.40-2.31 (m, 10H), 0.98 (t, J = 7.1 Hz, 3H) 442.3 (M + 1)
    7
    Figure US20200190095A1-20200618-C00481
         		13.42 (s, 1H), 11.62 (s, 1H), 8.45 (d, J = 6.8 Hz, 2H), 8.37 (s, 1H), 8.03 (d, J = 7.3 Hz, 2H), 7.69-7.58 (m, 5H), 3.43 (m, 10H) 414.0 (M + 1)
    8
    Figure US20200190095A1-20200618-C00482
         		11.68 (s, 1H), 8.42 (d, J = 6.2 Hz, 2H), 8.30 (s 1H), 7.75 (d, J = 8.9 Hz, 2H), 7.57 (d, J = 8.9 Hz, 2H), 7.04 (d, J = 8.9 Hz, 2H), 3.08-3.07 (m, 4H), 2.86-2.85 (m, 4H) 400.3 (M + 1)
    9
    Figure US20200190095A1-20200618-C00483
         		13.42 (s,1H), 11.63 (s, 1H), 8.47- 8.45 (m, 2H), 8.37 (s, 1H), 8.01 (d, J = 8.3 Hz, 2H), 7.63-7.57 (m, 5H), 3.63-3.55 (m, 8H) 429.2 (M + 1)
    10
    Figure US20200190095A1-20200618-C00484
         		13.28 (s, 1H), 11.23 (s, 1H), 8.42- 8.4 (d, J = 9.2 Hz, 2H), 8.27 (s, 1H), 7.66 (d, J = 9.2 Hz, 2H), 7.59-7.55 (m, 3H), 6.80 (d, J = 8.8 Hz, 2H), 4.77 (t, J = 5.4 Hz, 2H), 3.58 (dd, J = 5.9 Hz, 11.7 Hz, 4H), 3.47-3.44 (m, 4H) 419.3 (M + 1)
    11
    Figure US20200190095A1-20200618-C00485
         		13.34 (s, 1H), 11.35 (s, 1H), 8.45- 8.42 (m, 2H), 8.3 (s, 1H), 8.11 (s, 2H), 7.80 (d, J = 8.8 Hz, 2H), 7.61-7.56 (m, 3H), 7.15 (d, J = 7.3 Hz, 2H), 3.7 (m, 2H), 3.27-3.22 (m, 4H) 457.2 (M + 1)
    12
    Figure US20200190095A1-20200618-C00486
         		13.32 (s, 1H), 11.31 (s, 1H), 8.42 (d, J = 7.0 Hz, 2H), 8.3 (s, 1H), 7.76 (d, J = 9.2 Hz, 2H), 7.62-7.55 (m, 3H), 7.07 (d, J = 9.2 Hz, 2H), 3.35-3.29 (m, 8H), 2.79 (s, 2H) 458.1 (M + 1)
    13
    Figure US20200190095A1-20200618-C00487
         		13.31 (s, 1H), 12.3 (s, 1H), 11.31 (s, 1H), 8.43-8.41 (m, 2H), 8.3 (s, 1H), 7.74 (d, J = 9.3 Hz, 2H), 7.6- 7.55 (m, 3H), 7.07 (d, J = 8.8 Hz, 2H), 3.69-3.66 (m, 2H), 2.79 (t, J = 10.8 Hz, 2H), 2.43-2.39 (m, 1H), 1.94-1.91 (m, 2H), 1.72-1.66 (m, 2H) 443.0 (M + 1)
    14
    Figure US20200190095A1-20200618-C00488
         		11.5 (s, 1H), 8.42-8.41 (m, 2H), 8.31 (s, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 7.4 Hz, 3H), 7.09 (d, J = 9.3 Hz, 2H), 3.39 (m, 4H), 3.17 (m, 8H) 457.3 (M + 1)
    15
    Figure US20200190095A1-20200618-C00489
         		13.1 (s, 1H), 11.6 (s, 1H), 8.45 (d, J = 6.4 Hz, 2H), 8.36 (s, 1H), 7.97 (d, J = 7.4 Hz, 2H), 7.59 (m, 3H), 7.53 (d, J = 7.9 Hz, 2H), 3.36 (br, 2H), 2.99 (s, 3H), 2.2-2.0 (m, 6H), 1.85 (s, 2H) 444.4 (M + 1)
    16
    Figure US20200190095A1-20200618-C00490
         		13.31 (s, 1H), 11.31 (s, 1H), 8.42 (dd, J = 1.4, 7.8 Hz, 2H)8.31 (d, J = 9.2 Hz, 2H), 7.74 (d, J = 9.2 Hz, 2H), 7.61-7.57 (m, 3H), 7.09 (d, J = 9.2 Hz, 2H), 3.22-3.2 (m, 4H), 2.66-2.65 (m, 2H), 1.84-1.78 (m, 24H) 454.1 (M + 1)
    17
    Figure US20200190095A1-20200618-C00491
         		13.31 (s, 1H), 11.29 (s, 1H), 8.43- 8.40 (m, 2H), 8.29 (s, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.6-7.64 (m, 3H), 7.07 (d, J = 9.2 Hz, 2H), 4.36 (s, 4H), 3.13 (t, J = 5.4 Hz, 4H), 1.91 (t, J = 5.4 Hz, 4H) 441.4 (M + 1)
    18
    Figure US20200190095A1-20200618-C00492
         		12.73 (s, 1H), 11.13 (s, 1H), 7.87 (s, 1H), 7.58 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 9.2 Hz, 2H), 3.89 (br, 4H), 3.73 (t, J = 4.9 Hz, 4H), 3.09 (t, J = 4.9 Hz, 4H), 1.4 (d, J = 4.6 Hz, 4H), 0.38 (s, 4H) 434.0 (M + 1)
    19
    Figure US20200190095A1-20200618-C00493
         		13.3 (s, 1H), 12.02 (s, 1H), 11.30 (s, 1H), 8.42 (d, J = 6.7 Hz, 2H), 8.28 (s, 1H), 7.73 (d, J = 8.9 Hz, 2H), 7.6-7.55 (m, 3H), 7.07 (d, J = 9.2 Hz, 2H), 3.28-3.27 (m, 2H), 3.1-3.05 (m, 1H), 2.5 (t, J = 1.6 Hz, 2H), 1.8-1.5 (m, 4H), 0.99- 0.96 (m, 2H) 469.3 (M + 1)
    20
    Figure US20200190095A1-20200618-C00494
         		13.31 (s, 1H), 11.31 (s, 1H), 8.43- 8.41 (m, 2H), 8.39 (s, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.62-7.54 (m, 3H), 7.08 (d, J = 9.3 Hz, 2H), 4.11-4.06 (m, 2H), 3.26-3.19 (m, 2H), 3.07-3.02 (m, 1H), 2.42 (t, J = 2.0 Hz, 2H), 1.84-1.5 (m, 4H), 1.19 (t, J = 7.1 Hz, 3H), 1.06-1.02 (m, 2H) 497.0 (M + 1)
    21
    Figure US20200190095A1-20200618-C00495
         		13.4 (s, 1H), 11.55 (s, 1H), 8.45 (d, J = 7.8 Hz, 2H), 8.35 (s, 1H), 7.93 (d, J = 7.8 Hz, 2H), 7.63-7.58 (m, 3H), 7.5 (d, J = 8.3 Hz, 2H), 1.75 (m, 2H), 1.54-1.50 (m, 2H), 0.93 (m, 2H) 483.0 (M + 1)
    22
    Figure US20200190095A1-20200618-C00496
         		8.47 (s, 1H), 8.39 (dd, J = 3.2, 6.6 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H), 7.58-7.57 (m, 3H), 7.08 (d, J = 9.3 Hz, 2H), 3.14 (t, J = 5.4 Hz, 2H), 2.56 (t, J = 2.0 Hz, 2H), 1.86-1.76 (m, 2H), 1.69-1.47 (m, 2H), 1.34- 1.31 (m, 1H), 0.85-0.83 (m, 1H), 0.55-0.52 (m, 1H) 469 (M + 1)
    23
    Figure US20200190095A1-20200618-C00497
         		13.39 (s, 1H), 11.5 (s, 1H), 8.44 (d, J = 6.3 Hz, 2H), 8.34 (s, 1H), 7.86 (t, J = 8.1 Hz, 2H), 7.62 (d, J = 7.4 Hz, 2H), 7.48 (d, J = 6.8 Hz, 1H), 7.40 (d, J = 6.9 Hz, 2H), 4.27 (s, 4H), 3.44 (s, 2H), 2.33-2.28 (m, 4H), 1.76 (m, 4H) 455.0 (M + 1)
    24
    Figure US20200190095A1-20200618-C00498
         		13.39 (s, 1H), 11.61 (s, 1H), 9.61 (br 2H), 8.52 (d, J = 1.9 Hz, 1H), 8.31 (s, 1H), 8.02 (d, J = 9.3 Hz, 2H), 7.85-7.84 (m, 1H), 7.75-7.72 (m, 3H), 4.40 (s, 2H), 3.49-3.42 (m, 4H), 2.50 (t, J = 2.0 Hz, 4H) 420 (M + 1)
    25
    Figure US20200190095A1-20200618-C00499
         		12.86 (s, 1H), 11.51 (s, 1H), 9.67 (s, 2H), 7.95 (s, 1H), 7.82 (d, J = 7.8 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 4.36 (br, 2H), 4.12-3.92 (m, 4H), 3.5-3.37 (m, 5H), 3.35-3.23 (m, 2H), 1.74-1.52 (m, 6H), 1.06- 1.02 (m, 2H) 491.3 (M + 1)
    26
    Figure US20200190095A1-20200618-C00500
         		12.8 (s, 1H), 11.17 (s, 1H), 7.88 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.8 (m, 4H), 3.67 (m, 4H), 3.29 (m, 4H), 3.13-3.11 (m, 4H), 2.37-2.35 (m, 2H), 1.03 (t, J = 7.1 Hz, 3H) 437.3 (M + 1)
    27
    Figure US20200190095A1-20200618-C00501
         		13.48 (s, 1H), 11.64 (s, 1H), 9.42 (br, 2H), 8.53 (d, J = 8.3 Hz, 2H), 8.4 (s, 1H), 8.14 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 7.8 Hz, 2H), 7.73 (br, 2H), 4.40 (br, 2H), 3.63 (m, 4H), 3.51-3.39 (m, 4H) 458.0 (M + 1)
    28
    Figure US20200190095A1-20200618-C00502
         		13.36 (s, 1H), 11.33 (s, 1H), 8.51 (d, J = 8.8 Hz, 2H), 8.31 (s, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 9.3 Hz, 2H), 3.30 (m, 4H), 3.19-3.16 (m, 4H), 2.39-2.33 (m, 4H), 1.05 (t, J = 7.1 Hz, 3H) 512.2 (M + 1)
    29
    Figure US20200190095A1-20200618-C00503
         		13.4 (br, 1H), 11.6 (br, 1H), 8.52 (d, J = 8.3 Hz, 2H), 8.33 (s, 1H), 8.14 (d, J = 8.3 Hz, 2J), 7.77 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 3.91 (s, 3H), 3.77 (t, J = 4.7 Hz, 4H), 3.15 (t, J = 4.7 Hz, 4H) 459.2 (M + 1)
    30
    Figure US20200190095A1-20200618-C00504
         		12.87 (s, 1H), 11.51 (s, 1H), 9.8 (br, 2H), 7.96 (s, 1H), 7.82 (d, J = 7.8 Hz, 2H), 6.68 (d, J = 8.3 Hz, 2H), 4.82 (m, 6H), 4.38 (s, 2H), 3.86 (m, 4H), 3.48 (m, 4H), 1.66 (m, 2H), 1.09 (m, 2H) 421.1 (M + 1)
    31
    Figure US20200190095A1-20200618-C00505
         		13.43 (s, 1H), 11.59 (s, 1H), 9.47 (br, 2H), 8.37 (s, 1H), 8.05-8.03 (m, 3H), 7.98 (s, 1H), 7.74 (d, J = 7.8 Hz, 2H), 7.51 (t, J = 8.1 Hz, 1H), 7.2 (dd, J = 4.0, 8.3 Hz, 1H), 4.41 (br, 2H), 3.89 (s, 3H), 3.45 (t, J = 4.9 Hz, 4H), 3.23 (m, 4H) 443.9 (M + 1)
    32
    Figure US20200190095A1-20200618-C00506
         		12.99 (s, 1H), 11.53 (s, 1H), 9.6 (br, 2H), 9.35 (br, 2H), 7.98 (s, 1H), 7.9 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 7.8 Hz, 2H), 4.36 (br, 2H), 4.08 (m, 4H), 3.44 (m, 4H), 3.39 (m, 8H) 422.2 (M + 1)
    33
    Figure US20200190095A1-20200618-C00507
         		13.37 (s, 1H), 11.59 (s, 1H), 9.4 (br, 2H), 8.32 (s, 1H), 8.09 (dd, J = 1.5, 8.5 Hz, 1H), 8.0 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 1.5 Hz, 1H), 7.71 (d, J = 6.4 Hz, 2H), 7.12 (d, J = 8.3 Hz, 1H), 6.17 (s, 2H), 4.4 (br, 2H), 3.65-3.49 (m, 4H), 2.51- 2.5 (m, 4H) 458.1 (M + 1)
    34
    Figure US20200190095A1-20200618-C00508
         		13.2 (s, 1H), 11.29 (s, 1H), 8.42- 8.4 (m, 2H), 8.28 (s, 1H), 7.72 (d, J = 9.3 Hz, 2H), 7.6-7.54 (m, 3H), 7.04 (d, J = 8.8 Hz, 2H), 3.72-3.69 (m, 2H), 2.71-2.66 (m, 2H), 2.47- 2.41 (m, 1H), 2.2-2.18 (m, 2H), 1.84-1.76 (m, 2H), 1.35-1.27 (m, 2H) 455 (M − 1)
    35
    Figure US20200190095A1-20200618-C00509
         		13.37 (s, 1H), 11.51 (s, 1H), 8.45- 8.43 (m, 2H), 8.33 (s, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.62-7.56 (m, 3H), 7.44 (d, J = 8.3 Hz, 2H), 3.58 (m, 2H), 2.85 (m, 2H), 2.49-2.14 (m, 3H), 1.84-1.81 (m, 2H), 1.64- 1.59 (m, 2H) 457 (M + 1)
    36
    Figure US20200190095A1-20200618-C00510
         		13.42 (s, 1H), 11.56 (s, 1H), 9.63 (br, 2H), 8.34 (s, 1H), 8.10 (d, J = 8.8 Hz, 2H), 7.84 (dd, J = 1.7, 7.6 Hz, 1H), 7.71 (d, J = 8.3 Hz, 2H), 5.56-7.52 (m, 1H), 7.26 (d, J = 8.3 Hz, 2H), 7.10 (t, J = 7.1 Hz, 1H), 4.39 (s, 2H), 3.94 (s, 3H), 3.64 (m, 4H), 3.47-3.37 (m, 4H) 444.1 (M + 1)
    37
    Figure US20200190095A1-20200618-C00511
         		13.28 (s, 1H), 11.30 (s, 1H), 8.46 (d, J = 1.9 Hz, 1H), 8.24 (s, 1H), 7.81-7.80 (m, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.69 (dd, J = 3.2, 5.2 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 3.32-3.3 (m, 8H), 2.39-2.33 (m, 2H), 1.05 (t, J = 7.3 Hz, 3H) 434.0 (M + 1)
    38
    Figure US20200190095A1-20200618-C00512
         		13.11 (b, 1H), 12.87 (s, 1H), 11.56 (s, 1h), 9.61 (b, 2H), 7.95 (s, 1h), 7.88 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 5.05 (s, 2H), 3.89 (m, 4H), 3.54 (m, 4H), 3.01 (s, 4H), 2.75 (m, 4H), 1.60 (m, 4H) 475.0 (M + 1)
    39
    Figure US20200190095A1-20200618-C00513
         		12.0 (br, 1H), 8.46-8.45 (m, 1H), 8.23 (s, 1H), 7.81 (dd, J = 1.0, 4.9 Hz, 1H), 7.74 (d, J = 9.3 Hz, 2H), 7.69 (dd, J = 3.0, 4.9 Hz, 1H), 7.07 (d, J = 9.3 Hz, 2H), 3.27-3.2 (m, 2H), 3.19-3.08 (m, 1H), 2.61- 2.53 (m, 2H), 1.81-1.77 (m, 2H), 1.60-1.55 (m, 2H), 1.01-0.95 (m, 2H) 475.0 (M + 1)
    40
    Figure US20200190095A1-20200618-C00514
         		13.44 (s, 1H), 11.62 (s, 1H), 9.5 (b, 2H), 8.42 (d, J = 8.8 Hz, 2H), 8.35 (s, 1H), 7.98 (d, J = 7.8 Hz, 2H), 7.71 (b, 2H), 7.66 (d, J = 8.3 Hz, 2H), 4.4 (b, 2H), 3.95 (m, 4H), 3.41 (m, 4H) 448.0 (M + 1)
    41
    Figure US20200190095A1-20200618-C00515
         		13.36 (s, 1H), 11.60 (s, 1H), 9.68 (b, 2H), 8.40 (d, J = 8.8 Hz, 2H), 8.31 (s, 1H), 8.01 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 4.41 (s, 2H), 3.87-3.75 (m, 7H), 3.49-3.45 (m, 4H) 444.0 (M + 1)
    42
    Figure US20200190095A1-20200618-C00516
         		12.80 (s, 1H), 11.95 (br, 1H), 11.17 (s, 1H), 7.88 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 3.81 (m, 4H), 3.67 (m, 4H), 3.23-3.16 (m, 4H), 3.06- 3.03 (m, 1H), 1.77-1.76 (m, 2H), 1.56-1.53 (m, 2H), 0.98-0.94 (m, 2H) 478 (M + 1)
    43
    Figure US20200190095A1-20200618-C00517
         		12.84 (s, 1H), 11.95 (br, 1H), 11.49 (s, 1H), 9.62 (br, 2H), 7.93 (s, 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 4.8-4.6 (m, 2H), 4.36 (br, 2H), 3.65 (br, 4H), 3.46 (br, 4H), 3.1-4.04 (m, 1H), 2.2-2.09 (m, 2H), 2.02 (br, 2H), 1.82-1.79 (m, 2H), 1.23-1.19 (m, 2H) 479 (M + 1)
    44
    Figure US20200190095A1-20200618-C00518
         		12.93 (s, 1H), 11.41 (s, 1H), 8.72 (br, 2H), 7.98 (s, 1H), 7.75 (d, J = 7.3 Hz, 2H), 7.43 (d, J = 7.3 Hz, 2H), 4.62-4.53 (m, 2H), 4.0-3.94 (m, 2H), 3.82 (br, 2H), 3.19 (br, 4H), 2.95-2.83 (m, 8H) 455 (M + 1)
    45
    Figure US20200190095A1-20200618-C00519
         		13.02 (s, 1H), 11.55 (s, 1H), 11.18 (br, 1H), 9.67 (br, 2H), 7.99 (s, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 7.4 Hz, 2H), 4.71 (br, 2H), 4.39 (s, 2H), 3.36 (br, 6H), 3.30- 3.09 (m, 8H), 2.80 (s, 3H) 436.2 (M + 1_
    46
    Figure US20200190095A1-20200618-C00520
         		11.23 (s, 1H), 8.34 (d, J = 8.8 Hz, 2H), 8.2 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 9.2 Hz, 2H), 3.85 (s, 3H), 3.27-3.22 (m, 8H), 3.09-3.06 (m, 1H), 1.55-1.49 (m, 2H) 479.73 (M − 1)
    47
    Figure US20200190095A1-20200618-C00521
         		11.35 (s, 1H), 8.27 (s, 1H), 7.98 (d, J = 7.4 Hz, 2H), 7.93 (s, 1H), 7.69 (d, J = 7.8 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 7.8 Hz, 2H), 3.84 (s, 3H), 3.11 (br peak, 5H), 1.85 (br, 2H), 1.51-1.16 (m, 4H) 499.3 (M + 1)
    48
    Figure US20200190095A1-20200618-C00522
         		12.86 (s, 1H), 11.57 (s, 1H), 9.42 (br, 2H), 7.96 (s, 1H), 7.94 (d, J = 7.3 Hz, 2H), 7.61 (d, J = 6.9 Hz, 2H), 4.35 (br, 2H), 3.64-3.57 (m, 4H), 3.46-3.38 (m, 4H), 3.26-3.23 (m, 4H), 1.99 (m, 4H) 407.5 (M + 1)
    49
    Figure US20200190095A1-20200618-C00523
         		12.84 (s, 1H), 11.53 (s, 1H), 7.94 (s, 1H), 7.90 (d, J = 7.9 Hz, 2H), 7.62 (d, J = 6.9 Hz, 2H), 4.3 (br, 2H), 3.42 (m, 4H), 3.24 (s, 6H), 2.51 (m, 4H) 381.3 (M + 1)
    50
    Figure US20200190095A1-20200618-C00524
         		13.28 (s, 1H), 11.8 (br, 1H), 11.58 (s, 1H), 9.41 (br, 2H), 8.15 (s, 1H), 7.9 (d, J = 8.3 Hz, 2H), 7.78 (d, J = 7.8 Hz, 2H), 4.45 (q, J = 7.1 Hz, 2H), 4.37 (br, 2H), 3.47 (m, 4H), 3.39 (m, 4H), 1.38 (t, J = 7.1 Hz, 3H) 382.4 (M + 1)
    51
    Figure US20200190095A1-20200618-C00525
         		12.87 (s, 1H), 11.50 (s, 1H), 9.60 (br, 2H), 7.95 (s, 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 4.65-4.50 (m, 2H), 4.38 (s, 2H), 2.64-2.59 (m, 1H), 1.97-1.94 (m, 2H), 1.6 (s, 2H), 1.56-1.54 (m, 2H) 465.3 (M + 1)
    52
    Figure US20200190095A1-20200618-C00526
         		12.84 (s, 1H), 11.54 (s, 1H), 9.56 (br, 2H), 7.95 (s, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H), 4.37 (s, 2H), 3.84-3.79 (m, 8H), 2.51-2.50 (m, 4H), 1.81-1.77 (m, 4H), 1.53 (s, 4H) 433.1 (M − 1)
    53
    Figure US20200190095A1-20200618-C00527
         		13.29 (s, 1H), 11.95 (br, 1H), 11.26 (s, 1H), 8.25 (s, 1H), 7.78 (d, J = 9.2 Hz, 2H), 7.74 (dd, J = 1.7 Hz, J = 7.6 Hz, 1H), 7.52-7.48 (m, 1H), 7.2 (d, J = 7.8 Hz, 1H), 7.07 (t, J = 7.1 Hz, 1H), 6.99 (d, J = 9.3 Hz, 2H), 3.88 (s, 3H), 3.27- 2.15 (m, 4H), 3.05-3.03 (m, 1H), 1.79-1.75 (m, 2H), 1.58-1.50 (m, 2H), 0.98-0.92 (m, 2H) 499.3 (M + 1)
    54
    Figure US20200190095A1-20200618-C00528
         		12.81 (s, 1H), 11.53 (s, 1H), 9.35 (br, 2H), 7.93 (s, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 7.8 Hz, 2H), 4.33 (br, 2H), 3.7-3.66 (m, 6H), 3.29 (m, 4H), 1.19-1.18 (m, 12H) 437.2 (M + 1)
    55
    Figure US20200190095A1-20200618-C00529
         		13.4 (s, 1H), 11.58 (br, 1H), 9.70 (br, 2H), 8.45 (d, J = 8.3 Hz, 2H), 8.34 (s, 1H), 8.01 (d, J = 8.3 Hz, 2H), 7.86 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.3 Hz, 2H), 4.45 (m, 4H), 3.94-3.65 (m, 4H), 3.5 (m, 4H), 3.38-3.16 (m, 6H), 1.6 (s, 2H) 513.2 (M + 1)
    56
    Figure US20200190095A1-20200618-C00530
         		12.80 (s, 1H), 11.95 (br, 1H), 11.50 (s, 1H), 9.62 (br, 2H), 7.95 (s, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 4.37 (s. 2H), 4.17 (br, 2H), 3.75-3.63 (m, 4H), 3.47 (br, 6H), 3.36-3.18 (m, 3H), 1.79-1.76 (m, 2H) 446.3 (M + 1)
    57
    Figure US20200190095A1-20200618-C00531
         		13.01 (s, 1H), 11.95 (br, 1H), 11.02 (s, 1H), 9.59 (br, 2H), 8.0 (s, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 7.8 Hz, 2H), 4.8 (br, 2H), 4.37 (br, 2H), 3.65-3.61 (m, 8H), 3.39-3.04 (m, 8H), 1.29 (t, J = 7.4 Hz, 3H) 450.4 (M + 1)
    58
    Figure US20200190095A1-20200618-C00532
         		13.31 (s, 1H), 11.24 (s, 1H), 8.46- 8.44 (m, 2H), 8.34 (s, 1H), 8.3 (s, 1H), 7.93 (s, 1H), 7.62-7.56 (m, 3H), 4.31 (t, J = 6.3 Hz, 2H), 3.54 (t, J = 4.4 Hz, 4H), 2.75 (t, J = 6.4 Hz, 2H), 2.5-2.44 (m, 4H) 419.2 (M + 1)
    59
    Figure US20200190095A1-20200618-C00533
         		12.95 (s, 1H), 11.53 (s, 1H), 9.65 (br, 2H), 9.28-9.22 (m, 2H), 7.97 (s, 1H), 7.87-7.80 (m, 2H), 7.67 (d, J = 8.9 Hz, 2H), 4.37 (br, 2H), 4.09-4.04 (m, 2H), 3.96-3.90 (m, 2H), 3.52-3.20 (m, 10H), 2.12- 2.09 (m, 2H), 1.6 (s, 2H) 436.3 (M + 1)
    60
    Figure US20200190095A1-20200618-C00534
         		12.70 (s, 1H), 11.17 (s, 1H), 7.86 (s, 1H), 7.64 (d, J = 9.3 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 3.81-3.76 (m, 4H), 3.75-3.72 (m, 4H), 3.09 (t, J = 4.7 Hz, 4H), 1.76 (t, J = 4.4 Hz, 4H), 1.51 (m, 4H) 422.3 (M + 1)
    61
    Figure US20200190095A1-20200618-C00535
         		13.28 (s, 1H), 11.71 (s, 1H), 9.68 (br, 2H), 8.1 (s, 1H), 7.97 (d, J = 7.8 Hz, 2H), 7.68 (d, J = 6.8 Hz, 2H), 4.37 (br, 2H) 368.3 (M + 1)
    62
    Figure US20200190095A1-20200618-C00536
         		12.7 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.61 (d, J = 9.3 Hz, 2H), 6.98 (d, J = 9.3 Hz, 2H), 3.81 (t, J = 5.9 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.26-3.01 (m, 5H), 1.79-1.75 (m, 6H), 1.55-1.51 (m, 6H), 0.95- 0.92 (m, 2H), 3.65 (s, 3H), 3.53- 3.29 (m, 10H) 490.4 (M + 1)
    63
    Figure US20200190095A1-20200618-C00537
         		13.35 (s, 1H), 11.19 (s, 1H), 9.5 (br, 2H), 8.49-8.47 (m, 2H), 8.43 (s, 1H), 8.32 (s, 1H), 8.06 (s, 1H), 7.63-7.60 (m, 3H), 4.68 (br, 2H), 4.06-3.95 (m, 8H), 3.65 (m, 2H) 418.1 (M + 1)
    64
    Figure US20200190095A1-20200618-C00538
         		13.31 (s, 1H), 11.14 (s, 1H), 8.46 (d, J = 6.4 Hz, 2H), 8.31 (d, J = 8.3 Hz, 2H), 7.92 (s, 1H), 7.62- 7.58 (m, 3H), 4.29 (t, J = 6.1 Hz, 2H), 2.74 (t, J = 6.2 Hz, 2H), 2.45 (m, 4H), 2.28 (m, 4H), 2.09 (s, 3H) 432.2 (M + 1)
    65
    Figure US20200190095A1-20200618-C00539
         		13.31 (s, 1H), 11.14 (s, 1H), 8.32 (d, J = 10.7 Hz, 2H), 7.92 (s, 1H), 7.64-7.54 (m, 3H), 4.29 (t, J = 6.4 Hz, 2H), 2.74 (t, J = 6.4 Hz, 2H), 2.45-2.31 (m, 8H), 2.23 (q, J = 7.1 Hz, 2H) 446.1 (M + 1)
    66
    Figure US20200190095A1-20200618-C00540
         		12.75 (s, 1H), 12.0 (br, 1H), 11.14 (s, 1H), 7.88 (s, 1H), 7.56 (d, J = 9.3 Hz, 2H), 7.0 (d, J = 8.8 Hz, 2H), 4.72 (br, 2H), 3.27-3.14 (m, 4H), 3.06-2.96 (m, 4H), 1.97-1.91 (m, 1H), 1.84-1.75 (m, 4H), 1.60- 1.52 (m, 2H), 1.34-1.17 (m, 3H), 0.99-0.94 (m, 2H) 515.6 (M + 1)
    67
    Figure US20200190095A1-20200618-C00541
         		12.76 (s, 1H), 11.40 (s, 1H), 7.89 (s, 1H), 7.22 (s, 2H), 3.81 (m, 10H), 3.65 (s, 3H), 1.75 (m, 4H), 1.51 (m, 4H) 427.3 (M + 1)
    68
    Figure US20200190095A1-20200618-C00542
         		12.79 (s, 1H), 11.51 (s, 1H), 7.91 (s, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 3.84-3.77 (m, 4H), 3.61 (m, 4H), 3.51 (m, 4H), 1.81-1.76 (m, 4H), 1.52 (m, 4H) 450.3 (M + 1)
    69
    Figure US20200190095A1-20200618-C00543
         		12.7 (s, 1H), 12.1 (s, 1H), 7.86 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 9.3 Hz, 2H), 3.8 (t, J = 6.1 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.66-3.63 (m, 2H), 2.63 (m, 3H), 2.19 (d, J = 6.8 Hz, 2H), 1.77-1.74 (m, 6H), 1.51 (m, 4H), 1.4-1.2 (m, 2H) 478.3 (M + 1)
    70
    Figure US20200190095A1-20200618-C00544
         		12.80 (s, 1H), 12.10 (br, 1H), 11.15 (s, 1H), 7.89 (s, 1H), 7.55 (d, J = 8.3 Hz, 2H), 6.97 (s, 1H), 3.88 (m, 4H), 3.67 (s, 2H), 3.65- 3.64 (m, 2H), 2.68-2.62 (m, 2H), 2.55 (m, 4H), 2.19 (d, J = 6.4 Hz, 2H), 1.99 (m, 1H), 1.77-1.75 (m, 2H), 1.34 (t, J = 7.8 Hz, 4H) 504.3 (M + 1)
    71
    Figure US20200190095A1-20200618-C00545
         		12.75 (s, 1H), 11.13 (s, 1H), 7.87 (s, 1H), 7.55 (d, J = 9.3 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.72 (m, 2H), 3.66 (d, J = 11.7 Hz, 2H), 3.02-2.95 (m, 2H), 2.19 (d, J = 6.8 Hz, 2H), 2.00-1.97 (m, 1H), 1.84- 1.74 (m, 5H), 1.34-1.21 (m, 4H) 503.4 (M + 1)
    72
    Figure US20200190095A1-20200618-C00546
         		12.95 (s, 1H), 11.51 (s, 1H), 9.33- 9.29 (m, 2H), 7.98 (s, 1H), 7.9- 7.85 (m, 4H), 4.09-4.04 (m, 6H), 3.55 (m, 4H), 3.32-3.17 (m, 6H), 2.2-2.11 (m, 4H), 1.73-1.70 (m, 1H), 1.24-1.05 (m, 4H) 491.1 (M + 1)
    73
    Figure US20200190095A1-20200618-C00547
         		12.8 (s, 1H), 12.05 (br, 1H), 11.16 (s, 1H), 7.89 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 7.9 Hz, 2H), 3.87-3.81 (m, 6H), 3.27-3.16 (m, 4H), 3.04-3.03 (m, 2H), 1.82- 1.77 (m, 4H), 1.57-1.53 (m, 4H), 0.98-0.96 (m, 2H) 516.3 (M + 1)
    74
    Figure US20200190095A1-20200618-C00548
         		12.79 (s, 1H), 12.06 (s, 1H), 11.14 (s, 1H), 7.89 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 4.14 (m, 2H), 3.64-3.59 (m, 2H), 3.27-3.16 (m, 4H), 3.07-3.02 (m, 1H), 2.01-1.91 (m, 2H), 1.82- 1.73 (m, 4H), 1.61-1.52 (m, 4H), 0.99-0.93 (m, 2H) 501.4 (M + 1)
    75
    Figure US20200190095A1-20200618-C00549
         		12.79 (s, 1H), 12.05 (s, 1H), 11.13 (s, 1H), 7.89 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.15 (m, 2H), 3.67-3.59 (m, 4H), 3.2-3.16 (m, 2H), 2.65 (t, J = 11.8 Hz, 2H), 2.20 (d, J = 6.9 Hz, 2H), 1.95 (m, 2H), 1.78-1.75 (m, 5H), 1.31-1.24 (m, 2H) 489.2 (M + 1)
    76
    Figure US20200190095A1-20200618-C00550
         		12.84 (s, 1H), 12.05 (s, 1H), 11.35 (s, 1H), 7.91 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 4.16 (br, 2H), 3.42 (s, 2H), 3.22-3.17 (m, 2H), 2.75 (d, J = 11.3 Hz, 2H), 2.44 (t, J = 3.9 Hz, 1H), 2.18-2.15 (m, 1H), 1.99-1.95 (m, 4H), 1.79-1.76 (m, 4H), 1.58- 1.50 (m, 2H) 489.3 (M + 1)
    77
    Figure US20200190095A1-20200618-C00551
         		12.76 (s, 1H), 12.0 (s, 1H), 11.39 (s, 1H), 7.90 (s, 1H), 7.76 (d, J = 7.4 Hz, 2H), 7.34 (m, 2H), 3.82- 3.78 (m, 4H), 2.86 (m, 2H), 2.14 (m, 2H), 1.99 (m, 1H), 1.76-1.68 (m, 8H), 1.52 (m, 4H), 1.24-1.18 (m, 4H) 492.4 (M + 1)
