BROAD-SPECTRUM MACROCYCLIC ANTIBIOTICS

Abstract

Antibacterial compounds are provided herein, wherein some embodiments of the compounds have broad-spectrum bioactivity. In various embodiments, the compounds act by inhibiting the bacterial type 1 signal peptidases SpsB and / or LepB, an essential protein in bacteria. Pharmaceutical compositions and methods of treatment using the compounds described herein are also provided.

Description

BROAD SPECTRUM MACROCYCLIC ANTIBIOTICS CROSS REFERENCE TO RELATED REQUESTS MA / t / ZUZZ / U10 / 01 This application claims the benefit of priority of U.S. Provisional Patent Application No. 62 / 853,457, filed May 28, 2019, the contents of which are incorporated herein by reference in their entirety for all purposes. BACKGROUND Antibiotic resistance is a serious and growing phenomenon in contemporary medicine, and has become one of the major public health concerns of the 21st century. For example, certain antibacterial compounds have been described in International Patent Publication No. WO 2018 / 149419, the contents of which are incorporated herein by reference in their entirety. Some of these antibacterial compounds are shown in Table 1. Table 1 Comp. No. Structure Denomination 254 h2n L HO. Ηγχ I. IV- U Y N N Λ N N 0 J Y y - 0 0 \ 1 0 nh2 rac-(8S,11S,14S)-18-(2-aminoethoxy)N-(c i ano met i I)-3-hyd rox 1-11 - m et i I14-[methyl-[rac-(2S γ-ami no-2-[[2(4—te r-butylfeni I)—4,6—dimethyl-pyrimid in— 5-carbonyl]am¡ no]butanoyl]amino]10,13-d ioxo-9,12- diazatric¡clo[13.3.1.12,6]cosa1(18),2(20),3,5,15(19),16 -hexaen-8- carboxamide 561-15 nh2 0^ ho. 1 OH |1 L JL L J o hn 1 H II H 1 II Y Y^ Y^ o 1 0 1 0 1 nh2 acid rac-(8S.11S,14S) -4-(2-aminoethoxy)-3,18-dihydroxy¡-11-methyl- 14-[methyl-[rac-(2S)-4-amino-2-[[2(4-tert-butylphenyl) )—4,6—dimethyl-pyrimid in— 5-carbonyl]amino]butanoyl]amino]10,13-d ioxo-9,12-diazatricyclo[13.3.1.12,6]icosa1(18),2,4,6 (20),15(19),16-hexaen-8carboxylic 563 / NH2 H2KL k 2 > 0 XXX A \X ^ T^Y^ 0 HN 1 H II H 1 H X .A / N. 0 ΓΓ Y V Ό 1 0 1 O 1 nh2 acid rac-(8S,11S,14S)-4,18-bis(2aminoethoxy)-3-hydroxy-11 - m ethyl-14[methyl-[rac-(2S)-4-amino-2- [[2-(4ter-butylphenyl)^,6-dimethyl-pyrimidin-5carbonyl]amino]butanoyl]amino]-10,13dioxo-9,12-diazatricyclo[13.3.1.12,6]icosa1(18),2,4 ,6(20),15(19), 16-hexaen-8carboxylic 582 OH Η2Ν, ^\ / ΝΗ2 ΗΟ“ ΟΗ οχ ,.Λ,. L ϊ ,ν. , Ο Λ .* Y' ν Ο Υ ΗΝΓ 1 Η ¡ Η Ν<χ JL Y γ. γ. χΝ. ,Χ 0 Y Υ '0 0 0 ΝΗ o s-nh2 ό rac-(8S,11S, 14S)—Ν—(cyanomethyl)—18hydroxy—11—methyl—14—[methyl-[rac—(2S)— 2 —[[2—(4—tert—butylphenyl)—4,6—dimethyl—pyrimid in- 5-carbonyl]amino]- 3(sulfamoylamino)propano¡l]amino]10,13-d ioxo-3, 17-bis[rac-(2 R)-3amino-2-hydroxy¡-propoxy¡]-9,12-diazatricyclic[13.3.1.12,6]cosa1(18),2(20),3 ,5,15(19),16-hexaen-8carboxamide 586 ° Χ § i ,......< W Ζ / Χο Ο· / -? Ζ^ / , y / > 8 ο ( / ο—, ' \ / \ ζχ}, ,< )...ο / / \ / 1 ......Υ \ / \ / \ / ' Ζ ο 5 - “ ° \ ζτ ( \ % 'ζ rac-(8S,11S,14S)-N-(cyanomethyl)-18methoxy-11-methyl-14-[methyl-[rac-(2S)4-amino-2 -[[2-(4-tert-butylphenyl)-4,6dimethyl-pyrimidin—5—carbonyl]amino]butanyl]amino]-10,13dioxo-3,17-bis[rac- (2R)-3-amino-2hydroxy¡-propoxy]-9,12-diazatric¡cyclo[13.3.1.12,6]cosa- 1(18),2(20),3,5,15(19), 16-hexaen-8- carboxamide 633 / \ Μ ο=γ χ Ζ Ζ—< ΖΣ 2 Μ .......... / / τ \ \ ΙΌ ^=Ο Ο ζ =5γΑ ζχ \— / Υ ° \ ζχ k (8S,11S,14S)-14-[[(2S)^4—amino-2[[2—(4—ter—butylfenyl)—4,6—dimethylpyrimid in—5— carbo nil]am ino]b utane ¡I]—methyl-amino]-17,18-bis(2aminoethoxy)-N-(cyanornetyl)-3-h¡diOxy11—m ethyl—10,13-dioxo-9,12diazatricycle [13.3.1.12,6]icosa1(18),2(20),3,5,15(19),16-hexaen-8carboxamide 638 νη2 ΑΑΑ, ( ΧΧ^ U X\ γ^ γ^ 0 ύ ΗΝ >< Η II Η 1 II χ ι< ir ^1-amino-2-[[4,6-dimethyl-2-(4pentoxyphenyl)pyrimidin—5—carbonyl]amino]butanoyl]amino]-10,13dioxo-9,12-diazatricycle [13.3.1.12,6]thing- 1(18),2(20),3,5,15(19),16-hexaen-8- carboxylic 639 / Ζ-< ΖΙ Μ \ / χ \ Μ >° γ ο<ΧΧ ζχ \— / \—ζ lililí·»· / V 7 Μ λγ ο=\ [methyl-[rac- (2S)—4-am i no-2-[[2-[4-( 1 -ethylcyclopropoxy¡)phenyl]—4,6—dimethyl— pyrimid in-5- carbonyl]amino]butane ¡l]am¡no]-10,13- dioxo-9,12- diazatricyclo[13.3.1.12,6]cosa- 1(18),2(20),3,5,15(19),16- hexaen-8- carboxylic ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ 640 νη2 Η2Ν. ) χ. λΑΑ L· JL / L J ιι 0 HN X I H II H I II N^ J< ,Ν. x O -ami no-2-[[2-(4-ter-b uti If eni I )4—methyl-pyrimidin—5— carbonyl]amino]butano¡l]amino]-10,13dioxo-9,12 - diazatricyclo[13.3.1.12,6]icose— 1(18),2(20),3,5,15(19),16-hexaen-8carboxylic 641 i~O Y O= / \ ,z:E 1 / M í -C-J o=\ —\ °—\ ZI #-% '—I linm··· / \ / M ° \ 11 -methyl-14-[methyl-[rac(2S)^4-amino-2-[[2-(4-hexoxyphenyl)4,6-dimethyl-pyrimidin- 5-carbonyl]amino]butane ¡l]amino]-10,13- dioxo-9,12- diazatricyclo[13.3.1.12,6]¡cosa1(18),2(20),3,5,15(19),16-hexaen-8carboxylic 642 nh2 Λ OH |1 zk / VA CWx / U X 1 Η || H I II k A. .N. X )-4-amino-2-[[4,6dimethyl—2—(4—pentoxyphenyl)pyrimidin—5—carbonyl]amino]butano¡l]amino]-10,13dioxo-9,12- diazatricyclo[13.3. 1.12,6]icosa— 1(18),2(20),3,5,15(19), 16-hexaen-8carboxylic 643 „ZyY Y ^~r~i I y......ur IZ jj- rac acid-(8S,11S,14S)-18-(2- aminoethoxy¡)-3-hydroxy¡-11 —m ethyl— 14[ m et i l-[ rac-( 2S) -4-am ino-2-[[2-(4isopropoxyph enyl)—4,6-dimethyl-pyrimid in5-carbonyl]amino]butanoyl]amino ]10,13-d ioxo-9,12- diazatricyclo[13.3.1.12,6]icose— 1(18),2(20),3,5,15(19), 16-hexaen-8carboxylic 644 h2n k. HO L 4 L J 4 ,oh Η ° H HN Ϊ 'r r γ^χ a 0 O,! 0 nh2 acid rac-(8S,11S,14S)-18-(2- aminoethoxy)-3-hydroxy-11 —m ethyl—14[ m et i l-[ rac-( 2S) -4-am i no- 2-[[6-(4ter—butylphenyl)-2,4-dimethyl-pyrid in-3carbonyl]amino]butaníl]amino]-10,13dioxo-9,12-diazatricyclo[13.3.1.12,6 ]icose— 1(18),2(20),3,5,15(19),16-hexaen-8carboxylic ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ 645 Z--< ZI ......... -z / =\ / zz \\—z ......* o=\ x rac acid-(8S, 11 S,14S )-3 ,18-b is(2-aminoethoxy¡)-11 —methyl—14—[m ethyl—[rae— (2S γ-ami no-2-[[2-(4-ter-b uti If eni I )4 ,6-d imethyl-pyrimidin- 5- carbonyl]amino]butane¡l]amino]-10,13dioxo-9,12- diazatricyclo[13.3.1.12,6]icose— 1(18),2(20) ,3,5,15(19),16-hexaen-8carboxylic 646 I o X Q 1 > / \ IZX °o / γχ° - aminoethoxy)-3-hydroxy¡-11 - m ethyl-14- [ m et i l-[ rac-( 2S) -4-am i no-2-[ [ 2- (4ter—b utilf eni I )—4,6—dimethi l-pyrimid in—5— carbonyl] amino]butanoyl]amino]-10,13dioxo-9,12- diazatricyclo[13.3.1.12,6]ícosa- 1(18),2 (20),3,5,15(19), 16-hexaen-8carboxylic 647 Z--. ZT w \ - / x \ M >° r θχΧΧΧ^Ι ZI \ / .......... / ΛΛ RP or I acid rac-(8S,11S,14S)-3,18-bis(2aminoethoxy¡)-11 -methyl-14- [methyl-[rac(2S)^t-amino-2-[[2 -(1,1-dimethylindan—5—yl)—4,6—dimethyl—pyrimidin—5—carbonyl]amino]butanoyl]amino]-10,13-dioxo-9,12-diazatricyclo[13.3. 1.12,6]¡cosa- 1(18),2(20),3,5,15(19), 16-hexaen-8carboxylic 648 H ¿ χχι Cxu 1 Η II Η I 1 WRVA 1 ° 1 0 s nh2 acid rac-(8S,11S,14S)-18-(2-aminoethoxy)-3-hydroxy¡-11 —m ethyl—14[methyl-[rac-(2S)-4-amino-2-[[4,6d i methyl—2—(4—pentoxyph enyl)pyrim id in—5— carbonyl] amino]butaníl]amino]-10,13dioxo-9,12- diazatricícyclo[13.3.1.12,6]cosa1 (18),2(20),3,5,15(19), 16-hexaen-8carboxylic 649 nh2 % °cL*x NI hn i. 1. IL L JL / L J J^ / OH 0 HNX 1 H II H I II Nx A / N. X X A_ 0 । or χ^ । o nh2 acid o rac-(4S,7S, 10S)-10-(rac-(S Hamino-2-(2-(4-(tert-but¡l)phen¡l)-4,6d¡met¡lp rim¡din-5-carboxamido)-Nmethylbutanamido)-26-(2-am¡noethoxy¡)7—methyl—12,6,9—trioxo—12,13—dihydro—5,8-diaza -1(7,5)-benzo[d]oxazola2(1,3)-benzenecyclodecaf an-4carboxylic However, additional new classes of broad-spectrum antibiotics are still needed to treat particular multidrug-resistant pathogens. BRIEF DESCRIPTION OF THE INVENTION New macrocyclic compounds are described herein for the treatment of microbial infections, such as for the treatment of bacterial infections. In various embodiments, ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ The present disclosure provides macrocyclic lipopeptide compounds for the treatment of bacterial infections. In various embodiments, the present disclosure provides classes and subclasses of chemical compounds structurally related to arylomycin, for the treatment of bacterial infections. In various embodiments, the macrocyclic compounds act by inhibiting bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. In some embodiments, the signal peptidase is a Gram-negative signal peptidase. In some embodiments, the signal peptidase is LepB. The compounds of the invention are useful for the treatment of gram-negative bacterial infections, and particularly useful in the treatment of infections associated with non-termentatory bacteria. In one aspect, a compound of formula (I), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, is described herein: formula (I); where: R1 is H or -(Ci-C6)alkyl optionally substituted with one, two or three R1a; each R1ais independently halogen, -CN, -ORa, -SRa, -NRcRd, -NO2, -C(=O)Rb, -NRaC(=O)Rb, -C(=O)ORa, -C(=O) NRcRd, -NRaC(=O)NRcRd, -S(=O)2Rb, -S(=O)Rb, -S(=O)2NRcRd, -S(=O)NRcRd, NRaS(=O)2Rb, - NRaS(=O)2NRcRd, -NRaORa, -NRaC(=O)NRaORa, -O(Ci-C6)alkylene-NRcRd, NRaC(=NRc)Ra, -C(=NRa)NRcRd, -NRaC(=NRa) NRcRd, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R1aon the same carbon are taken together to form an oxo; R2 is H, -NRcRdo —(Ci—Ce)alkyl optionally substituted with one, two or three R2a; each R2ais independently halogen, -CN, -ORa, -SRa, -NRcRd, -NO2, -C(=O)Rb, -NRaC(=O)Rb, -C(=O)ORa, -C(=O) NRcRd, -NRaC(=O)NRcRd, -S(=O)2Rb, -S(=O)Rb, -S(=O)2NRcRd, -S(=O)NRcRd, NRaS(=O)2Rb, - NRaS(=O)2NRcRd, -NRaORa, -NRaC(=O)NRaORa, -O(Ci-C6)alkylene-NRcRd, NRaC(=NRc)Ra, -C(=NRa)NRcRd, -NRaC(=NRa) NRcRd, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R2aon the same carbon are taken together to form an oxo; R3 is H, -(C3-Csjcycloalkyl or —(C1—Ce)alkyl optionally substituted with one, two or three R3a; each R3ais independently halogen, -CN, -ORa, -SRa, -NRcRd, -NO2, -C(=O)Rb, -NRaC(=O)Rb, -C(=O)ORa, -C(=O) NRcRd, -NRaC(=O)NRcRd, -S(=O)2Rb, -S(=O)Rb, -S(=O)2NRcRd, -S(=O)NRcRd, NRaS(=O)2Rb, - NRaS(=O)2NRcRd, -NRaORa, -NRaC(=O)NRaORa, -O(Ci-C6)alkylene-NRcRd, NRaC(=NRc)Ra, -C(=NRa)NRcRd, -NRaC(=NRa) NRcRd, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R3aon the same carbon are taken together to form an oxo; R4 is H or -(Ci-C6)alkyl; X is (CI-C6) RENT, (C2-C6) Alkenene, (C2-C6) Alquinileno, (C3-C7) C¡cloalqu¡leno, (C2C7) Heterocycloquish, arileno or heteroarilene; wherein alkylene, alkenylene, alkynylene, cycloalkylene, heteroacycloalkylene, arylene and heteroarylene are optionally substituted with one, two or three Rx; each Rxis independently halogen, -CN, -ORa, -NRcRd, -NO2, -C(=O)Rb, -C(=O)ORa, C(=O)NRcRd, -(Ci-Cs)alkyl, -( Ci-Csjhaloalkyl, -(Ci-Cejheteroalkyl, -(C1 -Cejhydroxyalkyl, -(C1Cejaminoalkyl, -(C3-C7)cycloalkyl or -(C2-C7)heterocycloalkyl; or two Rxon the same carbon are taken together to form an oxo; Y is bond, -O-, -S-, (Ci-Cejalkylene, (C2-C6)alkenylene, (C2-C6)alkynylene, (C3-C7)cycloalkylene, (C2-C7)heterocycloalkylene, arylene or heteroarylene; in where alkylene, alkenylene, alkynylene, cycloalkylene, heteroacycloalkylene, arylene and heteroarylene are optionally substituted with one, two or three RY; each RYes