    78
    Figure US20200190095A1-20200618-C00552
         		1 12.81 (s, 1H), 12.0 (s, 1H), 11.39 (s, 1H), 7.91 (s, 1H), 7.72 (d, J = 7.3 Hz, 2H), 7.38 (d, J = 6.9 Hz, 2H), 4.8-4.71 (m, 2H), 3.65 (br, 2H), 3.02-2.90 (m, 4H), 2.33-2.29 (m, 4H), 2.01 (m, 2H), 1.86-1.83 (m, 4H), 1.62 (m, 2H), 1.23 (m, 2H) 503.3 (M + 1)
    79
    Figure US20200190095A1-20200618-C00553
         		13.23 (s, 1H), 12.09 (s, 1H), 11.21 (s, 1H), 8.16 (s, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 3.32-3.21 (m, 2H), 3.06 (m, 1H), 2.77-2.63 (m, 1H), 1.97 (m, 2H), 1.78-1.67 (m, 5H), 1.59-1.54 (m, 5H), 1.42-1.23 (m, 4H), 0.98- 0.95 (m, 2H) 475.4 (M + 1)
    80
    Figure US20200190095A1-20200618-C00554
         		12.7 (s, 1H), 11.61 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 9.2 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 3.81- 3.67 (m, 6H), 2.69-2.54 (m, 4H), 1.80-1.74 (m, 7H), 1.51 (m, 4H), 1.43-1.36 (m, 2H) 459.3 (M + 1)
    81
    Figure US20200190095A1-20200618-C00555
         		13.23 (s, 1H), 12.05 (brs, 1H), 11.20 (s, 1H), 8.16 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 3.26-3.20 (m, 4H), 3.19-3.13 (m, 1H), 2.93-2.90 (m, 1H), 2.02-1.91 (m, 2H), 1.82-1.76 (m, 6H), 1.63-1.52 (m, 9H), 0.99- 0.97 (m, 2H) 489.4 (M + 1)
    82
    Figure US20200190095A1-20200618-C00556
         		13.31 (s, 1H), 11.31 (s, 1H), 8.43- 8.41 (m, 2H), 8.29 (s, 1H), 7.74 (d, J = 9.3 Hz, 2H), 7.76-7.54 (m, 3H), 7.07 (d, J = 8.8 Hz, 2H), 3.76 (m, 2H), 2.72 (m, 2H), 2.57 (d, J = 6.3 Hz, 2H), 1.83-1.80 (m, 3H), 1.45-1.42 (m, 2H) 438.4 (M + 1)
    83
    Figure US20200190095A1-20200618-C00557
         		13.37 (s, 1H), 11.51 (s, 1H), 8.44 (dd, J = 1.7 Hz, 7.6 Hz, 2H), 8.33 (s, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.62-7.57 (m, 3H), 7.44 (d, J = 8.3 Hz, 2H), 5.37 (s, 1H), 3.9 (br, 1H), 3.52 (m, 4H), 2.39 (m, 4H), 1.30 (s, 6H) 500.3 (M + 1)
    84
    Figure US20200190095A1-20200618-C00558
         		12.75 (s, 1H), 11.38 (s, 1H), 7.90 (s, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 5.37 (s, 1H), 3.83-3.76 (m, 4H), 3.38 (s, 2H), 3.13-3.08 (m, 4H), 2.36 (m, 4H), 1.8-1.76 (m, 4H), 1.52 (m, 4H), 1.29 (s, 6H) 521.4 (M + 1)
    85
    Figure US20200190095A1-20200618-C00559
         		12.74 (s, 1H), 11.35 (s, 1H), 7.89 (s, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 4.12-4.11 (m, 4H), 3.81-3.77 (m, 6H), 2.35 (m, 4H), 2.16 (s, 1H), 1.85-1.75 (m, 4H), 1.51 (m, 4H) 449.3 (M + 1)
    86
    Figure US20200190095A1-20200618-C00560
         		13.35 (s, 1H), 11.48 (s, 1H), 8.45- 8.30 (m, 2H), 8.28 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.59-7.57 (m, 3H), 7.38 (d, J = 7.8 Hz, 2H), 3.50 (m, 6H), 2.73-2.68 (m, 2H), 1.91- 1.90 (m, 3H) 457.3 (M + 1)
    87
    Figure US20200190095A1-20200618-C00561
         		13.21 (s, 1H), 11.45 (s, 1H), 8.43- 8.31 (m, 2H), 8.30 (s, 1H), 7.82- 7.79 (m, 2H), 7.60-7.56 (m, 3H), 7.39-7.33 (m, 2H), 3.31 (s, 1H), 2.67 (m, 1H), 2.36 (m, 1H), 2.14 (d, J = 6.8 Hz, 2H), 1.85 (m, 2H), 1.64 (m,4H), 1.48 (m, 1H) 454.2 (M − 1)
    88
    Figure US20200190095A1-20200618-C00562
         		12.69 (s, 1H), 12.01 (s, 1H), 11.15 (s, 1H), 7.85 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 3.70 (m, 6H), 2.67 (m, 2H), 2.18 (d, J = 5.8 Hz, 2H), 1.79 (m, 7H), 1.21-1.51 (m, 8H) 492.3 (M + 1)
    89
    Figure US20200190095A1-20200618-C00563
         		12.89 (s, 1H), 1H), 12.28 (s, 1H), 1H), 11.30 (s, 1H), 9.78 (s, 2H), 8.02 (s, 1H), 7.73 (d, J = 9.2 Hz, 2H), 7.06 (d, J = 9.2 Hz, 2H), 4.43 (t, J = 4.8 Hz, 2H), 3.82 (t, J = 6 Hz, 2H), 3.75 (t, J = 6 Hz, 2H), 3.64-3.37 (m, 10H), 1.77 (m, 4H), 1.59 (m, 4H) 464.7 (M + 1)
    90
    Figure US20200190095A1-20200618-C00564
         		13.02 (s, 1H), 11.19 (s, 1H), 8.15 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 3.67 (d, J = 6.4 Hz, 2H), 2.92 (m, 1H), 2.65 (m, 2H), 2.18 (d, J = 6.4 Hz, 2H), 2.08 (m, 2H), 1.99-1.54 (m, 14H), 1.33-1.28 (m, 2H) 477.2 (M + 1)
    91
    Figure US20200190095A1-20200618-C00565
         		12.73 (s, 1H), 12.01 (s, 1H), 11.32 (s, 1H), 7.88 (s, 1H), 7.68 (m, 2H), 7.27 (m, 2H), 3.77 (m, 4H), 2.37 (m, 1H), 2.15 (d, J = 6.8 Hz, 2H), 1.80-1.60 (m, 9H), 1.57 (m, 4H), 1.51 (m, 4H) 477.3 (M + 1)
    92
    Figure US20200190095A1-20200618-C00566
         		12.71 (s, 1H), 11.16 (s, 1H), 7.85 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 3.96 (t, J = 6 Hz, 2H), 3.79 (t, J = 6 Hz, 2H), 3.72 (t, J = 6 Hz, 2H), 2.35 (t, J = 7.2 Hz, 2H), 1.92 (m, 2H), 1.74 (m, 4H), 1.50 (m, 4H) 439.1 (M + 1)
    93
    Figure US20200190095A1-20200618-C00567
         		12.71 (s, 1H), 11.17 (s, 1H), 7.86 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.08 (t, J = 5.4 Hz, 2H), 3.79 (t, J = 6.4 Hz, 2H), 3.73 (t, J = 6 Hz, 2H), 3.57 (t, J = 4.4 Hz, 4H), 2.68 (t, J = 5.4 Hz, 2H), 2.50 (m, 4H), 1.75 (m, 4H), 1.50 (m, 4H) 466 (M + 1)
    94
    Figure US20200190095A1-20200618-C00568
         		13.32 (s, 1H), 11.30 (s, 1H), 8.40 (d, J = 6.0 Hz, 2H), 8.30 (s, 1H), 7.78 (d, J = 7.2 Hz, 2H), 7.55 (m, 3H), 7.08 (d, J = 7.2 Hz, 2H), 4.13 (t, J = 5.4 Hz, 2H), 3.57 (t, J = 4.4 Hz, 4H), 2.68 (t, J = 5.4 Hz, 2H), 2.50 (m, 4H) 445.1 (M + 1)
    95
    Figure US20200190095A1-20200618-C00569
         		12.71 (s, 1H), 11.18 (s, 1H), 7.87 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 4.09 (t, J = 5.4 Hz, 2H), 3.80-3.74 (m, 4H), 2.68 (t, J = 5.4 Hz, 2H), 2.62 (s, 3H), 2.50 (m, 8H), 1.74 (m, 4H), 1.50 (m, 4H) 479 (M + 1)
    96
    Figure US20200190095A1-20200618-C00570
         		12.71 (s, 1H), 12.01 (s, 1H), 11.17 (s, 1H), 7.86 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.08 (t, J = 5.4 Hz, 2H), 3.79-3.74 (m, 4H), 2.96 (m, 2H), 2.75 (m, 2H), 2.13 (m, 4H), 1.75- 1.65 (m, 11H), 1.20 (m, 2H) 522.1 (M + 1)
    97
    Figure US20200190095A1-20200618-C00571
         		12.70 (s, 1H), 10.98 (s, 1H), 8.44 (d, J = 2.8 Hz, 1H), 7.95 (dd, J1 = 9.6 Hz, J2 = 2.8 Hz, 1H), 7.86 (s, 1H), 6.90 (d, J = 9.6 Hz, 1H), 4.3 (d, J = 13.2 Hz, 2H), 3.79 (t, J = 6.4 Hz, 2H), 3.70 (t, J = 6.0 Hz, 2H), 2.8 (m, 2H), 2.50 (m, 2H), 1.88 (m, 1H), 1.87-1.74 (m, 6H), 1.50-1.29 (m, 4H), 1.23 (m, 2H) 460.1 (M + 1)
    98
    Figure US20200190095A1-20200618-C00572
         		12.71 (s, 1H), 11.17 (s, 1H), 7.86 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.07 (t, J = 5.2 Hz, 2H), 3.80 (t, J = 5.6 Hz, 2H), 3.73 (t, J = 5.6 Hz, 2H), 2.87 (m, 2H), 2.45 (m, 2H), 2.19 (m, 3H), 1.80-1.77 (m, 6H), 1.59 (m, 6H) 508.4 (M + 1)
    99
    Figure US20200190095A1-20200618-C00573
         		12.70 (s, 1H), 10.97 (s, 1H), 8.43 (d, J = 2.8 Hz, 1H), 7.92 (dd, J1 = 9.6 Hz, J2 = 2.8 Hz, 1H), 7.86 (s, 1H), 7.26 (s, br, 1H), 6.87 (d, J = 9.6 Hz, 1H), 6.75 (s, br, 1H), 4.22 (d, J = 13.2 Hz, 2H), 3.79 (t, J = 6.4 Hz, 2H), 3.70 ( t, J = 6.0 Hz, 2H), 2.79 (m, 2H), 2.00 (d, J = 6.8 Hz, 2H), 1.91 (m, 1H), 1.89-168 (m, 6H), 1.50-1.19 (m, 4H), 1.15 (m, 2H) 478 (M + 1)
    100
    Figure US20200190095A1-20200618-C00574
         		12.75 (s, 1H), 12.01 (s, br, 1H), 11.12 (s, 1H), 7.87 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.89 (m, 2H), 3.65 (m, 2H), 2.9 (m, 2H), 2.64 (m, 2H), 2.18 (d, J = 6.0 Hz, 2H), 1.92-1.74 (m, 7H), 1.30 (s, 6H), 1.23 (m, 3H) 531.1 (M + 1)
    101
    Figure US20200190095A1-20200618-C00575
         		13.31 (s, 1H), 11.11 (s, 1H), 8.55 (d, J = 2.8 Hz, 1H), 8.36 (m, 2H), 8.29 (s, 1H), 8.04 (dd, J1 = 9.2 Hz, J2 = 2.8 Hz, 1H), 7.55 (m, 3H), 6.98 (d, J = 9.2 Hz, 1H), 4.35 (d, J = 12.8 Hz, 2H), 2.85 (t, J = 11.2 Hz, 2H), 2.50 (m, 2H), 1.90 (m, 1H), 1.89 (m, 2H), 1.27 (m, 2H) 439.1 (M + 1)
    102
    Figure US20200190095A1-20200618-C00576
         		13.31 (s, 1H), 11.11 (s, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.36 (d, J = 6.8 Hz, 2H), 8.30 (s, 1H), 8.04 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H), 7.57 (m, 3H), 7.27 (s, br, 1H), 6.97 (d, J = 9.2 Hz, 1H), 6.76 (s, br, 1H), 4.30 (d, J = 12.8 Hz, 2H), 2.83 (t, J = 12.4 Hz, 2H), 2.02 (d, J = 7.2 Hz, 2H), 1.74 (m, 3H), 1.19 (m, 2H) 457.2 (M + 1)
    103
    Figure US20200190095A1-20200618-C00577
         		12.75 (s, 1H), 11.13 (s, 1H), 7.87 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 4.89 (m, 2H), 3.7(d, J = 12.8 Hz, 2H), 2.98 (t, J = 11.2 Hz, 2H), 2.69-2.60 (m, 8H), 1.97-1.80 (m, 6H), 1.39 (m, 2H) 484.3 (M + 1)
    104
    Figure US20200190095A1-20200618-C00578
         		12.83 (s, 1H), 11.55 (s, 1H), 9.32 (s, br, 2H), 7.95 (s, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 3.84-3.73 (m, 8H), 3.15 (m, 4H), 1.81-1.76 (m,4H), 1.52-1.23 (m, 4H) 449.2 (M + 1)
    105
    Figure US20200190095A1-20200618-C00579
         		12.69 (s, 1H), 11.14 (s, 1H), 7.85 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.27 (s, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.75 (s, 1H), 3.79-3.74 (m, 4H), 3.63 (d, J = 11.6 Hz, 2H), 2.62 (t, J = 12.0 Hz, 2H), 2.02 (d, J = 6.8 Hz, 2H), 1.76-1.71 (m, 7H), 1.50 (m, 4H), 1.30 (m, 2H) 477.5 (M + 1)
    106
    Figure US20200190095A1-20200618-C00580
         		12.72 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.07 (s, br, 2H), 3.80 (s, br, 2H), 3.73 (s, br, 2H), 2.71-2.57 (m, 6H), 2.50- 2.32 (m, 6H), 1.99-1.62 (m, 4H), 1.50-1.32 (m, 4H) 523.3 (M + 1)
    107
    Figure US20200190095A1-20200618-C00581
         		12.69 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.06 (t, J = 5.6 Hz, 2H), 3.80 (t, J = 6.0 Hz, 2H), 3.73 (t, J = 6.0 Hz, 2H), 2.69-2.63 m, 6H), 2.39 (m, 4H), 1.98 (m, 4H), 1.50 (m, 4H) 465.2 (M + 1)
    108
    Figure US20200190095A1-20200618-C00582
         		12.70 (s, 1H), 12.15 (s, br, 1H), 10.97 (s, 1H), 8.43 (d, J = 2.4 Hz, 1H), 7.92 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.86 (s, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.23 (d, J = 12.8 Hz, 2H), 3.78 (t, J = 6 Hz, 2H), 3.70 (t, J = 6 Hz, 2H), 2.77 (t, J = 11.2 Hz, 2H), 2.17 (d, J = 6.8 Hz, 2H), 1.88 (m, 1H), 1.73 (m, 6H), 1.49 (m, 4H), 1.29 (m, 2H) 479.2 (M + 1)
    109
    Figure US20200190095A1-20200618-C00583
         		12.69 (s, 1H), 11.14 (s, 1H), 7.85 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 4.63 (t, J = 6 Hz, 1H), 3.79 (t, J = 6.0 Hz, 2H), 3.75 (t, J = 6.0 Hz, 2H), 3.63 (d, J = 12.4 Hz, 2H), 3.39 (m, 2H), 3.12 (m, 2H), 2.67 (m, 2H), 2.04 (m, 3H), 1.73 (m, 4H), 1.49 (m, 4H), 1.21 (m, 5H) 521.4 (M + 1)
    110
    Figure US20200190095A1-20200618-C00584
         		12.71 (s, 1H), 11.17 (s, 1H), 7.86 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.72 (t, J = 6.0 Hz, 1H), 3.95-3.73 (m, 9H), 3.50-3.38 (m, 5H), 1.75 (m, 4H), 1.50 (m, 4H) 483.2 (M + 1)
    111
    Figure US20200190095A1-20200618-C00585
         		12.69 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 3.79 (t, J = 6.0 Hz, 2H), 3.77 (m, 2H), 3.75 (t, J = 6.0 Hz, 211), 2.60 (t, J = 11.2 Hz, 2H), 1.88 (m, 7H), 1.48 (m, 6H), 1.31 (s, 6H) 487.4 (M + 1)
    112
    Figure US20200190095A1-20200618-C00586
         		12.69 (s, 1H), 11.14 (s, 1H), 7.85 (s, 1H), 7.85 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.01 (s, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.79 (s, 1H), 3.79 (m, 6H), 1.70-1.50 (m, 12H), 1.3 (m, 2H), 1.01 (s, 6H) 505.2 (M + 1)
    113
    Figure US20200190095A1-20200618-C00587
         		12.69 (s, 1H), 11.15 (s, 1H), 7.86 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.80 (t, J = 6.0 Hz, 2H), 3.75 (t, J = 6.0 Hz, 2H), 3.69 (d, J = 12.4 Hz, 2H), 2.68 -2.54 (m, 6H), 1.79 (m, 5H), 1.51 (m, 4H), 1.35 (m, 2H) 459.2 (M + 1)
    114
    Figure US20200190095A1-20200618-C00588
         		12.75 (s, 1H), 10.95 (s, 1H), 8.4 (s, 1H), 7.88 (s, 1H), 7.86 (s, 1H), 6.91 (d, J = 8.8 Hz, 1H), 5.75 (s, br, 2H), 4.30 (d, J = 12.4 Hz, 2H), 2.96 (t, J = 11.6 Hz, 2H), 2.80 (t, J = 12 Hz, 2H), 2.50 (m, 4H), 1.96- 1.75 (m, 6H), 1.26 (m, 4H) 485.0 (M + 1)
    115
    Figure US20200190095A1-20200618-C00589
         		12.71 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 5.37 (s, 1H), 4.09 (t, J = 5.6 Hz, 2H), 3.80 (t, J = 5.6 Hz, 2H), 3.73 (t, J = 6.0 Hz, 2H), 2.70 (t, J = 5.2 Hz, 2H), 2.50 (m, 8H), 1.75 (m, 4H), 1.50 (m, 4H), 1.30 (s, 6H) 551.1 (M + 1)
    116
    Figure US20200190095A1-20200618-C00590
         		12.75 (s, 1H), 12.07 (s, 1H), 10.95 (s, 1H), 8.39 (d, J = 2.4 Hz, 1H), 7.88 (s, 1H), 7.85 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H), 6.90 (d, J = 9.2 Hz, 1H), 4.56 (m, 2H), 4.24 (d, J = 12.8 Hz, 2H), 3.80 (t, J = 5.6 Hz, 2H), 3.73 (t, J = 6.1 Hz, 2H), 2.18 (d, J = 7.6 Hz, 2H), 1.96-1.72 (m, 8H), 1.19-1.14 (m, 4H) 504.1 (M + 1)
    117
    Figure US20200190095A1-20200618-C00591
         		12.73 (s, 1H), 12.01 (s, br, 1H), 11.19 (s, br, 1H), 7.88 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.67 (m, 2H), 3.65 (d, J = 12.4 Hz, 2H), 2.56 (m, 5H), 2.21 (d, J = 6 Hz, 2H), 1.79 (m, 4H), 1.57 (m, 4H), 0.92 (s, 6H) 491.4 (M+)
    118
    Figure US20200190095A1-20200618-C00592
         		12.69 (s, 1H), 11.14 (s, 1H), 7.85 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.81 (t, J = 5.6 Hz, 1H), 4.64 (t, J = 5.6 Hz, 1H), 4.13 (d, J = 2 Hz, 2H), 3.81- 3.75 (m, 6H), 3.51-3.44 (m, 6H), 2.50 (m, 4H), 2.30 (m, 5H), 1.75 (m, 4H), 1.50 (m, 4H) 565.1 (M + 1)
    119
    Figure US20200190095A1-20200618-C00593
         		13.30 (s, 1H), 11.30 (s, 1H), 8.41 (d, J = 6.4 Hz, 2H), 8.28 (s, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.58 (m, 3H), 7.06 (d, J = 8.8 Hz, 2H), 3.85 (d, J = 12.0 Hz, 2H), 2.65 (t, J = 10.8 Hz, 2H), 1.88 (d, J = 11.6 Hz, 2H), 1.49 (m, 3H), 1.36 (s, 6H) 466.2 (M + 1)
    120
    Figure US20200190095A1-20200618-C00594
         		12.70 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.07 (t, J = 5.4 Hz, 2H), 3.80 (t, J = 5.6 Hz, 2H), 3.73 (t, J = 6 Hz, 2H), 3.03 (d, J = 10 Hz, 2H), 2.67 (d, J = 1.6 Hz, 2H), 1.98 (m, 11H), 1.50 (m, 4H), 1.27 (s, 6H) 531.0 (M + 1)
    121
    Figure US20200190095A1-20200618-C00595
         		12.70 (s, 1H), 12.21 (s, 1H), 11.14 (s, 1H), 7.88 (s, 1H), 7.53 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.56 (m, 2H), 3.62 (m, 4H), 2.64 (t, J = 11.4 Hz, 4H), 2.19 (d, J = 6.8 Hz, 2H), 1.75 (m, 3H), 1.33 (m, 2H), 1.17 (d, J = 6.0 Hz, 6H) 494.1 (M + 1)
    122
    Figure US20200190095A1-20200618-C00596
         		11.32 (s, 1H), 11.30 (s, 1H), 8.40 (d, J = 6.4 Hz, 2H), 8.30 (s, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.57 (m, 3H), 7.08 (d, J = 8.8 Hz, 2H), 4.73 (t, J = 6 Hz, 1H), 4.00 (d, J = 4.8 Hz, 2H), 3.92-3.80 (m, 3H), 3.50- 3.39 (m, 5H) 462 (M + 1)
    123
    Figure US20200190095A1-20200618-C00597
         		12.73 (s, 1H), 12.01 (s, br, 1H), 11.32 (s, 1H), 7.88 (s, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 4.52 (s, br, 1H), 3.81-3.77 (m, 4H), 2.35 (m, 3H), 1.80-1.51 (m, 16H) 477.2 (M + 1)
    124
    Figure US20200190095A1-20200618-C00598
         		12.71 (s, 1H), 11.17 (s, 1H), 7.86 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.99-3.71 (m, 10H), 3.43 (m, 2H), 1.75 (m, 4H), 1.50 (m, 4H) 495.4 (M − 1)
    125
    Figure US20200190095A1-20200618-C00599
         		12.70 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.64 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.80 (t, J = 5.6 Hz, 2H), 3.75 (t, J = 5.6 Hz, 2H), 3.65-3.16 (m, 7H), 2.71-2.66 (m, 4H), 1.75 (m, 4H), 1.51 (m, 4H) 499.3 (M + 1)
    126
    Figure US20200190095A1-20200618-C00600
         		12.71 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 6.4 (d, J = 8.8 Hz, H), 3.98 (t, J = 6.4 Hz, 2H), 3.80 (t, J = 6.0 Hz, 2H), 3.73 (t, J = 6.0 Hz, 2H), 2.84 (m, 2H), 2.45 (m, 2H), 2.12 (d, J = 6.4 Hz, 2H), 1.88 (m, 7H), 1.75 (m, 4H), 1.50 (m, 4H), 1.19 (m, 2H) 536.0 (M + 1)
    127
    Figure US20200190095A1-20200618-C00601
         		12.63 (s, 1H), 12.08 (s, 1H), 11.17 (s, 1H), 7.86 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 3.42-3.10 (m, 4H), 1.99 (m, 4H), 1.39-1.22 (m, 11H), 0.97- 0.92 (m, 2H) 490.2 (M + 1)
    128
    Figure US20200190095A1-20200618-C00602
         		12.71 (s, 1H), 12.04 (s, 1H), 11.12 (s, 1H), 7.86 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 3.82 (m, 4H), 3.33-3.05 (m, 4H), 1.78 (m, 2H), 1.65-1.53(m, 9H), 0.98-0.92 (m, 2H) 476.2 (M + 1)
    129
    Figure US20200190095A1-20200618-C00603
         		12.73 (s, 1H), 12.06 (s, 1H), 11.30 (s, 1H), 7.87 (s, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 3.80 (t, J = 6.0 Hz, 2H), 3.76 (t, J = 5.2 Hz, 2H), 2.44 (m, 1H), 2.13 (d, J = 6.8 Hz, 2H), 1.79-1.51 (m, 9H), 1.47-1.23 (m, 6H), 1.15 (m, 2H) 475.4 (M − 1)
    130
    Figure US20200190095A1-20200618-C00604
         		12.69 (s, 1H), 12.03 (s, 1H), 11.14 (s, 1H), 7.85 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 3.79 (t, J = 5.6 Hz, 2H), 3.74 (t, J = 5.6 Hz, 2H), 3.64 (d, J = 12.8 Hz, 2H), 2.59 (t, J = 10.4 Hz, 2H), 2.25 (t, J = 7.6 Hz, 2H), 1.75 (m, 6H), 1.50 (m, 6H), 1.30 (m, 1H), 1.23 (m, 2H) 492.3 (M + 1)
    131
    Figure US20200190095A1-20200618-C00605
         		12.69 (s, 1H), 12.03 (s, 1H), 11.14 (s, 1H), 7.85 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 3.79 (t, J = 5.6 Hz, 2H), 3.74 (t, J = 5.6 Hz, 2H), 3.65 (d, J = 12.8 Hz, 2H), 2.59 (t, J = 10.4 Hz, 2H), 1.76 (m, 2H), 1.74 (m, 4H), 1.50 (m, 4H), 1.45 (m, 2H), 1.23 (m, 2H), 0.95- 0.92 (m, 3H) 504.1 (M + 1)
    132
    Figure US20200190095A1-20200618-C00606
         		12.59 (s, 2H), 11.28 (s, 1H), 8.40 (d, J = 6 Hz, 2H), 8.27 (s, 1H), 7.71 (d, J = 8.8 Hz, 2H), 7.56 (m, 3H), 7.04 (d, J = 8.8 Hz, 2H), 3.73 (d, J = 12.4 Hz, 2H), 2.64 (t, J = 12 Hz, 2H), 2.25 (t, J = 7.2 Hz, 2H), 1.76 (d, J = 11.6 Hz, 2H), 1.50 (d, J = 6.8 Hz, 2H), 1.38 (m, 1H), 1.25 (m, 2H) 471.3 (M + 1)
    133
    Figure US20200190095A1-20200618-C00607
         		13.01 (s, 2H), 11.26 (s, 1H), 8.39 (m, 2H), 8.23 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 3.29-3.15 (m, 4H), 1.80 (t, J = 5.8 Hz, 2H), 1.60-1.52 (m, 3H), 0.94- 0.80 (m, 2H) 471.3 (M + 1)
    134
    Figure US20200190095A1-20200618-C00608
         		12.70 (s, 1H), 12.0 (s, 1H), 10.98 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 7.94 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H), 7.86 (s, 1H), 6.90 (d, J = 9.2 Hz, 1H), 3.79 (t, J = 5.2 Hz, 2H), 3.70 (t, J = 5.2 Hz, 2H), 3.61 (m, 2H), 1.73 (m, 7H), 1.49 (m, 8H), 0.98-0.94 (m, 2H) 491.4 (M + 1)
    135
    Figure US20200190095A1-20200618-C00609
         		12.75 (s, 1H), 12.06 (s, 1H), 11.30 (s, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.88 (s, 1H), 7.29 (dd, J1 = 9.6 Hz, J2 = 2.4 Hz, 1H), 7.07(t, J = 9.6 Hz, 1H), 3.81 (t, J = 6.4 Hz, 2H), 3.76 (t, J = 5.6 Hz, 2H), 3.02-2.99 (m, 4H), 1.79 (m, 6H), 1.54 (m, 7H), 0.98- 0.92 (m, 2H) 508.4 (M + 1)
    136
    Figure US20200190095A1-20200618-C00610
         		12.89 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 3.99 (t, J = 6.4 Hz, 2H), 3.80 (t, J = 6.4 Hz, 2H), 3.73 (t, J = 6 Hz, 2H), 3.58 (s, 1H), 2.67 (m, 4H), 2.46-2.33 (m, 4H), 1.75 (m, 4H), 1.50 (m, 4H) 479.3 (M + 1)
    137
    Figure US20200190095A1-20200618-C00611
         		13.33 (s, 1H), 12.01 (s, 1H), 11.12 (s, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 8 Hz, 2H), 8.30 (s, 1H), 8.19 ( dd, J1 = 9.6 Hz, J2 = 2.4 Hz, 1H), 7.57 (m, 3H), 7.02 (d, J = 9.6 Hz, 1H), 3.33-3.30 (m, 4H), 1.73 (m, 2H), 1.58 (m, 3H), 1.00 (m, H) 470.2 (M + 1)
    138
    Figure US20200190095A1-20200618-C00612
         		13.05 (s, 2H), 11.35 (s, 1H), 8.80 (d, J = 3.6 Hz, 2H), 8.31 (s, 1H), 8.21 (d, J = 3.6 Hz, 2H), 7.70 (d, J = 7.6 Hz, 2H), 7.06 (d, J = 7.6 Hz, 2H), 3.10 (m, 4H), 1.80 (m, 2H), 1.57 (m, 3H), 0.98-0.93 (m, 2H) 470.1 (M + 1)
    139
    Figure US20200190095A1-20200618-C00613
         		12.69 (s, 2H), 11.14 (s, 1H), 7.85 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.11 (s, 1H), 3.79 (t, J = 6 Hz, 2H), 3.75 (t, J = 5.6 Hz, 2H), 3.72 (m, 2H), 2.50 (m, 2H), 1.78 (m, 6H), 1.50 (m, 4H), 1.34 (m, 3H), 1.06 (s, 6H) 478.2 (M + 1)
    140
    Figure US20200190095A1-20200618-C00614
         		12.70 (s, 2H), 11.16 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 3.80 (t, J = 6 Hz, 2H), 3.75 (t, J = 6 Hz, 2H), 3.16 (m, 4H), 2.76 (m, 4H), 1.75 (m, 4H), 1.50 (m, 4H), 1.25 (s, 6H) 507.2 (M + 1)
    141
    Figure US20200190095A1-20200618-C00615
         		12.75 (s, 1H), 12.0 (s, 1H), 11.14 (s, 1H), 7.84 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 3.75 (t, J = 6 Hz, 2H), 3.70 (t, J = 5.6 Hz, 2H), 3.21 (m, 3H), 1.79 (m, 8H), 1.51-1.41 (m, 8H), 0.84 (m, 4H), 0.66 (m, 1H) 504.2 (M + 1)
    142
    Figure US20200190095A1-20200618-C00616
         		12.69 (s, 1H), 12.02 (s, 1H), 11.14 (s, 1H), 7.85 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 3.79 (t, J = 5.6 Hz, 2H), 3.74 (t, J = 5.2 Hz, 2H), 3.70 (m, 2H), 2.5 (m, 2H), 1.76 (m, 4H), 1.60- 1.50 (m,7H), 1.37 (m, 2H), 1.05 (s, 6H) 506.2 (M + 1)
    143
    Figure US20200190095A1-20200618-C00617
         		13.30 (s, 1H), 12.4 (s, 1H), 11.30 (s, 1H), 8.41 (d, J = 6 Hz, 2H), 8.29 (s, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.58 (m, 3H), 7.05 (d, J = 8.8 Hz, 2H), 3.80 (d, J = 12 Hz, 2H), 2.61 (t, J = 11.2 Hz, 2H), 1.65- 1.62 (m, 3H), 1.43-1.37 (m, 2H), 1.07 (s, 6H) 485.0 (M + 1)
    144
    Figure US20200190095A1-20200618-C00618
         		12.71 (bs, 1H), 11.00 (bs, 1H), 8.46 (bs, 1H), 7.96-7.86 (m, 2H), 6.88 (bs, 1H), 3.78-3.70 (m, 4H), 3.49 (m, 4H), 3.19 (m, 4H), 2.66 (bs, 2H), 1.73-1.50 (m, 8H) 480.0
    145
    Figure US20200190095A1-20200618-C00619
         		12.67 (s, 1H), 11.09 (s, 1H), 7.84 (s, 1H), 7.57 (d, J = 9.3 Hz, 2H), 6.73 (d, J = 8.8 Hz, 2H), 3.81-3.73 (m, 6H), 3.57-3.43 (m, 4H), 2.98 (t, J = 4.4 Hz, 2H), 2.82 (t, J = 5.2 Hz, 2H), 1.96-1.94 (m, 2H), 1.78- 1.74 (m, 4H), 1.51 (m, 4H) 493.3
    146
    Figure US20200190095A1-20200618-C00620
         		12.75 (s, 1H), 11.13 (s, 1H), 7.84 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.12 (s, 1H), 4.65 (m, 2H), 3.76-3.74 (m, 2H), 3.01-2.95 (m, 2H), 2.55-2.53 (m, 4H), 1.97 (m, 1H), 1.84-1.77 (m, 4H), 1.35-1.21 (m, 4H), 1.06 (s, 6H) 503.4
    147
    Figure US20200190095A1-20200618-C00621
         		12.75 (s, 1H), 12.01 (s, 1H), 11.12 (s, 1H), 7.87 (s, 1H), 7.54 (d, J = 7.3 Hz, 2H), 6.97 (d, J = 7.4 Hz, 2H), 4.77 (m, 2H), 3.66 (m, 2H), 2.98 (m, 2H), 2.60 (m, 4H), 2.26 (m, 2H), 1.97 (m, 1H), 1.83-1.82 (m, 2H), 1.75-1.72 (m, 2H), 1.50- 1.37 (m, 3H), 1.23 (m, 4H) 517.3
    148
    Figure US20200190095A1-20200618-C00622
         		12.76 (s, 1H), 12.05 (s, 1H), 10.96 (s, 1H), 8.40 (s, 1H), 7.88 (s, 2H), 6.93 (s, 1H), 4.61-4.51 (m, 3H), 3.55-3.52 (m, 4H), 2.66-2.96 (m, 3H), 1.56-1.46 (m, 10H), 1.48-1.23 (m, 4H), 0.85-0.97 (m, 3H) 516.3
    149
    Figure US20200190095A1-20200618-C00623
         		12.80 (bs, 1H), 11.15 (s, 1H), 7.90 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 4.13 (m, 2H), 4.08 (t, J = 5.7 Hz, 4H), 3.64- 3.59 (m, 2H), 3.39-3.37 (m, 2H), 3.18 (t, J = 4.2 Hz, 2H), 2.79 (m, 4H), 2.68 (t, J = 5.9 Hz, 2H), 1.95 (q, J = 3.4 Hz, 2H), 1.76-1.73 (m, 2H) 476.1
    150
    Figure US20200190095A1-20200618-C00624
         		12.80 (bs, 1H), 11.15 (s, 1H), 7.89 (s, 1H), 7.61 (d, J = 9.3 Hz, 2H), 6.99 (d, J = 9.3 Hz, 2H), 4.80-4.60 (m, 3H), 4.07 (t, J = 5.9 Hz, 2H), 3.01-2.95 (m, 3H), 2.72-2.53 (m, 6H), 2.41-2.32 (m, 4H), 1.98-1.81 (m, 4H), 1.24-1.21 (m, 2H) 490.3
    151
    Figure US20200190095A1-20200618-C00625
         		12.72 (s, 1H), 11.18 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 9.3 Hz, 2H), 6.97 (d, J = 9.3 Hz, 2H), 4.07 (t, J = 5.7 Hz, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.74 (t, J = 5.9 Hz, 2H) 493.4
    152
    Figure US20200190095A1-20200618-C00626
         		11.31 (s, 1H), 8.40 (d, J = 6.3 Hz, 2H), 8.30 (s, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.61-7.54 (m, 3H), 7.06 (d, J = 8.8 Hz, 2H), 4.11 (t, J = 5.9 Hz, 2H), 2.70-2.66 (m, 6H), 2.42 (m, 4H) 444.2
    153
    Figure US20200190095A1-20200618-C00627
         		12.65 (bs, 1H), 11.1 (s, 1H), 7.87 (s, 1H), 7.60 (d, J = 9.3 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.07 (t, J = 5.7 Hz, 2H), 3.81 (m, 4H), 2.68 (m, 4H), 2.64 (t, J = 5.9 Hz, 2H), 2.39 (m, 4H), 1.65-1.64 (m, 2H), 1.55 (m, 4H) 451.3
    154
    Figure US20200190095A1-20200618-C00628
         		12.69 (s, 1H), 11.06 (s, 1H), 7.84 (s, 1H), 7.51 (d, J = 9.2 Hz, 2H), 6.73 (d, J = 8.8 Hz, 2H), 3.81 (m, 4H), 3.64-3.54 (m, 4H), 3.45 (t, J = 6.1 Hz, 2H), 2.97 (t, J = 4.4 Hz, 2H), 2.81 (t, J = 5.2 Hz, 2H), 1.93 (t, J = 5.1 Hz, 2H), 1.65-1.64 (m, 2H), 1.54 (m, 4H) 479.2
    155
    Figure US20200190095A1-20200618-C00629
         		12.79 (s, 1H), 11.30 (s, 1H), 7.90 (s, 1H), 7.72 (m, 2H), 7.38 (m, 2H), 4.74-4.65 (m, 2H), 3.17-2.98 (m, 4H), 1.99-1.91 (m, 3H), 1.74- 1.62 (m, 8H), 1.23-1.01 (m, 4H), 0.93 (d, J = 5.9 Hz, 3H) 490.3
    156
    Figure US20200190095A1-20200618-C00630
         		12.82 (s, 1H), 11.22 (s, 1H), 9.65 (s, 2H), 7.93 (s, 1H), 7.67 (d, J = 9.3 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 4.75-4.63 (m, 2H), 4.43 (d, J = 4.4 Hz, 2H), 3.83-3.50 (m, 8H), 2.97 (m, 2H), 1.73-1.70 (m, 4H), 1.11-1.07 (m, 3H), 0.93 (d, J = 6.4 Hz, 3H) 465.3
    157
    Figure US20200190095A1-20200618-C00631
         		12.72 (s, 1H), 11.18 (s, 1H), 7.87(s, 1H), 7.67 (d, J = 7.8 Hz, 2H), 6.98 (d, J = 7.8 Hz, 2H), 4.12 (s, 2H), 3.80-3.74 (m, 4H), 3.17- 3.07 (m, 4H), 2.78-2.69 (m, 4H), 1.76 (m, 4H), 1.51 (m, 4H) 479.0
    158
    Figure US20200190095A1-20200618-C00632
         		12.71 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 9.3 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.07 (t, J = 5.9 Hz, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.73 (t, J = 5.9 Hz, 2H), 2.69 (t, J = 5.9 Hz, 2H), 2.33-2.31 (m, 2H), 1.75-1.65 (m, 7H), 1.50-1.41 (m, 8H), 0.88-0.78 (m, 2H) 534.0
    159
    Figure US20200190095A1-20200618-C00633
         		12.72 (s, 1H), 11.19 (s, 1H), 7.87 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 4.07 (m, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.74 (t, J = 5.8 Hz, 2H), 3.0-2.80 (m, 2H), 2.68-2.53 (m, 4H), 1.76 (m, 4H), 1.51 (m,4H), 1.03 (m, 6H) 452.4
    160
    Figure US20200190095A1-20200618-C00634
         		12.67 (s, 1H), 11.18-11.11 (m, 1H), 7.87 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.08 (t, J = 5.9 Hz, 2H), 3.07-3.02 (m, 3H), 2.69-2.63 (m, 6H), 2.39 (m, 4H), 1.86-1.70 (m, 2H), 1.67- 1.53 (m, 6H), 1.40-1.14 (m, 4H) 479.0
    161
    Figure US20200190095A1-20200618-C00635
         		12.71 (s, 1H), 12.10 (bs, 1H), 11.15-11.08 (m, 1H), 7.86 (s, 1H), 7.59 (d, J = 8.3 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 3.65-3.60 (m, 2H), 3.06-3.03 (m, 3H), 2.67-2.61 (m, 2H), 2.19 (d, J = 6.3 Hz, 2H), 1.82- 1.52 (m, 10H), 1.50-1.14 (m, 6H) 492.1
    162
    Figure US20200190095A1-20200618-C00636
         		12.76 (s, 1H), 11.14 (s, 1H), 7.88 (s, 1H), 7.57 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 4.95-4.60 (m, 2H), 3.20-3.15 (m, 6H), 3.02- 2.99 (m, 2H), 2.72-2.67 (m, 4H), 2.55-2.53 (m, 4H), 2.1-1.95 (m, 1H), 1.84-1.81 (m, 2H), 1.24-1.21 (m, 2H) 504.2
    163
    Figure US20200190095A1-20200618-C00637
         		13.31 (s, 1H), 11.26 (s, 1H), 8.29 (s, 1H), 8.00 (d, J = 7.8 Hz, 2H), 7.95 (d, J = 2.5 Hz, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.48 (t, J = 7.6 Hz, 1H), 7.17 (dd, J1 = 2.4 Hz, J2 = 7.8 Hz, 1H), 7.05 (d, J = 9.3 Hz, 2H), 3.86 (s, 3H), 3.76 (m, 2H), 2.74- 2.56 (m, 4H), 1.83-1.80 (m, 3H), 1.42-1.38 (m, 2H) 466 (M − 1)
    164
    Figure US20200190095A1-20200618-C00638
         		11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 9.2 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.04 (t, J = 6.1 Hz, 2H), 3.80(t, J = 6.1 Hz, 2H), 3.74 (t, J = 5.9 Hz, 2H), 2.86 (t, J = 6.2 Hz, 2H), 2.79-2.67 (m, 7H), 1.75 (m, 4H), 1.69-1.63 (m, 2H), 1.50 (m, 4H) 491.4
    165
    Figure US20200190095A1-20200618-C00639
         		12.70 (s, 1H), 11.17 (s, 1H), 8.03 (s, 1H), 7.86 (s, 1H), 7.65 (d, J = 9.3 Hz, 2H), 6.97 (d, J = 9.2 Hz, 2H), 3.80 (t, J = 5.9 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.70 (s, 2H), 3.40-3.38 (m, 2H), 3.30-3.29 (m, 2H), 1.79-1.75 (m, 4H), 1.15 (m, 4H) 435.3
    166
    Figure US20200190095A1-20200618-C00640
         		11.27 (s, 1H), 8.03 (s, 1H), 8.01 (d, J = 7.3 Hz, 1H), 7.94 (s, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.16 (d, J = 7.3 Hz, 2H), 7.06 (d, J = 8.30 Hz, 2H), 4.11 (m, 2H), 3.86 (s, 3H), 2.71-2.67 (m, 6H), 2.42 (m, 4H) 474.2
    167
    Figure US20200190095A1-20200618-C00641
         		12.71 (s, 1H), 11.18 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.05 (t, J = 5.6 Hz, 2H), 3.80 (t, J = 6.2 Hz, 2H), 3.74 (t, J = 5.9 Hz, 2H), 2.65 (t, 5.6 Hz, 2H), 2.24 (s, 6H), 1.76 (m, 4H), 1.51 (m, 4H) 424.1
    168
    Figure US20200190095A1-20200618-C00642
         		11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.00 (t, J = 6.6 Hz, 2H), 3.80 (t, J = 6.2 Hz, 2H), 3.74 (t, J = 5.9 Hz, 2H), 2.91-2.89 (m, 2H), 2.43 (m, 2H), 1.76 (m, 4H), 1.65- 1.60 (m, 4H), 1.51 (m, 4H), 1.09- 1.01 (m, 2H) 464.1
    169
    Figure US20200190095A1-20200618-C00643
         		11.15 (s, 1H), 7.94 (s, 1H), 7.75 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.79-4.68 (m, 4H), 4.00 (t, J = 6.4 Hz, 2H), 3.02-2.90 (m, 4H), 2.45-2.42 (m, 2H), 1.97 (m, 1H), 1.84-1.81 (m, 2H), 1.64-1.54 (m, 4H), 1.34-1.23 (m, 2H), 1.12- 1.06 (m, 2H) 489.1
    170
    Figure US20200190095A1-20200618-C00644
         		12.70 (bs, 1H), 11.15-11.09 (m, 1H), 7.86 (s, 1H), 7.60 (d, J = 8.3 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.80-4.49 (m, 2H), 3.22-3.03 (m, 4H), 1.83-1.52 (m, 13H), 1.40-1.34 (m, 2H), 1.31-1.14 (m, 2H), 0.96- 0.91 (m, 2H) 502.3
    171
    Figure US20200190095A1-20200618-C00645
         		11.14 (s, 1H), 7.86 (s, 1H), 7.60 (d, J = 9.3 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.04 (t, J = 6.1 Hz, 2H), 3.81 (m, 4H), 2.86 (t, J = 6.2 Hz, 2H), 2.79-2.67 (m, 6H), 1.67-1.63 (m, 4H), 1.54 (m, 4H) 477.2
    172
    Figure US20200190095A1-20200618-C00646
         		12.71 (bs, 1H), 11.18 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.56 (bs, 1H), 4.07 (m, 2H), 3.80 (t, J = 5.7 Hz, 2H), 3.74 (t, J = 5.9 Hz, 2H), 3.46 (m, 1H) 2.8-2.67 (m, 4H), 1.75-1.74 (m, 6H), 2.33-2.16 (m, 2H), 1.51-1.40 (m, 4H), 1.30-1.17 (m, 2H) 480.1
    173
    Figure US20200190095A1-20200618-C00647
         		12.65 (bs, 1H), 11.29 (s, 1H), 7.88 (s, 1H), 7.67 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 3.80 (t, J = 5.7 Hz, 2H), 3.74 (t, J = 5.9 Hz, 2H), 2.68 (m, 4H) 2.56-2.54 (m, 2H), 2.25-2.20 (m, 6H), 1.74-1.67 (m, 6H), 1.51 (m, 4H) 463.4
    174
    Figure US20200190095A1-20200618-C00648
         		12.70 (bs, 1H), 11.27 (s, 1H), 7.90 (s, 1H), 7.61 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.3 Hz, 2H), 4.78-4.71 (m, 2H), 3.00 (m, 2H), 2.68 (m, 4H), 2.59-2.54 (m, 4H), 2.25-2.21 (m, 6H), 1.98 (m, 2H), 1.85-1.82 (m, 2H), 1.75-1.68 (m, 2H), 1.23- 1.22 (m, 2H) 488.2
    175
    Figure US20200190095A1-20200618-C00649
         		12.70 (bs, 1H), 11.17 (s, 1H), 7.86 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.3 Hz, 2H), 3.80 (t, J = 6.2 Hz, 2H), 3.77-3.74 (m, 4H), 3.46-3.41 (m, 4H), 3.39-3.35 (m, 2H), 1.79-1.75 (m, 4H), 1.51 (m, 4H), 1.07 (t, J = 7.1 Hz, 3H) 463.2
    176
    Figure US20200190095A1-20200618-C00650
         		12.82 (s, 1H), 11.18 (s, 1H), 7.90 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 4.07 (t, J = 5.9 Hz, 2H), 3.80 (m, 4H), 3.68- 3.67 (m, 4H), 2.72 (t, J = 4.7 Hz, 4H), 2.68-2.66 (m, 2H), 2.42-2.32 (m, 4H) 453.2
    177
    Figure US20200190095A1-20200618-C00651
         		12.82 (s, 1H), 11.50 (bs, 1H), 7.92 (s, 1H), 7.60 (d, J = 8.8 Hz, H), 6.99 (d, J = 9.3 Hz, 2H), 4.55 (m, 2H), 4.07 (t, J = 5.9 Hz, 2H), 3.57- 3.55 (m, 2H), 3.27-3.20 (m, 2H), 2.69-2.66 (m, 4H), 2.39-2.30 (m, 6H), 1.16 (d, J = 5.8 Hz, 6H) 481.0
    178
    Figure US20200190095A1-20200618-C00652
         		12.76 (s, 1H), 11.15 (s, 1H), 7.88 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 9.3 Hz, 2H), 4.78-4.71 (m, 2H), 3.75 (s, 2H), 3.48-3.43 (m, 4H), 3.38 (q, J = 7.1 Hz, 2H), 3.02-2.96 (m, 2H), 2.55-2.54 (m, 2H), 2.55-2.54 (m, 2H), 1.98-1.97 (m, 1H), 1.84-1.81 (m, 2H), 1.23- 1.21 (m, 4H), 1.07 (t, J = 7.1 Hz, 3H); MS m/z 488.3
    179
    Figure US20200190095A1-20200618-C00653
         		12.73 (s, 1H), 11.29 (s, 1H), 7.88 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 4.51 (d, J = 3.9 Hz, 1H), 3.81 (t, J = 6.1 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.4 (m, 1H), 2.67 (m, 2H), 2.56 (t, J = 7.6 Hz, 2H), 2.23 (t, J = 6.9 Hz, 2H), 1.97-1.92 (m, 2H), 1.76-1.68 (m, 8H), 1.51 (m, 4H), 1.38-1.21 (m, 2H) 478.3
    180
    Figure US20200190095A1-20200618-C00654
         		12.7 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.63 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 9.3 Hz, 2H), 3.51 (t, J = 6.2 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.27-3.14 (m, 4H), 2.45 (m, 6H), 1.77-1.75 (m, 4H), 1.51 (m, 4H), 1.05 (t, J = 7.1 Hz, 3H) 449.1
    181
    Figure US20200190095A1-20200618-C00655
         		12.70 (bs, 1H), 11.03 (s, 1H), 8.47 (d, J = 1.4 Hz, 1H), 7.98 (dd, J1 = 2.2 Hz, J2 = 8.6 Hz, 1H), 7.88 (s, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.34 (t, J = 5.9 Hz, 2H), 3.79 (m, 4H), 2.67-2.62 (m, 7H), 2.38-2.33 (m, 4H), 1.63 (m, 2H), 1.54 (m, 4H) 452.1
    182
    Figure US20200190095A1-20200618-C00656
         		12.70 (bs, 1H), 11.06 (s, 1H), 8.49 (d, J = 2.5 Hz, 1H), 8.05 (dd, J1 = 2.8 Hz, J2 = 9.1 Hz, 1H), 7.88 (s, 1H), 6.85 (d, J = 9.3 Hz, 1H), 4.34 (t, J = 6.2 Hz, 2H), 3.79 (t, J = 6.1 Hz, 2H), 3.69 (t, J = 5.9 Hz, 2H), 2.68-2.67 (m, 4H), 2.63 (t, J = 5.9 Hz, 2H), 2.38 (m, 4H), 1.72 (m, 4H), 1.50 (m, 4H) 466.4
    183
    Figure US20200190095A1-20200618-C00657
         		12.73 (s, 1H), 11.14 (s, 1H), 7.87 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 4.57 (bs, 1H), 4.08 (m, 2H), 3.81 (m, 4H), 3.46 (m, 1H), 2.82-2.53 (m, 4H), 2.33-2.18 (m, 2H), 1.73-1.37 (m, 10H) 466.4
    184
    Figure US20200190095A1-20200618-C00658
         		12.72 (s, 1H), 11.19 (s, 1H), 7.87 (s, 1H), 7.68 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 4.14-4.07 (m, 3H), 3.80 (t, J = 6.1 Hz, 2H), 3.74 (t, J = 5.9 Hz, 2H), 3.18-3.16 (m, 6H), 1.91 (m, 4H), 1.76 (m, 8H), 1.13 (s, 3H) 494.4
    185
    Figure US20200190095A1-20200618-C00659
         		12.77 (s, 1H), 11.16 (s, 1H), 7.87 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 4.80-4.68 (m, 3H), 4.10 (m, 3H), 3.02-2.95 (m, 2H), 2.70-2.53 (m, 6H), 1.98- 1.95 (m, 1H), 1.84-1.81 (m, 2H), 1.49 (m, 4H), 1.26-1.21 (m, 4H), 1.11 (s, 3H) 519.3
    186
    Figure US20200190095A1-20200618-C00660
         		12.69 (s, 1H), 11.14 (s, 1H), 7.86 (s, 1H), 7.60 (d, J = 9.3 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.66 (d, J = 3.9 Hz, 1H), 3.80 (t, J = 6.2 Hz, 2H), 3.75 (d, J = 5.9 Hz, 2H), 3.62- 3.60 (m, 1H), 3.52-3.49 (m, 2H), 2.84-2.79 (m, 2H), 1.82-1.76 (m, 6H), 1.48-1.46 (m, 6H) 436.2
    187
    Figure US20200190095A1-20200618-C00661
         		12.75 (s, 1H), 11.14 (s, 1H), 7.88 (s, 1H), 7.57 (d, J = 7.4 Hz, 2H), 6.98 (d, J = 9.3 Hz, 2H), 4.80-4.60 (m, 2H), 3.15 (m, 4H), 3.02-2.96 (m, 2H), 2.57-2.53 (m, 6H), 2.45- 2.44 (m, 2H), 1.91 (m, 1H), 1.83 (m, 2H), 1.24 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H) 474.3
    188
    Figure US20200190095A1-20200618-C00662
         		12.72 (s, 1H), 11.18 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 9.3 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 3.92 (m, 2H), 3.80 (d, J = 6.1 Hz, 2H), 3.74 (d, J = 6.0 Hz, 2H), 3.05 (m, 2H), 2.87-2.76 (m, 2H), 1.76 (m, 4H), 1.51 (, 4H), 1.02 (m, 12H) 480.3
    189
    Figure US20200190095A1-20200618-C00663
         		12.75 (s, 1H), 11.12 (s, 1H), 7.87 (s, 1H), 7.53 (d, J = 9.3 Hz, 2H), 6.97 (d, J = 9.3 Hz, 2H), 4.76-4.71 (m, 2H), 6.66 (d, J = 4.4 Hz, 1H), 3.64-3.59 (m, 1H), 3.53-3.50 (m, 2H), 3.02-2.95 (m, 2H), 2.86-2.80 (m, 2H), 1.97-1.91 (m, 1H), 1.84- 1.80 (m, 4H), 1.49-1.46 (m, 2H), 1.27-1.21 (m, 4H) 461.1
    190
    Figure US20200190095A1-20200618-C00664
         		12.70 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 9.3 Hz, 2H), 4.44 (m, 1H), 3.80 (t, J = 6.2 Hz, 2H), 3.65 (t, J = 5.9 Hz, 2H), 3.54 (m, 2H), 3.12 (t, J = 4.9 Hz, 4H), 2.57 (t, J = 4.9 Hz, 4H), 2.45 (t, J = 6.1 Hz, 2H), 1.91-1.75 (m, 4H), 1.51 (m, 4H); MS m/z 465.3
    191
    Figure US20200190095A1-20200618-C00665
         		12.75 (s, 1H), 11.14 (s, 1H), 7.87 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 9.3 Hz, 2H), 4.77 (m, 2H), 4.44 (m, 1H), 3.56-3.52 (m, 2H), 3.13-3.11 (m, 4H), 3.02-2.95 (m, 2H), 2.56-2.52 (m, 4H), 2.46- 2.45 (m, 2H), 2.01-1.95 (m, 1H), 1.84-1.81 (m, 2H), 1.23-1.21 (m, 4H); MS m/z 490.1
    192
    Figure US20200190095A1-20200618-C00666
         		12.70 (s, 1H), 11.15 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 9.3 Hz, 2H), 3.80 (t, J = 6.2 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.05-3.03 (m, 4H), 2.85 (t, J = 4.4 Hz, 4H), 1.76 (m, 4H), 1.51 (m, 4H); MS m/z 421.1
    193
    Figure US20200190095A1-20200618-C00667
         		12.73 (s, 1H), 11.13 (s, 1H), 7.87 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.77-4.71 (m, 2H), 3.04 (m, 4H), 2.83 (m, 4H), 2.55-2.53 (m, 4H), 1.97-1.94 (m, 1H), 1.84-1.81 (m, 2H), 1.23- 1.21 (m, 2H) 446.1
    194
    Figure US20200190095A1-20200618-C00668
         		12.69 (s, 1H), 11.14 (s, 1H), 7.86 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 9.3 Hz, 2H), 4.36 (t, J = 5.1 Hz, 1H), 3.80 (t, J = 6.1 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.66- 3.63 (m, 2H), 3.39 (q, J = 5.1 Hz, 2H), 2.63-2.57 (m, 2H), 1.75-1.73 (m, 6H), 1.51-1.42 (m, 6H), 1.35- 1.30 (m, 1H), 1.28-1.19 (m, 4H) 478.2
    195
    Figure US20200190095A1-20200618-C00669
         		12.69 (s, 1H), 11.15 (s, 1H), 7.86 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 9.3 Hz, 2H), 4.36 (t, J = 5.2 Hz, 1H), 3.80 (t, J = 6.2 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.66- 3.63 (m, 2H), 3.47(q, J = 5.9 Hz, 2H), 2.63-2.57 (m, 2H), 1.75-1.73 (m, 6H), 1.51 (m, 5H), 1.40 (q, J = 6.9 Hz, 2H), 1.26-1.22 (m, 2H) 464.2
    196
    Figure US20200190095A1-20200618-C00670
         		12.75(s, 1H), 11.12 (s, 1H), 7.87 (s, 1H), 7.54 (d, J = 9.3 Hz, 2H), 6.97 (d, J = 9.3 Hz, 2H), 4.76 (m, 2H), 4.36 (t, J = 5.2 Hz, 1H), 3.01- 2.95 (m, 2H), 3.47(q, J = 6.4 Hz, 2H), 3.01-2.95 (m, 2H), 2.64-2.58 (m, 2H), 2.55-2.52 (m, 2H), 1.98- 1.94 (m, 1H), 1.84-1.81 (m, 2H), 1.76-1.72 (m, 2H), 1.56-1.51 (m, 1H), 1.40 (q, J = 6.4 Hz, 2H), 1.29- 1.20 (m, 2H) 489.1
    197
    Figure US20200190095A1-20200618-C00671
         		12.79 (s, 1H), 11.28 (s, 1H), 7.90 (s, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 4.79-4.71 (m, 2H), 3.01 (m, 2H), 2.75-2.71 (m, 2H), 2.55-2.54 (m, 6H), 2.33- 2.28 (m, 6H), 1.98-1.97 (m, 1H), 1.85-1.82 (m, 2H), 1.23-1.22 (m, 2H), 1.02 (t, J = 6.9 Hz, 3H) 502.3
    198
    Figure US20200190095A1-20200618-C00672
         		12.70 (bs, 1H), 11.30 (s, 1H), 7.88 (s, 1H), 7.67 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.3 Hz, 2H), 3.81 (t, J = 6.1 Hz, 2H), 3.76 (t, J = 5.9 Hz, 2H), 2.72-2.68 (m, 6H), 2.48-2.44 (m, 2H), 2.36 (m, 4H), 1.78-1.75 (m, 4H), 1.51 (m, 4H) 449.2
    199
    Figure US20200190095A1-20200618-C00673
         		11.17 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 9.3 Hz, 2H), 6.97 (d, J = 9.3 Hz, 2H), 3.96 (t, J = 5.6 Hz, 2H), 3.80 (t, J = 6.2 Hz, 2H), 3.74 (t, J = 6.1 Hz, 2H), 2.90 (t, J = 5.6 Hz, 2H), 1.75 (m, 4H), 1.51 (m, 4H) 396.2
    200
    Figure US20200190095A1-20200618-C00674
         		11.15 (s, 1H), 7.89 (s, 1H), 7.62 (d, J = 9.3 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 4.78-4.68 (m, 2H), 3.98 (t, J = 5.4 Hz, 2H), 3.02-2.94 (m, 4H), 2.55-2.53 (m, 4H), 1.97-1.94 (m, 1H), 1.84-1.81 (m, 2H), 1.23- 1.18 (m, 2H) 421.2
    201
    Figure US20200190095A1-20200618-C00675
         		12.75 (s, 1H), 11.35 (s, 1H), 7.89 (s, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 4.90 (m, 1H), 3.81(t, J = 5.9 Hz, 2H), 3.77 (t, J = 5.6 Hz, 2H), 3.6 (m, 2H), 3.16-3.13 (m, 2H), 2.92 (m, 4H), 1.85-1.77 (m, 5H), 1.52 (m, 6H) 464.2
    202
    Figure US20200190095A1-20200618-C00676
         		12.70 (s, 1H), 11.15 (s, 1H), 7.86 (s, 1H), 7.61 (d, J = 9.2 Hz, 2H), 6.95 (d, J = 9.3 Hz, 2H), 4.47 (t, J = 5.4 Hz, 1H), 4.34 (m, 2H), 3.80 (t, J = 6.2 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.69-3.66 (m, 2H), 3.29 (t, J = 5.9 Hz, 2H), 2.64-2.58 (m, 2H), 2.4-2.26 (m, 3H), 1.76-1.73 (m, 4H), 1.51 (m, 4H) 450.2
    203
    Figure US20200190095A1-20200618-C00677
         		12.71 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 9.3 Hz, 2H), 4.40 (t, J = 5.4 Hz, 1H), 4.07 (t, J = 5.7 Hz, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.74 (t, J = 5.9 Hz, 2H), 3.24 (t, J = 5.6 Hz, 2H), 2.96-2.94 (m, 2H), 2.68- 2.67 (m, 2H), 2.02 (m, 2H)H, 1.76 (m, 2044H), 1.65-1.62 (m, 2H), 1.51 (m, 4H), 1.43 (m, 1H), 1.15- 1.07 (m, 2H) 494.4
    204
    Figure US20200190095A1-20200618-C00678
         		12.52 (s, 1H), 8.90 (d, J = 6.9 Hz, 1H), 7.79 (s, 1H), 4.48-4.46 (m, 2H), 3.91-3.87 (m, 2H), 3.76 (t, J = 5.9 Hz, 2H), 3.71 (t, J = 5.8 Hz, 2H), 2.93-2.91 (m, 2H), 2.78 (m, 2H), 2.47-2.45 (m, 4H), 2.37-2.20 (m, 1H), 1.97-1.91 (m, 5H), 1.71- 1.48 (m, 12H) 494.4
    205
    Figure US20200190095A1-20200618-C00679
         		12.75 (s, 1H), 11.12 (s, 1H), 7.87 (s, 1H) 7.54 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 9.3 Hz, 2H), 4.76 (m, 2H), 4.36 (t, J = 5.1 Hz, 1H), 3.68- 3.65 (m, 2H), 3.39 (q, J = 6.3 Hz, 2H)(, 3.01-2.95 (m, 2H), 2.64-2.58 (m, 2H), 2.55-2.52 (m, 2H), 1.97- 1.94 (m, 1H), 1.84-1.81 (m, 2H), 1.75-1.73 (m, 2H), 1.50-1.44 (m, 2H), 1.43-1.31 (m, 1H), 1.28-1.20 (m, 6H) 503.5
    206
    Figure US20200190095A1-20200618-C00680
         		12.70 (s, 1H), 11.17 (s, 1H), 7.86 (s, 1H), 7.64 (d, J = 9.3 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 3.82-3.78 (m, 4H), 3.75 (t, J = 5.9 Hz, 2H), 3.17 (t, J = 4.7 Hz, 4H) 2.63 (t, J = 4.7 Hz, 4H), 1.78-1.75 (m, 4H), 1.51 (m, 4H) 460.3
    207
    Figure US20200190095A1-20200618-C00681
         		12.76 (s, 1H), 11.15 (s, 1H), 7.88 (s, 1H) 7.58 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 4.78-4.72 (m, 2H), 3.80 (s, 2H), 3.18 (t, J = 4.9 Hz, 4H), 2.63 (t, J = 4.9 Hz, 4H), 2.55-2.53 (m, 2H), 1.98-1.95 (m, 1H), 1.84-1.81 (m, 2H), 1.26- 1.18 (m, 2H) 485.3