independently halogen, -CN, -ORa, -NRcRd, -NO2, -C(=O)Rb, -C(=O)ORa, C(=O)NRcRd, -(Ci-C6)alkyl, -( Ci-C6)haloalkyl, -(Ci-Cejheteroalkyl, —(C1 —Cejhydroxyalkyl, —(C1—C6)aminoalkyl, -(C3-C7)cycloalkyl, or -(C2-C7)heterocycloalkyl; or two RYon the same carbon are they take together to form an oxo; Z is H, halogen, -CN, -OR10, -SR10, -NR12R13, -C(=O)R11, -C(=O)OR2, -C(=O)NR12R13, -(C1Ci2)alkyl, -( Ci-Ci2)heteroalkyl, -(C1-Ci2)haloalkyl, -(Ci-Ci2)hydroxyalkyl, -(Ci-Ci2)aminoalkyl, -(C2-Ci2)alkenyl, -(C2- Ci2)alkynyl, -(C3- C9)cycloalkyl, -(C2-C7)heterocycloalkyl, aryl or heteroaryl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heteroacycloalkyl, aryl and heteroaryl are optionally substituted with one, two or three Rz; each Rzes independently halogen, -CN, -OR10, -NR12R13, -NO2, -C(=O)R11, -C(=O)OR10, C(=O)NR12R13, —(Ci—Cejalkyl, -(Ci- C6)haloalkyl, -(Ci-Cejheteroalkyl, -(Ci-Cejhydroxyalkyl, -(C1Cejaminoalkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C7)cycloalkyl or -(C2-C7) heterocycloalkyl; or two Rzen the same carbon are taken together to form an oxo; Each R10 is independently -Czjcycloalkyl, (C2C7)heterocycloalkyl, aryl or heteroaryl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally independently substituted with one, two or three R10a; each R10a is independently halogen, -CN, -ORa, -NRcRd, -C(=O)Rb, -C(=O)ORa, -C(=O)NRcRd, —(Ci —Cejalkyl or —(Ci—Ce) haloalkyl; or two R10aon the same carbon are taken together to form a μλ / ε / zuzz / ui gold 1 οχο; each R11 is independently -(Ci-Ce)alkyl, -(Ci-C6)haloalkyl, -(Ci-C6)heteroalkyl, —(Ci—C6)hydroxyalkyl, -(Ci-C6)aminoalkyl, -(C2-C6) )alkenyl, -(C2-C6)alkynyl, -(C3-C7)cycloalkyl, (C2C7)heterocycloalkyl, aryl or heteroaryl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally independently substituted with one, two or three R11a; each R11a is independently halogen, -CN, -ORa, -NRcRd, -C(=O)Rb, -C(=O)ORa, -C(=O)NRcRd, -(Ci-C6)alkyl or -(Ci- Cejhaloalkyl; or two R11a on the same carbon are taken together to form an oxo; each R12 and R13 are independently H, -(Oí-Ce)alkyl, -(Ci-Ce)haloalkyl, -(Ci-C6)heteroalkyl, (C1-Cs)hydroxyalkyl, -(Ci-Cejaminoalkyl, -(C2-C6 )alkenyl, —(Ca—Ce)alkynyl, -(C3-C7)cycloalkyl, (C2-C7)heterocycloalkyl, aryl or heteroaryl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl they are optionally independently substituted with one, two or three R12a; or R12 and R13 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two or three R12b; each R12a is independently halogen, -CN, -ORa, -NRcRd, -C(=O)Rb, -C(=O)ORa, -C(=O)NRcRd, -(Ci-C6)alkyl, or -(C1 -Ce)haloalkyl; or two R12a on the same carbon are taken together to form an oxo; each R12bes independently halogen, -CN, -ORa, -NRcRd, -C(=O)Rb, -C(=O)ORa, -C(=O)NRcRd, —(C1 —Cejalkyl or -(Ci-Ce) haloalkyl; or two R12ben the same carbon are taken together to form an oxo; each Raes independently H, —(Ci—Cejalkyl, -(Ci-C6)haloalkyl, -(Ci-C6)heteroalkyl, —(C1—Ce)hydroxyalkyl, -(Ci-C6)aminoalkyl, -(C2-Ce)alkenyl , -(C2-C6)alkynyl, -(C3-C7)cycloalkyl, (C2C7)heterocycloalkyl, aryl or heteroaryl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally independently substituted with one, two or three halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH2o -(C1Cejalkyl ; each Rbes independently -(Ci-C6)alkyl, -(Ci-Cejhaloalkyl, -(Ci-Cejheteroalkyl, -(C1Cejhydroxyalkyl, -(Ci-Cejaminoalkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, - (C3-C7)cycloalkyl, (C2C7)heterocycloalkyl, aryl or heteroaryl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally independently substituted with one, two or three halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH2o -(C1C6)alkyl; and each Rcy Rdes independently H, -(Ci-C6)alkyl, -(Ci-C6)haloalkyl, -(Ci-C6)heteroalkyl, (Ci-C6)hydroxyalkyl, -(Ci-C6)aminoalkyl, -(C2-C6)alkenyl , -(C2-C6)alkynyl, -(C3-C7)cycloalkyl, (C2-C7)heterocycloalkyl, aryl or heteroaryl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally independently substituted with one , two or ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ three halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C (=O)NH2o -(C1C6)alkyl; or Rcy Rdse are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two or three oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, C(=O)OH, -C(=O)OMe, -C(=O)NH2o -(Ci-C6)alkyl. In some embodiments of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; The compound has the structure of formula (la): ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ formula (the) In some embodiments of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; The compound has the structure of formula (Ib): formula (Ib). Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof and a pharmaceutically acceptable excipient. Also disclosed herein is a method of treating a bacterial infection in a mammal, comprising administering to the mammal an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or stereoisomer of this, with a frequency and for a sufficient time to provide a beneficial effect to the mammal. Also disclosed herein is a method of treating a lepB-mediated infection in a mammal, comprising administering to the mammal an effective amount of a compound disclosed herein, or a technically acceptable salt, solvate or stereoisomer. pharmaceutical of this, with a frequency and for a time sufficient to provide a beneficial effect to the mammal. In some embodiments of a treatment method, the bacterial infection is an infection involving Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotroph orno ñas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escheríchia coli, Citrobacter freundii , Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteríae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxitoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgarís, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticous, Acinetobacter haemolyticus. Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus paral nflue nzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurelia haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homolog group ía, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicro n, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacteríum tuberculosis, Mycobacteríum avium, Mycobacteríum intracellulare, Mycobacteríum leprae, Corynebacteríum diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis , Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis or Staphylococcus saccharolyticus. In some embodiments of a treatment method, the bacterial infection is an infection involving Acinetobacter baumannii, Klebsiella pneumoniae, or Pseudomonas aeruginosa. In some embodiments of a treatment method, the bacterial infection is an infection involving Acinetobacter baumannii. In some embodiments of ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ a treatment method, bacterial infection is an infection that involves Gram-negative bacteria. In some embodiments of a treatment method, the method further comprises administering a second therapeutic agent. In some embodiments of a treatment method, the second therapeutic agent is not an inhibitor of SpsB or LepB. In some embodiments of a treatment method, the second therapeutic agent is an aminoglycoside antibiotic, fluoroquinolone antibiotic, β-lactam antibiotic, macrolide antibiotic, glycopeptide antibiotic, rifampicin, chloramphenicol, fluoramphenicol, colistin, mupirocin, bacitracin, daptomycin or linezolid . The method according to claim 48, wherein the second therapeutic agent is a β-lactam antibiotic. The method according to claim 50, wherein the β-lactam antibiotic is selected from penicillins, monobactams, cephalosporins, cephamycins and carbapenems. In some embodiments of a treatment method, the β-lactam antibiotic is selected from Azlocillin, Amoxicillin, Ampicillin, Doripenem, Meropenem, Biapenem, Cefamandol, Imipenem, Mezlocillin, Cefmetazole, Cefprozil, Piperacillin / tazobactam, Carbenicillin, Cefaclor, Cefalothin , Ertapenem, Cefazolin, Cefepime, Cefonicid, Cefoxitin, Ceftazidime, Oxacillin, Cefdinir, Cefixime, Cefotaxime, Cefotetan, Cefpodoxime, Ceftizoxime, Ceftriaxone, Faropenem, Mecillinam, Methicillin, Moxalactam, Ticarcillin, Tomopenem, Ceftobiprole, Ceftaroline, Flomoxef, Cefipro me and Cefozopran . In some embodiments of a treatment method, the method further comprises administering a β-lactamase inhibitor. INCORPORATION BY REFERENCE All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent or patent application were specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION Definitions As used herein and in the appended claims, the singular forms a, and and the include plural referents, unless the context clearly indicates otherwise. Thus, for example, reference to an agent includes a plurality of such agents, and reference to the cell includes reference to one or more cells (or a plurality of cells) and their equivalents known to those of mid-level skill. , etc. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments are intended to be included. The expression around when referring to a number or numerical range means that the number or numerical range referred to is an approximation within the experimental variability (or within the statistical experimental error) and therefore the number or numerical range, in some cases, will vary between 1% and 15% of the established number or numerical range. The expression comprising (and related expressions such as comprising or comprising or having or including) is not intended to exclude that, in certain other embodiments, for example, a form of ΜΛ / Ε / ΖυΖΖ / υΊ Oí ΟΊ embodiment of any composition of matter, composition, method or process, or the like, described herein, consists of or consists essentially of the characteristics described. As used in the specification and the accompanying claims, unless otherwise specified, the following terms have the meanings indicated below. Alkyl refers to an optionally substituted straight chain or optionally substituted branched chain saturated hydrocarbon monoradical, having from one to about ten carbon atoms or from one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, npropyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-1-butyl, 2-methyl-1-butyl. -methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1 —pentyl, 3-methyl-1 —pentyl, 4-methyl-1 —pentyl, 2-methyl-2-pentyl, 3-methyl -2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec- butyl, t-butyl, n-pentyl, isopentyl, neopentyl, ter-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever appearing herein, a numerical range such as C1-C6 alkyl means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the appearance of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C20 alkyl, a C1-C10 alkyl, a C1-C9 alkyl, a C1Cs alkyl, a C1-C7 alkyl, a C1-C6 alkyl, a C1-C5 alkyl, a C1 -C4 alkyl, a C1-C3 alkyl, a C1C2 alkyl or a C1 alkyl. Unless otherwise specifically specified in the specification, an alkyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CFs, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, the alkyl is optionally substituted with halogen. Alkenyl refers to an optionally substituted straight chain or optionally substituted branched chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from two to about ten carbon atoms, more preferably two to about six. carbon atoms. The group may be in the cis or trans conformation around the double bonds, and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever appearing herein, a numerical range such as C2-C6 alkenyl means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the appearance of the term alkenyl where no numerical range is designated. In some embodiments, the alkenyl is a C2-C20 alkenyl, a C2-C10 alkenyl, a C2-C9 alkenyl, a C2-C8 alkenyl, a C2-C7 alkenyl, a C2-C6 alkenyl, a C2-C5 alkenyl. , a C2-C4 alkenyl, a C2-C3 alkenyl or a C2 alkenyl. Unless otherwise specifically specified in the specification, an alkenyl group is optionally substituted as described below, for example, with oxo, halogen, amino, ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen. Alkynyl refers to an optionally substituted straight chain or optionally substituted branched chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having two to about ten carbon atoms, more preferably two to about six. carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever appearing herein, a numerical range such as C2-C6 alkynyl means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the appearance of the term alkynyl where no numerical range is designated. In some embodiments, the alkynyl is a C2-C20 alkynyl, a C2-C10 alkynyl, a C2-C9 alkynyl, a C2-C8 alkynyl, a C2-C7 alkynyl, a C2-C6 alkynyl, a C2-C5 alkynyl. , a C2-C4 alkynyl, a C2-C3 alkynyl or a C2 alkynyl. Unless otherwise specifically specified in the specification, an alkynyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl and the like. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, an alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen. Alkylene refers to a divalent linear or branched hydrocarbon chain. Unless otherwise specifically specified in the specification, an alkylene group may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl , heterocycloalkyl, heteroaryl and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, OMe, -NH2 or -NO2. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CFs, -OH or -OMe. In some embodiments, the alkylene is optionally substituted with halogen. Alkoxy refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. Unless otherwise specifically specified in the specification, an alkoxy group may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl , heterocycloalkyl, heteroaryl and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen. IVIA / C / ZUZZ / U I 0 / 0 I Aryl refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused systems (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is linked through an aromatic ring atom) or ring systems. on bridge. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, asindacene, s-indacene, indane, indene, naphthalene, phenalene , phenanthrene, pleiadene, pyrene and triphenylene. In some embodiments, the aryl sphenyl. Unless otherwise specifically indicated in the specification, an aryl may be optionally substituted as described below, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl , cycloalkyl, heterocycloalkyl, heteroaryl and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, CFs, -OH or -OMe. In some embodiments, the aryl is optionally substituted with halogen or methyl. In some embodiments, the aryl is optionally substituted with halogen. Cycloalkyl refers to a stable, partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused ring systems (when fused to an aryl or heteroaryl ring, the cycloalkyl is linked through a non-aromatic ring atom) or bridge ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having three to fifteen carbon atoms (C3-C15 cycloalkyl), three to ten carbon atoms (C3-C10 cycloalkyl), three to eight carbon atoms (Ca-Cs cycloalkyl), three to six carbon atoms (C3-C6 cycloalkyl), three to five carbon atoms (C3-C5 cycloalkyl) or three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[ 2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane and bicyclo[3.3.2]decane and 7,7-dimethyl—bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Unless otherwise specifically specified in the specification, a cycloalkyl is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy , aryl, cycloalkyl, heterocycloalkyl, heteroaryl and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some ways ΜΛ / Ε / ZUZZ / Ul Of 01 embodiment, the cycloalkyl is optionally substituted with halogen or methyl. In some embodiments, the cycloalkyl is optionally substituted with halogen. Halo or halogen refers to bromine, chlorine, fluorine or iodine. In some embodiments, halogen is fluorochlorine. In some embodiments, halogen is fluorine. Haloalkyl refers to an alkyl radical, as defined above, that is substituted with one or more halo radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2 -difluoroethyl, 3-bromo-2-f luoropropyl, 1,2dibromoethyl and the like. Aminoalkyl refers to an alkyl radical, as defined above, that is substituted with one or more -NH2, for example, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -ΟΗ(ΝΗ2)ΟΗ3, CH2CH(NH2)CH3, -CH (NH2)CH2CH3 and the like. Hydroxyalkyl refers to an alkyl radical, as defined above, that is substituted with one or more -OH, for example, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH(OH)CH3, CH2CH(OH)CH3, -CH (OH)CH2CH3 and the like. Heterocycloalkyl refers to a stable 3- to 24-membered, partially or fully saturated ring radical comprising 2 to 23 carbon atoms and one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur. Unless otherwise specifically stated in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused ring systems (when fused with an aryl or heteroaryl ring, the heterocycloalkyl is linked through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a (C2C7)heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, midazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2oxopiperidin ilo, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahyd rof uryl, tritianyl, tetrahyd ropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1 ,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl and 2-oxo-1,3-dioxol-4- ilo. The term heterocycloalkyl also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise noted, heterocycloalkyls have 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the ΜΛ / Ε / ΖυΖΖ / υΊ ΟΖΟΊ heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Unless otherwise specifically specified in the specification, a heterocycloalkyl is optionally substituted as described below, for example, with oxo, halogen, amino, nitrite, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy , arite, cycloalkyl, heterocycloalkyl, heteroaryl and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, CF3, -OH or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen or methyl. In some embodiments, the heterocycloalkyl is optionally substituted with halogen. Heteroalkyl refers to an alkyl group in which one or more alkyl skeletal atoms are selected from an atom other than carbon, for example, oxygen, nitrogen (for example, -NH-, N(alkyl)-), sulfur or combinations of these. A heteroalkyl is attached to the rest of the molecule on a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl with one, two or three heteroatoms selected from oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), or sulfur. In one aspect, a heteroalkyl is a C1-C6 heteroalkyl with one or two heteroatoms selected from oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), or sulfur. Unless otherwise specifically indicated in the specification, a heteroalkyl is optionally substituted as described below, for example, with oxo, halogen, amino, nitrite, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, arite, cycloalkyl, heterocycloalkyl, heteroaryl and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen. Heteroaryl refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur, and al minus one aromatic ring. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused ring systems (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is linked through an aromatic ring atom) or systems of bridge rings; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, bencindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodium xolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, IVIA / t / ZUZZ / UΊ O / 01 benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyrádinyl, carbazolyl, cinolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl , isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2oxoazepinyl, oxazolyl, oxiranyl, 1 —oxidopyridinyl, 1 —oxidopyrimidinyl, 1-oxidopyrazinyl, 1oxidopyridazinyl, 1-phenyl -1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl , triazolyl, tetrazolyl, triazinyl and thiophenyl (i.e. thienyl). Unless otherwise specifically specified in the specification, a heteroaryl is optionally substituted as described below, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl , cycloalkyl, heterocycloalkyl, heteroaryl and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CFs, -OH, -OMe, -NH2 or -NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, CN, -CF3, -OH or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen or methyl. In some embodiments, the heteroaryl is optionally substituted with halogen. The term oxo means =0. The terms treat, prevent, ameliorate and inhibit, as well as words derived from them, as used herein, do not necessarily imply 100% or all of the treatment, prevention, amelioration or inhibition. On the contrary, there are various degrees of treatment, prevention, improvement and inhibition, which a person of the mid-level profession recognizes as having a potential benefit or therapeutic effect. In this regard, the disclosed methods may provide any amount of any level of treatment, prevention, amelioration or inhibition of the disorder in a mammal. For example, a disorder, including its symptoms or conditions, may be reduced, for example, by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%. , around 40%, around 30%, around 20% or around 10%. Additionally, the treatment, prevention, improvement or inhibition provided by the methods disclosed herein may include treatment, prevention, improvement or inhibition of one or more conditions or symptoms of the disorder, for example, cancer or an inflammatory disease. Additionally, for the purposes herein, treatment, prevention, amelioration, or inhibition encompasses delaying the onset of the disorder, or a symptom or condition thereof. The terms "effective amount" or "therapeutically effective amount" as used herein refer to a sufficient amount of a compound disclosed herein that is administered that will alleviate to some extent one or more of the symptoms of the disease or condition being treated. , for example, cancer or an inflammatory disease. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms or causes of a disease, or any other desired alteration of a biological system. For example, an effective amount for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to ΜΛ / Ε / ΖυΖΖ / υΊ Oí ΟΊ provide a clinically significant decrease in the symptoms of the disease. In some embodiments, an appropriate effective amount in any individual case is determined through the use of techniques, such as a dose escalation study. As used herein, individual (as in the subject of treatment) means both mammals and non-mammals. Mammals include, for example, humans; non-human primates, for example, apes and monkeys; and non-primates, for example, dogs, cats, cows, horses, sheep and goats. Non-mammals include, for example, fish and birds. The term disease or disorder or ailment are used interchangeably, and are used to refer to diseases or conditions where a bacterial SPase plays a role in the biochemical mechanisms involved in the disease or ailment, such that a therapeutically beneficial effect can be achieved by act on the enzyme. Acting on the SPase may include binding to the SPase and / or inhibiting the bioactivity of a SPase. The term prodrug, as used herein, means compounds with one or more moieties that can be metabolized in vivo. For example, prodrugs are metabolized in vivo by esterases or other mechanisms to obtain active drugs. Examples of prodrugs and their uses are known in the art (see, for example, Pharmaceutical Salts, J. Pharm. Sel. 66:1-19). Prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid or hydroxyl form with a suitable esterifying agent. Hydroxyl groups can be converted to esters through treatment with a carboxylic acid. Examples of prodrug moieties include branched or unbranched, substituted or unsubstituted lower alkyl ester moieties (e.g., propionic acid esters), lower alkenyl esters, di-lower alkylamino-lower amino esters (e.g., ester dimethylaminoethyl), acylamino-lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl lower alkyl esters (e.g., benzyl ester ), substituted esters (for example, with methyl, halo or methoxy substituents) of aryl and aryl-lower alkyl, amides, lower alkyl amides, di-lower alkyl amides and hydroxy amides. Substantially as the term is used herein means completely or almost completely; For example, a composition that is substantially free of a component has none of the components, or contains a minimum amount, such that no relevant functional property of the composition is affected by the presence of the minimum amount, or a compound It is substantially pure when only negligible traces of impurities are present. Compounds In one aspect, compounds of formula (I), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, are described herein: ΜΛ / Ε / ΖυΖΖ / υΊ ΟΖΟΊ IVIA / t / ZUZZ / U I O / Ο I formula (I); where: R1 is H or -(Ci-C6)alkyl optionally substituted with one, two or three R1a; each R1ais independently halogen, -CN, -ORa, -SRa, -NRcRd, -NO2, -C(=O)Rb, -NRaC(=O)Rb, -C(=O)ORa, -C(=O) NRcRd, -NRaC(=O)NRcRd, -S(=O)2Rb, -S(=O)Rb, -S(=O)2NRcRd, -S(=O)NRcRd, NRaS(=O)2Rb, - NRaS(=O)2NRcRd, -NRaORa, -NRaC(=O)NRaORa, -O(Ci-C6)alkylene-NRcRd, NRaC(=NRc)Ra, -C(=NRa)NRcRd, -NRaC(=NRa) NRcRd, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R1aon the same carbon are taken together to form an oxo; R2 is H, -NRcRd or -(Ci-C6)alkyl optionally substituted with one, two or three R2a; each R2ais independently halogen, -CN, -ORa, -SRa, -NRcRd, -NO2, -C(=O)Rb, -NRaC(=O)Rb, -C(=O)ORa, -C(=O) NRcRd, -NRaC(=O)NRcRd, -S(=O)2Rb, -S(=O)Rb, -S(=O)2NRcRd, -S(=O)NRcRd, NRaS(=O)2Rb, - NRaS(=O)2NRcRd, -NRaORa, -NRaC(=O)NRaORa, -O(Ci-C6)alkylene-NRcRd, NRaC(=NRc)Ra, -C(=NRa)NRcRd, -NRaC(=NRa) NRcRd, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R2aon the same carbon are taken together to form an oxo; R3 is H, -(Ca-Cejcycloalkyl or -(Ci-Cejalkyl optionally substituted with one, two or three R3a; each R3ais independently halogen, -CN, -ORa, -SRa, -NRcRd, -NO2, -C(=O)Rb, -NRaC(=O)Rb, -C(=O)ORa, -C(=O) NRcRd, -NRaC(=O)NRcRd, -S(=O)2Rb, -S(=O)Rb, -S(=O)2NRcRd, -S(=O)NRcRd, NRaS(=O)2Rb, - NRaS(=O)2NRcRd, -NRaORa, -NRaC(=O)NRaORa, -O(Ci-Cs)alkylene-NRcRd, NRaC(=NRc)Ra, -C(=NRa)NRcRd, -NRaC(=NRa) NRcRd, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R3aon the same carbon are taken together to form an oxo; R4is H or -(Ci-Cejalkyl; x is arylene and heteroarylene are optionally substituted with one, two or three Rx; each Rxis independently halogen, -CN, -ORa, -NRcRd, -NO2, -C(=O)Rb, -C(=O)ORa, C(=O)NRcRd, -(Ci—Csjaalkyl, -(Ci-C6)haloalkyl, -(Ci-C6)heteroalkyl, -(Ci-C6)hydroxyalkyl, —(Ci— C6)aminoalkyl, -(C3-C7 )cycloalkyl or -(C2-C7)heterocycloalkyl; or two Rxon the same carbon are taken together to form an oxo; Y is bond, -O-, -S-, (Ci-C6)alkylene, (C2-C6)alkenylene, (C2-C6)alkynylene, (C3-C7)cycloalkylene, (C2-C7)heterocycloalkylene, arylene or heteroarylene ; wherein alkylene, alkenylene, alkynylene, cycloalkylene, heteroacycloalkylene, arylene and heteroarylene are optionally substituted with one, two or three RY; each RYes independently halogen, -CN, -ORa, -NRGRd, -NO2, -C(=O)Rb, -C(=O)ORa, C(=O)NRcRd, -(Ci-C6)alkyl, -( Ci-C6)haloalkyl, -(Ci-C6)heteroalkyl, -(Ci-C6)hydroxyalkyl, —(Ci— Cejaminoalkyl, -(C3-C7)cycloalkyl or -(C2-C7)heterocycloalkyl; or two RYon the same carbon they are taken together to form an oxo; Z is H, halogen, -CN, -OR10, -SR10, -NR12R13, -C(=O)R11, -C(=O)OR2, -C(=O)NR12R13, -(C1Ci2)alkyl, -( Ci-Ci2)heteroalkyl, -(Ci-Ci2)haloalkyl, -(Ci—C12)hydroxyalkyl, -(Ci-Ci2)aminoalkyl, -(C2-Ci2)alkenyl, —(C2—Ci2)alkynyl, —( C3—C9)cycloalkyl, -(C2-C7)heterocycloalkyl, aryl or heteroaryl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one, two or three Rz; each Rzes independently halogen, -CN, -OR10, -NR12R13, -NO2, -C(=O)R11, -C(=O)OR10, C(=O)NR12R13, -(C1-C6)alkyl, -( Ci-C6)haloalkyl, -(Ci-Cejheteroalkyl, -(Ci-Cejhydroxyalkyl, —(C1—C6)aminoalkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, —(C3—C7)cycloalkyl or -(C2-C7)heterocycloalkyl; or two Rzen the same carbon are taken together to form an oxo; each R10 is independently H, -(Ci-C6)alkyl, -(Ci-C6)haloalkyl, -(Ci-C6)heteroalkyl, —(C1—C6)hydroxyalkyl, -(Ci-C6)aminoalkyl, -(C2-C6) )alkenyl, -(C2-C6)alkynyl, -(C3-C7)cycloalkyl, (C2C7)heterocycloalkyl, aryl or heteroaryl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally independently substituted with one, two or three R10a; each R10a is independently halogen, -CN, -ORa, -NR°Rd, -C(=O)Rb, -C(=O)ORa, -C(=O)NRcRd, -(Ci —Csjalkyl or -(Ci- Cejhaloalkyl; or two R10a on the same carbon are taken together to form an oxo; each R11 is independently -(Ci-C6)alkyl, -(Ci-C6)haloalkyl, -(Ci-Cejheteroalkyl, -(C1Cejhydroxyalkyl, -(Ci-Cejaminoalkyl, -(C2-C6)alkenyl, -(C2-C6) )alkynyl, -(C3-C7)cycloalkyl, (C2C7)heterocycloalkyl, aryl or heteroaryl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally independently substituted with one, two or three R11a; each R11a is independently halogen, -CN, -ORa, -NRcRd, -C(=O)Rb, -C(=O)ORa, -C(=O)NRcRd, -(Ci-C6)alkyl or -(Ci- C6)haloalkyl; or two R11a on the same carbon are taken together to form an oxo; each R12 and R13 are independently H, -(Ci-C6)alkyl, -(Ci-C6)haloalkyl, -(Ci-C6)heteroalkyl, (Ci-C6)hydroxyalkyl, -(Ci-Cejaminoalkyl, -(C2-C6) )alkenyl, -(C2-C6)alkynyl, -(C3-C7)cycloalkyl, IVIA / t / ZUZZ / U I OI Ο I (C2-C7)heterocycloalkyl, aryl or heteroaryl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally independently substituted with one, two or three R12a; or R12 and R13 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two or three R12b; each R12a is independently halogen, -CN, -ORa, -NRcRd, -C(=O)Rb, -C(=O)ORa, -C(=O)NRcRd, —(Ci —Cojalkyl or -(Ci-Cejhaloalkyl ; or two R12a on the same carbon are taken together to form an oxo; each R12bes independently halogen, -CN, -ORa, -NRcRd, -C(=O)Rb, -C(=O)ORa, -C(=O)NRcRd, -(Ci-Cejalkyl or -(Ci-Cejhaloalkyl; or two R12ben the same carbon are taken together to form an oxo; each Raes independently H, -(Ci-C6)alkyl, -(Ci-Cs)haloalkyl, -(Ci-Cs)heteroalkyl, -(CiC6)hydroxyalkyl, -(Ci-Cejaminoalkyl, -(C2-C6 )alkenyl, -(C2-C6)alkynyl, -(Cs-C / jcycloalkyl, (C2Cyjheterocycloalkyl, aryl or heteroaryl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally independently substituted with one, two or three halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, - C(=O)OH, -C(=O)OMe, -C(=O)NH2, or - (C1C6)alkyl; each Rbes independently -(Ci-Cs)alkyl, -(Ci-Cejhaloalkyl, -(Ci-Cejheteroalkyl, -(C1—C6)hydroxyalkyl, -(Ci-Cejaminoalkyl, -(C2-C6)alkenyl, -(C2-C6) )alkynyl, -(C3-C7)cycloalkyl, (C2C7)heterocycloalkyl, aryl or heteroaryl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally independently substituted with one, two or three halogen, -CN , -OH, -OMe, -NH2, -C(=O)Me, - C(=O)OH, -C(=O)OMe, -C(=O)NH2o -(C1C6)alkyl; and each Rcy Rdes independently H, -(Ci-Cejalkyl, -(Ci-C6)haloalkyl, -(Ci-Cejheteroalkyl, (Ci-C6)hydroxyalkyl, -(Ci-Cejaminoalkyl, -(C2-C6)alkenyl, -(C2- Cejalkynyl , -(C3-C7)cycloalkyl, (C2-C7)heterocycloalkyl, aryl or heteroaryl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally independently substituted with one, two or three halogen, -CN , -OH, - OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH2o -(C1Cejalkyl; or Rcy Rdse are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two or three oxo, halogen, -CN, -OH, -OMe, -NH2, -C(=O)Me, C(=O)OH, -C(=O)OMe, -C(=O)NH2o -(Ci-C6)alkyl. In some embodiments of a compound of formula (I), R2 is H or -(Ci-Cejalkyl optionally substituted with one, two or three R2a. In some embodiments of a compound of formula (I), R2 is H or - (Ci-C6)alkyl optionally substituted with a R2a. In some embodiments of a compound of formula (I), R2 is H or -(Ci-Cejalkyl. In some embodiments of a compound of formula (I), R2 is H. In some embodiments of a compound of formula (I), each R2a is ΜΛ / Ε / ΖυΖΖ / υΊ Oí ΟΊ independently halogen, -CN, -ORa, -NRcRd, -NRcC(=O)Rb, -NRcC(=O)NRcRd, -NRcS(=O)2Rbo NRcS(=O)2NRcRd . In some embodiments of a compound of formula (I), each R2a is independently -NRcRdo-NRcS(=O)2NRcRd. In some embodiments of a compound of formula (I), R3 is H or —(Ci—C6)alkyl optionally substituted with one, two or three R3a. In some embodiments of a compound of formula (I), R3 is H or -(Ci-C6)alkyl optionally substituted with an R3a. In some embodiments of a compound of formula (I), R3 is H or -(Ci-Cejalkyl. In some embodiments of a compound of formula (I), R3 is H. In some embodiments of a compound of formula (I), R3es-(Ci-C6)alkyl. In some embodiments of a compound of formula (I), R3es methyl. In some embodiments of a compound of formula (I), each R3a is independently halogen, -CN, -ORa, -NRcRd, -NRcC(=O)Rb, -NRcC(=O)NRcRd, -NRcS(=O) 2Rbo NRcS(=O)2NRcRd. In some embodiments of a compound of formula (I), each R3a is