    208
    Figure US20200190095A1-20200618-C00682
         		12.70 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 9.3 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.11-3.10 (m, 4H), 2.61-2.60 (m, 2H), 2.55-2.54 (m, 4H), 2.44- 2.40 (m, 2H), 1.77-1.75 (m, 4H), 1.51 (m, 4H) 493.4
    209
    Figure US20200190095A1-20200618-C00683
         		12.70 (s, 1H), 11.90 (s, 1H), 7.86 (s, 1H), 7.91 (s, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 3.78 (m, 4H), 2.72-2.55 (m, 4H), 2.33-2.26 (m, 10H), 1.76 (m, 4H), 1.51 (m, 4H), 0.98 (t, J = 7.1 Hz, 3H) 477.3
    210
    Figure US20200190095A1-20200618-C00684
         		12.73 (s, 1H), 11.30 (s, 1H), 7.88 (s, 1H), 7.67 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.3 Hz, 2H), 4.08 (s, 1H), 3.81 (t, J = 5.9 Hz, 2H), 3.76 (t, J = 5.9 Hz, 2H), 2.72-2.68 (m, 2H), 2.43-2.33 (m, 4H), 1.79-1.75 (m, 4H), 1.51 (m, 4H), 1.47-1.44 (m, 4H), 1.09 (s, 3H) 478.0
    211
    Figure US20200190095A1-20200618-C00685
         		12.74 (s, 1H), 11.30 (s, 1H), 7.88 (s, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.7 Hz, 2H), 4.51-4.44 (m, 1H), 3.81 (t, J = 6.2 Hz, 2H), 3.76 (t, J = 5.9 Hz, 2H), 3.49 (q, J = 6.2 Hz, 2H), 2.73-2.68 (m, 2H), 2.45-2.32 (m, 6H), 2.28-2.24 (m, 6H), 1.79-1.75 (m, 4H) 493.4
    212
    Figure US20200190095A1-20200618-C00686
         		12.79 (s, 1H), 11.28 (s, 1H), 7.90 (s, 1H), 7.62 (d, J = 7.8 Hz, 2H), 7.26 (d, J = 7.9 Hz, 2H), 4.80-4.70 (m, 2H), 4.41 (m, 1H), 3.49 (m, 2H), 3.27-3.01 (m, 2H), 2.72-2.67 (m, 2H), 2.60 (m, 8H), 2.45-2.33 (m, 8H), 1.98 (m, 1H), 1.85-1.82 (m, 2H) 518.3
    213
    Figure US20200190095A1-20200618-C00687
         		12.77 (s, 1H), 11.19 (s, 1H), 7.89 (s, 1H), 7.63 (d, J = 6.8 Hz, 2H), 7.06 (m, 2H), 4.72 (m, 2H), 3.59 (m, 8H), 3.00 (m, 2H), 1.98 (m, 1H), 1.84-1.82 (m, 2H), 1.55 (s, 6H), 1.24 (m, 4H) 532.4
    214
    Figure US20200190095A1-20200618-C00688
         		12.70 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 9.3 Hz, 2H), 5.46 s, 1H), 3.80 (t, J = 6.0 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.29 (m, 4H), 3.12 (m, 4H), 1.77-1.75 n(m, 4H), 1.51 (m, 4H), 1.34 (s, 6H) 507.3
    215
    Figure US20200190095A1-20200618-C00689
         		12.71 (s, 1H), 11.18 (s, 1H), 7.87 (s, 1H), 7.65 (d, J = 9.3 Hz, 2H), 7.00 (d, J = 9.3 Hz, 2H), 4.10 (s, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.61 (t, J = 5.2 Hz, 2H), 3.17 (t, J = 5.2 Hz, 2H), 3.11 (t, J = 5.2 Hz, 2H), 1.77-1.75 (m, 4H), 1.51 (m, 4H) 488.4
    216
    Figure US20200190095A1-20200618-C00690
         		12.75 (s, 1H), 11.12 (s, 1H), 7.87 (s, 1H), 7.54 (d, J = 9.3 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.71 (m, 2H), 4.47 (t, J = 5.4 Hz, 1H), 3.70- 3.67 (m, 2H), 3.29 (t, J = 5.9 Hz, 2H), 3.01-2.95 (m, 2H), 2.62-2.52 (m, 4H), 1.97 (m, 1H), 1.84-1.81 (m, 2H), 1.76-1.73 (m, 2H), 1.51- 1.28 (m, 1H), 1.25-1.21 (m, 4H) 475.2
    217
    Figure US20200190095A1-20200618-C00691
         		12.70 (s, 1H), 10.97 (s, 1H), 8.43 (d, J = 2.5 Hz, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.86 (s, 1H), 6.88 (d, J = 9.3 Hz, 1H), 4.68 (d, J = 4.4 Hz, 1H), 4.00-3.94 (m, 2H), 3.79 (t, J = 5.9 Hz, 2H), 3.70 (t, J = 5.9 Hz, 2H), 3.67-3.66 (m, 1H), 3.08-3.02 (m, 2H), 1.79-1.73 (m, 6H), 1.50 (m, 4H), 1.41-1.32 (m, 2H) 437.3
    218
    Figure US20200190095A1-20200618-C00692
         		12.77 (s, 1H), 11.15 (s, 1H), 7.88 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 9.3 Hz, 2H), 4.86-4.68 (m, 2H), 4.40 (t, J = 5.1 Hz, 1H), 4.07 (d, J = 5.7 Hz, 2H), 3.24 (t, J = 5.9 Hz, 2H), 3.1-2.92 (m, 4H), 2.67 (m, 4H), 2.55-2.53 (m, 1H), 1.99-1.96 (m, 5H), 1.84-1.81 (m, 4H), 1.64-1.61 (m, 4H), 1.34-1.33 (m, 1H), 1.26-1.11 (m, 4H) 519.3
    219
    Figure US20200190095A1-20200618-C00693
         		12.70 (s, 1H), 11.17 (s, 1H), 7.88 (s, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 5.53-5.43 (m, 2H), 3.80 (t, J = 6.2 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.27-3.06 (m, 3H), 1.77-1.70 (m, 6H), 1.59- 1.51 (m, 6H), 1.13-1.09 (m, 2H) 598.4
    220
    Figure US20200190095A1-20200618-C00694
         		12.75 (s, 1H), 11.14 (s, 1H), 7.88 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 4.80-4.60 (m, 2H), 3.13-3.11 (m, 4H), 3.02- 2.95 (m, 2H), 2.61-2.52 (m, 6H), 2.42 (t, J = 7.1 Hz, 4H), 1.97 (m, 1H), 1.84-1.81 (m, 2H), 1.23-1.21 (m, 2H) 516.4
    221
    Figure US20200190095A1-20200618-C00695
         		12.75 (s, 1H), 10.98 (s, 1H), 8.45 (d, J = 2.5 Hz, 1H), 7.94 (dd, J1 = 2.4 Hz, J2 = 9.3 Hz, 1H), 7.87 (s, 1H), 6.84 (d, J = 9.3 Hz, 1H), 3.79 (t, J = 5.9 Hz, 2H), 3.70 (t, J = 5.7 Hz, 2H), 3.37-3.35 (m, 4H), 2.78 (m, 4H), 1.73 (m, 4H), 1.50 (m, 4H) 422.1
    222
    Figure US20200190095A1-20200618-C00696
         		12.80 (s, 1H), 1.58 (s, 1H), 8.08 (d, J = 8.8 Hz, 2H), 7.97 (d, J = 8.3 Hz, 2H), 7.91 (s, 1H), 5.09 (t, J = 5.4 Hz, 1H), 4.75 (t, J = 4.9 Hz, 2H), 3.97-3.96 (m, 2H), 3.83 (t, J = 6.4 Hz, 4H), 1.84-1.76 (m, 4H), 1.53 (m, 4H) 449.3
    223
    Figure US20200190095A1-20200618-C00697
         		12.76 (s, 1H), 11.15 (s, 1H), 7.88 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 5.46 (s, 1H), 4.90-4.60 (m, 2H), 4.10-3.60 (m, 4H), 3.30-3.10 (m, 4H), 3.02- 2.96 (m, 2H), 2.55-2.52 (m, 4H), 1.98 (m, 1H), 1.84-1.81 (m,2H), 1.34 (s, 6H) 477.2
    224
    Figure US20200190095A1-20200618-C00698
         		12.78 (s, 1H), 11.17 (s, 1H), 7.89 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 7.8 Hz, 2H), 4.79-4.68 (m, 2H), 4.20-4.00 (m, 4H), 3.02- 2.96 (m, 2H), 2.55-2.53 (m, 4H), 1.98-1.91 (m, 1H), 1.84-1.81 (m, 2H), 1.24-1.08 (m, 10H)
    225
    Figure US20200190095A1-20200618-C00699
         		— 433.4
    226
    Figure US20200190095A1-20200618-C00700
         		12.70 (s, 1H), 11.58 (s, 1H), 8.11 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.8 Hz, 2H), 7.84 (s, 1H), 5.00-4.80 (m, 2H), 4.73 (q, J = 7.3 Hz, 2H), 3.10-2.95 (m, 2H), 2.47 (d, J = 6.4 Hz, 2H), 2.10-1.93 (m, 3H), 1.66 (t, J = 7.4 Hz, 3H), 1.36-1.34 (m, 2H) 458.3
    227
    Figure US20200190095A1-20200618-C00701
         		12.82 (s, 1H), 11.61 (s, 1H), 8.07 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.8 Hz, 2H), 7.93 (s, 1H), 3.83 (q, J = 6.4 Hz, 4H), 1.84-1.77 (m, 4H), 1.53 (m, 4H) 403.2 (M − 1)
    228
    Figure US20200190095A1-20200618-C00702
         		12.76 (s, 1H), 10.97 (s, 1H), 8.42 (d, J = 2.4 Hz, 1H), 7.90-7.87 (m, 2H), 6.90 (d, J = 9.3 Hz, 1H), 4.58- 4.49 (m, 2H), 3.46 (m, 4H), 3.00- 2.94 (m, 2H), 2.54-2.53 (m, 2H), 2.39 (m, 6H), 1.97-1.95 (m, 1H), 1.83-1.80 (m, 2H), 1.25-1.19 (m, 2H), 1.05 (t, J = 7.1 Hz, 3H) 476 (M + 2)
    229
    Figure US20200190095A1-20200618-C00703
         		12.71 (s, 1H), 11.00 (s, 1H), 8.46 (d, J = 2.9 Hz, 1H), 7.96 (dd, J1 = 2.8 Hz, J2 = 9.1 Hz, 1H), 7.87 (s, 1H), 6.88 (d, J = 9.3 Hz, 1H), 3.79 (t, J = 6.1 Hz, 2H), 3.70 (t, J = 5.6 Hz, 2H), 3.45 (t, J = 4.9 Hz, 4H), 2.45 (t, J= 4.9 Hz, 4H), 2.36 (q, J = 7.3 Hz, 2H), 1.74 (m, 4H), 1.50 (m, 4H), 1.04 (t, J = 7.1 Hz, 3H) 450.0
    230
    Figure US20200190095A1-20200618-C00704
         		12.80 (bs, 1H), 11.17 (s, 1H), 7.90 (s, 1H), 7.61 (d, J = 8.3 Hz, 1H), 6.99 (d, J = 8.3 Hz, 2H), 4.07 (t, J = 5.6 Hz, 2H), 3.87 (m, 4H), 3.81 (m, 2H), 2.72 (t, J = 4.2 Hz, 4H), 2.66 (t, J = 5.7 Hz, 2H), 2.55 (m, 4H), 2.42 (m, 4H) 491.1
    231
    Figure US20200190095A1-20200618-C00705
         		12.80 (bs, 1H), 10.96 (s, 1H), 8.41 (d, J = 2.4 Hz, 1H), 7.87 (s, 1H), 7.86-7.85 (m, 1H), 6.86 (d, J = 9.3 Hz, 1H), 4.48-4.61 (m, 2H), 2.99- 2.93 (m, 2H), 2.78 (m, 4H), 2.54- 2.53 (m, 6H), 1.96-1.95 (m, 1H), 1.83-1.80 (m, 2H), 1.24-1.19 (m, 2H) 445.2 (M − 1)
    232
    Figure US20200190095A1-20200618-C00706
         		12.70 (s, 1H), 10.96 (s, 1H), 8.41 (d, J = 2.4 Hz, 1H), 7.94 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz, 1H), 7.86 (s, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.17- 4.10 (m, 2H), 3.79 (t, J = 5.9 Hz, 2H), 3.70 (t, J = 5.9 Hz, 2H), 2.83- 2.77 (m, 2H), 2.61-2.50 (m, 2H), 2.28-2.11 (m, 2H), 1.90-1.86 (m, 1H), 1.83-1.65 (m, 6H), 1.50-1.42 (m, 4H) 479.3
    233
    Figure US20200190095A1-20200618-C00707
         		12.71 (s, 1H), 11.16 (s, 1H), 7.85 (s, 1H), 7.59 (d, J = 9.3 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 3.80 (t, J = 5.9 Hz, 2H), 3.75 (t, J = 6.1 Hz, 2H), 3.70-3.55 (m, 3H), 1.90-1.60 (m, 10H), 1.51 (m, 6H) 478.2
    234
    Figure US20200190095A1-20200618-C00708
         		12.72 (s, 1H), 11.01 (s, 1H), 8.49 (d, J = 2.5 Hz, 1H), 7.99 (dd, J1 = 2.7 Hz, J2 = 9.1 Hz, 1H), 7.87 (s, 1H), 6.94 (d, J = 8.8 Hz, 1H), 4.10 (s, 2H), 3.79 (t, J = 5.9 Hz, 2H), 3.71 (t, J = 6.1 Hz, 2H), 3.59-3.47 (m, 8H), 1.74 (m, 4H), 1.50 (m, 4H) 489.3
    235
    Figure US20200190095A1-20200618-C00709
         		12.80 (s, 1H), 11.55 (s, 1H), 8.06 (d, J = 8.8 Hz, 2H), 7.95 (d, J = 8.8 Hz, 2H), 7.90 (s, 1H), 5.15 (s, 2H), 3.84-3.78 (m, 4H), 1.83-1.76 (m, 4H), 1.52 (m, 4H) 461.3 (M − 1)
    236
    Figure US20200190095A1-20200618-C00710
         		12.70 (s, 1H), 10.97 (s, 1H), 8.42 (d, J = 3.0 Hz, 1H), 7.92 (dd, J1 = 2.8 Hz, J2 = 9.1 Hz, 1H), 7.86 (s, 1H), 6.86 (d, J = 9.3 Hz, 1H), 4.36 (t, J = 5.2 Hz, 1H), 4.25-4.21 (m, 2H), 3.79 (t, J = 6.2 Hz, 2H), 3.70 (t, J = 5.9 Hz, 2H), 3.47 (q, J = 6.2 Hz, 2H), 2.77-2.74 (m, 2H), 1.73- 1.71 (m, 6H), 1.64-1.59 (m, 1H), 1.50 (m, 4H), 1.38 (q, J = 6.3 Hz, 2H), 1.14-1.10 (m, 2H) 465.3
    237
    Figure US20200190095A1-20200618-C00711
         		12.77 (s, 1H), 10.98 (s, 1H), 8.45 (d, J = 2.5 Hz, 1H), 7.93 (dd, J1 = 2.7 Hz, J2 = 9.1 Hz, 1H), 7.89 (s, 1H), 6.95 (d, J = 9.3 Hz, 1H), 4.79- 4.61 (m, 2H), 4.11 (s, 2H), 3.60- 3.54 (m, 4H), 3.51-3.46 (m, 4H), 3.00-2.94 (m, 2H), 2.55-2.53 (m, 2H), 1.97-1.94 (m, 1H), 1.83-1.80 (m, 2H), 1.23-1.17 (m, 2H) 512.4 (M − 1)
    238
    Figure US20200190095A1-20200618-C00712
         		— 508.4
    239
    Figure US20200190095A1-20200618-C00713
         		12.71 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.40 (bs, 1H), 4.05 (t, J = 5.9 Hz, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.74 (t, J = 5.9 Hz, 2H), 3.48 (t, J = 6.2 Hz, 2H), 2.67 (t, J = 5.6 Hz, 2H), 2.54 (m, 4H), 2.42-2.33 (m, 6H), 1.76 (m, 4H), 1.51 (m, 4H) 509.3
    240
    Figure US20200190095A1-20200618-C00714
         		12.76 (s, 1H), 11.16 (s, 1H), 7.88 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 4.78-4.71 (m, 2H), 4.10 (s, 2H), 3.61 (t, J = 4.9 Hz, 2H), 3.50 (t, J = 4.9 Hz, 2H), 3.18 (t, J = 4.9 Hz, 2H), 3.13 (t, J = 5.2 Hz, 2H), 3.02-2.96 (m, 2H), 2.55-2.52 (m, 2H), 1.98-1.95 (m, 1H), 1.84-1.81 (m, 2H), 1.26- 1.23 (m, 2H) 513.4
    241
    Figure US20200190095A1-20200618-C00715
         		12.90 (s, 1H), 11.90 (bs, 1H), 8.09 (d, J = 8.3 Hz, 2H), 7.95 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 4.94 (s, 2H), 4.80-4.77 (m, 2H), 3.06-3.00 (m, 2H), 2.56-2.54 (m, 4H), 1.99 (m, 1H), 1.89-1.86 (m, 2H) 486.4 (M − 1)
    242
    Figure US20200190095A1-20200618-C00716
         		12.71 (s, 1H), 11.99 (s, 1H), 8.47 (d, J = 2.9 Hz, 1H), 7.95 (dd, J1 = 2.7 Hz, J2 = 9.1 Hz, 1H), 7.87 (s, 1H), 6.88 (d, J = 9.3 Hz, 1H), 3.79 (t, J = 6.1 Hz, 2H), 3.70 (t, J = 5.9 Hz, 2H), 3.45 (t, J = 4.7 Hz, 4H), 2.40 (t, J = 4.9 Hz, 4H), 2.22 (s, 3H), 1.74 (m, 4H), 1.50 (m, 4H) 436.3
    243
    Figure US20200190095A1-20200618-C00717
         		12.76 (s, 1H), 10.97 (s, 1H), 8.42 (d, J = 2.5 Hz, 1H), 7.88 (dd, J1 = 2.7 Hz, J2 = 9.1 Hz, 1H), 7.87 (s, 1H), 6.90 (d, J = 8.8 Hz, 1H), 4.79- 4.61 (m, 2H), 3.46 (t, J = 4.9 Hz, 4H), 3.00-2.94 (m, 2H), 2.54-2.53 (m, 2H), 2.40 (t, J = 4.9 Hz, 4H), 2.22 (s, 3H), 1.98-1.95 (m, 1H), 1.82-1.80 (m, 2H), 1.23-1.19 (m, 2H) 461.4
    244
    Figure US20200190095A1-20200618-C00718
         		12.70 (s, 1H), 11.17 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 7.3 Hz, 2H), 6.97 (m, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.67- 3.64 (m, 2H), 2.89-2.87 (m, 2H), 2.67-2.59 (m, 2H), 1.89 (m, 1H), 1.75-1.68 (m, 6H), 1.51 (m, 4H), 1.37-1.35 (m, 2H) 502.5
    245
    Figure US20200190095A1-20200618-C00719
         		16.70 (s, 1H), 12.87 (s, 1H), 11.60 (s, 1H), 8.09 (d, J = 8.3 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.94 (s, 1H), 4.82-4.74 (m, 2H), 3.06 (m, 2H), 2.57-2.53 (m, 2H), 2.01-1.91 (m, 1H), 1.86 (m, 2H), 1.26-1.23 (m, 2H) 428.3 (M − 1)
    246
    Figure US20200190095A1-20200618-C00720
         		16.04 (bs, 1H), 12.75 (s, 1H), 11.13 (s, 1H), 7.87 (s, 1H), 7.55 (d, J = 9.3 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.78 (m, 2H), 3.69-3.66 (m, 2H), 3.02-2.95 (m, 2H), 2.88- 2.86 (m, 2H), 2.67-2.60 (m, 2H), 2.55-2.30 (m, 2H), 1.97-1.91 (m, 1H), 1.90-1.81 (m, 3H), 1.70-1.67 (m, 2H), 1.39-1.33 (m, 2H), 1.24- 1.21 (m, 2H) 525.5 (M − 1)
    247
    Figure US20200190095A1-20200618-C00721
         		— 435.5
    248
    Figure US20200190095A1-20200618-C00722
         		12.75 (s, 1H), 11.13 (s, 1H), 7.88 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 9.3 Hz, 2H), 4.78-4.73 (m, 2H), 3.13 (t, J = 4.7 Hz, 4H), 3.02-2.95 (m, 2H), 2.55-2.52 (m, 2H), 2.47 (m, 4H), 2.24 (s, 3H), 1.97-1.95 (m, 1H), 1.84-1.81 (m, 2H), 1.23-1.22 (m, 2H) 460.5
    249
    Figure US20200190095A1-20200618-C00723
         		12.76 (s, 1H), 10.94 (s, 1H), 8.38 (d, J = 2.5 Hz, 1H), 7.89-7.86 (m, 2H), 6.87 (d, J = 9.3 Hz, 1H), 4.78- 4.61 (m, 2H), 4.19-4.10 (m, 2H), 3.00-2.94 (m, 2H), 2.65-2.55 (m, 2H), 2.54-2.53 (m, 2H), 2.45-2.28 (m, 2H), 1.96-1.80 (m, 6H), 1.23- 1.19 (m, 4H) 504.5
    250
    Figure US20200190095A1-20200618-C00724
         		12.74 (bs, 1H), 11.13 (s, 1H), 7.87 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.78 (m, 2H), 3.62-3.55 (m, 2H), 3.01-2.95 (m, 2H), 2.55-2.53 (m, 2H), 2.30- 2.09 (m, 2H), 1.98 (m, 2H), 1.84- 1.51 (m, 6H), 1.12-1.09 (m, 2H) 503.4
    251
    Figure US20200190095A1-20200618-C00725
         		12.77 (s, 1H), 10.98 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 7.92 (dd, J1 = 2.7 Hz, J2 = 9.1 Hz, 1H), 7.88 (s, 1H), 6.93 (d, J = 9.3 Hz, 1H), 5.47 (s, 1H), 4.54 (m, 2H), 4.06-4.00 (m, 2H), 3.50-3.47 (m, 4H), 3.00- 2.94 (m, 2H), 2.55-2.52 (m, 4H), 2.00-1.94 (m, 1H), 1.83-1.80 (m, 2H), 1.34 (s, 6H), 1.25-1.19 (m, 2H) 531.2
    252
    Figure US20200190095A1-20200618-C00726
         		16.10 (bs, 1H), 12.71 (s, 1H), 10.98 (s, 1H), 8.43 (d, J = 2.4 Hz, 1H), 7.94 (dd, J1 = 2.7 Hz, J2 = 9.1 Hz, 1H), 7.87 (s, 1H), 6.88 (d, J = 9.3 Hz, 1H), 4.26-4.23 (m, 2H), 3.79 (t, J = 5.9 Hz, 2H), 3.70 (t, J = 5.9 Hz, 2H), 2.85 (d, J = 6.9 Hz, 2H), 2.79-2.73 (m, 2H), 2.00-1.95 (m, 1H), 1.73-1.65 (m, 6H), 1.50 (m, 4H), 1.23-1.21 (m, 2H) 503.6
    253
    Figure US20200190095A1-20200618-C00727
         		16.04 (bs, 1H), 12.76 (s, 1H), 10.95 (s, 1H), 8.39 (d, J = 2.9 Hz, 1H), 7.88 (s, 1H), 7.87 (dd, J1 = 2.7 Hz, J2 = 9.1 Hz, 1H), 6.90 (d, J = 9.3 Hz, 1H), 4.79-4.62 (m, 2H), 4.27-4.24 (m, 2H), 3.00-2.94 (m, 2H), 2.87-2.85 (m, 2H), 2.80-2.74 (m, 2H), 2.54-2.53 (m, 4H), 2.01- 1.95 (m, 2H), 1.82-1.80 (m, 2H), 1.82-1.80 (m, 2H), 1.68-1.65 (m, 2H), 1.28-1.19 (m, 4H) 528.5
    254
    Figure US20200190095A1-20200618-C00728
         		12.76 (s, 1H), 11.19 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 9.3 Hz, 2H), 4.42-4.40 (m, 1H), 3.80 (t, J = 5.9 Hz, 2H), 3.74 (t, J = 5.9 Hz, 2H), 3.13 (s, 2H), 2.95-2.92 (m, 2H), 2.67-2.62 (m, 2H), 2.46-2.40 (m, 2H), 1.98 (m, 2H), 1.75-1.70 (m, 6H), 1.51 (m, 4H) 494.3
    255
    Figure US20200190095A1-20200618-C00729
         		12.70 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 9.3 Hz, 2H), 3.80 (t, J = 6.0 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.47 (t, J = 5.6 Hz, 2H), 3.25 (s, 3H), 3.11 (m, 4H), 2.56 (m, 6H), 1.78-1.74 (m, 4H), 1.51 (m, 4H) 479.0
    256
    Figure US20200190095A1-20200618-C00730
         		12.76 (s, 1H), 11.14 (s, 1H), 7.88 (s, 1H), 7.56 (d, J = 9.3 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.78-4.71 (m, 2H), 3.48 (t, J = 5.7 Hz, 2H), 3.12 (s, 3H), 3.07-2.96 (m, 6H), 2.55-2.53 (m, 8H), 1.98-1.97 (m, 1H), 1.84-1.81 (m, 2H), 1.23-1.20 (m, 2H) 504.2
    257
    Figure US20200190095A1-20200618-C00731
         		11.14 (s, 1H), 7.87 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 3.98 (m, 2H), 3.12 (m, 4H), 3.07 (m, 2H), 3.07-2.95 (m, 2H), 2.67-2.64 (m, 2H), 2.55-2.53 (m, 4H), 2.37-2.33 (m, 2H), 1.97 (m, 1H), 1.84-1.81 (m, 2H), 1.23- 1.20 (m, 2H) 489.4
    258
    Figure US20200190095A1-20200618-C00732
         		12.70 (s, 1H), 11.15 (s, 1H), 7.86 (s, 1H), 7.61 (d, J = 9.3 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.41 (t, J = 5.2 Hz, 1H), 3.80 (t, J = 6.2 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.56- 3.38 (m, 1H), 3.36-3.35 (m, 2H), 3.30-3.23 (m, 1H), 3.13-3.05 (m, 2H), 1.78-1.66 (m, 5H), 1.51 (m, 6H), 1.37-1.27 (m, 1H), 0.89-0.82 (m, 1H), 0.48-0.45 (m, 1H), 0.17- 0.15 (m, 1H) 476.4
    259
    Figure US20200190095A1-20200618-C00733
         		12.75 (s, 1H), 11.13 (s, 1H), 7.88 (s, 1H), 7.55 (d, J = 9.3 Hz, 2H), 6.99 (d, J = 9.3 Hz, 2H), 4.76 (m, 2H), 4.41 (t, J = 5.4 Hz, 1H), 3.56- 3.51 (m, 1H), 3.37-3.34 (m, 1H), 3.30-3.25 (m, 1H), 3.14-3.06 (m, 2H), 3.02-2.96 (m, 2H), 2.55-2.53 (m, 2H), 1.97-1.96 (m, 1H), 1.84- 1.81 (m, 2H), 1.72-1.68 (m, 1H), 1.54-1.47 (m, 2H), 1.36-1.09 (m, 4H), 0.88-0.82 (m, 1H), 0.48-0.45 (m, 1H), 0.18-0.15 (m, 1H) 501.2
    260
    Figure US20200190095A1-20200618-C00734
         		12.70 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 9.3 Hz, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.46 (t, J = 6.1 Hz, 2H), 3.12 (m, 4H), 2.41-2.38 (m, 2H), 1.77- 1.74 (m, 4H), 1.63-1.60 (m, 2H), 1.51 (m, 4H) 479.4
    261
    Figure US20200190095A1-20200618-C00735
         		12.76 (s, 1H), 11.14 (s, 1H), 7.88 (s, 1H), 7.56 (d, J = 9.3 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 4.78-4.71 (m, 2H), 3.46 (t, J = 6.4 Hz, 2H), 3.13 (m, 4H), 3.02-2.95 (m, 2H), 2.55-2.53 (m, 6H), 2.42-2.38 (m, 2H), 1.97-1.96 (m, 1H), 1.84-1.81 (m, 2H), 1.65-1.58 (m, 2H), 1.23- 1.22 (m, 2H) 504.4
    262
    Figure US20200190095A1-20200618-C00736
         		12.78 (s, 1H), 11.17 (s, 1H), 7.89 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 4.45-4.44 (m, 2H), 4.43 (m, 1H), 3.22 (s, 2H), 3.02-2.96 (m, 4H), 2.74-2.67 (m, 2H), 2.67 (t, J = 1.8 Hz, 2H), 2.55-2.54 (m, 2H), 2.03-2.00 (m, 3H), 1.84-1.81 (m, 2H), 1.77-1.73 (m, 2H) 519.4
    263
    Figure US20200190095A1-20200618-C00737
         		12.67 (s, 1H), 11.08 (s, 1H), 7.84 (s, 1H), 7.55 (d, J = 9.3 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 4.39 (m, 1H), 3.79 (t, J = 6.1 Hz, 25H), 3.74 (t, J = 5.9 Hz, 2H), 3.49-3.42 (m, 6H), 2.79 (m, 2H), 2.62-2.56 (m, 4H), 1.87 (t, J = 5.1 Hz, 2H), 1.77- 1.74 (m, 4H), 1.51 (m, 4H) 479.4
    264
    Figure US20200190095A1-20200618-C00738
         		12.73 (s, 1H), 11.06 (s, 1H), 7.86 (s, 1H), 7.50 (d, J = 9.3 Hz, 2H), 6.73 (d, J = 8.8 Hz, 2H), 4.76 (m, 2H), 4.73 (m, 1H), 3.49 (m, 4H), 3.45 (t, J = 6.1 Hz, 2H), 3.00-2.94 (m, 2H), 2.80 (m, 2H), 2.59-2.53 (m, 6H), 1.97-1.94 (m, 1H), 1.88- 1.81 (m, 4H), 1.23-1.21 (m, 2H) 504.4
    265
    Figure US20200190095A1-20200618-C00739
         		12.69 (s, 1H), 11.15 (s, 1H), 7.86 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.28 (m, 1H), 3.80 (t, J = 5.9 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.09 (m, 4H), 2.70 (m, 4H), 1.77-1.74 (m, 4H), 1.51 (m, 4H), 1.23 (s, 6H) 493.5
    266
    Figure US20200190095A1-20200618-C00740
         		12.75 (s, 1H), 11.13 (s, 1H), 7.87 (s, 1H), 7.55 (d, J = 9.3 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.72 (m, 2H), 4.27 (m, 1H), 3.09 (m, 4H), 3.02-2.95 (m, 2H), 2.69-2.68 (m, 4H), 2.55-2.53 (m, 2H), 1.99-1.95 (m, 1H), 1.84-1.81 (m, 2H), 1.34- 1.17 (m, 4H), 0.98 (s, 6H) 518.2
    267
    Figure US20200190095A1-20200618-C00741
         		— 492.5
    268
    Figure US20200190095A1-20200618-C00742
         		12.75 (s, 1H), 11.14 (s, 1H), 7.88 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 3.12-3.11 (m, 4H), 3.02-2.95 (m, 2H), 2.55- 2.53 (m, 6H), 2.23 (s, 6H), 1.99- 1.97 (m, 1H), 1.84-1.81 (m, 2H), 1.34-1.23 (m, 6H) 517.5
    269
    Figure US20200190095A1-20200618-C00743
         		12.72 (s, 1H), 11.19 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 9.3 Hz, 2H), 4.80 (s, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.74 (t, J = 5.9 Hz, 2H), 3.46 (m, 6H), 2.33-2.32 (m, 4H), 1.76 (m, 4H), 1.51 (m, 4H), 1.01 (t, J = 7.1 Hz, 3H) 507.3
    270
    Figure US20200190095A1-20200618-C00744
         		— 532.4
    271
    Figure US20200190095A1-20200618-C00745
         		12.77 (s, 1H), 11.16 (s, 1H), 7.89 (s, 1H), 7.61 (d, J = 7.8 Hz, 2H), 6.97 (d, J = 8.3 Hz, 2H), 4.81 (s, 2H), 4.69 (m, 2H), 3.51-3.46 (m, 6H), 2.99 (m, 2H), 2.67 (m, 2H), 2.34-2.27 (m, 4H), 2.19 (s, 3H), 1.99-1.91 (m, 1H), 1.84-1.81 (m, 2H) 518.4
    272
    Figure US20200190095A1-20200618-C00746
         		12.69 (s, 1H), 11.15 (s, 1H), 7.86 (s, 1H), 7.61 (d, J = 9.2 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.41 (t, J = 5.1 Hz, 1H), 3.80 (t, J = 6.1 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.59- 3.56 (m, 2H), 3.52-3.47 (m, 2H), 1.77-1.69 (m, 8H), 1.51-1.42 (m, 8H) 464.5
    273
    Figure US20200190095A1-20200618-C00747
         		12.70 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 9.3 Hz, 2H), 4.44 (m, 1H), 3.80 (t, J = 6.2 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.65 (d, J = 5.4 Hz, 1H), 3.35-3.33 (m, 2H), 3.12 (t, J = 4.4 Hz, 4H), 2.59-2.53 (m, 4H), 2.46-2.42 (m, 2H), 2.33-2.27 (m, 1H), 1.78-1.74 (m, 4H), 1.51 (m, 4H) 495.2
    274
    Figure US20200190095A1-20200618-C00748
         		12.75 (s, 1H), 11.14 (s, 1H), 7.88 (s, 1H), 7.56 (d, J = 9.3 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 4.71 (m, 2H), 4.45 (m, 1H), 3.65 (m, 1H), 3.35-3.33 (m, 2H), 3.13 (m, 4H), 3.02-2.96 (m, 2H), 2.60 (m, 4H), 2.52-2.51 (m, 2H), 2.46-2.45 (m, 2H), 2.33-2.01 (m, 1H), 1.99-1.95 (m, 1H), 1.84-1.81 (m, 2H), 1.23- 1.21 (m, 2H) 520.4
    275
    Figure US20200190095A1-20200618-C00749
         		12.70 (s, 1H), 11.16 (s, 1H), 7.86(s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.64 (t, J = 4.9 Hz, 1H), 4.52 (t, J = 4.9 Hz, 1H), 3.80 (t, J = 6.1 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.13 (t, J = 4.9 Hz, 4H), 2.71 (t, J = 4.9 Hz, 1H), 2.64 (t, J = 4.9 Hz, 1H), 2.60 (t, J = 4.7 Hz, 4H), 1.78-1.74 (m, 4H), 1.51 (m, 4H) 467.3
    276
    Figure US20200190095A1-20200618-C00750
         		12.75 (s, 1H), 11.14 (s, 1H), 7.87 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 4.77-4.71 (m, 2H), 4.64 (t, J = 4.9 Hz, 1H), 4.52 (t, J = 4.9 Hz, 1H), 3.14 (t, J = 4.9 Hz, 4H), 3.02-2.95 (m, 2H), 2.71 (t, J = 4.4 Hz, 1H), 2.67 (t, J = 2.0 Hz, 1H), 2.64 (t, J = 4.9 Hz, 4H), 2.60-2.53 (m, 2H), 1.98-1.95 (m, 1H), 1.84-1.82 (m, 2H), 1.23- 1.21 (m, 2H) 492.4
    277
    Figure US20200190095A1-20200618-C00751
         		12.70 (s, 1H), 10.96 (s, 1H), 8.42 (d, J = 2.5 Hz, 1H), 7.92 (dd, J1 = 2.4 Hz, J2 = 9.3 Hz, 1H), 7.87 (s, 1H), 6.85 (d, J = 9.3 Hz, 2H), 4.82 (d, J = 4.4 Hz, 1H), 4.16-4.13 (m, 1H), 3.95-3.92 (m, 1H), 3.79 (t, J = 6.1 Hz, 2H), 3.70 (t, J = 4.9 Hz, 2H), 3.51-3.48 (m, 1H), 1.73 (m, 6H), 1.50-1.33 (m, 8H) 437.4
    278
    Figure US20200190095A1-20200618-C00752
         		— 437.4
    279
    Figure US20200190095A1-20200618-C00753
         		12.70 (s, 1H), 11.18 (s, 1H), 7.86 (s, 1H), 7.64 (d, J = 9.3 Hz, 2H), 7.92 (d, J = 8.9 Hz, 2H), 3.80 (t, J = 6.2 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.32-3.30 (m, 4H), 2.10-2.01 (m, 4H), 1.78-1.75 (m, 4H), 1.51 (m, 4H) 456.2
    280
    Figure US20200190095A1-20200618-C00754
         		12.76 (s, 1H), 11.16 (s, 1H), 7.88 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 9.3 Hz, 2H), 4.80-4.60 (m, 2H), 3.34-3.31 (m, 4H), 3.02- 2.96 (m, 2H), 2.55-2.53 (m, 2H), 2.11-2.01 (m, 4H), 1.99-1.97 (m, 1H), 1.84-1.81 (m, 2H), 1.23-1.21 (m, 2H) 479.1
    281
    Figure US20200190095A1-20200618-C00755
         		— 436.3
    282
    Figure US20200190095A1-20200618-C00756
         		— 461.5
    283
    Figure US20200190095A1-20200618-C00757
         		12.72 (s, 1H), 11.19 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.80 (s, 2H), 3.80 (t, J = 5.9 Hz, 2H), 3.74 (t, J = 5.9 Hz, 2H), 3.45 (m, 4H), 2.46-2.26 (m, 4H), 2.18 (s, 3H), 1.76 (m, 4H), 1.51 (m, 4H) 493.2
    284
    Figure US20200190095A1-20200618-C00758
         		12.75 (s, 1H), 11.13 (s, 1H), 7.88 (s, 1H), 7.87 (s, 1H), 7.55 (d, J = 9.3 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.72 (m, 2H), 4.53 (t, J = 5.2 Hz, 1H), 3.68-3.57 (m, 2H), 3.36- 3.34 (m, 2H), 3.01-2.95 (m, 2H), 2.66-2.60 (m, 1H), 2.55-2.53 (m, 2H), 2.43-2.38 (m, 1H), 1.96-1.94 (m, 1H), 1.84-1.82 (m, 2H), 1.73- 1.71 (m, 4H), 1.59-1.54 (m, 1H), 1.23-1.21 (m, 2H) 475.6
    285
    Figure US20200190095A1-20200618-C00759
         		12.69 (s, 1H), 11.15 (s, 1H), 7.86 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 4.53 (m, 2H), 3.80 (t, J = 6.2 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.69-3.54 (m, 2H), 2.67-2.53 (m, 1H), 2.46-2.33 (m, 1H), 1.78-1.71 (m, 8H), 1.57 (m, 1H), 1.51 (m, 4H), 1.23 (m, 2H) 450.3
    286
    Figure US20200190095A1-20200618-C00760
         		12.75 (s, 1H), 11.13 (s, 1H), 7.55 (d, J = 9.3 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.80 (m, 2H), 4.41 (t, J = 5.1 Hz, 1H), 3.60-3.53 (m, 4H), 2.99 (m, 2H), 2.55-2.53 (m, 4H), 2.0 (m, 1H), 1.85-1.69 (m, 6H), 1.34-1.22 (m, 4H) 489.4
    287
    Figure US20200190095A1-20200618-C00761
         		12.75 (s, 1H), 11.13 (s, 1H), 7.87 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 9.3 Hz, 2H), 4.90-4.60 (m, 2H), 3.50-3.45 (m, 2H), 3.35- 3.33 (m, 1H), 3.27 (s, 3H), 3.01- 2.84 (m, 4H), 2.55-2.52 (m, 2H), 1.98-1.81 (m, 5H), 1.56-1.48 (m, 2H), 1.23-1.21 (m, 2H) 475.2
    288
    Figure US20200190095A1-20200618-C00762
         		12.70 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 7.3 Hz, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.48-3.44 (m, 3H), 3.27 (s, 3H), 2.87 (m, 2H), 1.95-1.93 (m, 2H), 1.77-1.74 (m, 4H), 1.51 (m, 6H) 450.4
    289
    Figure US20200190095A1-20200618-C00763
         		12.70 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 9.3 Hz, 2H), 6.99 (d, J = 9.3 Hz, 2H), 4.89-4.77 (m, 1H), 3.80 (t, J = 6.2 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.36-3.35 (m, 2H), 3.13-3.07 (m, 2H), 2.00- 1.92 (m, 2H), 1.82-1.75 (m, 6H), 1.51 (m, 4H) 438.0
    290
    Figure US20200190095A1-20200618-C00764
         		12.75 (s, 1H), 11.14 (s, 1H), 7.88 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.01(d, J = 9.3 Hz, 2H), 4.92-4.75 (m, 3H), 3.37-3.34 (m, 2H), 3.15- 3.09 (m, 2H), 3.02-2.96 (m, 2H), 2.55-2.52 (m, 4H), 2.03-1.92 (m, 3H), 1.84-1.74 (m, 4H), 1.24-1.21 (m, 2H) 463.4
    291
    Figure US20200190095A1-20200618-C00765
         		12.78 (s, 1H), 11.19 (s, 1H), 7.90 (s, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 6.9 Hz, 2H), 5.30 (m, 1H), 4.90-4.70 (m, 2H), 4.50 (m, 1H), 3.73 (m, 2H), 3.30-2.96 (m, 6H), 2.56-2.54 (m, 4H), 2.20-2.16 (m, 2H), 1.98-1.81 (m, 5H) 505.2
    292
    Figure US20200190095A1-20200618-C00766
         		12.75 (s, 1H), 11.23 (s, 1H), 8.64 (s, 2H), 7.90 (s, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 9.3 Hz, 2H), 4.64-4.61 (m, 1H), 3.81 (t, J = 6.1 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.39-3.37 (m, 2H), 3.24-3.08 (m, 2H), 2.12-2.07 (m, 2H), 1.84- 1.76 (m, 6H), 1.51 (m, 4H) 436.4
    293
    Figure US20200190095A1-20200618-C00767
         		12.70 (s, 1H), 11.15 (s, 1H), 7.89 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 9.3 Hz, 2H), 4.86 (t, J = 5.4 Hz, 1H), 4.80-4.69 (m, 2H), 3.99 (t, J = 5.1 Hz, 2H), 3.72 (t, J = 5.1 Hz, 2H), 3.02-2.95 (m, 2H), 2.55-2.53 (m, 2H), 1.97 (m, 1H), 1.84-1.81 (m, 2H), 1.24 (m, 2H) 420.3 (M − 1)
    294
    Figure US20200190095A1-20200618-C00768
         		12.71 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 9.3 Hz, 2H), 6.97 (d, J = 9.3 Hz, 2H), 4.85 (t, J = 5.6 Hz, 1H), 3.99 (t, J = 4.9 Hz, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.76- 3.69 (m, 4H), 1.76 (m, 4H), 1.51 (m, 4H) 397.2
    295
    Figure US20200190095A1-20200618-C00769
         		12.76 (s, 1H), 11.20 (s, 1H), 7.89 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 9.3 Hz, 2H), 4.73 (m, 2H), 4.54 (m, 1H), 4.04 (t, J = 6.4 Hz, 2H), 3.56 (t, J = 6.1 Hz, 2H), 3.01-2.95 (m, 2H), 2.55-2.53 (m, 2H), 1.99-1.89 (m, 1H), 1.87-1.81 (m, 4H), 1.23-1.21 (m, 2H) 436.4
    296
    Figure US20200190095A1-20200618-C00770
         		12.71 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 9.3 Hz, 2H), 4.54 (t, J = 5.4 Hz, 1H), 4.03 (t, J = 6.4 Hz, 2H), 3.80 (t, J = 5.9 Hz, 2H), 3.74 (t, J = 5.9 Hz, 2H), 3.58-3.54 (m, 2H), 1.86 (t, J = 6.4 Hz, 2H), 1.76 (m, 4H), 1.51 (m, 4H) 411.3
    297
    Figure US20200190095A1-20200618-C00771
         		12.72 (s, 1H), 11.05 (s, 1H), 7.86 (s, 3H), 7.49 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 8.8 Hz, 2H), 4.75 (m, 2H), 3.51 (t, J = 5.4 Hz, 4H), 3.29 (m, 2H), 3.00-2.67 (m, 5H), 2.55- 2.53 (m, 2H), 1.97-1.94 (m, 1H), 1.83-1.81 (m, 4H), 1.23-1.21 (m, 4H), 1.00 (s, 6H) 532.3
    298
    Figure US20200190095A1-20200618-C00772
         		12.69 (s, 1H), 11.15 (s, 1H), 7.86 (s, 1H), 7.61 (d, J = 9.3 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.60 (t, J = 5.9 Hz, 1H), 4.48 (t, J = 5.9 Hz, 1H), 3.80 (t, J = 6.1 Hz, 2H), 3.76 (t, J = 5.9 Hz, 2H), 3.67-3.64 (m, 2H), 2.66-2.59 (m, 2H), 1.78-1.76 (m, 6H), 1.64-1.58 (m, 3H), 1.51 (m, 4H), 1.31-1.23 (m, 2H) 466.4
    299
    Figure US20200190095A1-20200618-C00773
         		12.75 (s, 1H), 11.13 (s, 1H), 7.87 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 9.3 Hz, 2H), 4.77-4.71 (m, 2H), 4.60 (t, J = 6.1 Hz, 1H), 4.48 (t, J = 5.9 Hz, 1H), 3.68-3.65 (m, 2H), 3.01-2.95 (m, 2H), 2.67- 2.60 (m, 2H), 2.55-2.53 (m, 2H), 1.98-1.95 (m, 1H), 1.84-1.76 (m, 4H), 1.67 (q, J = 6.4 Hz, 1H), 1.62- 1.52 (m, 2H), 1.34-1.21 (m, 4H)
    300
    Figure US20200190095A1-20200618-C00774
         		12.81 (s, 1H), 11.37 (s, 1H), 7.90 (s, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.27 (t, J = 2.2 Hz, 1H), 3.76 (s, 6H), 3.03 (m, 2H), 2.55-2.53 (m, 2H), 1.99-1.96 (m, 1H), 1.84-1.81 (m, 2H), 1.25-1.23 (m, 2H) 422.3
    301
    Figure US20200190095A1-20200618-C00775
         		12.83 (s, 1H), 11.44 (s, 1H), 7.92 (s, 1H), 7.86-7.82 (m, 2H), 7.42 (d, J = 8.3 Hz, 2H), 4.80-4.67 (m, 2H), 3.02 (m, 2H), 2.56-2.53 (m, 2H), 2.00-1.96 (m, 1H), 1.86-1.84 (m, 2H), 1.25-1.23 (m, 2H) 446.3
    302
    Figure US20200190095A1-20200618-C00776
         		12.76 (s, 1H), 11.43 (s, 1H), 7.89 (s, 1H), 6.99 (d, J = 1.9 Hz, 2H), 6.26 (t, J = 2.2 Hz, 1H), 3.80 (q, J = 5.4 Hz, 4H), 3.76 (m, 6H), 1.76 (s, 6H), 1.76 (m, 4H), 1.51 (m, 4H) 379.3
    303
    Figure US20200190095A1-20200618-C00777
         		12.78 (s, 1H), 11.45 (s, 1H), 7.91 (s, 1H), 7.89 (d, J = 9.3 Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H), 3.82 (q, J = 6.1 Hz, 2H), 3.76 (t, J = 5.9 Hz, 2H), 1.77 (t, J = 5.6 Hz, 4H), 1.51 (m, 4H) 421.3
    304
    Figure US20200190095A1-20200618-C00778
         		12.73 (s, 1H), 11.31 (s, 1H), 7.88 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.3 Hz, 2H), 3.81 (t, J = 6.1 Hz, 2H), 3.76 (t, J = 5.9 Hz, 2H), 2.81 (t, J = 7.6 Hz, 2H), 2.55- 2.53 (m, 2H), 1.79-1.75 (m, 4H), 1.51 (m, 4H) 409.5
    305
    Figure US20200190095A1-20200618-C00779
         		12.79 (s, 1H), 11.29 (s, 1H), 7.90 (s, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 4.90-4.60 (m 2H), 3.02 (m, 2H), 2.82 (t, J = 7.3 Hz, 2H), 2.56-2.53 (m, 4H), 1.98-1.97 (m, 1H), 1.85-1.82 (m, 2H), 1.23 (m, 2H) 434.0
    306
    Figure US20200190095A1-20200618-C00780
         		12.67 (s, 1H), 11.05 (s, 1H), 7.84 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 4.73 (t, J = 5.4 Hz, 2H), 3.79 (t, J = 5.9 Hz, 2H), 3.74 (t, J = 5.9 Hz, 2H), 3.56- 3.52 (m, 4H), 3.42-3.39 (m, 4H), 1.75 (t, J = 4.4 Hz, 4H), 1.51 (m, 4H) 440.4
    307
    Figure US20200190095A1-20200618-C00781
         		12.72 (s, 1H), 11.03 (s, 1H), 7.86 (s, 1H), 7.48 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 9.3 Hz, 2H), 4.75-4.42 (m, 4H), 3.57-3.52 (m, 4H), 3.43- 3.40 (m, 4H), 3.00-2.97 (m, 2H), 2.55-2.52 (m, 2H), 2.00-1.90 (m, 1H), 1.84-1.81 (m, 2H), 1.23-1.22 (m, 2H) 465.3
    308
    Figure US20200190095A1-20200618-C00782
         		12.73 (s, 1H), 11.30 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.8 Hz, 2H), 4.45 (t, J = 5.2 Hz, 1H), 3.80 (t, J = 6.2 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.42 (q, J = 7.9 Hz, 2H), 1.78-1.70 (m, 6H), 1.51 (m, 4H) 395.3
    309
    Figure US20200190095A1-20200618-C00783
         		12.76 (s, 1H), 11.28 (s, 1H), 7.90 (s, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 4.80-4.60 (m, 2H), 4.46 (t, J = 5.6 Hz, 1H), 3.42 (q, J = 6.4 Hz, 2H), 3.04-3.01 (m, 2H), 2.60 (t, J = 7.6 Hz, 2H), 2.55-2.52 (m, 2H), 1.99-1.96 (m, 1H), 1.85-1.82 (m, 2H), 1.76-1.69 (m, 2H), 1.23-1.22 (m, 2H) 420.3
    310
    Figure US20200190095A1-20200618-C00784
         		12.76 (s, 1H), 11.39 (s, 1H), 7.89 (s, 1H), 7.86 (s, 1H), 7.59-7.57 (m, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H), 5.21 (t, J = 5.6 Hz, 1H), 4.52 (d, J = 5.9 Hz, 2H), 3.83-3.78 (m, 4H), 1.80-1.76 (m, 4H), 1.52 (m, 4H) 367.3
    311
    Figure US20200190095A1-20200618-C00785
         		12.81 (s, 1H), 11.35 (s, 1H), 7.91 (s, 1H), 7.86 (s, 1H), 7.51 (d, J = 9.3 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.05 (d, J = 7.3 Hz, 1H), 5.24 (t, J = 5.9 Hz, 1H), 4.79 (m, 2H), 4.53 (d, J = 5.9 Hz, 2H), 3.04-2.98 (m, 2H), 2.56-2.52 (m, 2H), 1.99- 1.98 (m, 1H), 1.86-1.82 (m, 2H), 1.23 (m, 2H) 392.3
    312
    Figure US20200190095A1-20200618-C00786
         		12.79 (s, 1H), 11.30 (s, 1H), 7.89 (s, 1H), 7.64 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 4.79-4.70 (m, 2H), 4.52 (t, J = 5.8 Hz, 1H), 4.40 (t, J = 5.9 Hz, 1H), 3.00 (m, 2H), 2.67 (t, J = 7.6 Hz, 2H), 2.55- 2.54 (m, 2H), 2.09-1.89 (m, 3H), 1.85-1.82 (m, 2H), 1.24 (m, 2H) 420.3
    313
    Figure US20200190095A1-20200618-C00787
         		12.74 (s, 1H), 11.29 (s, 1H), 7.88 (s, 1H), 7.79-7.76 (m, 2H), 7.25- 7.20 (m, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.73 (t, J = 5.9 Hz, 2H), 1.76- 1.75 (m, 4H), 1.50 (m, 4H) 355.4
    314
    Figure US20200190095A1-20200618-C00788
         		12.72 (s, 1H), 11.25 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 4.87 (t, J = 5.9 Hz, 1H), 3.80 (t, J = 6.1 Hz, 2H), 3.74 (t, J = 6.1 Hz, 2H), 3.38 (d, J = 5.9 Hz, 2H), 1.75 (m, 4H), 1.51 (m, 4H), 1.19 (m, 6H) 425.3
    315
    Figure US20200190095A1-20200618-C00789
         		12.78 (s, 1H), 11.24 (s, 1H), 7.89 (s, 1H), 7.62-7.60 (m, 2H), 7.05 (dd, J1 = 2.0, J2 = 6.9 Hz, 2H), 4.88 (t, J = 5.6 Hz, 1H), 4.80-4.60 (m, 2H), 3.38 (d, J = 5.9 Hz, 2H), 2.99 (m, 2H), 2.55-2.53 (m, 2H), 1.99 (m, 1H), 1.85-1.82 (m, 2H), 1.24- 1.23 (m, 2H), 1.19 (s, 6H) 449.1
    316
    Figure US20200190095A1-20200618-C00790
         		13.00 (s, 1H), 12.72 (s, 1H), 11.20 (s, 1H), 7.87 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 3.80 (t, J = 5.9 Hz, 2H), 3.73 (t, J = 5.9 Hz, 2H), 1.75-1.74 (m, 4H), 1.50 (m, 10H) 437.2
    317
    Figure US20200190095A1-20200618-C00791
         		12.76 (s, 1H), 11.18 (s, 1H), 7.87 (s, 1H), 7.58 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 4.78-4.66 (m, 2H), 3.01-2.95 (m, 2H), 2.55- 2.53 (m, 2H), 2.00-1.93 (m, 1H), 1.84-1.81 (m, 2H), 1.51 (s, 6H), 1.26-1.18 (m, 2H) 462.2 (M − 1)
    318
    Figure US20200190095A1-20200618-C00792
         		12.72 (s, 1H), 12.28 (s, 1H), 7.87 (s, 1H), 7.54 (d, J = 2.5 Hz, 1H), 7.16 (dd, J1 = 2.4 Hz, J2 = 8.8 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 3.82- 3.80 (m, 4H), 3.79 (s, 3H), 3.75 (s, 3H), 1.75 (m, 4H), 1.51 (m, 4H) 397.2
    319
    Figure US20200190095A1-20200618-C00793
         		12.78 (s, 1H), 11.22 (s, 1H), 7.89 (s, 1H), 7.56 (d, J = 4.4 Hz, 1H), 7.08 (dd, J1 = 2.3 Hz, J2 = 8.6 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 4.78 (m, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.00 (m, 2H), 2.55-2.52 (m, 2H), 1.98-1.96 (m, 1H), 1.83-1.80 (m, 2H), 1.23 (m, 2H) 420.0 (M − 1)
    320
    Figure US20200190095A1-20200618-C00794
         		12.76 (s, 1H), 11.44 (s, 1H), 7.90 (s, 1H), 7.62 (t, J = 2.2 Hz, 1H), 7.28 (t, J = 8.3 Hz, 1H), 7.15 (dd, J1 = 1.2 Hz, J2 = 8.1 Hz, 1H), 6.69 (dd, J1 = 2.0 Hz, J2 = 8.3 Hz, 1H), 3.82 (t, J = 6.1 Hz, 4H), 3.78 (s, 3H), 1.77-1.76 (m, 4H), 1.52 (m, 4H) 367.2
    321
    Figure US20200190095A1-20200618-C00795
         		12.81 (s, 1H), 11.39 (s, 1H), 7.91 (s, 1H), 7.58 (t, J = 2.0 Hz, 1H), 7.36 (t, J = 8.1 Hz, 1H), 7.10 (d, J = 9.3 Hz, 1H), 6.71 (dd, J1 = 2.2 Hz, J2 = 8.1 Hz, 1H), 4.79 (m, 2H), 3.79 (s, 3H), 3.03 (m, 2H), 2.56- 2.59 (m, 2H), 2.09-1.98 (m, 1H), 1.84-1.82 (m, 2H), 1.23 (m, 2H) 390.3 (M − 1)
    322
    Figure US20200190095A1-20200618-C00796
         		12.73 (s, 1H), 11.31 (s, 1H), 7.88 (s, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.3 Hz, 2H), 4.63 (t, J = 5.7 Hz, 1H), 3.81 (t, J = 6.1 Hz, 2H), 3.77 (t, J = 5.9 Hz, 2H), 3.60 (q, J = 7.3 Hz, 2H), 2.71 (t, J = 6.9 Hz, 2H), 1.78-1.75 (m, 4H), 1.51 (m, 4H) 379.3 (M − 1)
    323
    Figure US20200190095A1-20200618-C00797
         		12.79 (s, 1H), 11.29 (s, 1H), 7.90 (s, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 4.71 (m, 2H), 4.63 (t, J = 5.1 Hz, 1H), 3.61 (q, J = 7.1 Hz, 2H), 3.01 (m, 2H), 2.72 (t, J = 7.1 Hz, 2H), 2.72 (t, J = 7.1 Hz, 2H), 2.55-2.54 (m, 2H), 1.98 (m, 1H), 1.85-1.82 (m, 2H), 1.23 (m, 2H) 404.2 (M − 1)
    324
    Figure US20200190095A1-20200618-C00798
         		12.71 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.66 (dd, J1 = 2.0 Hz, J2 = 6.9 Hz, 2H), 6.96 (dd, J1 = 2.2 Hz, J2 = 7.1 Hz, 2H), 4.10-4.08 (m, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.73 (t, J = 5.9 Hz, 2H), 3.67-3.64 (m, 2H), 3.31 (s, 3H), 1.75 (m, 4H), 1.50 (m, 4H) 411.3
    325
    Figure US20200190095A1-20200618-C00799
         		12.77 (s, 1H), 11.15 (s, 1H), 7.89 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 9.2 Hz, 2H), 4.90-4.60 (m, 2H), 4.10 (t, J = 4.7 Hz, 2H), 3.66 (t, J = 4.7 Hz, 2H), 3.02-2.95 (m, 2H), 2.55-2.53 (m, 2H), 2.09- 1.97 (m, 1H), 1.84-1.81 (m, 2H), 1.24-1.10 (m, 2H) 436.5
    326
    Figure US20200190095A1-20200618-C00800
         		12.81 (s, 1H), 11.31 (s, 1H), 7.91 (s, 1H), 7.10 (s, 2H), 4.80 (m, 2H), 3.81 (s, 6H), 3.65 (s, 3H), 3.02 (m, 2H), 2.55-2.53 (m, 2H), 1.99 (m, 1H), 1.83-1.80 (m, 2H), 1.24 (m, 2H) 452.3
    327
    Figure US20200190095A1-20200618-C00801
         		12.70 (s, 1H), 11.41 (s, 1H), 7.88 (s, 1H), 7.63 (s, 1H), 7.02 (dd, J1 = 1.9 Hz, J2 = 8.3 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.03 (s, 2H), 3.80 (t, J = 5.9 Hz, 2H), 3.73 (t, J = 5.7 Hz, 2H), 1.75 (m, 4H), 1.51 (m, 4H) 381.3
    328
    Figure US20200190095A1-20200618-C00802
         		11.20 (s, 1H), 7.89 (s, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.05 (dd, J1 = 2.0 Hz, J2 = 8.3 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.01 (s, 2H), 4.80 (m, 2H), 3.04-2.97 (m, 2H), 2.04-2.01 (m, 1H), 1.89-1.85 (m, 2H), 1.29- 1.25 (m, 2H) 406.2
    329
    Figure US20200190095A1-20200618-C00803
         		— 480.4
    330
    Figure US20200190095A1-20200618-C00804
         		7.83 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 9.3 Hz, 2H), 5.62 (bs, 2H), 4.50 (m, 2H), 3.90-3.86 (m, 1H), 3.49-3.46 (m, 2H), 2.88- 2.83 (m, 4H), 2.53 (d, J = 6.4 Hz, 2H), 2.07-2.05 (m, 3H), 1.89-1.86 (m, 2H), 1.74-1.68 (m, 2H), 1.22- 1.20 (m, 2H) 569.0 (M − 1)
    331
    Figure US20200190095A1-20200618-C00805
         		12.74 (s, 1H), 11.33 (s, 1H), 7.89 (s, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 5.15 (t, J = 5.8 Hz, 1H), 4.48 (d, J = 5.9 Hz, 2H), 3.81 (t, J = 6.1 Hz, 2H), 3.77 (t, J = 5.9 Hz, 2H), 1.79-1.75 (m, 4H), 1.51 (m, 4H) 365.0 (M − 1)
    332
    Figure US20200190095A1-20200618-C00806
         		12.80 (s, 1H), 11.30 (s, 1H), 7.90 (s, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 5.16 (t, J = 5.6 Hz, 1H), 4.79-4.71 (m, 2H), 4.49 (d, J = 5.9 Hz, 2H), 3.01-2.98 (m, 2H), 2.55-2.54 (m, 2H), 2.01- 1.95 (m, 1H), 1.85-1.82 (m, 2H), 1.23 (m, 2H) 390.3 (M − 1)
    333
    Figure US20200190095A1-20200618-C00807
         		12.88 (s, 1H), 11.71 (s, 1H), 8.00- 7.94 (m, 5H), 4.81-4.70 (m, 2H), 3.21 (s, 3H), 3.04 (m, 2H), 2.57- 2.55 (m, 2H), 2.01-2.00 (m, 1H), 1.87 (m, 2H), 1.25-1.23 (m, 2H) 440.3
    334
    Figure US20200190095A1-20200618-C00808
         		12.83 (s, 1H), 11.72 (s, 1H), 8.03 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 5.4 Hz, 2H), 7.92 (s, 1H), 3.84-3.78 (m, 4H), 3.21 (s, 3H), 1.83-1.76 (m, 4H), 1.52 (m, 4H) 415.4
    335
    Figure US20200190095A1-20200618-C00809
         		15.68 (s, 1H), 12.86 (s, 1H), 11.63 (s, 1H), 8.53 (s, 1H), 7.99-7.94 (m, 2H), 7.38 (bs, 1H), 4.80 (m, 2H), 3.07 (m, 2H), 2.58-2.56 (m, 2H), 2.02-1.99 (m, 1H), 1.88 (m, 2H), 1.27-1.23 (m, 2H) 401.4 (M − 1)
    336
    Figure US20200190095A1-20200618-C00810
         		12.77 (s, 1H), 11.29 (s, 1H), 10.80 (s, 1H), 11.60 (s, 1H), 7.91 (s, 1H), 7.89 (s, 1H), 7.67 (d, J = 1.0 Hz, 1H), 7.02-7.00 (m, 1H), 7.00-6.91 (m, 1H), 4.78-4.71 (m, 2H), 3.03- 2.97 (m, 2H), 2.56-2.54 (m, 2H), 1.99-1.93 (m, 1H), 1.86 (m, 2H), 1.24-1.23 (m, 2H) 416.2 (M − 1)
    337
    Figure US20200190095A1-20200618-C00811
         		12.79 (s, 1H), 11.30 (s, 1H), 7.89 (s, 1H), 7.64 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 4.79-4.70 (m, 2H), 4.52 (t, J = 5.9 Hz, 1H), 4.40 (t, J = 5.9 Hz, 1H), 3.00 (m, 2H), 2.67 (t, J = 7.6 Hz, 2H), 2.55- 2.54 (m, 2H), 2.01-1.91 (m, 3H), 1.85-1.82 (m, 2H), 1.24 (m, 2H) 420.3 (M − 1)
    338
    Figure US20200190095A1-20200618-C00812
         		12.81 (s, 1H), 11.33 (s, 1H), 7.91 (s, 1H), 7.77 (dd, J1 = 2.0 Hz, J2 = 6.8 Hz, 2H), 7.25-7.21 (m, 2H), 4.80-4.67 (m, 2H), 3.04-2.98 (m, 2H), 2.56-2.53 (m, 2H), 2.01-1.96 (m, 1H), 1.86-1.83 (m, 2H), 1.24- 1.21 (m, 2H) 426.0 (M − 1)
    339
    Figure US20200190095A1-20200618-C00813
         		15.67 (s, 1H), 12.81 (s, 1H), 11.68 (s, 1H), 8.63 (s, 1H), 8.00 (m, 1H), 7.92 (s, 1H), 7.33 (m, 1H), 3.84 (t, J = 5.9 Hz, 4H), 1.86-1.78 (m, 4H), 1.54 (m, 4H) 378.2
  • The following compounds are anticipated to result in MS having M+ values noted in the following Table B.