independently -NRcRdo -NRcS(=O)2NRcRd. In some embodiments of a compound of formula (I), R4 is H. In some embodiments of a compound of formula (I), R4 is -(Ci-C6)alkyl. In some embodiments of a compound of formula (I), R4 is methyl. In some embodiments of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; The compound has the structure of formula (la): MA / E / zUZZ / Ul Ο / ΟΊ formula (the). In some embodiments of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; The compound has the structure of formula (Ib): ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ formula (Ib). In some embodiments of a compound of formula (I), (la) or (Ib), R1 is —(Oí—C6)alkyl optionally substituted with one, two or three R1a. In some embodiments of a compound of formula (I), (la) or (Ib), R1 is -(Ci-C6)alkyl optionally substituted with one or two R1a. In some embodiments of a compound of formula (I), (la) or (Ib), R1 is -(Ci-C6)alkyl substituted with a R1a. In some embodiments of a compound of formula (I), (la) or (Ib), R1 is -CH2CH2NH2, -CH2CH2NHSO2NH2 or -CH2NHSO2NH2. In some embodiments of a compound of formula (I), (la) or (Ib), R1 is -CH2CH2NH2. In some embodiments of a compound of formula (I), (la) or (Ib), R1 is -CH2CH2NHSO2NH2. In some embodiments of a compound of formula (I), (la) or (Ib), R1 is -CH2NHSO2NH2. In some embodiments of a compound of formula (I), (la) or (Ib), each R1a is independently halogen, -CN, -ORa, -NRcRd, -NRcC(=O)Rb, -NRcC(=O) NRcRd, -NRcS(=O)2Rbo NRcS(=O)2NRcRd. In some embodiments of a compound of formula (I), (la) or (Ib), each R1a is independently -NRcRdo -NRcS(=O)2NRcRd. In some embodiments of a compound of formula (I), (la) or (Ib), each R1a is independently -NRcRd. In some embodiments of a compound of formula (I), (la) or (Ib), each R1a is independently -NRcS(=O)2NRcRd. In some embodiments of a compound of formula (I), (la) or (Ib), X is (C2C7)heterocycloalkylene or heteroarylene; each optionally replaced with one, two or three Rx. In some embodiments of a compound of formula (I), (la) or (Ib), X is (C2C7)heterocycloalkylene or heteroarylene; each optionally replaced with one or two Rx. In some embodiments of a compound of formula (I), (la) or (Ib), X is (C2-C7)heterocycloalkylene or heteroarylene; each optionally replaced with an Rx. In some embodiments of a compound of formula (I), (la) or (Ib), X is (C2-C7)heterocycloalkylene optionally substituted with one, two or three Rx. In some embodiments of a compound of formula (I), (la) or (Ib), X is (C2C7)heterocycloalkylene optionally substituted with one or two Rx. In some embodiments of a compound of formula (I), (la) or (Ib), X is (C2-C7)heterocycloalkylene optionally substituted with an Rx. In some embodiments of a compound of formula (I), (la) or (Ib), X is heteroarylene optionally substituted with one, two or three Rx. In some embodiments of a compound of formula (I), (la) or (Ib), X is heteroarylene optionally substituted with one or two Rx. In some embodiments of a compound of formula (I), (la) or (Ib), X is heteroarylene optionally substituted with an Rx. In some embodiments of a compound of formula (I), (la) or (Ib), X is pyrimidinylene optionally substituted with one or two Rx. In some embodiments of a compound of formula (I), (la) or (Ib), X is pyridinylene optionally substituted with one, two or three Rx. In some embodiments of a compound of formula (I), (la) or (Ib), each Rxis independently halogen, -ORa, -NRcRd, -(Ci-C6)alkyl or -(Ci-Cejhaloalkyl; or two Rxen the same carbon are taken together to form an oxo. In some embodiments of a compound of formula (I), (la) or (Ib), each Rxis independently -NRcRdo -(Ci-Cejalkyl; or two Rxeson the same carbon taken together to form an oxo. In some embodiments of a compound of formula (I), (la) or (Ib), each Rxes independently -NRcRdo -(Ci-C6)alkyl. In some embodiments of a compound of formula (I), (la) or (Ib), each Rx is independently Cl, -CN, methyl, ethyl, -CF2H, -CF3, -CH2NH2, cyclopropyl or 3-aminoazetidine-1-yl In some embodiments of a compound of formula (I), (la) or (Ib), each Rx is independently Cl, -CN, methyl or -CH2NH2. In some embodiments of a compound of formula (I), (la) or (Ib), each Rxis independently Cl, methyl or -CH2NH2. In some embodiments of a compound of formula (I), (la) or (Ib), each Rx is independently methyl or -CH2NH2. In some embodiments of a compound of formula (I), (la) or (Ib), a Rxes 3-aminoazetidin-1-yl. In some embodiments of a compound of formula (I), (la) or (Ib), each Rx is independently methyl. In some embodiments of a compound of formula (I), (la) or (Ib), Y is -(C2C7)heterocycloalkylene or arylene; each optionally substituted with one, two or three RY. In some embodiments of a compound of formula (I), (la) or (Ib), Y is -(C2-C7)heterocycloalkylene or arylene. In some embodiments of a compound of formula (I), (la) or (Ib), Y is -(C2C7)heterocycloalkylene or arylene; each optionally replaced with one or two RY. In some embodiments of a compound of formula (I), (la) or (Ib), Y is -(C2-C7)heterocycloalkylene or arylene; each optionally substituted with an RY. In some embodiments of a compound of formula (I), (la) or (Ib), Y is arylene optionally substituted with one, two or three RY. In some embodiments of a compound of formula (I), (la) or (Ib), Y is arylene optionally substituted with one or two RY. In some embodiments of a compound of formula (I), (la) or (Ib), Y is arylene optionally substituted with an RY. In some embodiments of a compound of formula (I), (la) or (Ib), Y is arylene. In some embodiments of a compound of formula (I), (la) or (Ib), Y is phenylene optionally substituted with one, two or three RY. In some embodiments of a compound of formula (I), (la) or (Ib), Y is a bond. In some embodiments of a compound of formula (I), (la) or (Ib), each RYes independently halogen, -ORa, -NRcRd, -(Ci-C6)alkyl or -(Ci-C6)haloalkyl; or two RYin the ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ same carbon are taken together to form an oxo. In some embodiments of a compound of formula (I), (la) or (Ib), each RYes independently halogen, -ORa, -NRcRd, -(Ci-C6)alkyl or (Ci-Ce)haloalkyl. In some embodiments of a compound of formula (I), (la) or (Ib), each RYes independently halogen, -(Ci-C6)alkyl or -(Ci-C6)haloalkyl. In some embodiments of a compound of formula (I), (la) or (Ib), each RYes independently F or -OH. In some embodiments of a compound of formula (I), (la) or (Ib), each RYes F. In some embodiments of a compound of formula (I), (la) or (Ib), Z is H, halogen, CN, -OR10, -SR10, -NR12R13, -C(=O)R11, -C( =O)OR2, -C(=O)NR12R13, -(Ci-Ci2)alkyl, -(CiCi2)heteroalkyl, -(Ci-Ci2)haloalkyl, - (Ci- C12) hydroxyalkyl, -(Ci-Ci2)aminoalkyl , -(C2Ci2)alkenyl, -(C2-Ci2)alkynyl, -(C3-C7)cycloalkyl, -(C2-C7)heterocycloalkyl, aryl or heteroaryl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heteroacycloalkyl, aryl and heteroaryl are optionally substituted with one, two or three Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is halogen, OR10, -NR12R13, -(Ci-Ci2)alkyl, -(Ci-Ci2)heteroalkyl, -(Ci -Ci2)haloalkyl, -(C1—Ci2)hydroxyalkyl, (Ci-Ci2)aminoalkyl, -(C3-C9)cycloalkyl or -(C2-C7)heterocycloalkyl; wherein the alkyl, cycloalkyl and heteroacycloalkyl are optionally substituted with one, two or three Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is halogen, -OR10, -NR12R13, -(C1-Ci2)alkyl, -(Ci-Ci2)heteroalkyl, —( Ci—Cisjhaloalkyl, -(Ci-Ci2)hydroxyalkyl, -(Ci-Ci2)aminoalkyl, -(C3C9)cycloalkyl or -(C2-C7)heterocycloalkyl; wherein the alkyl, cycloalkyl and heteroacycloalkyl are optionally substituted with one or two Rz In some embodiments of a compound of formula (I), (la) or (Ib), Z is halogen, -OR10, -NR12R13, -(C1 -Ci2)alkyl, -(Ci-Ci2)heteroalkyl, — (Ci—Ci2)haloalkyl, -(C1-Ci2)hydoxyalkyl, -(Ci-Ci2)aminoalkyl, —(C3—Cejcycloalkyl or -(C2C7)heterocycloalkyl; wherein alkyl, cycloalkyl and heteroacycloalkyl are optionally substituted with a Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is halogen, -OR10, -NR12R13, -(C1-Ci2)alkyl, -(Ci-Ci2)heteroalkyl, —(Ci—Ci2)haloalkyl, —(Ci—Ci2)hydroxyalkyl, -(Ci-Ci2)aminoalkyl, -(C3-C9)cycloalkyl or -(C2-C7)heterocycloalkyl. In some embodiments of a compound of formula (I), (la) or (Ib), Z is halogen, OR10, —NR12R13, -(Ci-Ci2)alkyl, -(Ci-Ci2)heteroalkyl, -(Ci -Ci2)haloalkyl, -(C1 -Ci2)hydroxyalkyl, (Ci-Ci2)aminoalkyl, -(C3-C7)cycloalkyl or -(C2-C7)heterocycloalkyl; wherein the alkyl, cycloalkyl and heteroacycloalkyl are optionally substituted with one, two or three Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is halogen, -OR10, -NR12R13, —(Ci—Ci2)alkyl, -(Ci-Ci2)heteroalkyl, - ( C1-Ci2)haloalkyl, -(C1-Ci2)hydroxyalkyl, -(Ci-Ci2)aminoalkyl, -(C3C7)cycloalkyl or -(C2-C7)heterocycloalkyl; wherein the alkyl, cycloalkyl and heteroacycloalkyl are optionally substituted with one or two Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is halogen, -OR10, -NR12R13, -(C1 -Ci2)alkyl, -(Ci-Ci2)heteroalkyl, -( C1Ci2)haloalkyl, -(C1-Ci2)hydoxyalkyl, -(Ci-Ci2)aminoalkyl, -(C3-C7)cycloalkyl or -(C2C7)heterocycloalkyl; wherein the alkyl, cycloalkyl and heteroacycloalkyl are optionally substituted with an Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is ΜΛ / Ε / ΖυΖΖ / υΊ Oí ΟΊ halogen, -OR10, -NR12R13, —(Ci—Ci2)alkyl, -(Ci-Ci2)heteroalkyl, —(Ci— Ci2)haloalkyl, —(Ci— Ci2)hydroxyalkyl, - (Ci-Ci2)aminoalkyl, -(C3-C7)cycloalkyl or -(C2-C7)heterocycloalkyl. In some embodiments of a compound of formula (I), (la) or (Ib), Z is -OR10, -(Ci—Ci2)alkyl, -(Ci-Ci2)haloalkyl or -(03-C9)cycloalkyl ; wherein the alkyl and cycloalkyl are optionally substituted with one, two or three Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is -OR10, -(Oí-Ci2)alkyl, -(Ci-Ci2)haloalkyl or -(C3-C9)cycloalkyl ; wherein the alkyl and cycloalkyl are optionally substituted with one or two Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is -OR10, -(Ci-Ci2)alkyl, -(Ci-Ci2)haloalkyl or -(C3-C9)cycloalkyl. it; wherein the alkyl and cycloalkyl are optionally substituted with an Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is -OR10, -(Ci-Ci2)alkyl, (Ci-Ci2)haloalkyl or -(C3-C9)cycloalkyl. In some embodiments of a compound of formula (I), (la) or (Ib), Z is -OR10, -(CiCi2)alkyl, -(Ci-Ci2)haloalkyl or -(C3-C7)cycloalkyl ; wherein the alkyl and cycloalkyl are optionally substituted with one, two or three Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is -OR10, -(Oí-Ci2)alkyl, -(Ci-Ci2)haloalkyl or -(C3-C7)cycloalkyl ; wherein the alkyl and cycloalkyl are optionally substituted with one or two Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is -OR10, -(Ci-Ci2)alkyl, -(Ci-Ci2)haloalkyl or -(C3-C7)cycloalkyl ; wherein the alkyl and cycloalkyl are optionally substituted with an Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is -OR10, —(Ci—Ci2)alkyl, (Ci-Ci2)haloalkyl or -(C3-C7)cycloalkyl. In some embodiments of a compound of formula (I), (la) or (Ib), Z is -OR10. In some embodiments of a compound of formula (I), (la) or (Ib), Z