  • TABLE B
    Structure IUPAC Name M+
    Figure US20200190095A1-20200618-C00814
         		2-(2,6-dimethylpiperidin-1-yl)-4-((4-(piperazin- 1-ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one 448.3
    Figure US20200190095A1-20200618-C00815
         		2-(1-(4-((2-(2,6-dimethylpiperidin-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetic acid 491.3
    Figure US20200190095A1-20200618-C00816
         		6-(4-((2-(2,6-dimethylpiperidin-1-yl)-5-oxo- 5,6-dihydropyrimido [4,5-d]pyridazin-4-yl)amino)phenyl)- 6-azaspiro[2.5]octane-1-carboxylic acid 503.3
    Figure US20200190095A1-20200618-C00817
         		2-(1-(4-((2-(2,6-dimethylpiperidin-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetonitrile 472.3
    Figure US20200190095A1-20200618-C00818
         		2-(2,6-dimethylpiperidin-1-yl)-4-((4-(4-(2- hydroxy-2-methylpropanoyl)piperazin-1- yl)phenyl)amino)pyrimido[4,5-d]pyridazin- 5(6H)-one 519.3
    Figure US20200190095A1-20200618-C00819
         		2-(1-(5-((2-(2,6-dimethylpiperidin-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid 492.3
    Figure US20200190095A1-20200618-C00820
         		2-(3,5-dimethylpiperidin-1-yl)-4-((4-(piperazin- 1-ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one 448.3
    Figure US20200190095A1-20200618-C00821
         		2-(1-(4-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetic acid 491.3
    Figure US20200190095A1-20200618-C00822
         		6-(4-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid 503.3
    Figure US20200190095A1-20200618-C00823
         		2-(1-(4-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetonitrile 472.3
    Figure US20200190095A1-20200618-C00824
         		2-(3,5-dimethylpiperidin-1-yl)-4-((4-(4-(2- hydroxy-2-methylpropanoyl)piperidin-1- yl)phenyl)amino)pyrimido[4,5-d]pyridazin- 5(6H)-one 519.3
    Figure US20200190095A1-20200618-C00825
         		2-(1-(5-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid 492.3
    Figure US20200190095A1-20200618-C00826
         		2-(2,6-dimethylmorpholino)-4-((4-(piperazin-1- ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one 450.1
    Figure US20200190095A1-20200618-C00827
         		2-(1-(4-((2-(2,6-dimethylmorpholino)-5-oxo- 5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetic acid 493.2
    Figure US20200190095A1-20200618-C00828
         		6-(4-((2-(2,6-dimethylmorpholino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid 505.2
    Figure US20200190095A1-20200618-C00829
         		2-(1-(4-((2-(2,6-dimethylmorpholino)-5-oxo- 5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetonitrile 474.3
    Figure US20200190095A1-20200618-C00830
         		2-(2,6-dimethylmorpholino)-4-((4-(4-(2- hydroxy-2-methylpropanoyl)piperidin-1- yl)phenyl)amino)pyrimido[4,5-d]pyridazin- 5(6H)-one 502.3
    Figure US20200190095A1-20200618-C00831
         		2-(1-(5-((2-(2,6-dimethylmorpholino)-5-oxo- 5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid 494.2
    Figure US20200190095A1-20200618-C00832
         		2-(diisopropylamino)-4-((4-(piperazin-1- ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one 436.3
    Figure US20200190095A1-20200618-C00833
         		2-(1-(4-((2-(diisopropylamino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetic acid 479.3
    Figure US20200190095A1-20200618-C00834
         		6-(4-((2-(diisopropylamino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid 491.3
    Figure US20200190095A1-20200618-C00835
         		2-(1-(4-((2-(diisopropylamino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetonitrile 460.3
    Figure US20200190095A1-20200618-C00836
         		2-(diisopropylamino)-4-((4-(4-(2-hydroxy-2- methylpropanoyl)piperidin-1- yl)phenyl)amino)pyrimido[4,5-d]pyridazin- 5(6H)-one 507.3
    Figure US20200190095A1-20200618-C00837
         		2-(1-(5-((2-(diisopropylamino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid 480.3
    Figure US20200190095A1-20200618-C00838
         		2-(2-methylpiperidin-1-yl)-4-((4-(piperazin-1- ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one 434.3
    Figure US20200190095A1-20200618-C00839
         		2-(1-(4-((2-(2-methylpiperidin-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetic acid 477.3
    Figure US20200190095A1-20200618-C00840
         		6-(4-((2-(2-methylpiperidin-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid 489.3
    Figure US20200190095A1-20200618-C00841
         		2-(1-(4-((2-(2-methylpiperidin-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetonitrile 458.3
    Figure US20200190095A1-20200618-C00842
         		4-((4-(4-(2-hydroxy-2- methylpropanoyl)piperidin-1-yl)phenyl)amino)- 2-(2-methylpiperidin-1-yl)pyrimido[4,5- d]pyridazin-5(6H)-one 505.3
    Figure US20200190095A1-20200618-C00843
         		2-(1-(5-((2-(2-methylpiperidin-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid 478.2
    Figure US20200190095A1-20200618-C00844
         		1-(4-((2-(azepan-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidine-4-carboxylic acid 463.2
    Figure US20200190095A1-20200618-C00845
         		1-(4-((2-(azepan-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)benzyl)piperidine-4-carboxylic acid 477.3
    Figure US20200190095A1-20200618-C00846
         		4-((4-((4-(2H-tetrazol-5-yl)piperidin-1- yl)methyl)phenyl)amino)-2-(azepan-1- yl)pyrimido[4,5-d]pyridazin-5(6H)-one 501.3
    Figure US20200190095A1-20200618-C00847
         		4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1- yl)methyl)phenyl)amino)-2-(azepan-1- yl)pyrimido[4,5-d]pyridazin-5(6H)-one 515.3
    Figure US20200190095A1-20200618-C00848
         		2-(1-(4-((2-cycloheptyl-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetic acid 476.3
    Figure US20200190095A1-20200618-C00849
         		1-(4-((2-cycloheptyl-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidine-4-carboxylic acid 462.2
    Figure US20200190095A1-20200618-C00850
         		6-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid 500.2
    Figure US20200190095A1-20200618-C00851
         		2-(1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetic acid 488.2
    Figure US20200190095A1-20200618-C00852
         		1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidine-4-carboxylic acid 474.2
    Figure US20200190095A1-20200618-C00853
         		1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)benzyl)piperidine-4-carboxylic acid 488.2
    Figure US20200190095A1-20200618-C00854
         		1-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1- yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2- yl)piperidine-3-carbonitrile 512.3
    Figure US20200190095A1-20200618-C00855
         		2-(1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)benzyl)piperidin-4-yl)acetic acid 502.2
    Figure US20200190095A1-20200618-C00856
         		1-(4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1- yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2- yl)piperidine-3-carbonitrile 526.3
    Figure US20200190095A1-20200618-C00857
         		1-(4-((2-cycloheptyl-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)benzyl)piperidine-4-carboxylic acid 476.3
    Figure US20200190095A1-20200618-C00858
         		4-((4-((4-(2H-tetrazol-5-yl)piperidin-1- yl)methyl)phenyl)amino)-2- cycloheptylpyrimido[4,5-d]pyridazin-5(6H)-one 500.3
    Figure US20200190095A1-20200618-C00859
         		2-(1-(4-((2-cycloheptyl-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)benzyl)piperidin-4-yl)acetic acid 490.3
    Figure US20200190095A1-20200618-C00860
         		4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1- yl)methyl)phenyl)amino)-2- cycloheptylpyrimido[4,5-d]pyridazin-5(6H)-one 514.3
    Figure US20200190095A1-20200618-C00861
         		1-(4-((2-(4-cyanopiperidin-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidine-4-carboxylic acid 474.2
    Figure US20200190095A1-20200618-C00862
         		1-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1- yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2- yl)piperidine-4-carbonitrile 512.3
    Figure US20200190095A1-20200618-C00863
         		1-(4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1- yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2- yl)piperidine-4-carbonitrile 526.3
    Figure US20200190095A1-20200618-C00864
         		1-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)benzyl)piperidine-4-carboxylic acid 502.2
    Figure US20200190095A1-20200618-C00865
         		2-(1-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1- yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2- yl)piperidin-4-yl)acetonitrile 526.3
    Figure US20200190095A1-20200618-C00866
         		2-(1-(4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1- yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2- yl)piperidin-4-yl)acetonitrile 540.3
    Figure US20200190095A1-20200618-C00867
         		1-(4-((2-(4-(cyanomethyl)piperazin-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidine-4-carboxylic acid 489.2
    Figure US20200190095A1-20200618-C00868
         		1-(4-((2-(4-(cyanomethyl)piperazin-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)benzyl)piperidine-4-carboxylic acid 503.2
    Figure US20200190095A1-20200618-C00869
         		2-(4-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1- yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2- yl)piperazin-1-yl)acetonitrile 527.3
    Figure US20200190095A1-20200618-C00870
         		2-(1-(4-((2-(4-(cyanomethyl)piperazin-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)benzyl)piperidin-4-yl)acetic acid 517.3
    Figure US20200190095A1-20200618-C00871
         		2-(4-(4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1- yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2- yl)piperazin-1-yl)acetonitrile 541.3
    Figure US20200190095A1-20200618-C00872
         		6-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid 490.2
    Figure US20200190095A1-20200618-C00873
         		2-(1-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetic acid 478.2
    Figure US20200190095A1-20200618-C00874
         		1-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidine-4-carboxylic acid 464.2
    Figure US20200190095A1-20200618-C00875
         		1-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4- yl)amino)benzyl)piperidine-4-carboxylic acid 452.2
    Figure US20200190095A1-20200618-C00876
         		6-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid 543.2
    Figure US20200190095A1-20200618-C00877
         		2-(1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetic acid 531.2
    Figure US20200190095A1-20200618-C00878
         		1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidine-4-carboxylic acid 517.2
    Figure US20200190095A1-20200618-C00879
         		1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)benzyl)piperidine-4-carboxylic acid 531.2
    Figure US20200190095A1-20200618-C00880
         		3-(4-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1- yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2- yl)piperazin-1-yl)-3-oxopropanenitrile 555.3
    Figure US20200190095A1-20200618-C00881
         		2-(1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)benzyl)piperidin-4-yl)acetic acid 545.3
    Figure US20200190095A1-20200618-C00882
         		4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1- yl)methyl)phenyl)amino)-2-(4-(2- isocyanoacetyl)piperazin-1-yl)pyrimido[4,5- d]pyridazin-5(6H)-one 569.3
    Figure US20200190095A1-20200618-C00883
         		6-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid 542.2
    Figure US20200190095A1-20200618-C00884
         		2-(1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetic acid 530.2
    Figure US20200190095A1-20200618-C00885
         		1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidine-4-carboxylic acid 516.2
    Figure US20200190095A1-20200618-C00886
         		1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidine-4-carboxylic acid 530.2
    Figure US20200190095A1-20200618-C00887
         		3-(4-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1- yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2- yl)piperidin-1-yl)-3-oxopropanenitrile 554.3
    Figure US20200190095A1-20200618-C00888
         		2-(1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)benzyl)piperidin-4-yl)acetic acid 544.3
    Figure US20200190095A1-20200618-C00889
         		4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1- yl)methyl)phenyl)amino)-2-(1-(2- isocyanoacetyl)piperidin-4-yl)pyrimido[4,5- d]pyridazin-5(6H)-one 568.3
    • Example 340: Inhibition of Enzymatic Syk Kinase Activity
  • The objective of this assay was to examine by radiometric method the ability of compounds to inhibit Syk kinase enzyme.
    • A. Background
  • Spleen tyrosine kinase (Syk) is a cytosolic protein tyrosine kinase that plays a crucial role in inflammatory and allergic responses. Syk triggers IgE and IgG receptor mediated signaling in mast cells, basophils, and macrophages leading to degranulation and cytokine release. Abnormal function of Syk has also been implicated in several instances of hematopoietic malignancies.
  • Syk is capable of phosphorylating substrates such as VAV, LAT, SLP-76, which in turn activate MAPK, PLCy signaling pathways. Crystallization studies of the Syk catalytic domain (360-635) showed more activity compared to the full length Syk enzyme. This in vitro assay tests the ability of syk to phosphorylate a substrate peptide in the presence of ATP. By using a radio-labeled form of ATP, it is possible to measure the amount of phosphorylation of the substrate. The enzyme transfers a radio-labeled phosphate group from γ32 P labeled ATP to pG4T. Briefly the enzyme was incubated with substrate, radio-labeled & cold ATP and substrate in buffer with or without compounds. At the end of the reaction, the reaction mixture was transferred on to a Multiscreen filter plate and unreacted γ32P ATP was washed off. The filter plate was dried and the radioactivity was measured on a scintillation counter to estimate the incorporated radioactivity on the substrate. The percent inhibition of activity of the enzyme was calculated by comparing counts in the presence and absence of compounds.
    • B. Reagents and Instruments
  • TABLE 3
    Reagent Supplier
    Poly (Glu, Tyr) sodium salt (4:1) Sigma, Cat #P0275
    Syk (356-635 amino acids) - catalytic n/a
    domain of the full length Syk enzyme*
    Whatman ® P81 Chromatography paper Whatman Cat #3698-915
    Microtest ™ V-Bottom plates Tarsons, Cat #941396
    ATP Sigma, Cat #A7699)
    [γ-32P] ATP Jonaki Lab, Hyderabad,
    Cat #PLC101
    Microscint-O ™ reagent Perkin-Elmer, Cat #6013611
    DMSO Sigma, Cat #D2650
    Top Count ® NXL instrument Perkin Elmer
    Optiplate ® 96 well microplate Perkin-Elmer; Cat #6005299
    TopSeal-A ® 96 well microplate Perkin Elmer; Cat #6005185
    *See, FIG. 2A of Law, “Molecular Cloning of Human Syk”, J. Biol. Chem., 269(16): 12310-12319 (1994) which provides the full-length amino acid sequence for human Syk. the fragment utilized included a C′-terminal tag of 4 amino acids and a stretch of 15 amino acids N-terminal to the kinase domain, starting at amino acid 356.

    See, also, Yagi, “Cloning of the cDNA for the Deleted SYK Kinase Homologous to ZAP-70 from Human Basophilic Leukemia Cell Line (KU812)”, Biochem. Biophys. Res. Commun., 200(1):28-34 (1994). Both of these publications are incorporated by reference herein.
  • TABLE 4
    Tris Buffer composition
    Reagent Supplier
    50 mM tris-hydrochloride (Tris) Sigma, Cat #T5941
    10 mM magnesium chloride (MgCl2) Sigma, Cat #M9272
    2.5 mM Di thiotretol (DTT) Sigma, Cat #D-0632
    500 μM sodium orthovanadate Sigma, Cat. #S6508
    500 μM ethylene glycol tetra acetic acid Sigma, Cat#E3889
    (EGTA)
    0.001% Triton ® X-100 reagent Loba Chemie, CAS #9002-93-1
    (surfactant with molecule formula
    of C14H22O(C2H4O)n
    (n = 9-10)
    • C. Protocol
  • 2.5 μL of 10% DMSO or compound in 10% DMSO was added to the wells in a 96 well V-bottom plate. Optimized concentration of in-house Syk enzyme (different batches of Syk (356-635) kinase domain) were used at optimized concentrations) ranging from 0.035 ng to 7.5 ng/reaction diluted in assay buffer was added to a total volume of 12.5 μL). Compound and protein were incubated for 30 minutes at room temperature on a plate shaker. Ten μL of a substrate mix containing 100 μM ATP (0.25 μL), γ-P32-ATP (0.1 μL; 10 μgCi/μL), pG4T (0.25 μL; 10 mg/mL) and 1× assay buffer (9.4 μL) was added to all the wells. Samples were incubated at 30° C. for 10 minutes after mixing. The reaction was stopped by the addition of 8N HCl (13 μL) containing 100 mM ATP. Thirty μL of sample was transferred to the center of a 2×2 cm2 Whatman® P81 chromatography paper. After allowing the sample to dry for one minute, the assay squares were washed 3 times for 5 minutes each in ortho-phosphoric acid (0.5%) and once in acetone. Assay squares were dried for 15 minutes in a 30° C. oven and transferred to 96 well optiplate. Microscint-O® reagent (100 μL, Perkin Elmer) was added to each well, the plate was sealed with Topseal®-A microplates and incubated for 10 minutes at room temperature at very low speed on rocker and the plate was read in the Topcount® NXL instrument.
  • The following calculations were made:

  • Fold induction=radioactivity counts(uncorrected values) in positive control/substrate control.
  • Percent inhibition was calculated with the corrected values:
  • % inhibition = 100 - { CPM for reaction containing compound * 100 } ( CPM for positive control )
  • The % inhibitions of the compound vs. concentrations of NCE were plotted using Graphpad® Prism software to calculate the IC50 of the active NCE.
  • See, Rossi, J. Allergy Clin. Immunol. (2006), 118(3):749-755 and Eva Papp, “Steady State Kinetics of Spleen Tyrosine Kinase Investigated by a Real Time Fluorescence Assay”, Biochemistry (2007) 46:15103-15114, which are hereby incorporated by reference.
    • Example 341: Inhibition of Enzymatic JAK2 Kinase Activity
  • The objective of this assay was to screen compounds in a Time-resolved fluorescence resonance energy transfer (TR-FRET) Enzymatic assay method for their potential to inhibit JAK2 (Janus kinase) activity. Compounds which inhibit Syk and JAK2 in these studies may be potentially used in treating inflammation.
    • A. Background
  • JAK 2 (Janus kinase 2) is a family of intracellular non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. These kinases have apparent molecular weight of about 130 Kda. They were initially named “just another kinase” 1 & 2 (since they were just two of a large number of discoveries in a PCR-based screen of kinases), but were ultimately published as “Janus kinase”. JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity while the other negatively regulates the kinase activity of the first. They are crucial signal transducers for a variety of cytokines, growth factors and interferons.
  • TR-FRET assays are homogeneous proximity assays where Eu-labeled antiphosphotyrosine antibody binds to the phosphorylated substrates labeled with Ulight fluorescence acceptor. Eu can transfer energy to Ulight accepter in the complex and the interaction of two dye-labeled binding partners is detected by the energy transfer between a donor and an acceptor dye, and the subsequent light emission by the acceptor dye. The intensity of the light emission is proportional to the level of Ulight peptide phosphorylation. See, Rodig, “Disruption of the Jakl gene demonstrates obligatory and nonredundant roles of the JAKs in cytokine-induced biologic responses”, Cell, 93(3):373-83 (1998) and Yamaoka, “The Janus kinases (Jaks)”, Genome Biology, 5:253 (2004), which are incorporated herein by reference.
    • B. Reagents and Equipment
  • TABLE 5
    Reagent Supplier
    Ultra light poly GT (4:1) substrate Perkin Elmer; Cat #TRF-0100-D
    JAK2 Upstate; Cat #14-640
    Lance ® Eu-W1024 Anti- Perkin Elmer; Cat #AD0203
    phosphotyrosine
    (P-Tyr-100) reagent
    dimethyl sulfoxide (DMSO) SpectroChem; Cat #0704209
    ATP Sigma; Cat #A7699
    Wallac ® 1420 multilabel counter Perkin Elmer, Finland
    victor
    3 instrument
    Lumitrac ® 200 384-well plates, Greiner-Bio; Cat #781075
    medium binding, flat bottom,
    white color
  • TABLE 6
    Tris Buffer composition
    Reagent Supplier
    50 mM Tris Sigma, Cat #T5941
    20 mM MgCl2 Sigma, Cat #M9272
    2 mM DTT Sigma, Cat #D-0632
    0.01% Tween ® 20 reagent Sigma; Cat #1379
    (Polyoxyethylene (20) sorbitan
    monolaurate surfactant)
    • C. Protocol
  • Two μL of 10% DMSO in blank, substrate control and positive control wells and 2 μL of test compound in test wells was added. Thirteen μL of assay buffer in blank and substrate control wells and 13 μL of Enzyme buffer mix in positive and test wells was added. The reaction mixture was incubated for 30 minutes at RT on a plate shaker. Ultra Light-pGT substrate (5 μL) [poly Glu-Tyr (4:1) labeled with U Light™ dye, a tyrosine kinase substrate] and ATP mix was added to all wells. The reaction plate was incubated for 60 minutes at RT on a plate shaker. The reaction was stopped by adding 40 mM EDTA (10 μL) in buffer. Ten μL of antibody was added to all the wells. The plate was read in a Wallac® 1420 Multilabel Counter Victor 3 instrument (Ex: 340 nm Em: 615 & 665 nm) The following calculations were made:
  • F@ 665 Value-Buffer blank
  • F@ 615 Value-Buffer blank
  • Ratio: (F@665 Buffer blank/F@615 Buffer blank)*10000
  • Ratio of F@665/F@615-Substrate Blank
  • % Activity=(Test Sample/Positive control)*100
  • % Inhibition=(100-% Activity)
  • TABLE 7
    IC50
    ≥100 nM = A; ≤100 nM = B;
    ≤50 nM = C; ≤10 nM = D
    Ex. # Structure Syk JAK
     1
    Figure US20200190095A1-20200618-C00890
         		C C
     2
    Figure US20200190095A1-20200618-C00891
         		B A
     3
    Figure US20200190095A1-20200618-C00892
         		A B
     4
    Figure US20200190095A1-20200618-C00893
         		B C
     5
    Figure US20200190095A1-20200618-C00894
         		D C
     6
    Figure US20200190095A1-20200618-C00895
         		C C
     7
    Figure US20200190095A1-20200618-C00896
         		C C
     8
    Figure US20200190095A1-20200618-C00897
         		D D
     9
    Figure US20200190095A1-20200618-C00898
         		A —
     10
    Figure US20200190095A1-20200618-C00899
         		C B
     11
    Figure US20200190095A1-20200618-C00900
         		C B
     12
    Figure US20200190095A1-20200618-C00901
         		C D
     13
    Figure US20200190095A1-20200618-C00902
         		C D
     14
    Figure US20200190095A1-20200618-C00903
         		D —
     15
    Figure US20200190095A1-20200618-C00904
         		A —
     16
    Figure US20200190095A1-20200618-C00905
         		A —
     17
    Figure US20200190095A1-20200618-C00906
         		A —
     18
    Figure US20200190095A1-20200618-C00907
         		A C
     19
    Figure US20200190095A1-20200618-C00908
         		C D
     20
    Figure US20200190095A1-20200618-C00909
         		A —
     21
    Figure US20200190095A1-20200618-C00910
         		A —
     22
    Figure US20200190095A1-20200618-C00911
         		B C
     23
    Figure US20200190095A1-20200618-C00912
         		C B
     24
    Figure US20200190095A1-20200618-C00913
         		D B
     25
    Figure US20200190095A1-20200618-C00914
         		C B
     26
    Figure US20200190095A1-20200618-C00915
         		D B
     27
    Figure US20200190095A1-20200618-C00916
         		A A
     28
    Figure US20200190095A1-20200618-C00917
         		A A
     29
    Figure US20200190095A1-20200618-C00918
         		A —
     30
    Figure US20200190095A1-20200618-C00919
         		C C
     31
    Figure US20200190095A1-20200618-C00920
         		C A
     32
    Figure US20200190095A1-20200618-C00921
         		B A
     33
    Figure US20200190095A1-20200618-C00922
         		C A
     34
    Figure US20200190095A1-20200618-C00923
         		C C
     35
    Figure US20200190095A1-20200618-C00924
         		C C
     36
    Figure US20200190095A1-20200618-C00925
         		A B
     37
    Figure US20200190095A1-20200618-C00926
         		D B
     38
    Figure US20200190095A1-20200618-C00927
         		A —
     39
    Figure US20200190095A1-20200618-C00928
         		C C
     40
    Figure US20200190095A1-20200618-C00929
         		C A
     41
    Figure US20200190095A1-20200618-C00930
         		B A
     42
    Figure US20200190095A1-20200618-C00931
         		B C
     43
    Figure US20200190095A1-20200618-C00932
         		C B
     44
    Figure US20200190095A1-20200618-C00933
         		A A
     45
    Figure US20200190095A1-20200618-C00934
         		A A
     46
    Figure US20200190095A1-20200618-C00935
         		B B
     47
    Figure US20200190095A1-20200618-C00936
         		B B
     48
    Figure US20200190095A1-20200618-C00937
         		B B
     49
    Figure US20200190095A1-20200618-C00938
         		B B
     50
    Figure US20200190095A1-20200618-C00939
         		D A
     51
    Figure US20200190095A1-20200618-C00940
         		A A
     52
    Figure US20200190095A1-20200618-C00941
         		D D
     53
    Figure US20200190095A1-20200618-C00942
         		A B
     54
    Figure US20200190095A1-20200618-C00943
         		D D
     55
    Figure US20200190095A1-20200618-C00944
         		A A
     56
    Figure US20200190095A1-20200618-C00945
         		A C
     57
    Figure US20200190095A1-20200618-C00946
         		— —
     58
    Figure US20200190095A1-20200618-C00947
         		A C
     59
    Figure US20200190095A1-20200618-C00948
         		C A
     60
    Figure US20200190095A1-20200618-C00949
         		D D
     61
    Figure US20200190095A1-20200618-C00950
         		A —
     62
    Figure US20200190095A1-20200618-C00951
         		D D
     63
    Figure US20200190095A1-20200618-C00952
         		A —
     64
    Figure US20200190095A1-20200618-C00953
         		A —
     65
    Figure US20200190095A1-20200618-C00954
         		A —
     66
    Figure US20200190095A1-20200618-C00955
         		C
     67
    Figure US20200190095A1-20200618-C00956
         		A
     68
    Figure US20200190095A1-20200618-C00957
         		B
     69
    Figure US20200190095A1-20200618-C00958
         		D
     70
    Figure US20200190095A1-20200618-C00959
         		B A
     71
    Figure US20200190095A1-20200618-C00960
         		A A
     72
    Figure US20200190095A1-20200618-C00961
         		C B
     73
    Figure US20200190095A1-20200618-C00962
         		B —
     74
    Figure US20200190095A1-20200618-C00963
         		A —
     75
    Figure US20200190095A1-20200618-C00964
         		B —
     76
    Figure US20200190095A1-20200618-C00965
         		A —
     77
    Figure US20200190095A1-20200618-C00966
         		C D
     78
    Figure US20200190095A1-20200618-C00967
         		B —
     79
    Figure US20200190095A1-20200618-C00968
         		C D
     80
    Figure US20200190095A1-20200618-C00969
         		C D
     81
    Figure US20200190095A1-20200618-C00970
         		C D
     82
    Figure US20200190095A1-20200618-C00971
         		A —
     83
    Figure US20200190095A1-20200618-C00972
         		C C
     84
    Figure US20200190095A1-20200618-C00973
         		C D
     85
    Figure US20200190095A1-20200618-C00974
         		C D
     86
    Figure US20200190095A1-20200618-C00975
         		C C
     87
    Figure US20200190095A1-20200618-C00976
         		C B
     88
    Figure US20200190095A1-20200618-C00977
         		D D
     89
    Figure US20200190095A1-20200618-C00978
         		C C
     90
    Figure US20200190095A1-20200618-C00979
         		B C
     91
    Figure US20200190095A1-20200618-C00980
         		D C
     92
    Figure US20200190095A1-20200618-C00981
         		D C
     93
    Figure US20200190095A1-20200618-C00982
         		C C
     94
    Figure US20200190095A1-20200618-C00983
         		B —
     95
    Figure US20200190095A1-20200618-C00984
         		C C
     96
    Figure US20200190095A1-20200618-C00985
         		D D
     97
    Figure US20200190095A1-20200618-C00986
         		A —
     98
    Figure US20200190095A1-20200618-C00987
         		C C
     99
    Figure US20200190095A1-20200618-C00988
         		D C
    100
    Figure US20200190095A1-20200618-C00989
         		C C
    101
    Figure US20200190095A1-20200618-C00990
         		A A
    102
    Figure US20200190095A1-20200618-C00991
         		C A
    103
    Figure US20200190095A1-20200618-C00992
         		D D
    104
    Figure US20200190095A1-20200618-C00993
         		C D
    105
    Figure US20200190095A1-20200618-C00994
         		D D
    106
    Figure US20200190095A1-20200618-C00995
         		C C
    107
    Figure US20200190095A1-20200618-C00996
         		D C
    108
    Figure US20200190095A1-20200618-C00997
         		D D
    109
    Figure US20200190095A1-20200618-C00998
         		D D
    110
    Figure US20200190095A1-20200618-C00999
         		D C
    111
    Figure US20200190095A1-20200618-C01000
         		C A
    112
    Figure US20200190095A1-20200618-C01001
         		C D
    113
    Figure US20200190095A1-20200618-C01002
         		A D
    114
    Figure US20200190095A1-20200618-C01003
         		D C
    115
    Figure US20200190095A1-20200618-C01004
         		C C
    116
    Figure US20200190095A1-20200618-C01005
         		C C
    117
    Figure US20200190095A1-20200618-C01006
         		C D
    118
    Figure US20200190095A1-20200618-C01007
         		C D
    119
    Figure US20200190095A1-20200618-C01008
         		A —
    120
    Figure US20200190095A1-20200618-C01009
         		C C
    121
    Figure US20200190095A1-20200618-C01010
         		C C
    122
    Figure US20200190095A1-20200618-C01011
         		A —
    123
    Figure US20200190095A1-20200618-C01012
         		D D
    124
    Figure US20200190095A1-20200618-C01013
         		D D
    125
    Figure US20200190095A1-20200618-C01014
         		D D
    126
    Figure US20200190095A1-20200618-C01015
         		B C
    127
    Figure US20200190095A1-20200618-C01016
         		C C
    128
    Figure US20200190095A1-20200618-C01017
         		C C
    129
    Figure US20200190095A1-20200618-C01018
         		D D
    130
    Figure US20200190095A1-20200618-C01019
         		D D
    131
    Figure US20200190095A1-20200618-C01020
         		D D
    132
    Figure US20200190095A1-20200618-C01021
         		C D
    133
    Figure US20200190095A1-20200618-C01022
         		B C
    134
    Figure US20200190095A1-20200618-C01023
         		C D
    135
    Figure US20200190095A1-20200618-C01024
         		D D
    136
    Figure US20200190095A1-20200618-C01025
         		C C
    137
    Figure US20200190095A1-20200618-C01026
         		A —
    138
    Figure US20200190095A1-20200618-C01027
         		A —
    139
    Figure US20200190095A1-20200618-C01028
         		C D
    140
    Figure US20200190095A1-20200618-C01029
         		D D
    141
    Figure US20200190095A1-20200618-C01030
         		C D
    142
    Figure US20200190095A1-20200618-C01031
         		C D
    143
    Figure US20200190095A1-20200618-C01032
         		C A
    144
    Figure US20200190095A1-20200618-C01033
         		B B
    145
    Figure US20200190095A1-20200618-C01034
         		D D
    146
    Figure US20200190095A1-20200618-C01035
         		D C
    147
    Figure US20200190095A1-20200618-C01036
         		D C
    148
    Figure US20200190095A1-20200618-C01037
         		C C
    149
    Figure US20200190095A1-20200618-C01038
         		A —
    150
    Figure US20200190095A1-20200618-C01039
         		C A
    151
    Figure US20200190095A1-20200618-C01040
         		C C
    152
    Figure US20200190095A1-20200618-C01041
         		C A
    153
    Figure US20200190095A1-20200618-C01042
         		C B
    154
    Figure US20200190095A1-20200618-C01043
         		C C
    155
    Figure US20200190095A1-20200618-C01044
         		C C
    156
    Figure US20200190095A1-20200618-C01045
         		C B
    157
    Figure US20200190095A1-20200618-C01046
         		C C
    158
    Figure US20200190095A1-20200618-C01047
         		C D
    159
    Figure US20200190095A1-20200618-C01048
         		C D
    160
    Figure US20200190095A1-20200618-C01049
         		C C
    161
    Figure US20200190095A1-20200618-C01050
         		C D
    162
    Figure US20200190095A1-20200618-C01051
         		D D
    163
    Figure US20200190095A1-20200618-C01052
         		A —
    164
    Figure US20200190095A1-20200618-C01053
         		C D
    165
    Figure US20200190095A1-20200618-C01054
         		B D
    166
    Figure US20200190095A1-20200618-C01055
         		C C
    167
    Figure US20200190095A1-20200618-C01056
         		C D
    168
    Figure US20200190095A1-20200618-C01057
         		C C
    169
    Figure US20200190095A1-20200618-C01058
         		C C
    170
    Figure US20200190095A1-20200618-C01059
         		C D
    171
    Figure US20200190095A1-20200618-C01060
         		C C
    172
    Figure US20200190095A1-20200618-C01061
         		C D
    173
    Figure US20200190095A1-20200618-C01062
         		C C
    174
    Figure US20200190095A1-20200618-C01063
         		C C
    175
    Figure US20200190095A1-20200618-C01064
         		D D
    176
    Figure US20200190095A1-20200618-C01065
         		A —
    177
    Figure US20200190095A1-20200618-C01066
         		A —
    178
    Figure US20200190095A1-20200618-C01067
         		D D
    179
    Figure US20200190095A1-20200618-C01068
         		D D
    180
    Figure US20200190095A1-20200618-C01069
         		D D
    181
    Figure US20200190095A1-20200618-C01070
         		A A
    182
    Figure US20200190095A1-20200618-C01071
         		B D
    183
    Figure US20200190095A1-20200618-C01072
         		D C
    184
    Figure US20200190095A1-20200618-C01073
         		D D
    185
    Figure US20200190095A1-20200618-C01074
         		D C
    186
    Figure US20200190095A1-20200618-C01075
         		D B
    187
    Figure US20200190095A1-20200618-C01076
         		D C
    188
    Figure US20200190095A1-20200618-C01077
         		C C
    189
    Figure US20200190095A1-20200618-C01078
         		D C
    190
    Figure US20200190095A1-20200618-C01079
         		D D
    191
    Figure US20200190095A1-20200618-C01080
         		D D
    192
    Figure US20200190095A1-20200618-C01081
         		D D
    193
    Figure US20200190095A1-20200618-C01082
         		D D
    194
    Figure US20200190095A1-20200618-C01083
         		A —
    195
    Figure US20200190095A1-20200618-C01084
         		D D
    196
    Figure US20200190095A1-20200618-C01085
         		D D
    197
    Figure US20200190095A1-20200618-C01086
         		D D
    198
    Figure US20200190095A1-20200618-C01087
         		D D
    199
    Figure US20200190095A1-20200618-C01088
         		D D
    200
    Figure US20200190095A1-20200618-C01089
         		D C
    201
    Figure US20200190095A1-20200618-C01090
         		D D
    202
    Figure US20200190095A1-20200618-C01091
         		C D
    203
    Figure US20200190095A1-20200618-C01092
         		C D
    204
    Figure US20200190095A1-20200618-C01093
         		A —
    205
    Figure US20200190095A1-20200618-C01094
         		C C
    206
    Figure US20200190095A1-20200618-C01095
         		C D
    207
    Figure US20200190095A1-20200618-C01096
         		D D
    208
    Figure US20200190095A1-20200618-C01097
         		D D
    209
    Figure US20200190095A1-20200618-C01098
         		D C
    210
    Figure US20200190095A1-20200618-C01099
         		C D
    211
    Figure US20200190095A1-20200618-C01100
         		C C
    212
    Figure US20200190095A1-20200618-C01101
         		C C
    213
    Figure US20200190095A1-20200618-C01102
         		D C
    214
    Figure US20200190095A1-20200618-C01103
         		D D
    215
    Figure US20200190095A1-20200618-C01104
         		D D
    216
    Figure US20200190095A1-20200618-C01105
         		D D
    217
    Figure US20200190095A1-20200618-C01106
         		C C
    218
    Figure US20200190095A1-20200618-C01107
         		C C
    219
    Figure US20200190095A1-20200618-C01108
         		D D
    220
    Figure US20200190095A1-20200618-C01109
         		D D
    221
    Figure US20200190095A1-20200618-C01110
         		C D
    222
    Figure US20200190095A1-20200618-C01111
         		B C
    223
    Figure US20200190095A1-20200618-C01112
         		D D
    224
    Figure US20200190095A1-20200618-C01113
         		C C
    225
    Figure US20200190095A1-20200618-C01114
         		A —
    226
    Figure US20200190095A1-20200618-C01115
         		A —
    227
    Figure US20200190095A1-20200618-C01116
         		C D
    228
    Figure US20200190095A1-20200618-C01117
         		C C
    229
    Figure US20200190095A1-20200618-C01118
         		C D
    230
    Figure US20200190095A1-20200618-C01119
         		A —
    231
    Figure US20200190095A1-20200618-C01120
         		C B
    232
    Figure US20200190095A1-20200618-C01121
         		C D
    233
    Figure US20200190095A1-20200618-C01122
         		D D
    234
    Figure US20200190095A1-20200618-C01123
         		C D
    235
    Figure US20200190095A1-20200618-C01124
         		C C
    236
    Figure US20200190095A1-20200618-C01125
         		B C
    237
    Figure US20200190095A1-20200618-C01126
         		C D
    238
    Figure US20200190095A1-20200618-C01127
         		C D
    239
    Figure US20200190095A1-20200618-C01128
         		B C
    240
    Figure US20200190095A1-20200618-C01129
         		C D
    241
    Figure US20200190095A1-20200618-C01130
         		A —
    242
    Figure US20200190095A1-20200618-C01131
         		C C
    243
    Figure US20200190095A1-20200618-C01132
         		C C
    244
    Figure US20200190095A1-20200618-C01133
         		D D
    245
    Figure US20200190095A1-20200618-C01134
         		C C
    246
    Figure US20200190095A1-20200618-C01135
         		D D
    247
    Figure US20200190095A1-20200618-C01136
         		D D
    248
    Figure US20200190095A1-20200618-C01137
         		D D
    249
    Figure US20200190095A1-20200618-C01138
         		C C
    250
    Figure US20200190095A1-20200618-C01139
         		C D
    251
    Figure US20200190095A1-20200618-C01140
         		C C
    252
    Figure US20200190095A1-20200618-C01141
         		C D
    253
    Figure US20200190095A1-20200618-C01142
         		C D
    254
    Figure US20200190095A1-20200618-C01143
         		D C
    255
    Figure US20200190095A1-20200618-C01144
         		C D
    256
    Figure US20200190095A1-20200618-C01145
         		D C
    257
    Figure US20200190095A1-20200618-C01146
         		D C
    258
    Figure US20200190095A1-20200618-C01147
         		B —
    259
    Figure US20200190095A1-20200618-C01148
         		C C
    260
    Figure US20200190095A1-20200618-C01149
         		C C
    261
    Figure US20200190095A1-20200618-C01150
         		D C
    262
    Figure US20200190095A1-20200618-C01151
         		C D
    263
    Figure US20200190095A1-20200618-C01152
         		D D
    264
    Figure US20200190095A1-20200618-C01153
         		D D
    265
    Figure US20200190095A1-20200618-C01154
         		D D
    266
    Figure US20200190095A1-20200618-C01155
         		D C
    267
    Figure US20200190095A1-20200618-C01156
         		D D
    268
    Figure US20200190095A1-20200618-C01157
         		D C
    269
    Figure US20200190095A1-20200618-C01158
         		C C
    270
    Figure US20200190095A1-20200618-C01159
         		C C
    271
    Figure US20200190095A1-20200618-C01160
         		D C
    272
    Figure US20200190095A1-20200618-C01161
         		C D
    273
    Figure US20200190095A1-20200618-C01162
         		D D
    274
    Figure US20200190095A1-20200618-C01163
         		D D
    275
    Figure US20200190095A1-20200618-C01164
         		D D
    276
    Figure US20200190095A1-20200618-C01165
         		D C
    277
    Figure US20200190095A1-20200618-C01166
         		D C
    278
    Figure US20200190095A1-20200618-C01167
         		C C
    279
    Figure US20200190095A1-20200618-C01168
         		A —
    280
    Figure US20200190095A1-20200618-C01169
         		C D
    281
    Figure US20200190095A1-20200618-C01170
         		C D
    282
    Figure US20200190095A1-20200618-C01171
         		C D
    283
    Figure US20200190095A1-20200618-C01172
         		D D
    284
    Figure US20200190095A1-20200618-C01173
         		D D
    285
    Figure US20200190095A1-20200618-C01174
         		C C
    286
    Figure US20200190095A1-20200618-C01175
         		C C
    287
    Figure US20200190095A1-20200618-C01176
         		C C
    288
    Figure US20200190095A1-20200618-C01177
         		C C
    289
    Figure US20200190095A1-20200618-C01178
         		C D
    290
    Figure US20200190095A1-20200618-C01179
         		C C
    291
    Figure US20200190095A1-20200618-C01180
         		C C
    292
    Figure US20200190095A1-20200618-C01181
         		D D
    293
    Figure US20200190095A1-20200618-C01182
         		B C
    294
    Figure US20200190095A1-20200618-C01183
         		C C
    295
    Figure US20200190095A1-20200618-C01184
         		C C
    296
    Figure US20200190095A1-20200618-C01185
         		B —
    297
    Figure US20200190095A1-20200618-C01186
         		D C
    298
    Figure US20200190095A1-20200618-C01187
         		A —
    299
    Figure US20200190095A1-20200618-C01188
         		C C
    300
    Figure US20200190095A1-20200618-C01189
         		A —
    301
    Figure US20200190095A1-20200618-C01190
         		A —
    302
    Figure US20200190095A1-20200618-C01191
         		A —
    303
    Figure US20200190095A1-20200618-C01192
         		A —
    304
    Figure US20200190095A1-20200618-C01193
         		D D
    305
    Figure US20200190095A1-20200618-C01194
         		D C
    306
    Figure US20200190095A1-20200618-C01195
         		D D
    307
    Figure US20200190095A1-20200618-C01196
         		D D
    308
    Figure US20200190095A1-20200618-C01197
         		C D
    309
    Figure US20200190095A1-20200618-C01198
         		C C
    310
    Figure US20200190095A1-20200618-C01199
         		A —
    311
    Figure US20200190095A1-20200618-C01200
         		A —
    312
    Figure US20200190095A1-20200618-C01201
         		A —
    313
    Figure US20200190095A1-20200618-C01202
         		A —
    314
    Figure US20200190095A1-20200618-C01203
         		C D
    315
    Figure US20200190095A1-20200618-C01204
         		C C
    316
    Figure US20200190095A1-20200618-C01205
         		C D
    317
    Figure US20200190095A1-20200618-C01206
         		A —
    318
    Figure US20200190095A1-20200618-C01207
         		A —
    319
    Figure US20200190095A1-20200618-C01208
         		A —
    320
    Figure US20200190095A1-20200618-C01209
         		A —
    321
    Figure US20200190095A1-20200618-C01210
         		A —
    322
    Figure US20200190095A1-20200618-C01211
         		C D
    323
    Figure US20200190095A1-20200618-C01212
         		C C
    324
    Figure US20200190095A1-20200618-C01213
         		C C
    325
    Figure US20200190095A1-20200618-C01214
         		C C
    326
    Figure US20200190095A1-20200618-C01215
         		A —
    327
    Figure US20200190095A1-20200618-C01216
         		A —
    328
    Figure US20200190095A1-20200618-C01217
         		A —
    329
    Figure US20200190095A1-20200618-C01218
         		D D
    330
    Figure US20200190095A1-20200618-C01219
         		A —
    331
    Figure US20200190095A1-20200618-C01220
         		C A
    332
    Figure US20200190095A1-20200618-C01221
         		B —
    333
    Figure US20200190095A1-20200618-C01222
         		A —
    334
    Figure US20200190095A1-20200618-C01223
         		C D
    335
    Figure US20200190095A1-20200618-C01224
         		C C
    336
    Figure US20200190095A1-20200618-C01225
         		C C
    337
    Figure US20200190095A1-20200618-C01226
         		C C
    338
    Figure US20200190095A1-20200618-C01227
         		B A
    339
    Figure US20200190095A1-20200618-C01228
         		D C
    • Example 342: Degranulation Assay
  • The objective of this assay was to examine by Fluorescence method the effect of compounds on β-hexosaminidase release during immune complex mediated degranulation in RBL2H3 cells.
    • A. Introduction
  • Auto-antibodies and their immune complexes (ICs) reacting with self antigens through immunoglobulin receptors have been implicated widely in inflammation and chronic inflammatory disease such as rheumatoid arthritis. Activation of the high affinity receptor for immunoglobulin E (IgE), FcεRI, which is expressed on the surface of mast cells and basophils, plays a central role in the initiation of these allergic responses. Following aggregation of the receptor by ICs, the mast cell release a variety of potent biologically active molecules, including cytokines, lipid-derived mediators, amines, protease, and proteoglycans. Anti-DNP (anti-dinitrophenyl) IgE treated RBL2H3 cells on stimulation with DNP-BSA leads to FcϵR1 cross linking which mediates release of various pro-inflammatory molecules including β-hexosaminidase.
  • Compounds were tested for their ability to inhibit the ability of this immune complex to mediate β-hexosaminidase release, in an enzyme assay with p-nitrophenyl-β-D-glucosaminide as substrate. The fluorescence of the product 4-methylumbellifernone was monitored (Excitation 355 nm; Emission 460 nm).
    • B. Reagents and Instruments
  • TABLE 8
    Reagent Supplier
    Rat Basophilic Leukemia cell line ATCC, Cat # CRL-2256
    (RBL2H3 cell line)
    Minimum Essential Medium (MEM) GIBCO, Cat # 12571
    Fetal Bovine Serum (FBS) Hyclone, Cat # SH30071.03
    Pencilin (10000 unit/mL)- GIBCO, Cat #15140-122
    Streptomycin (10,000 μg/mL)
    (Penstrep ® reagent)
    MEM Sodium Pyruvate solution, GIBCO, Cat # 11360
    100 mM
    Nonessential amino acid (NEAA) GIBCO, Cat # 11140
    0.1% Trypsin and 0.1% EDTA SAFC Biosciences, Cat # 59417C
    (0.1% TE)
    96-well flat bottom plate Falcon, Cat # 3072
    100% Dimethyl Sulfoxide SIGMA-D-5879
    (DMSO; Vehicle)
    SPE-7 Anti-Dinitrophenyl (DNP)
    Monoclonal Rat IgE, Clone SPE-7
    (Sigma, Cat #D8406)
    2,4-Dinitrophenylated Albumin from Invitrogen, Cat #A23018
    bovine serum (DNP-BSA)
    4-Methylumbelliferyl N-acetyl-β-D- Sigma, Cat #2133
    glucosaminide dihydrate (β-NAG)
    0.1M Sodium Carbonate/Sodium Na2CO3: Sigma, Cat # S5761
    Bicarbonate, pH 10.08 NaHCO3: Sd fine - Chemicals Ltd,
    (Stop Solution) Cat # 40121
    Phosphate Buffer Saline (PBS) Himedia, Cat # TS1006
    96 well View Plate PerkinElmer, Part #6005182
    24 well plate Falcon, Cat # 3047
    Victor ™ X5 Multi label plate Perkin-Elmer, Product #2030-
    Fluorescence Reader 0050
  • TABLE 9
    Pipes Buffer composition
    Reagent Supplier
    25 mM piperazine-1,4-bis(2-ethanesulfonic acid) Sigma Cat # P1851
    (Pipes)
    125 mM sodium chloride (NaCl) Qualigens Cat # 15918
    2.7 mM potassium chloride (KCl) Sigma Cat # P9541
    5.6 mM anhydrous D-glucose Qualigens Cat # 24415
    1 mM calcium chloride (CaCl2) Qualigens Cat # 22205
    0.1% bovine serum albumin (BSA) Sigma Cat # A7030
    • C. Protocols
  • (i) Protocol A: 24 Well Format
  • RBL2H3 cells were maintained in MEM complete media containing 10% FBS at 70%-80% confluence in a mammalian cell culture CO2 incubator with 5% CO2 at 37° C. 2×105 cells/well were plated in 1 mL of complete media and incubated for 5 hours for cell attachment. Complete media was replaced with 1 mL of serum free MEM media containing 1.2 μg/mL of anti-DNP rat IgE as sensitizing agent and further incubated overnight with 5% CO2 at 37° C. The following day, cells were washed with serum free media and further treated with various concentrations of test compounds (in 0.1% DMSO) for 45 minutes at 37° C. and 5% CO2. Cells were further stimulated with 5 μg/mL of DNP-BSA for 60 minutes. Plates were centrifuged for 5 minutes at 1000 rpm and 25 μL of culture supernatant was transferred from each assay well into a 96 well black coated plate. 25 μL P-NAG substrate was added to this mixture and incubated at room temperature for 30 minutes. The reaction was terminated with 100 μL of stop solution and fluorescence was monitored. (Excitation 355 nm; Emission 460 nm) See, Sanderson, (2010), Cellular Immunology, 262(1): 28-34 and Silverman, (2006) MCB, 26(5):1826-1838, which are incorporated herein by reference.
  • The % release of β-Hexosaminidase for the test compound was calculated using the following formula:
  • % β - Hexosaminidase release = ( test comoound - DMSO contro1 IgE control - DMSO Contro1 ) × 100
  • (ii) Protocol B: 96 Well Format
  • RBL2H3 cells were maintained in MEM complete media containing 10% FBS at 70-80% confluence in a mammalian cell culture CO2 incubator with 5% CO2 at 37° C. 5×104 cells/well were plated in 200 μL of complete media containing 0.3 μg/mL of anti-DNP rat IgE as sensitizing agent for 24 hours at 37° C. & 5% CO2. The following day, cells were washed twice with PIPES buffer for 10 minutes at 37° C. and replenished with serum free MEM media. Cells were treated with various concentrations of test compounds (in 0.5% DMSO) for 15 minutes at 37° C. and 5% CO2. The cells were further stimulated with 0.1 μg/mL of DNP-BSA for 45 minutes. The plates were spun for 5 minutes at 2000 rpm and 25 μL of culture supernatant was then transferred from each assay well into a 96 well black coated plate. Fifth μL P-NAG substrate was added and incubated at RT for 30 minutes. After incubation with substrate, 150 μL of stop solution was added and fluorescence was monitored. (Excitation 355 nm; Emission 460 nm). See, Yamamoto, JPET, 306(3):1174-1181 (2003) and Taylor, MCB, 15(8): 4149-4157 (1995), which are herein incorporated by reference.
  • Release of β-hexosaminidase during the degranulation process by immune complex mediated FcεRI stimulation is through the SYK pathway. The % inhibition of β-hexosaminidase release by Syk inhibitor gives information with regard to its Syk inhibition potency. Thus compounds having lower EC50 values are more potent in inhibiting immune complex mediated Syk signaling during degranulation process.
  • TABLE 10
    Degranulation % Degranulation
    Ex. # inhibition at 1 μM EC50 (nM) Assay Protocol
    1 85 — A
    5 100 39 A
    6 50 — A
    7 92 86 A
    8 98 — A
    10 100 — A
    11 100 — A
    13 100 47 A
    19 100 19 A
    24 83 — B
    25 79 — A
    26 67 — B
    30 99 — B
    33 58 — B
    34 80 378 B
    35 19 — B
    39 100 — B
    43 13 — B
    47 100 132 B
    48 100 — B
    50 49 — B
    52 100 1 B
    54 100 13 B
    60 100 18 B
    62 100 49 B
    66 75 352 B
    68 100 1.2 B
    69 100 31 B
    71 65 1017 B
    88 100 76 B
    89 100 — B
    91 100 154 B
    92 100 111 B
    93 49 — B
    95 35 — B
    96 85 280 B
    98 62 593 B
    99 94 44 B
    103 87 32 B
    104 100 110 B
    107 91 94 B
    108 98 68 B
    116 65 273 B
    117 89 95 B
    118 87 153 B
    121 98 156 B
    123 90 116 B
    125 38 238 B
    131 98 35 B
    132 99 24 B
    133 98 25 B
    145 52 98 B
    146 66 26 B
    147 49 152 B
    151 — 24 B
    153 47 324 B
    154 23 2320 B
    155 — 27 B
    157 70 42 B
    158 53 162 B
    159 68 56 B
    161 74 39 B
    162 27 281 B
    164 — 55 B
    169 17 230 B
    170 39 107 B
    172 50 101 B
    173 66 29 B
    174 99 15 B
    175 98 6 B
    178 73 39 B
    179 45 9 B
    180 70 3 B
    183 41 83 B
    184 65 33 B
    185 83 29 B
    186 93 10 B
    187 100 12 B
    189 98 14 B
    190 83 21 B
    191 92 21 B
    192 82 27 B
    193 93 17 B
    200 71 66 B
    201 88 31 B
    208 21 14 B
    209 81 29 B
    210 79 22 B
    211 53 49 B
    212 71 28 B
    213 78 33 B
    214 78 19 B
    215 96 12 B
    216 92 21 B
    218 33 123 B
    219 45 96 B
    231 0 367 B
    232 0 619 B
    233 20 174 B
    244 23 306 B
    248 99 19 B
    254 24 1200 B
    256 73 33 B
    261 87 39 B
    264 75 54 B
    265 79 30 B
    266 99 10 B
    267 90 21 B
    268 93 20 B
    273 91 21 B
    274 59 81 B
    275 73 15 B
    276 91 24 B
    277 74 42 B
    283 71 39 B
    284 92 21 B
    287 97 20 B
    290 100 20 B
    292 65 83 B
    297 99 18 B
    304 70 55 B
    305 17 834 B
    306 100 15 B
    307 14 312 B
    329 69 62 B
    339 83 31 B
    • Example 343: In Vivo Assay—Chronic Study A. Introduction
  • Collagen Induced Arthritis (CIA) is a well characterized model of human rheumatoid arthritis (RA) that can be induced in susceptible animals following immunization with type II collagen (cII) in Freund's adjuvant. CIA exhibits several features of human RA such as severe swelling/inflammation of joints, synovial hyperplasia, cartilage destruction and bone erosion. Pathophysiology of CIA consists of T cell component, as evidenced by increased infiltration of T-cells in joint synovium and also, by attenuation of CIA in T-cell deficient mice. CIA development involves B cell component too, as is evidenced by circulating cII antibody in disease animals and also, failure to develop the disease in xid mice/B cell deficient mice/CXCR5 null mice. Recently, a significant role of macrophages has also been suggested in the pathogenesis of CIA as well as human RA. See, Pine, “Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor”, Clin. Immunol., 2007, 124(3):244-57; Xiong cha, “Suppression of the onset and progression of collagen-induced arthritis in rats by QFGJS, a preparation from an anti-arthritic Chinese herbal formula”, J. Ethnopharmacology (2007) 110:39-48; and Stolina, “The evolving systemic and local biomarker milieu at different stages of disease progression in rat collagen induced arthritis”, Biomarkers (2008) 13(7-8):692-712, which are herein incorporated by reference.
    • B. Method
  • (i) Induction of CIA:
  • Female Lewis rats (8 per group, 6-8 weeks old) were immunized on day 1 with type II collagen (Immunization grade Bovine type II; Chondrex; Cat #20021) emulsified with Complete Freund's Adjuvant (Sigma; Cat # F5881) at a final concentration of 1.2 mg/mL). For the initial immunization, the animals were injected at the base of the tail with 300 μg of the cII (0.25 mL/rat). A booster injection of the same type II collagen emulsified with Incomplete Freund's Adjuvant (Sigma, Cat # F5506) (0.25 mL/rat) was given to the animals on day 8 at the base of the tail (100 μg). The final cII concentration in the booster was 0.4 μg/mL.
  • (ii) Dosage Regimen
  • Animals with an arthritic score of ≥1 were grouped and dosing with test compound (30 mg/kg bid) or methotrexate (0.5 mg/kg) started between about day 12 to day 14, with daily dosing of their respective compounds continuing for 10 days.
  • (iii) Measurements:
  • Edema: Paw volumes are measured by Plethysmometry for the animals before induction of CIA (Basal readings) and on Day 1, 3, 6 and 9 of dosing period. Both hind paw volumes were measured and edema was calculated by subtracting from the basal mean.