is —(Ci—Ci2)alkyl optionally substituted with one, two or three Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is —(Ci—Ci2)alkyl optionally substituted with one or two Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is —(Ci—Ci2)alkyl optionally substituted with an Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is -(Ci-Ci2)alkyl. In some embodiments of a compound of formula (I), (la) or (Ib), Z is 2,2-dimethylpropyl. In some embodiments of a compound of formula (I), (la) or (Ib), Z is tert-butyl. In some embodiments of a compound of formula (I), (la) or (Ib), Z is isobutyl. In some embodiments of a compound of formula (I), (la) or (Ib), Z substituted with a cyclopropylmethyl Rzes. In some embodiments of a compound of formula (I), (la) or (Ib), Z substituted with a cyclobutylmethyl Rzes. In some embodiments of a compound of formula (I), (la) or (Ib), Z substituted with a 1-fluoro-2-methylpropyl Rzes. In some embodiments of a compound of formula (I), (la) or (Ib), Z substituted with two 1,1-difluoro-2-methylpropyl Rzes. In some embodiments of a compound of formula (I), (la) or (Ib), Z is -(CiCi2)haloalkyl optionally substituted with one, two or three Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is -(Ci-Ci2)haloalkyl optionally substituted with one or two Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is —(Ci— IVIA / t / ZUZZ / U I 0 / Ο I Ci2)haloalkyl optionally substituted with an Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is -(Ci-Ci2)haloalkyl. In some embodiments of a compound of formula (I), (la) or (Ib), Z is -(C3C9)cycloalkyl optionally substituted with one, two or three Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is -(C3-C9)cycloalkyl optionally substituted with one or two Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is -(C3-C9)cycloalkyl optionally substituted with an Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is -(C3-C9)cycloalkyl. In some embodiments of a compound of formula (I), (la) or (Ib), Z is -(CsC7)cycloalkyl optionally substituted with one, two or three Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is -(C3-C7)cycloalkyl optionally substituted with one or two Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is -(C3-C7)cycloalkyl optionally substituted with an Rz. In some embodiments of a compound of formula (I), (la) or (Ib), Z is -(C3-C7)cycloalkyl. In some embodiments of a compound of formula (I), (la) or (Ib), Z is 2,3-dihydro-1H-inden-5-yl. In some embodiments of a compound of formula (I), (la) or (Ib), each Rzes independently halogen, -OR10, -NR12R13o -(Ci-C6)alkyl. In some embodiments of a compound of formula (I), (la) or (Ib), each Rzes independently -(Ci-C6)alkyl. In some embodiments of a compound of formula (I), (la) or (Ib), each Rzes independently methyl. In some embodiments of a compound of formula (I), (la) or (Ib), each Rzes independently F. In some embodiments of a compound of formula (I), (la) or (Ib), R10 is H, -(CiC6)alkyl, -(Ci-C6)haloalkyl or -(C3-C7)cycloalkyl. In some embodiments of a compound of formula (I), (la) or (Ib), R10 is -(Ci-C6)alkyl, -(Ci-C6)haloalkyl or -(C3-C7)cycloalkyl. In some embodiments of a compound of formula (I), (la) or (Ib), R10 is -(Ci-C6)alkyl or -(03C7)cycloalkyl. In some embodiments of a compound of formula (I), (la) or (Ib), R10 is 2,2dimethylbutyl. In some embodiments of a compound of formula (I), (la) or (Ib), R10 is isopropyl. In some embodiments of a compound of formula (I), (la) or (Ib), R10 is cyclohexyl. In some embodiments of a compound of formula (I), (la) or (Ib), R11 is -(C1Cejalkyl, -(Ci-C6)haloalkyl or -(C3-C7)cycloalkyl. In some embodiments of a compound of formula (I), (la) or (Ib), R11 is -(Ci-C6)alkyl or -(C3-C7)cycloalkyl. In some embodiments of a compound of formula (I), (la) or (Ib), R12 and R13 are independently H, -(Ci-C6)alkyl, -(Ci-Ce)haloalkyl or -(C3-C7)cycloalkyl. . In some embodiments of a compound of formula (I), (la) or (Ib), R12 and R13 are independently H, -(O1-C6)alkyl or -(03-C7)cycloalkyl. In some embodiments of a compound of formula (I), (la) or (Ib), -X-Y-Z is ΜΛ / Ε / ΖυΖΖ / υΊ ΟΖΟΊ ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ In some embodiments of a compound of formula (I), (la) or (Ib), -X-Y-Z is ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ In some embodiments of a compound of formula (I), (la) or (Ib), -X-Y-Z is In some embodiments of a compound of formula (I), (la) or (Ib), -X-Y-Z is In some embodiments of a compound of formula (I), (la) or (Ib), -X-Y-Z is In some embodiments of a compound of formula (I), (la) or (Ib), each Ra is independently H, -(Ci-C6)alkyl, -(Ci-C6)haloalkyl or -(C3-C7)cycloalkyl . In some embodiments of a compound of formula (I), (la) or (Ib), each Ra is independently H or -(CiCe)alkyl. In some embodiments of a compound of formula (I), (la) or (Ib), each Raes H. In some embodiments of a compound of formula (I), (la) or (Ib), each Raes independently -(Ci-C6)alkyl. In some embodiments of a compound of formula (I), (la) or (Ib), each Ra is independently -(Ci-C6)alkyl, -(Ci-C6)haloalkyl or —(Cs—Czjcycloalkyl. In some forms embodiment of a compound of formula (I), (la) or (Ib), eachRais independently -(Ci-C6)alkyl. In some embodiments of a compound of formula (I), (la) or (Ib), each Rc and Rdes independently H, -(Ci-C6)alkyl, -(Ci-C6)haloalkyl or -(C3-C7) cycloalkyl. In some embodiments of a compound of formula (I), (la) or (Ib), each Rcy and Rdes independently H or —(Ci—C6)alkyl. In some embodiments of a compound of formula (I), (la) or (Ib), each Rcy Rdes H. In some embodiments of a compound of formula (I), (la) or (Ib), each Rc and Rdes independently -(Ci-C6)alkyl. In some embodiments, the compound of formula (I), (la) or (Ib) is selected from a compound of Table 2 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ Table 2 m z • 0 Q. W Structure Designation 1 UH h2n NH2 I HO* η OH |] 1 L Js^ ..OH ’N > 0 f HN 71 I η II h i ii .N. ,N^ A- 0 Cr ητ tr V γ 0 o k 0 = NH 1 o=s—NH2 II 0 acid (8S, 11S,14S)—18—hydroxy—11—methyl— 14-[methyl-[(2S) -2-[[1-(4-tert-butylphen¡l)-6oxo-pyridaz¡n-4-carbonyl]amino]-3(sulfamoylamino)propanoyl]amino]-10,13dioxo-3,17 -bis[(2R)-3-amino-2-hydroxy¡propoxy¡]-9,12- diazatricyclo[13.3.1.12,6]icosa- 1 (18),2(20),3,5 ,15(19),16-hexaen-8- carboxylic 2 X 0 .) dHo......( >—\ zz o— / / “V x / —O z—ώ=Ο >... ......7 ¿ £ - * “x 1 z z^y_ z acid (8S,11S, 14S)—18—hydroxy—11 —m ethyl— 14-[methyl-[(2S)-2-[[ 4-amino-2-(4-tertbutylphenyl)—6—methyl—pyrimídin—5—carbonyl]amino]-3- (sulfamoylamino)propanoyl]amino]-10,13dioxo-3,17-bis [(2R)-3-amino-2-hydroxy¡propoxy¡]-9,12- d¡azatricyclo[13.3.1.12,6]cosa- 1 (18),2(20),3, 5,15(19),16-hexaen-8carboxylic 3 OH \ / H?N \ N H? V, kZAA .γθγ ^.Ν. JL .Ν. Α. 0 Γ ί ι Γ ί 0 NH, O V 1 Ο ΝΗ 1 o=s=o 1 ΝΗ, acid (8S,11 S,14S)—18—hydroxy—11—methyl— 14-[methyl-[(2S)-2-[[4-amí no-2-[ 4-(3,3dimethylbutoxy)phenyl]—6—methyl—pyrimidin—5—carbonyl]amino]-3- (sulfamoylamino)propanoyl]amino]-10,13dioxo-3,17-bis[(2R)-3 -amino-2-hydroxy¡propoxy¡]-9,12- diazatricyclo[13.3.1.12,6]cosa1(18),2(20),3,5,15(19), 16-hexaen -8carboxylic φ Ό ο ζ ΰΓ Structure Designation 4 qh / Η2Ν α- ° ϊ Ί Η ϊ Τ Η Ηι τ ο^ιΓ * |ΊΓ i Ο V 1 ο NH O=¿—ΝΗ, II ο acid (8S,11S,14S) -18-hydroxyl-11-methyl-14-[methyl-[(2S)-2-[[1-[4-(3,3-dimethylbutoxy)phenyl]—6—oxo—pyridazin—4—carbonyl ]amino]-3- (sulfamoylamino)propanoyl]amino]-10,13dioxo-3,17-b¡s[(2R)-3-amino-2-hydroxy¡propoxy¡]-9, 12- diazatricyclo[13.3.1.12,6]icosa- 1 (18),2(20),3,5,15( 19), 16-hexaen-8- carboxylic 5 ζ=^~~^ ( / Ο=\ x 1? ι ΛΛ <; 1 ϋ \— / * ο ¡l)phenyl]pyrimidin—5—carbonyl]amino]-3- (sulfamoylamino)propanoyl]amino]-10,13dioxo-3,17-bis[(2R)-3-amino-2-h¡ droxypropoxy]-9,12-diazatricyclo[13.3.1.12,6]icosa1(18),2(20),3,5,15(19),16-hexaen-8carboxylic 6 °^f S ΖΤ Q Ζ ° / ......( J / ·^ Ο=ω—ζ )=0 Ο—' i 1 ~\ / ={* _VVV ° ο=\ —\ °—\ ζτ \— / \ ......0 ..........Γ -θ ( 3 ο \Μ ο=\ ο ζ acid (8S, 11S, 14S)—18—hydroxy—11 —m ethyl— 14- [methyl-[(2S)-2-[[4-amí no-6-methyl-2[4—(1—methylcyclopropyl)phenyl]pyrimidin—5—carbonyl]amino]-3- (sulfamoylamino)propanoyl]am no]-10,13dioxo-3,17-bis[(2R)-3-amino-2-hydroxy¡propoxy¡]-9,12- diazatricyclo[13.3.1.12,6]thing- 1 (18),2(20),3,5,15(19), 16-hexaen-8carboxylic 7 Ο=\ ' ζ J ΖΧ ο ζ / ......( ο Ο=ω—ζ Ο—f ί / =< J JVJ 5 ......Γ Q C Γ\_Γ ί ο -[[2-(4-tert-butylphen¡l)4,6-dimethyl-pyr¡m¡din-5-carbon¡l]amino]-3(sulfamo¡lamino)propanoyl ]amino]-10,13dioxo-3,17-b¡s[(2R)-3-amino-2-hydroxy¡propoxy¡]-9,12- diazatricyclo[13.3.1.12,6]cosa1 (18),2(20),3,5,15(19),16-hexaen-8carboxylic ΜΛ / Ε / ζυΖΖ / υΊ ΟζΟΊ φ Ό ο ζ ΰΓ Structure Designation 8 OH HjN | ΗΟ'· η ΟΗ0'^^ 0χν ϊ η ϊ Υ η Hfr Ν. _N. 0 i ί i ° 0 V 1 0 NH 1 O=S—NH, II or acid (8S,11S,14S)—18—hydroxy—11—methyl— 14-[methyl-[(2S)-2-[[ 2-(4-tert-butylphen¡l)-4methyl-pyr¡m¡d¡n-5-carbon¡l]amino]-3(sulfamo¡lamino)propanoyl]amino]-10, 13dioxo-3,17-b¡s[(2R)-3-amino-2-hydroxy¡propoxy¡]-9,12- diazatric¡clo[13.3.1.12,6]icosa- 1 (18) ,2(20),3,5,15(19),16-hexaen-8carboxylic 9 I o >=o x ) O .......... o >—< xz '—o / —λ > =o £ ΥΥΥ χ J [methyl-[(2S)-2-[[1-[4- (cyclohexoxy)phen¡l]-6-oxo-pyr¡daz¡rMcarbonyl]amino]-3- (sulfamoylamino)propanoyl]amino ]-10,13dioxo-3,17-bis[(2R)-3-amino-2-hydroxy¡propoxy¡]-9,12- diazatricyclo[13.3.1.12,6]icosa- 1(18) ,2(20),3,5,1 5(19), 16-hexaen-8- carboxylic 10 T or ? Y^Y >-· / < 12 xyY £ Y7 / -x f / —O O=< z—«=O / / )... / ¿ Z b XZ * 1 O”° acid (8S,11S,14S )-18-hydroxy¡-11-methyl14-[methyl-[(2S)-2-[[2-[4-(1,1-difluoro-2methyl-propyl)phenyl]-4-methyl l—pyrimidin—5—carbonyl]amino]-3- (sulfamoylamino)propanoyl]amino]-10,13dioxo-3,17-bis[(2R)-3-amino-2-h ¡droxy¡propoxy¡]-9,12- diazatricyclo[13.3.1.12,6]icosa1(18),2(20),3,5,15(19), 16-hexaen-8carboxylic 11 X 0 / =c ϊ / -(Ζύ 8......? O J....... °x _Y^\Y° °--\ / --\ X ,—□ □= / z—Ji=o / \ / II / —ζ )......... 0 z b ~ xz £ x x \ x z / =° / X X z acid (8S,11S, 14S)—18—hydroxy—11 —m ethyl— 14- [methyl-[(2S)-2-[[3-am¡no-5-(4-tertbutylfenyl)pyraz n-2-carbonyl]amino]-3(sulfamo¡lamino)propanoyl]amino]-10 ,13dioxo-3,17-bis[(2R)-3-amino-2-hydroxy¡propoxy¡]-9,12- diazatricyclo[13.3.1.12,6]icosa- 1 (18),2( 20),3,5,15(19), 16-hexaen-8carboxylic ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ Φ Ό ο ζ ΰΓ Structure Denomination 12 \ / —C Η 7“ τ ΐ / —Ο Ο=< ζ— ω=Ο / \ / II / —< ) ' ο ζ b ιζ ' ' )G \=ζ 7 acid (8S,11S, 14S)— 18-hydroxy-11-methyl-14-[methyl-[(2S)-2-[[4-amino-2-(4-tertbutyl-1-piperidyl)-6-methyl-pyrimidin-5-carbonyl ]amino]-3- (sulfamoylamino)propanoyl]amino]-10,13dioxo-3,17-bis[(2R)-3-amino-2-hydroxypropoxy¡]-9,12- diazatricyclo[13.3. 1.12,6]icosa- 1 (18),2(20),3,5,15(19),16-hexaen-8carboxylic 13 / 7 ο=\ \ ϊ 1 ζχ Q ζ ° / ...... ...( ο=^ζ >ο μΙ JvT° ζζ \— / ) 0 ........\ 1 0=f ο X acid (8S,11S,14S)-18-hydroxy¡-11- methyl14-[methyl-[(2S)-2-[[2-(4-isopropoxyphen¡l)4,6-dimethyl-pyrimidin-5-carbon¡l ]am¡no]-3(sulfamoylamino)propanoyl]am¡no]-10,13dioxo-3,17-bis[(2R)-3-am¡no-2-hydroxy¡propoxy¡]-9,12- diazatric ¡clo[13.3.1.12,6]icosa- 1(18),2(20),3,5,15(19),16-hexaen-8carboxylic 14 ΟΗ Η2Ν. 'Ύ' Η Ο'' 'η ΟΗθ^^Λ, tlT-r rV -V Jk ,NL A. A. ^k O Ϊ u 1 I 1 NH 1 O=S—NH, II 0 acid (8S,11S,14S) —18—hydroxy—11—methyl— 14-[methyl-[(2S)-2-[[2-(4-isopropoxyphenyl)4-methyl-pyrimidin-5- carbon¡l]amino]-3(sulfamo¡lamino)propanoyl]amino]-10,13dioxo-3,17-bis[(2R)-3-am¡no-2-hydroxy¡propoxy¡]- 9,12- diazatricyclo[13.3.1.12,6]icosa1(18),2(20),3,5,15(19), 16-hexaen-8carboxylic 15 k^3 0=\ \ X 1 ZI z 11 / .......( . / Ο=ω—z 7=0 O—' 1 Z-z( / =( zx \— / y...... .......... / = (Λ ( 1 a \' w o=f 0 2-[4—(1met¡lc¡cloprop¡l)phen¡l]pyrimidín-5- carbonyl]amino]-3- (sulfamoylam¡no)propanoyl]amino]-10,13dioxo-3,17 -bis[(2R)-3-amino-2-hydroxy¡propoxy¡]-9,12- diazatricyclo[13.3.1.12,6]icosa- 1 (18),2(20),3,5 ,15( 19), 16-hexaen-8- carboxylic ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ Φ Ό ο ζ ΰΓ Structure Denomination 16 °\ I ο ^=ο ί χ ) Ο* 1 / .......... Ο.....( ?—ξ τζ '—Ο \- λ )=Ο ο—Ζ y-- / χ / “θ'- ζ Τ / ^° ο=( Μ / ......... ° ζ ο ΧΖ - * Αθ ζά λ d' acid (8S ,11S,14S)-18-hydroxy¡-11-methyl- 14-[methyl-[(2S)-2-[[2-[4-(3,3-dimethylbutoxy¡)phen¡l]^- met¡l-pyr¡m¡din-5carbonyl]amino]-3- (sulfamoylamino)propanoyl]amino]-10,13dioxo-3,17-b¡s[(2R)-3-amino-2 -hydroxypropoxy]-9,12- diazatricyclo[13.3.1.12,6]icosa- 1(18),2(20),3,5,1 5(19),16-hexaen-8- carboxylic 17 οη η2ν^_ ^Λ^^.νη2 Hcd' η οη γΧ . ° Ν Υ Ο ΗΝ >< Η II H 11 Α χ JL .ν. ό i Π ί° νη9 acid (8S,11S, 14S)—18 —hydroxy—11-methyl14-[methyl-[(2S)-4-amino-2-[[1-(4-tert-butylphenyl)—6-oxo- p iridazin—4carbonyl]amino]butanoyl]amino ]-10,13dioxo-3,17-bis[(2R)-3-amino-2-hydroxy¡propoxy¡]-9,12- diazatricyclo[13.3.1.12,6]icosa- 1 (18) ,2(20),3,5,15(19),16-hexaen-8carboxylic 18 £ ΟΗ / Η2Ν. χ\ / ΝΗ2 ,Ί Αχ θγ-γ. lAA· Ν. -Ν. X _Χ J< X. Ο ΥΎ ί ϊ ιΓ ί 0 ΝΗΖ Ο V 1 ο νη2 acid (8S,11S,14S)—18—hydroxy—11—methyl— 14-[methyl-[(2S)-4-amino-2-[[4- amino-2[4—(3,3—dimethylbutoxy)phenyl]—6—methyl—pyrimidín-5-carbon¡l]amino]butane¡l]amino]10,13-dioxo-3,17- bis[(2R)-3-amino-2hydroxy-propoxy¡]-9,12-diazatricyclo[13.3.1.12,6]icosa- 1(18),2(20),3,5,15(19), 16 -hexaen-8carboxylic 19 °Α' ζ t ζτ Q ζ ........¿ y---7 ζ— / \=Ο Ο— * — Ζ / = / Ο=\ -X °-\ ΖΤ \-- / )-Μ< 3 0=\ ο 2-(4-tert-butylphen¡l)-4,6A¡methyl-pyrim¡din-5carbonyl]amino]butanoyl]amino]-10,13dioxo-3,17-bis[(2R) -3-amino-2-hydroxypropoxy]-9,12-diazatricyclo[13.3.1.12,6]icosa- 1 (18),2(20),3,5,15( 19), 16-hexaen-8carboxylic ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ Φ Ό ο ζ ΰΓ Structure Denomination 20 “Ο X J ZX Q Ζ / \__ / ylUm-í J—f ζ— / \=Ο Ο—' * —τ. = / ΥχΥ- ° Ο=\ —\ °—\ ζτ \— / / -«Ο ......ζ ζ Ο X 1 οζ \' α=\ X acid (8S,11S,14S)-18- hydroxy¡-11-methyl-14-[methyl-[(2S)^l-amino-2-[[2-(4isopropoxyphen¡l)-4-methyl-pyr¡m¡din-5carbonyl ]am¡no]butane¡l]amino]-10,13dioxo-3,17-bis[(2R)-3-am¡no-2-hydroxy¡propoxy¡]-9,12- d¡azatricyclo[ 13.3.1.12,6] ¡cosa- 1 (18),2(20),3,5,1 5(19),16-hexaen-8carboxylic 21 Ο=\r ι τ ¥τ “ .KM·»· / y-----' ρο ^y “ —Ζ / = / o=¿ —\ 7°—\ ζχ \— / ).......0 ......G ρ y Γ yy ? o=f -(1-methylcyclopropyl)f en¡l]pyrimidin- 5carbonyl]amino]butanoyl]amino]-10,13dioxo-3,17-bis[(2R)-3-amino-2- hydroxypropoxy]-9,12-diazatricyclo[13.3.1.12,6]icosa- 1 (18),2(20),3,5,1 5(19),16-hexaen-8carboxylic 22 τ ο 7 fpp° τ / VJ / .......... Ο.......( 7—{ΧΖ '—θ λ—λ ?=θ 5 \ ΛΑ Vf y---- ( 2.......... ζ b χζ - 1 2γο ^y 7 '—ο acid (8S,11S,14S)—18—hydroxy—11—methyl— 14-[methyl-[(2S) -4-amino-2-[[1-[4-(3,3dimethylbutox¡)phen¡l]- 6-oxo-pyridazin -4carbonyl]amino]butanoyl]amino]-10,13dioxo-3,17-bis[ (2R)-3-amino-2-hydroxy¡propoxy¡]-9,12-diazatricyclo[13.3.1.12,6]icosa1(18),2(20),3,5,15(19) ,16-hexaen-8carboxylic 23 71 \ / . ......... / : · J _ζ^° / °^ ζχ \— / >·· ο / #Α / 1 1 X acid (8S,11S ,14S)-18-hydroxy¡-11-methyl¡l14-[methyl-[(2S)-4-amino-2-[[2-(4-tertbutylphenyl) -4-methyl-pyrimidin- 5carbonyl]amino]butanoyl]amino]-10,13dioxo-3,17-bis[(2R)-3-amino-2-hydroxy¡propoxy¡]-9,12- diazatricyclo[13.3.1.12 ,6]icosa1(18),2(20),3,5,15(19), 16-hexaen-8carboxylic ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ Φ Ό ο ζ ΰΓ Structure Denomination 24 OH Η2Ν. ^Α.^,ΗΗ2 I HO OH γΛ y ψ γψ> XAvA 1 ^NH? acid (8S,11S,14S)—18—hydroxy—11—methyl— 14-[methyl-[(2S)-4-amino-2-[[4-amino-2(4—tert—butylphenyl)— 6—methyl—pyrimidin—5—carbonyl]amino]butanoyl]amino]-10,13dioxo-3,17-bis[(2R)-3-arrino-2-hydroxypropox ¡]-9,12- diazatric¡cyclo[13.3.1.12,6]icosa1(18),2(20),3,5,15(19),16-hexaen-8carboxylic 25 OH HjN^_ ^<\ / NH2 i HO'*X OH L 1 -L· ^OH q τ 1 Η ​​0 Η II N NH2 O L । 0 1 NH2 acid (8S,11S,14S)—18—hydroxy—11—methyl— 14-[methyl-[(2S)-4-amino-2-[[4-amino-2(4—tert—butyl— 1—piperidyl)—6—met¡l—p¡r¡m¡din— 5-carbonyl]amino]butanoyl]amino]-10,13dioxo-3,17-b¡s[(2R)-3- amino-2-hydroxy¡propoxy¡]-9,12- diazatric¡clo[13.3.1.12,6]cosa- 1(18),2(20),3,5,1 5(19), 16 -hexaen-8carboxylic 26 OH HZN. ^Α^γΝΗΣ iL ”’xXXF Xa xx x- N O X UN >< 1 H II h I II A\ >k X >N. A. 0 o^ ir rr Αχ S 4 1 Ϊ i nh2 acid (8S,11S,14S)-18-hydroxy¡-11-met¡l14-[methyl-[(2S)-4-amino-2-[[ 1-[4(cyclohexox¡)phen¡l]-6-oxo-pyrádaz¡n-4~ carbonyl]amino]butane¡l]amino]-10,13dioxo-3,17-b¡s[ (2R)-3-amino-2-hydroxy¡propoxy¡]-9,12-diazatricyclo[13.3.1.12,6]icosa- 1 (18),2(20),3,5,15( 19) , 16-hexaen-8carboxylic 27 / °A_y ==\ )\)~ I O=\ —X °—X ZX \—Z ).......o / / X / 1 XyJ^ > o=\ o X acid (8S,11S,14S)- 18-hydroxy¡-11-methyl¡l14-[methyl-[(2S)-4-amino-2-[[2-[4-(3,3dimethylbutoxy¡)phen¡l]^4-methyl-p ¡r¡m¡d¡n-5carbonyl]amino]butane¡l]amino]-10,13dioxo-3,17-bis[(2R)-3-amino-2-hydroxy¡propoxy¡ ]-9,12- diazatricyclo[13.3.1.12,6]icosa- 1 (18),2(20),3,5,15( 19), 16-hexaen-8carboxylic 28 5...... / W J....... 5 r°~rl -------ζ ¾ % 1 \ acid (8S,11S,14S)-18-hydroxy¡-11- methyl14-[methyl-[(2S)-4-amino-2-[[4-methyl-2[4-(1-methylcyclopropyl)phenyl]pyrimidin-5carbonyl]amino]butanoyl ]am¡no]-10,13dioxo-3,17-bis[(2R)-3-am¡no-2-hydroxy¡propoxy¡]-9,12- diazatricyclo[13.3.1.12,6]icosa1( 18),2(20),3,5,15(19), 16-hexaen-8carboxylic ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ φ Ό o z üT Structure Denomination 29 T 0.......< y—i iz 'syyJ-0 / 7 / z— £ / —° ° X. / —z ,—( Y· / / v / 2 O IZ - r \o rL \ / Z—Vi o acid (8S,11S,14S)—18—hydroxy—11—methyl— 14-[methyl-[(2S)-4-amino-2-[[1 - [4-(1methylcyclopropyl)phenyl]-6-oxo-pyridazin-4carbonyl]amino]butanoyl]amino]-10,13dioxo-3,17-bis[(2R )-3-amino-2-hydroxypropoxy]-9,12-diazatr¡cycle[13.3.1.12,6]cosa- 1 (18),2(20),3,5 ,1 5(19),16-hexaen-8carboxylic 30 OH H2N ^ / \ / Nh2 ”λτΥ1 U*YY U ^o» VrVrVY^ 1 0 V 1 o nh2 acid (8S,11S,14S)-18-hydroxy- 11-methyl14-[methyl-[(2S)-3-amino-2-[[2-(4-tertbutylphenyl)—4,6^d imethyl—pyrimidin—5—carbonyl]amino]propane¡l]am¡ no]-10,13dioxo-3,17-b¡s[(2R)-3-amino-2-hydroxy¡propoxy¡]-9,12- diazatricyclo[13.3.1.12,6]icosa- 1(18 ),2(20),3,5,15(19), 16-hexaen-8carboxylic 31 o Z=\ 0=^ z X ZZ Q Z / \__ / / in»»··. / ; ' 0=\ —\ °—Y zz \— / ) O ........( 1 or -3-amino-2-[[2-(4-tert-butylphenyl)—4—methyl—pyrimidin—5—carbonyl]amino]propanoyl]amino]-10,13dioxo-3,17-bís [(2R)-3-amino-2-hydroxy¡propoxy¡]-9,12- diazatricyclo[13.3.1.12,6]icosa- 1(18),2(20),3,5,1 5(19), 16-hexaen-8carboxylic 32 OH HjN. 1 ho’*' η oh Y ^N. .NH, L J ΛΗ Y O HN ΤΓ II H II H II -amino-2-[[2-(4-tertbutylphenyl)—4—amino—6—difluoromethyl—pyrimidin-5-carbon—l]amino]butane—l]amino]10 ,13-dioxo-3,17-bis[(2R)-3-amino-2hydroxy-propoxy¡]-9,12-diazatricyclo[13.3.1.12,6]¡cosa- 1 (18),2(20 ),3,5,15( 19), 16-hexaen-8carboxylic 33 Z \ / K> \ / 0=\ T 1 zx C. z ii / .....(_ Ο=ω-ζ / =° °—' “x ° \ —\ °—Y zz \— / >||O ......(_z y3 ¿ 1 o=x o z acid (8S, 11S, 14S)-14-[[(2S) -2-[[4-amino-2-[4-(1,1-dimethylpropyl)-2-fluorophenyl]-6-methyl-pyrimidin-5-carbonyl]amino]3-( sulfamo¡lamino)propan¡l]-meth¡amino]-3,17-b¡s[(2R)-3-am¡no-2-hydroxy¡propoxy]-18-hydroxy¡-11 —methyl —10,13- d ioxo-9,12-diazatricyclo[13.3.1.12,6] icosa1 (18),2(20),3,5,15(19),16-hexaen-8carboxylic φ Ό ο ζ ΰΓ Structure Denomination 34 0= / 2 ....<1 o=€ o z acid (8S, 11S, 14S)-14-[[(2S)-2-[[4- amino-2-[4-(c¡clopropylmethyl)phen¡l ]-6-methylpyrim¡din-5-carbon¡l]amino]-3(sulfamoylam¡no)propanoyl]-methyl-amino]3,17-bis [(2 R)- 3-amino-2-hydroxypropoxy]—18—hydroxy—11 —methyl—10,13dioxo-9,12-diazatricyclo[13.3.1.12,6]cosa1 (18),2(20),3,5, 1 5(19),16-hexaen-8carboxylic 35 OH H2N. ^NH o=s-nh2 II o acid (8S, 11S, 14S)-14-[[(2S)-2-[[2- amino-6-(4-tert-butyl-2-fluoro-phenyl)- 4methyl-pyridn-3-carbonyl]amino]-3(sulfamoylamino)propanoyl]-methyl-amino]3,17-bis [(2 R)-3-amino- 2-hydroxy¡propoxy]-18-hydroxy¡-11 —methyl—10,13d ioxo-9,12-diazatricyclo[13.3.1.12,6]icosa1 (18),2(20),3,5,15(19 ),16-hexaen-8carboxylic 36 X o r=o « / —C p . S ...... on Y 7—\ IZ )= / z— 2 « / / r II z y—O O=\ z—m—z )..... / s Z ó ΞΕΖ X \__ X \ / O ^1 / 1 acid (8S, 11S, 14S)-14-[[ (2S)-2-[[4- amino—2—(4—butylphenyl)—6—methyl—pyrimidin— 5- carbonyl]amino]-3- (sulfamoylamino)propanoyl]-methyl-amino]- 3,17-bis[(2 R)-3-amino-2-hydroxypropoxy]-18-hydroxy -11-methyl-10,13d ioxo-9,12—d iazatricyclo[13.3.1.12,6]icosa1(18),2(20),3,5,15(19), 16-hexaen-8carboxylic 37 X o ^=o X / —\ / ° ..' or 5 ΐ £ x z / =o / i / =z acid (8S, 11S, 14S)-14-[[(2S)-2-[[4- amino- 6-(4-tert-butylphenyl )-2-chloropyrid in3-carbonyl]amino]-3- (sulfamoylamino)propanoyl]-methyl-amino]- 3,17-bis[(2 R)-3-amino-2-hydroxy¡ propoxy]-18-hydroxy¡-11 —methyl—1 0,13d ioxo-9,12—d iazatricyclo[13.3.1.12,6]icosa1 (18),2(20),3,5,15( 19), 16-hexaen-8carboxylic ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ φ Ό ο ζ ΰΓ Structure Denomination 38 oh Η2Ν ^Λ^ΝΗ2 F F ​​ΗΟ'·^] ΟΗθγ^ V η ϊ Υ η Ηΐ^ Ν γ Υ'ΎύΆ ο νη2 Ο \ 1 ο = ΝΗ 1 o=s-nh2 II ο acid (8S, 11S, 14S)-14-[[(2S)-2-[[4- amino-2-[4-(1,1 —d if luoro-2-methylpropyl)ph enyl]-6-methyl -pyrimidin—5carbonyl]amino]-3- (sulfamoylamino)propanoyl]-methyl-amino]3,17-bis[(2 R)-3-amino-2-hydroxypropoxy]-18- hydroxy-11 —methyl —10,13dioxo-9,12-diazatricyclo[13.3.1.12,6]cosa1 (18),2(20),3,5,15( 19), 16-hexaen-8carboxylic 39 ΟΗ Η2Ν ^\ / ΝΗ2 Ηο'·'' η ΟΗθΎ^ Υχ^ wV |Γ Η {] Η ΐΓ Ν ΝΗ, 0 % Ο ΝΗ 1 o=s-nh2 II 0 acid (8S, 11S, 14S)-14- [[(2S)-2-[[4-amino-2-(4-tert-butyl-2-cyano-phenyl)-6methyl-pyrimidin-5-carbonyl]amino] -3(sulfamoylamino)propanoyl]-methyl-amino]3,17-bis[(2 R)-3-amino-2-hydroxypropoxy]-18-hydroxy-11 —methyl—10,13- dioxo-9,12-d¡azatr¡cyclo[13.3.1.12,6]icosa- 1 (18),2(20),3,5,15( 19), 16-hexaen-8carboxylic 40 ζ Ο Ϊ=Ο <Μ / Ο Λ Q ...... Ο|ζ \--£ ΙΖ Η Υ ο— / 2—V * / —O Ο=Υ ζ-ώ-Ο Γ-Τ )..... / ί) Ζ Ο Ν τζ £ χ γ_>° acid (8S, 11S, 14S)-14-[[(2S)-2-[[2- amino- 6-(4-tert-butylphenyl)—4—chloro - pyrid in3-carbonyl]amino]-3- (sulfamollamino)propanoyl]-methyl-amino]3,17-bis[(2 R)-3-amino-2-hydroxy¡propoxl]-18-hydrox ¡-11 —methyl—10,13— dioxo-9,12-diazatricycle[13.3.1.12,6]cosa1(18),2(20),3,5,15(19), 16-hexaen- 8carboxylic 41 Τ \ / Ν> )==( °^\ ΣΤ ζζ ο, ζ Μ / .....( ζ—ω—ζ ta=o Ο— / / ° \ —\ °—κ ζζ Υ— / Υιιο ......