  • Arthritic score: Animals were scored for the symptoms of arthritis every day starting from Day of onset of disease till the end of the study. Both the hind paws were scored and the total scores were averaged and compared with control. The scoring pattern was as follows:
  • TABLE 11
    Severity
    score Gross pathology
    0 No evidence of erythema or swelling
    1 Erythema and mild swelling confined to
    mid foot or ankle joint
    2 Erythema and moderate swelling extending
    from ankle to mid foot
    3 Erythema and moderate swelling extending
    from ankle to metatarsal joints
    4 Erythema and severe swelling ankle,
    foot and digits
    • C. Results
  • (i) Calculations
  • The percent inhibition of Edema was calculated with respect to control by the formula:
  • % inhibition of Edema = ( 1 - { Mean Edema in treated animals on day n ′ ′ _ ( Mean Edema in treated animals on day 0 ′ ′ ) ( Mean Edema in control animals on day n ′ ′ ) ( Mean Edema in control animals on day 0 ′ ′ ) } ) × 100
  • The percent inhibition of Arthritic score was calculated with respect to control by the formula:
  • % inhibition of Score = ( 1 - { Mean score in treated animals on day n ′ ′ _ ( Mean score in treated animals on day 0 ′ ′ ) ( Mean score in control animals on day n ′ ′ ) ( Mean score in control animals on day 0 ′ ′ ) } ) × 100
  • (ii) Statistical Analysis
  • Means of different groups were compared with control using one way ANOVA followed by Dunnett's test. Significance is represented as follows.
  • This example illustrates that the compounds may be utilized for treating inflammation. See FIGS. 1-2.
  • TABLE 12
    Percent inhibition of Percent inhibition of
    Edema Arthritic score
    Group (Day 9 of dosing) (Day 10 of dosing)
    Control 0  0 
    Example 19 (2 × 30 mg/Kg) 5** 20* 
    Methotrexate (0.5 mg/Kg) 6  15  
    Example 62 (2 × 30 mg/Kg) 69*** 81***
    Example 108 (2 × 30 mg/Kg) 42*** 53***
    Example 189 (2 × 30 mg/Kg) 90*** 94***
    Example 191 (2 × 30 mg/Kg) 90*** 100*** 
    *p < 0.05,
    **p < 0.01,
    ***p < 0.001
    • Example 344: In Vivo Assay—Acute Study A. Introduction
  • Arthus reaction is a type of local type III hypersensitivity reaction. Type III hypersensitivity reactions are immune complex-mediated, and involve the deposition of antigen/antibody complexes mainly in the vascular walls, serosa (pleura, pericardium, synovium), and glomeruli. This involves formation of antigen/antibody complexes after the intradermal injection of an antibody. If the animal was previously injected with antigen and dye (has circulating antigen), an Arthus reaction occurs. This manifests as local vasculitis due to deposition of immune complexes in dermal blood vessels. Activation of complement and recruitment of PMNs ensue, resulting in an inflammatory response and extravasation of dye to the skin. Compounds which can inhibit this complex process can have therapeutic implications in wide range of inflammatory and auto-immune disorders. See, Pine, “Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor”; Clin. Immunol. (2007) 124 (3): 244-57; and Sylvia, “R-406, an Orally Available Spleen Tyrosine Kinase Inhibitor Blocks Fc Receptor Signaling and Reduces Immune Complex-Mediated Inflammation”, JPET 319:998-1008, 2006, which are herein incorporated by reference.
    • B. Immunization and Challenge
  • Female c57BL/6 mice were given an antigen injection in which the antigen was 0.1% Ovalbumin (OVA) in PBS containing 1% Evans blue (EB) at the concentration of 10 mL/kg intravenously under Isoflurane anesthesia [2.5 mg/mouse with a body weight of 25 g]. Ten minutes after antigen injection; the animals were injected with the rabbit anti-OVA IgG (50 μg in 25 μL/site) (Polysciences; Cat #23744) intradermally on the shaved back at two top locations. Animals were also injected with phosphate buffered saline (PBS, 25 μL) intradermally on the back at two bottom and opposite locations to serve as negative control. The mice were euthanized by cervical dislocation 4 hours after antigen (Ovalbumin) challenge. Skin tissue was assessed for edema by tracing the edema area on to a transparent plastic sheet. Punch biopsies of the injection sites were collected.
    • C. Measurements
  • (i) Area of extravasation
  • Edema area was measured manually by scale. Two diameters were taken and averaged for each animal.
  • (ii) Extent of Dye Extravasation
  • Punch biopsies of the injection sites (using 10 mm skin biopsy punches) were incubated in 2 mL of sodium sulfate: acetone mixture (0.6+1.4 mL) at room temperature for 16-18 hours. The supernatants were removed from digested tissues by centrifuging at 4000 rpm for 10 minutes, filtered and were read spectrophotometrically at 610 nm.
    • D. Data Analysis
  • The percent inhibition of dye leakage was calculated with respect to control by the formula:
  • Percent inhibition of OD = { 1 - [ Mean OD in treated animals Mean OD in control animals ] } × 100
  • The percent inhibition of edema area was calculated with respect to control by the formula:
  • Percent inhibition of edema area = { 1 - [ Mean edema area in treated animals Mean edema area in control animals ] } × 100
    • E. Statistical Analysis:
  • Means of different groups were compared with control using One way ANOVA followed by Dunnett's test. Significance was represented as follows.
  • This example illustrates that the compounds described herein may be utilized in treating inflammation.
  • TABLE 13
    Efficacy of NCEs in Arthus reaction model in mice
    Dose Edema area OD
    Example (mg/Kg) % Inhibition % Inhibition
    7 30 74*** 65***
    10 53*** 36  
    10 30   NE
    13 10 53*** 27  
    30 40**  30  
    19 3 48*** 53***
    30 60*** 60***
    7 3 41*** 40***
    10 45*** 41***
    30 68*** 67***
    *p < 0.05,
    **p < 0.01,
    ***p < 0.001
  • All publications cited in this specification are incorporated herein by reference. While the invention has been described with reference to particular embodiments, it will be appreciated that modifications can be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the appended claims.

Claims (24)

What is claimed is:
1. A compound of Formula (I):
Figure US20200190095A1-20200618-C01229
wherein:
R1 is NR4R5, optionally substituted C1 to C6 alkoxy, optionally substituted C6 to C14 aryl, optionally substituted heteroaryl, optionally substituted 3-10 membered monocyclic or bicyclic cycloalkyl, or optionally substituted 3-10 membered monocyclic or bicyclic heterocyclyl, wherein:
(i) 3-4 membered cycloalkyl and heterocyclyl are saturated;
(ii) hydrogen atoms on the same carbon atom of said cycloalkyl or heterocyclyl are optionally replaced with an optionally substituted 3-6 membered cycloalkyl or heterocyclyl to form a spirocycloalkyl or spiroheterocyclyl; and
(iii) hydrogen atoms on the same atom of said cycloalkyl or heterocyclyl are optionally replaced with O to form an oxo substituent;
R2 is optionally substituted phenyl, —O—(C1 to C6 alkyl)-optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl, with the proviso that when R2 is 4-pyridyl, the 4-pyridyl lacks a carbonyl substituent at the 2nd position;
R4 and R5 are:
(a) independently selected from the group consisting of H, C1 to C6 alkyl, C1 to C6 hydroxyalkyl, C3 to C8 cycloalkyl, and —(C1 to C6 alkyl)N(C1 to C6 alkyl)(C1 to C6 alkyl);
(b) joined to form an optionally substituted 3-8 membered heterocyclyl, wherein;
(bi) hydrogen atoms on the same carbon atom of said heterocyclyl are optionally replaced with an optionally substituted 3-6 membered cycloalkyl or heterocyclyl to form a spirocycloalkyl or spiroheterocyclyl; and
(bii) hydrogen atoms on the same atom of said heterocyclyl (b), cycloalkyl (bi), or heterocyclyl (bi), are optionally replaced with O to form an oxo substituent;
or a pharmaceutically acceptable salt or ester thereof.
2. The compound according to claim 1, wherein R2 is phenyl substituted with C(O)NR4R5.
3. The compound according to claim 1, where R2 is phenyl substituted with NR4R5.
4. The compound according to claim 1, where R2 is phenyl substituted with (C1 to C6 alkyl)NR4R5.
5. The compound according to claim 1, wherein R4 and R5 are joined to form an optionally substituted piperidine or diazepane.
6. The compound according to claim 1, where R2 is phenyl substituted with (C1 to C6 alkyl)NR4R5.
7. The compound according to claim 6, wherein R4 and R5 are (C1 to C6 hydroxyalkyl).
8. The compound according to claim 6, wherein R4 and R5 are joined to form an optionally substituted 6-membered ring.
9. The compound according to claim 1, wherein R2 is a heteroaryl substituted with (C1 to C6 alkyl)NR4R5.
10. The compound according to claim 1, wherein R2 is a heteroaryl substituted with NR4R5.
11. The compound according to claim 1, wherein R2 is phenyl substituted with one or more C1 to C6 alkoxy, (C1 to C6 alkyl)halogen, C1 to C6 trifluoroalkoxy, (C1 to C6 alkyl)C(O(OH, halogen, optionally substituted C3 to C8 cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —O—(C1 to C6 alkyl)C(O)OH, —O—(C1 to C6 alkyl)-NR4R5, —O-(optionally substituted heterocycle), —O(C1 to C6 alkyl)-N(C1 to C6 alkyl)(C1 to C6 alkyl), —O—(C1 to C6 alkyl)NH2, C1 to C6 hydroxyalkyl, —O—(C1 to C6 hydroxyalkyl), O—(C1 to C6 alkyl)-C(O)OH, —C1 to C6 alkoxy-C1 to C6 alkoxy, O-(heterocycle)-(C1 to C6 hydroxyalkyl), SO2—(C1 to C6 alkyl), or —(C1 to C6 alkyl)-(C1 to C6 alkoxy)-halogen.
12. The compound according to claim 1, wherein R2 is —O—(C1 to C6 alkyl)NR4R5.
13. The compound according to claim 1, wherein R2 is aryl substituted with —O—(C1 to C6 alkyl)-heterocycle.
14. The compound according to claim 1, wherein R1 is N(C1 to C6 alkyl)(C1 to C6 alkyl) or C1 to C6 alkoxy.
15. The compound according to claim 1, wherein R1 is optionally substituted phenyl.
16. The compound according to claim 1, wherein R1 is optionally substituted 5-9 membered saturated heterocyclyl.
17. The compound according to claim 1, wherein R1 is a heterocyclyl of the structure:
Figure US20200190095A1-20200618-C01230
wherein:
f, g, h, j, and m are, independently, absent, (CH2), CH(R3), Z, or C═O;
R3 is H, C(O)OH, or C(O)O(C1 to C6 alkyl);
R45, R46, R47, and R48 are, independently, H or C1 to C6 alkyl; and
Z is O, S, SO, SO2, or NH.
18. The compound according to claim 1, wherein R1 is a heteroaryl.
19. The compound according to claim 1, wherein R1 is a monocyclic C3 to C8 cycloalkyl.
20. The compound according to claim 1, wherein R1 is piperidine substituted with C(O)(C1 to C6 alkyl)CN.
21. The compound according claim 1 which is a salt of an acid.
22. The compound according to claim 21, wherein said acid is selected from the group consisting of acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, trifluoroacetic, and camphorsulfonic.
23. The compound according to claim 1, which is:
4-(4-morpholinophenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;
methyl 4-(5-oxo-4-(4-(piperazin-1-ylmethyl)phenylamino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)benzoate hydrochloride;
2-morpholino-4-(4-(piperazin-1-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
4-(4-(morpholinomethyl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;
4-(4-(4-ethylpiperazin-1-yl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;
4-(4-((4-ethylpiperazin-1-yl)methyl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;
2-phenyl-4-(4-(piperazin-1-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
2-phenyl-4-(4-(piperazin-1-yl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-one;
4-(4-(morpholine-4-carbonyl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;
4-(4-(bis(2-hydroxyethyl)amino)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;
4-(4-(4-(2-aminoacetyl)piperazin-1-yl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
2-(4-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)phenyl)piperazin-1-yl)acetic acid;
1-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)phenyl)piperidine-4-carboxylic acid;
4-(4-(4-(2-aminoacetyl)piperazin-1-yl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;
N-(2-(dimethylamino)ethyl)-N-methyl-4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)benzamide;
4-(4-(2-oxo-1,7-diazaspiro[3.5]nonan-7-yl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;
4-(4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;
4-(4-morpholinophenylamino)-2-(6-azaspiro[2.5]octan-6-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;
6-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
ethyl 6-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)phenyl)-6-azaspiro[2.5]octane-1-carboxylate;
6-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)benzyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
sodium 6-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)phenyl)-6-azaspiro[2.5]octane-1-carboxylate;
4-(4-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;
4-(4-(piperazin-1-ylmethyl)phenylamino)-2-(thiophen-3-yl)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
6-(5-oxo-4-(4-(piperazin-1-ylmethyl)phenylamino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)-6-azaspiro[2.5]octane-1-carboxylic acid hydrochloride;
4-(4-(4-ethylpiperazin-1-yl)phenylamino)-2-morpholinopyrimido[4,5-d]pyridazin-5(6H)-one;
4-(5-oxo-4-(4-(piperazin-1-ylmethyl)phenylamino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)benzoic acid hydrochloride;
4-(4-(4-ethylpiperazin-1-yl)phenylamino)-2-(4-(trifluoromethoxy)phenyl)pyrimido[4,5-d]pyridazin-5(6H)-one;
methyl 4-(4-(4-morpholinophenylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)benzoate;
4-(4-(piperazin-1-ylmethyl)phenylamino)-2-(piperidin-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
2-(3-methoxyphenyl)-4-(4-(piperazin-1-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
2-(piperazin-1-yl)-4-(4-(piperazin-1-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-one dihydrochloride;
2-(benzo[d][1,3]dioxol-5-yl)-4-(4-(piperazin-1-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
2-(1-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)phenyl)piperidin-4-yl)acetic acid;
1-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)benzyl)piperidine-4-carboxylic acid;
2-(2-methoxyphenyl)-4-(4-(piperazin-1-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
4-(4-(4-ethylpiperazin-1-yl)phenylamino)-2-(thiophen-3-yl)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
9-(5-oxo-4-(4-(piperazin-1-ylmethyl)phenylamino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)-3,9-diazaspiro[5.5]undecane-2,4-dione hydrochloride;
6-(4-(5-oxo-2-(thiophen-3-yl)-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-(4-chlorophenyl)-4-(4-(piperazin-1-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
2-(4-methoxyphenyl)-4-(4-(piperazin-1-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
6-(4-((2-morpholino-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-(1-(5-oxo-4-((4-(piperazin-1-ylmethyl)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetic acid hydrochloride;
2-(1-oxidothiomorpholino)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
2-(4-methylpiperazin-1-yl)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
6-(4-((2-(4-methoxyphenyl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
6-(4-((2-(3-methoxyphenyl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
4-((4-(piperazin-1-ylmethyl)phenyl)amino)-2-(pyrrolidin-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
2-(dimethylamino)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
2-ethoxy-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
1-(5-oxo-4-((4-(piperazin-1-ylmethyl)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-carboxylic acid hydrochloride;
2-(azepan-1-yl)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
6-(4-((2-(2-methoxyphenyl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-(diisopropylamino)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
2-(4-(morpholinomethyl)phenyl)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
1-(5-oxo-4-((4-(piperazin-1-ylmethyl)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-carbonitrile hydrochloride;
2-(4-ethylpiperazin-1-yl)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
4-((1-(2-morpholinoethyl)-1H-pyrazol-4-yl)amino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1,4-diazepan-1-yl)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one dihydrochloride;
2-(azepan-1-yl)-4-((4-morpholinophenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-methoxy-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
6-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-phenyl-4-((1-(2-(piperazin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
4-((1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;
4-((1-(2-(4-ethylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;
6-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-(azepan-1-yl)-4-((3,4,5-trimethoxyphenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((4-(morpholine-4-carbonyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid;
2-(1-(4-((2-(4-(cyanomethyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid;
2-(1-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid;
6-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid hydrochloride;
6-(4-((2-(4-(cyanomethyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
6-(4-((2-(4-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-(1-(4-((2-(4-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid;
1-(4-((2-(4-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid;
2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-yl)acetic acid;
1-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid;
6-(4-((2-cyclohexyl-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile;
6-(4-((2-cycloheptyl-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-(1-(4-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile;
4-((4-((4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl)methyl)phenyl)amino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((4-((4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl)methyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5 (6H)-one;
2-(azepan-1-yl)-4-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(4-(4-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-1-yl)acetic acid;
2-(4-(4-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)cyclohexyl)acetic acid;
2-(1-(4-((2-(azocan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid;
2-(azepan-1-yl)-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
2-(1-(4-((2-cycloheptyl-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid;
2-(4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)cyclohexyl)acetic acid;
4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)butanoic acid;
2-(azepan-1-yl)-4-((4-(2-morpholinoethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
4-((4-(2-morpholinoethoxy)phenyl)amino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(2-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)ethyl)piperidin-4-yl)acetic acid;
2-(1-(5-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetonitrile;
1-(2-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)ethyl)piperidine-4-carboxylic acid;
2-(1-(5-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetamide;
2-(1-(4-((2-(4-(2-cyanopropan-2-yl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid;
2-(1-(5-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetonitrile;
2-(1-(5-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetamide;
2-(1-(5-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(piperazine-1-carbonyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetamide;
2-(4-(2-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)ethyl)piperazin-1-yl)acetic acid;
2-(azepan-1-yl)-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(5-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid;
2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)-N-(2-hydroxyethyl)acetamide;
2-(azepan-1-yl)-4-((4-(((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5 (6H)-one;
2-(4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)-2-methylpropanenitrile;
2-(4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)-2-methylpropanamide;
2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile;
2-(1-(5-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(2-(4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(5-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid;
2-(1-(4-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid;
2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)-N,N-bis(2-hydroxyethyl)acetamide;
2-methyl-2-(1-(4-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)propanenitrile;
2-(4-(2-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)ethyl)piperazin-1-yl)-2-methylpropanenitrile;
2-(1-(4-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid;
4-((4-(((2 S, 5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)amino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;
2-((1S,4S)-4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)cyclohexyl)acetic acid;
(2R,5S)-5-((4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)methyl)-1,4-dioxane-2-carboxylic acid;
2-(4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)acetic acid;
2-(1-(3-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)propyl)piperidin-4-yl)acetic acid;
6-(4-((2-(cyclohexylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)spiro[2.5]octane-1-carboxylic acid;
6-(4-((5-oxo-2-(piperidin-1-yl)-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)spiro[2.5]octane-1-carboxylic acid;
2-((1R,4R)-4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)cyclohexyl)acetic acid;
3-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)propanoic acid;
2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)cyclopropanecarboxylic acid;
3-(1-(4-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)propanoic acid;
6-(4-((2-(4-fluorophenyl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
6-(5-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)-6-azaspiro[2.5]octane-1-carboxylic acid;
6-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)-2-fluorophenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-(azepan-1-yl)-4-((4-(3-(piperazin-1-yl)propoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
6-(5-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)-6-azaspiro[2.5]octane-1-carboxylic acid;
6-(4-((5-oxo-2-(pyridin-4-yl)-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-(azepan-1-yl)-4-((4-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)-2-methylpropanoic acid;
6-(4-((2-(azocan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)-2-methylpropanoic acid;
2-methyl-2-(1-(4-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)propanoic acid;
2-(2,6-dimethylpiperidin-1-yl)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((2-(2,6-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid;
6-(4-((2-(2,6-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-(1-(4-((2-(2,6-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile;
2-(2,6-dimethylpiperidin-1-yl)-4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(5-((2-(2,6-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid;
2-(3,5-dimethylpiperidin-1-yl)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid;
6-(4-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-(1-(4-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile;
2-(3,5-dimethylpiperidin-1-yl)-4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(5-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid;
2-(2,6-dimethylmorpholino)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid;
6-(4-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-(1-(4-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile;
2-(2,6-dimethylmorpholino)-4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(5-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid;
2-(diisopropylamino)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((2-(diisopropylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid;
6-(4-((2-(diisopropylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-(1-(4-((2-(diisopropylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile;
2-(diisopropylamino)-4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(5-((2-(diisopropylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid;
2-(2-methylpiperidin-1-yl)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((2-(2-methylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid;
6-(4-((2-(2-methylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-(1-(4-((2-(2-methylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile;
4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperidin-1-yl)phenyl)amino)-2-(2-methylpiperidin-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(5-((2-(2-methylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid;
1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid;
1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid;
4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-2-(azepan-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;
4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-2-(azepan-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((2-cycloheptyl-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid;
1-(4-((2-cycloheptyl-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid;
6-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-(1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid;
1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid;
1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid;
1-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-3-carbonitrile;
2-(1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-yl)acetic acid;
1-(4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-3-carbonitrile;
1-(4-((2-cycloheptyl-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid;
4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-2-cycloheptylpyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((2-cycloheptyl-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-yl)acetic acid;
4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-2-cycloheptylpyrimido[4,5-d]pyridazin-5(6H)-one;
1-(4-((2-(4-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid;
1-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-carbonitrile;
1-(4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-carbonitrile;
1-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid;
2-(1-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(1-(4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyidazin-2-yl)piperidin-4-yl)acetonitrile;
1-(4-((2-(4-(cyanomethyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid;
1-(4-((2-(4-(cyanomethyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid;
2-(4-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperazin-1-yl)acetonitrile;
2-(1-(4-((2-(4-(cyanomethyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-yl)acetic acid;
2-(4-(4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperazin-1-yl)acetonitrile;
6-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-(1-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid;
1-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid;
1-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid;
6-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-(1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid;
1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid;
1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid;
3-(4-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperazin-1-yl)-3-oxopropanenitrile;
2-(1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-yl)acetic acid;
4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-2-(4-(2-isocyanoacetyl)piperazin-1-yl)pyrimido[4,5-d]pyridazin-5 (6H)-one;
6-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-(1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid;
1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid;
1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid;
3-(4-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-1-yl)-3-oxopropanenitrile;
2-(1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-yl)acetic acid;
4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-2-(1-(2-isocyanoacetyl)piperidin-4-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(4-(5-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperazin-1-yl)acetic acid;
2-(4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-1,4-diazepan-1-yl)acetic acid;
2-(1-(4-((4-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
3-(1-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)propanoic acid;
6-(5-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)-6-azaspiro[2.5]octane-1-carboxylic acid;
1-(5-oxo-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-carbonitrile;
2-(1-(5-oxo-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(2-(4-ethylpiperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-phenyl-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)-2-(piperidin-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(4-(4-((5-oxo-2-(piperidin-1-yl)-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-1,4-diazepan-1-yl)acetic acid;
6-(4-((2-(4-methylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-(4-methylpiperidin-1-yl)-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
2-(azepan-1-yl)-4-((4-(2-(3-oxopiperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
6-(2-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)ethyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
2-(azepan-1-yl)-4-((4-(2-(diethylamino)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(cyclohexyl(methyl)amino)-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((2-(cyclohexyl(methyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid;
2-(4-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)acetic acid;
2-(1-(4-((2-(3-methoxyphenyl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile;
4-((4-(2-(1,4-diazepan-1-yl)ethoxy)phenyl)amino)-2-(azepan-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((4-(3-oxopiperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(3-methoxyphenyl)-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((4-(2-(dimethylamino)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((4-(2-(piperidin-4-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(5-oxo-4-((4-(2-(piperidin-4-yl)ethoxy)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
6-(4-((2-(cyclohexyl(methyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid;
4-((4-(2-(1,4-diazepan-1-yl)ethoxy)phenyl)amino)-2-(piperidin-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((4-(2-(4-hydroxypiperidin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((4-(3-(piperazin-1-yl)propyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(5-oxo-4-((4-(3-(piperazin-1-yl)propyl)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(4-ethyl-3-oxopiperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-morpholino-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(2,6-dimethylmorpholino)-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(4-ethyl-3-oxopiperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(3-(4-hydroxypiperidin-1-yl)propyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
4-((6-(2-(piperazin-1-yl)ethoxy)pyridin-3-yl)amino)-2-(piperidin-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((6-(2-(piperazin-1-yl)ethoxy)pyridin-3-yl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
4-((4-(2-(4-hydroxypiperidin-1-yl)ethoxy)phenyl)amino)-2-(piperidin-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((4-(2-(4-hydroxy-4-methylpiperidin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(2-(4-hydroxy-4-methylpiperidin-1-yl)ethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(2-(diisopropylamino)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(5-oxo-4-((4-(piperazin-1-yl)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(4-(3-hydroxypropyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(1-(4-((4-(2-(4-ethylpiperazin-1-yl)ethyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(2-(piperazin-1-yl)ethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
4-((4-(2-aminoethoxy)phenyl)amino)-2-(azepan-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(2-aminoethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(2-(4-hydroxypiperidin-1-yl)ethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((4-(2-(4-(hydroxymethyl)piperidin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(2-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)piperidin-1-yl)ethyl)piperidin-4-yl)acetonitrile;
2-(1-(4-((4-(4-(3-hydroxypropyl)piperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)acetonitrile;
2-(1-(4-((4-(4-(cyanomethyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
3-(4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)propanoic acid;
2-(azepan-1-yl)-4-((4-(2-(4-ethylpiperazin-1-yl)ethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((4-(2-(4-hydroxy-4-methylpiperidin-1-yl)ethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(4-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)-2-methylpropanoic acid;
2-(azepan-1-yl)-4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
3-(4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)-3-oxopropanenitrile;
2-(1-(4-((4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(2-(4-(hydroxymethyl)piperidin-1-yl)ethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
(phosphonooxy)methyl 6-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylate;
3-(4-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)propanoic acid;
2-(azepan-1-yl)-4-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((4-(2-(2-hydroxyethyl)-2H-tetrazol-5-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(1-(4-((4-(2-(diethylamino)ethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(2-ethyl-2H-tetrazol-5-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(2-ethyl-2H-tetrazol-5-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
4-((4-(2H-tetrazol-5-yl)phenyl)amino)-2-(azepan-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((6-(4-ethylpiperazin-1-yl)pyridin-3-yl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((6-(4-ethylpiperazin-1-yl)pyridin-3-yl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(4-(5-oxo-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperazin-1-yl)acetonitrile;
2-(1-(5-oxo-4-((6-(piperazin-1-yl)pyridin-3-yl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-3-yl)acetic acid;
2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-3-yl)acetic acid;
3-(4-(5-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperazin-1-yl)-3-oxopropanenitrile;
2-(5-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-2H-tetrazol-2-yl)acetic acid;
2-(azepan-1-yl)-4-((6-(4-(2-hydroxyethyl)piperidin-1-yl)pyridin-3-yl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
3-(4-(5-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperazin-1-yl)-3-oxopropanenitrile;
2-(azepan-1-yl)-4-((6-(4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl)pyridin-3-yl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
3-(4-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)-3-oxopropanenitrile;
2-(5-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-2H-tetrazol-2-yl)acetic acid;
2-(azepan-1-yl)-4-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
4-((4-(4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)phenyl)amino)-2-(azepan-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(2H-tetrazol-5-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(1-(4-((4-(4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(1-(5-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)acetic acid;
2-(1-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-3-yl)acetic acid;
2-(1-(4-((6-(4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl)pyridin-3-yl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyidazin-2-yl)piperidin-4-yl)acetonitrile;
4-((6-(4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)pyridin-3-yl)amino)-2-(azepan-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((6-(4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)pyridin-3-yl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)piperidin-1-yl)acetic acid;
2-(azepan-1-yl)-4-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(1-(4-((4-(4-(2-aminoethyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(1-(hydroxymethyl)-6-azaspiro[2.5]octan-6-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(1-(hydroxymethyl)-6-azaspiro[2.5]octan-6-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(4-(3-hydroxypropyl)piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(4-(3-hydroxypropyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(4-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)piperidin-1-yl)acetic acid;
2-(azepan-1-yl)-4-((4-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(4-(1-hydroxy-2-methylpropan-2-yl)piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(4-(1-hydroxy-2-methylpropan-2-yl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(2-(4-ethylpiperazin-1-yl)-2-oxoethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(2-(4-ethylpiperazin-1-yl)-2-oxoethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(1-(4-((4-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(3-(2-hydroxyethyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((4-(4-(2,3-dihydroxypropyl)piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(4-(2,3-dihydroxypropyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((6-(3-hydroxypiperidin-1-yl)pyridin-3-yl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((6-(3-hydroxypiperidin-1-yl)pyridin-3-yl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(4,4-difluoropiperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(4,4-difluoropiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(3-hydroxypiperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(3-hydroxypiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(3-(hydroxymethyl)piperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(3-(hydroxymethyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(3-(2-hydroxyethyl)piperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(1-(4-((4-(4-methoxypiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(4-methoxypiperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((4-(4-fluoropiperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(4-fluoropiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(1-(4-((4-((1-(2-hydroxyethyl)piperidin-4-yl)oxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(piperidin-4-yloxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one hydrochloride;
2-(1-(4-((4-(2-hydroxyethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(2-hydroxyethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(3-hydroxypropoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(3-hydroxypropoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(4-(1-hydroxy-2-methylpropan-2-yl)-1,4-diazepan-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(4-(2-fluoroethyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(4-(2-fluoroethyl)piperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(1-(4-((3,5-dimethoxyphenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(1-(5-oxo-4-((4-(trifluoromethoxy)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((3,5-dimethoxyphenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((4-(trifluoromethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
3-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)propanoic acid;
3-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)propanoic acid;
2-(azepan-1-yl)-4-((4-(bis(2-hydroxyethyl)amino)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(bis(2-hydroxyethyl)amino)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(3-hydroxypropyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(3-hydroxypropyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((3-(hydroxymethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((3-(hydroxymethyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(1-(4-((4-fluorophenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-fluorophenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(azepan-1-yl)-4-((4-((1-hydroxy-2-methylpropan-2-yl)oxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-((1-hydroxy-2-methylpropan-2-yl)oxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)-2-methylpropanoic acid;
2-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)-2-methylpropanoic acid;
2-(azepan-1-yl)-4-((3,4-dimethoxyphenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((3,4-dimethoxyphenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((3-methoxyphenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((3-methoxyphenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(2-hydroxyethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(2-hydroxyethyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(2-methoxyethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(2-methoxyethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(1-(5-oxo-4-((3,4,5-trimethoxyphenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-(benzo[d][1,3]dioxol-5-ylamino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-(benzo[d][1,3]dioxol-5-ylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-((1-(2-hydroxyethyl)piperidin-4-yl)oxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
sodium (2-(4-(cyanomethyl)piperidin-1-yl)-4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-5-oxopyrimido[4,5-d]pyridazin-6(5H)-yl)methyl phosphate;
2-(azepan-1-yl)-4-((4-(hydroxymethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((4-(hydroxymethyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(1-(4-((4-(methylsulfonyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(azepan-1-yl)-4-((4-(methylsulfonyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;
2-(1-(4-((1H-benzo[d][1,2,3]triazol-5-yl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(1-(5-oxo-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(1-(4-((4-(3-fluoropropyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;
2-(1-(4-((4-(difluoromethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile; or
4-((1H-benzo[d][1,2,3]triazol-5-yl)amino)-2-(azepan-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one.
24. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
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