{ι Ο {1 ϋ \—' ο ζ acid (8S, 11S, 14S)-14-[[(2S)-2-[[4- amino-2-(4-c¡ clobutylphenyl)-6-methyl-pyrimidin-5-carbonyl]amino]-3- (sulfamoylamino)propanoyl]-methylamino]3,17-bis[(2 R)- 3-amino-2-hydroxypropoxy]—18—hydroxy—11 —methyl—10,13dioxo-9,12-diazatricyclo[13.3.1.12,6]cosa1 (18),2(20),3,5, 15(19), 16-hexaen-8carboxylic ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ φ Ό o z üT Structure Denomination 42 X O 0.1 \ / —\ TZ OT= O—C / --V ^\- acid (8S, 11S, 14S)-14-[[(2S)-2-[[4- amino-2-[4-(2,2-dimethylprop¡l)phen¡l]-6methyl -p¡r¡m¡d¡n-5-carbon¡l]amino]-3(sulfamoylamino)propanoyl]-methyl-amino]3,17-bis [(2 R)-3-amino -2-hydroxypropoxy]-18-hydroxy-11-methyl-10,13dioxo-9,12-diazatricyclo[13.3.1.12,6]cosa1 (18),2(20),3,5 ,1 5(19),16-hexaen-8carboxylic 43 O^C X \ / z=¿ -O2 'r x ZI M o z j.....c r M -Z / —( y^Vo / \ / '^X °—X ZI \— / )··ιο ......f X O {1 O o=\ o X acid o (8S, 11S, 14S)-14-[[( 2S)-4- am i no-2[[4- amino- 2-(4-tert-butyl-2-hyd roxy-phenyl)6-methyl-pyrimid i n-5carbonyl]amino]butano¡l]-methyl-am ¡no]3,17-bis[(2 R)-3-amino-2-hydroxy¡propoxy]-18-hydroxy¡-11 —methyl—1 0,13dioxo-9,12-diazatricycle[13.3.1.12 ,6]!thing1 (19),2(20),3,5,15,17-hexaen-8carboxylic 44 I X / M \--- / °=( ' X 1 zx □, z ? / .... .( O=w-z / ^° °—f z — / =\ * _y\z / ° ° \ —X °—\ zx \— / and not ......up < O y ' M ° X o I acid (8S, 11S, 14S)-14-[[(2S)-2-[[4- amino- 2-(4-tert-butyl-2- hydroxy—phenyl)-6methyl-pyrimid¡ n-5-carbonyl]amino]-3(sulfamoylamno)propanoyl]-methyl-amino]3,17-bis[(2 R)-3-amino-2-hydroxypropoxy]- 18-hydroxy¡-11 —methyl—10,13dioxo-9,12-diazatricycle[13.3.1.12,6]cosa1 (18),2(20),3,5,15( 19), 16-hexaen -8carboxylic 45 í-í^ Μ \ / O=\ ' x = zx q, z ° / .....( O=cn-z °—' z —r=\ ° \ —\ °—\ ZI z —¿ / C ......Y < ' O J--' M o=\ □ -[4-(1,1-dimethylpropyl)phenyl]-6methyl-pyrmidin-5-carbonyl]amino]-3(sulfamoylamino)propanoyl]-methyl amino]3,17-bis[(2 R)-3-amino-2-hydroxy¡propoxy]-18-hydroxy¡-11-methyl-10,13-dioxo-9,12-diazatricycle [13.3.1.12,6]thing1(18),2(20),3,5,15(19), 16-hexaen-8carboxylic φ Ό ο ζ ΰΓ Structure Denomination 46 ΟΗ Η2Ν ^\^ΝΗ2 >φ. Η°' i / Xk L· JL .Ν. ,ΝΗ2 II J Χ.ΟΗ Υ η 5 j η Ηϊ ιΓ 0 \ I Ο = ΝΗ I O=s-ΝΗ, II 0 acid (8S,11S,14S)-14-[[(2S)-2-[[4 - am¡no-2-(4-tert-butylphen¡l)p¡r¡m¡d¡n-5carbonyl]amino]-3- (sulfamoylamino)propanoyl]-methyl-amino]- 3, 17-bis[(2 R)-3-amino-2-hydroxypropoxy]-18-hydroxy-11 —methyl-10,13-dioxo-9,12-diazatricyclo[13.3.1.12,6]cosa1 (18),2(20),3,5,15(19),16-hexaen-8carboxylic 47 ÜH Α χχι XX JL^ -ΝΗ2 0 = νη2 acid (8S,11S,14S)—18—hydroxy—11—methyl— 14-[methyl-[(2S)-4-amino-2-[[4-amino-2(1,1-d¡ met¡landan-5-yl)-6-methyl-pyr¡m¡d¡n5-carbonyl]amino]butano¡l]amino]-10,13dioxo-3,17-b¡s[ (2R)-3-amino-2-hydroxy¡propoxy¡]-9,12-diazatricyclo[13.3.1.12,6]icosa1(18),2(20),3,5,15(19), 16 -hexaen-8carboxylic 48 ΟΗ Η2Ν χΧΥ Υΐ ΝΧ 0 ΝΗ, O amino-2-(4-tert-butyl-2-hydroxy¡-6-met¡lfen¡l)-6-met¡l-pyrimidin-5-carbon¡l]amino]3-( sulfamoylamino)propan¡l]-methylámino]-3,17-b¡s[(2R)-3-amino-2-hydroxy¡propoxy]—18—hydroxy—11 —methyl—10,13d ioxo-9,12-diazatricyclo[13.3.1.12,6] icosa1 (18),2(20),3,5,15( 19), 16-hexaen-8carboxylic 49 ΟΗ Η2Ν |Α\^ΝΗ2 χγχ 1 0 χ 1 0 ΝΗ 1 O=s-NH2 II ο acid (8S, 11S, 14S)-14-[[ (2S)-2- [ [2- amino- 6-(4-tert-butylphenyl)-4- methyl - pyrid in3-carbonyl]amino]-3- (sulfamoylamino)propanoyl]-methyl-amino]- 3,17-bis[(2 R)-3-amino-2-hydroxypropoxy]- 18-hydroxyl-11 —methyl—1 0.13d ioxo-9,12—d iazatricyclo[13.3.1.12,6]icosa1(18),2(20),3,5,15(19), 16-hexaen -8carboxylic ΜΛ / Ε / ZUZZ / UIO / OI Φ Ό ο ζ ΰΓ Structure Denomination 50 ζ Ο \=Ο μ / y Ο Λ Q ...... οι'\ / —\ χζ ς / Λh° ο— / y—£ / —O o=¿ ζ- ώ-Ο Γ-ζ )... / ¿ Ζ Ο χζ £ χ \_ χ ξ >=Ο ) ( <Ν acid (8S, 11S, 14S)-14-[[(2S)-2-[ [4- amino-2-(4-tert-butylphenyl)-6-methylpyrim¡din-5-carbon¡l]amino]-3- (sulfamoylamino)propanoyl]-methyl-amino]3- [(2 R)-3-am¡ no-2-hydroxy-propoxy¡]-17[(2S)-3-amino-2-hydroxy-propoxy¡]-18hydroxy-11 —m ethyl—10,13-dioxo -9,12diazatricyclo[13.3.1.12,6]icosa- 1 (19),2(20),3,5,15,17-hexaen-8carboxylic 51 ü O J...... Λ<^5>ί Ζ Ο (Ν ΤΖ £ X Τ \ τ ζ 2=ο ο acid (8S,11S,14S)—18—hydroxy—11—methyl—14-[ methyl-[(2S)-4-amino-2-[[4-amino-6- (4—tert—butylphenyl)—2—chloro—pyridin—3— carbonyl]amino]butanoyl]amino] -10,13dioxo-3,17-bis[(2R)-3-amino-2-hydroxylpropoxy]-9,12-diazatricyl[13.3.1.12,6]icosa- 1 (18 ),2(20),3,5,15(19),16-hexaen-8carboxylic 52 ÜH Η2Ν hoxV η OH°h^% Υγ^Υ°Η ^ΝΗ2 ί J Υ.0Η Υ η ? η Η7 ιΓ ΟΗ 1 0 \ 1 0 ΝΗ 1 O = S-NH? II Ο acid (8S,11S, 14S)—18—hydroxy—11 —m ethyl— 14-[methyl-[(2S)-2-[[4-am ¡ no-2-(4,6dih¡drox¡-1,1-dimethyl-¡ndan-5-yl)-6-methyl-pyrimidín-5-carbon¡l]amino]- 3(sulfamoylam¡no)propane¡l]am¡no]-10,13dioxo-3,17-bis[(2R)-3-amino-2-hydroxy¡propoxy¡]-9,12- diazatricycle [13.3.1.12,6]icosa- 1(18),2(20),3,5,15(19), 16-hexaen-8carboxylic 53 OH Η?Ν ^\χΝΗ? 1 Η0'ν h 0Η°Ύ^% AyCUk ? τ η Λ“ η¥ ;ύΆ 0 CI Ο \ 1 ο - ΝΗ 1 O = s —ΝΗ? II 0 acid (8S, 11S, 14S)-14-[[(2S)-2-[[4-amino-2-(4-tert-butylphenyl)-6-chloropyrimidin-5 -carbon¡l]amino]-3- (sulfamoylamino)propanoyl]-methyl-amino]3,17-bis[(2 R)-3-amino-2-hydroxy¡propoxy]-18-hydroxy¡ -11-methyl-10,13dioxo-9,12-diazatricycle[13.3.1.12,6]cosa1(18),2(20),3,5,1 5(19), 16-hexaen- 8carboxylic ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ φ Ό ο ζ ΰΓ Structure Denomination 54 OH Η;Ν Ο. ηο' η ο ι g X ks. ^NH? \ J J>^ .ΟΗ Υ ο ΗΝ I η II Η I II ''χΛ / Κ 0 Υϊ έ fY έ ° 1 0 1 0 = Ν·Ι 1 ο=$=ο 1 Ν·Ι? acid (8S, 11S, 14S)-14-[[(2S)—2-[[4- amino—2—[6—(3,3—dimethylbutoxy)—3—pyridyl]— 6-methyl-pyr ¡m¡d¡n-5-carbonyl]amino]-3(sulfamoylam¡no)propanoyl]-methyl-amino]3,17-bis[(2 R)-3-amino-2- hydroxypropoxy]—18—hydroxy—11 —methyl—10,13dioxo-9,12-diazatricyclo[13.3.1.12,6]cosa1 (18),2(20),3,5,15(19) ,16-hexaen-8carboxylic 55 ΟΗ Η2Ν ^x^xNH¿ - ϊ γ - Λ° YVY / y Υ ° ΝΗ? 0 1 0 - ΝΗ? acid (8S,11S,14S)—18—hydroxy—11—methyl— 14-[methyl-[(2S)-4-amino-2-[[4-amino-2(4—tert—butylphenyl)—6— chloro—pyrimidin—5—carbonyl]am¡no]butano¡l]amino]-10,13dioxo-3,17-b¡s[(2R)-3-am¡no-2-hydroxy¡propoxy¡] -9,12- diazatrichyl[13.3.1.12,6]icosa- 1 (18),2(20),3,5,1 5(19),16-hexaen-8carboxylic 56 ΟΗ Η2Ν ^\^χΝΗ2 > c. ΗΥγΥΥ Μ 1 ΟΗ V Η Η I Η Η? 1Γ ΥΤΎ^ΧΓυ^ ° ΗΝ Ο Υ । Ο = \ ΝΗ 1 O=s—ΝΗ? II 0 acid (8S, 11S, 14S)-3,17-bis[(2R)-3- amino-2-hydroxy¡-propoxy]-14-[[(2S)-2-[[2(4 —tert—butylphenyl)—4—methyl—6— (methylamino)pyrimidin-5-carbonoo]amino]-3(sulfamoylamino)propanoyl]-methyl-amino]18—hydroxy —11 —methyl—10,13-d ioxo-9,12- diazatricyclo[13.3.1.12,6]icosa- 1 (18),2(20),3,5,1 5( 19),16-hexaen- 8carboxylic 57 ?Υ ° u Λ 1 \ τ F ΖΙ Ο ζ Η / .....( Ο—ω—ζ / =° °—' ° \ —\ °—\ ζχ \— / Υυο ..... .< ι Χ> <ζ 1 ο ' κ' Ο=Λ Ο I acid (8S,11S,14S)—18—hydroxy—11—methyl— 14-[methyl-[(2S)-2-[[4- amino-2-(6-hydroxy¡1,1-dimet¡l-¡ndan-5-¡l)-6-met¡l-pyrám¡n- 5-carbonyl]amino] -3- (sulfamoylamino)propane¡l]amino]-10,13dioxo-3,17-bis[(2R)-3-amino-2-hydroxy¡propoxy¡]-9,12- diazatricycle [13.3.1.12,6]icosa- 1 (18),2(20),3,5,15( 19), 16-hexaen-8- carboxylic ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ Φ Ό ο ζ ΰΓ Structure Designation 58 OH Η2Ν . .. > A. ^Ν^ ,Ν. Ο ΗΟ ιΓ ιΓ 0 ΝΗ2 Ο Α I 0 = ΝΗ I o=s—νη2 II 0 acid (8S, 11S, 14S)-14-[[(2S)-2-[[4- amino—2—[4— tert—butyl—2—(hydroxymethyl)phenyl]— 6-methyl-pyr¡m¡d¡n-5-carbon¡l]am¡no]-3(sulfamoylam¡no)propanoyl]-methyl- amino]3,17-bis [(2 R)-3-amino-2-hydroxypropoxy]-18-hydroxy-11-methyl-10,13-dioxo-9,12-diazatricyclo[13.3 .1.12,6]thing- 1 (18),2(20),3,5,1 5(19),16-hexaen-8carboxylic 59 οη η2ν ^ΧΑ XA Υ - Λ ΧΥΥ Τϊ ΑΧ Υ^° νη2 ο ν 1 ο ΝΗ 1 O=s —ΝΗ? II 0 acid (8S, 11S, 14S)-14-[[(2S)-2-[[4-amino-2-(4-tert-butyl-2-methyl-pheníl)-6methyl-pyr ¡m¡din-5-carbonyl]am¡no]-3(sulfamoylamino)propanoyl]-methyl-am¡no]3,17-bis[(2 R)-3-amino-2-hydroxy¡propoxy] -18-hydroxy-11 —methyl—10,13- d ioxo-9,12-diazatricyclo[13.3.1.12,6]icosa- 1 (18),2(20),3,5,15( 19), 16 -hexaen-8carboxylic 60 ο ΑΆ Τ \___ / —\ ζι \— / )ίΙΟ ......yj / ¿ ζ οζ \-- / o=f ο X acid (8S, 11S, 14S)-14-[[(2S)-2-[[4 - amino-2-(4-tert-but¡l-3-fluoro-phen¡l)-6methyl-pyr¡m¡din-5-carbonyl]amino]-3(sulfamoylamino)propan¡l] -met¡l-am¡no]3,17-bis[(2 R)-3-amino-2-hydroxy¡propoxy]-18-hydroxy¡-11-met¡l-10,13d ioxo-9,12 —d iazatricyclo[13.3.1.12,6] icosa1(18),2(20),3,5,15(19),16-hexaen-8carboxylic 61 ΟΗ Η2Ν |Χ^^^ΝΗ2 ΑΧΑ ΎιΓ ι ϊ ιΓ ί 0 CI 0 1 0 = ΝΗ 1 O=s—ΝΗ? II 0 acid (8S,11S, 14S)—18—hydroxy—11 —methyl— 14-[methyl-[(2S)-2-[[4-amí no-6-(4-tertbutyl-2-h ¡drox¡-phen¡l)-2-chloro-pyr¡din-3carbonyl]amino]-3- (sulfamoylamino)propanoyl]amino]-10,13dioxo-3,17-bis[(2R )-3-amino-2-hydroxypropoxy]-9,12-diazatricyclo[13.3.1.12,6]icosa- 1 (18),2(20),3,5,15(19) , 16-hexaen-8carboxylic ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ Φ Ό ο ζ ΰΓ Structure Designation 62 oh η2ν ηοχ'' η 0Η°Υ »νΧ Ύ VXX 1 ο ν 1 ο ΝΗ 1 o=s-nh2 II 0 acid (8S, 11S, 14S)-14-[[(2S )-2-[[4-amino-2-(4-tert-butyl-2-fluoro-phenyl)-6methyl-pyr¡m¡din-5-carbonyl]amino]-3(sulfamoylamino )propanoyl]-methyl-amino]3,17-bis[(2 R)-3-amino-2-hydroxypropoxy]-18-hydroxy-11-methyl-10,13— d ioxo -9,12—d iazatricyclo[13.3.1.12,6] icosa1 (18),2(20),3,5,1 5(19),16-hexaen-8carboxylic 63 OH Η?Ν ι Η0'ν ι 0Η °Ύ^ιΐ Λχ Χν X Η η ] Η Ηι Τ ° J ο ν । ο - Η2Ν ΝΗ O=S—ΝΗ? II 0 acid (8S, 11S, 14S)-3,17-bis[(2R)-3- amino-2-hydroxy¡-propoxy]-14-[[(2S)-2-[[4(am i no m et i I )-6-(4-ter-b uti If eni l)-2-met i Ipyrid¡n-3-carbonyl]am¡no]-3- (sulfamoylam¡no)propan¡l]-met l-amino]18-hydroxy-11-methyl-10,13-dioxo-9,12diazatricyclo[13.3.1.12,6]icosa- 1 (18),2(20),3,5,15(19 ),16-hexaen-8carboxylic 64 ΟΗ η2ν ^Ϊ^^νη2 1 ΗΟ^ η OH XX II JL Ν ^ΝΗ; IL J / L· ,ΟΗ ίΧ Υ ο ΗΝ Τι 1 Η II Η 1 II Ν^Χ X X, ✓Ν. Α. ο η Χ^ Ν [| Χ^ 0 1 0^1 0 = ΝΗ 1 O=s— ΝΗ, II 0 acid (8S, 11S, 14S)-14-[[ (2S)-2-[[4- amino- 2-(4-ter -butylphenyl)-6-methyl—pyrimidín-5-carbon¡l]amino]-3(sulfamoylamino)propanoyl]-methyl-amino]3,17-bis[(2S)-3-ami no-2-hydroxypropoxy]—18—hydroxy—11 —methyl—10,13d ioxo-9,12—d iazatricyclo[13.3.1.12,6]icosa1 (18),2(20),3,5,15(19 ),16-hexaen-8carboxylic 65 ΟΗ Η2Ν ^Χ^ΝΗ2 Χ·Χν »WxYY ° ΗΧ Υη 1 O=S—ΝΗ, II 0 acid (8S,11S,14S)-3,17-bis[(2R)- 3amino-2-hydroxy¡-propoxy]-14-[[(2S)-2-[[4(am i no m et i I )-6-( 4-ter-b uti l-2-hyd roxyphenyl)- 2-methyl-pyridin-3-carbon¡l]amino]-3(sulfamoylamino)propanoyl]-methyl-amino]18-hydroxy-11-methyl-10,13- dioxo- 9,12diazatricyclo[13.3.1.12,6]icosa1(19),2(20),3,5,15,17-hexaen-8carboxylic ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ φ Ό ο ζ ΰΓ Structure Designation 66 ÜH Η2Ν ΗΟ'' η ΟΗ°'Χ|ΥΥ ntvG ΑΧ ° 1 Ο \ 1 ο = ΝΗ 1 O = S-NH? II 0 acid (8S, 11S, 14S)-14-[[(2S)-2-[[4- amino-2-(1,1 -d imethylindan- 5-yl)- 6-m ethyl—pyrimíd ¡n-5-carbon¡l]amino]-3(sulfamoylam¡no)propanoyl]-methyl-amino]3,17—b¡ s [(2 R)-3-amino-2-hydroxy¡ propoxy]—18—hydroxy—11 —methyl—10,13dioxo-9,12-diazatricyclo[13.3.1.12,6]cosa1 (18),2(20),3,5,1 5(19),16- hexaen-8carboxylic 67 oh Η2Ν ^Χ\χΝΗ2 | F HO'''R ΧχΑγ™ θνΧΧ UG^ U Rh Η Η ] Η Η| I Ντϊ 0 ΝΗ. 0 R 1 0 = ΝΗ 1 O = S —ΝΗ. II ο acid (8S,11S, 14S)—18—hydroxy—11 —methyl— 14-[methyl-[(2S)-2-[[4-amí no-2-(4-tertbutyl—3—f luo ro—2—hydroxy—phenyl)—6—m ethyl—pyrimídin-5-carbon¡l]amino]-3- (sulfamoylam¡no)propanoyl]amino]-10,13dioxo-3 ,17-bis[(2R)-3-amino-2-hydroxy¡propoxy¡]-9,12- diazatricyclo[13.3.1.12,6]icosa- 1 (18),2(20),3 ,5,15(19),16-hexaen-8carboxylic 68 ο Ζ \__ / ζ - ΖΙ Ο ζ η / .....( ζ—ω—ζ ^=Ο ο—' χ II χ / / Χ· / \ / ζ °—\ ζζ \-- / >ΐ|Ο ......X / ζ 1 O )---' 0 acid (8S, 11S, 14S)-14-[[(2S)- 2¿[2-amino-6-(4-tert-butílphenyl)-5-cyano-4methyl-pyridín-3-carboryyl]amino]-3(sulfamoylamino)propanoyl] -methyl-amino]3,17-bis[(2 R)-3-amino-2-hydroxypropoxy]-18-hydroxyl-11-methyl-10,13dioxo-9,12- diazatricycle[13.3.1.12,6]cosa1 (19),2(20),3,5,15,17-hexaen-8carboxylic 69 ΟΗ Η2Ν ^\ζΝΗ2 1 Ηθ' η ΧΑγ^ ΝκΧζΝ. 0 - (difluoromet¡l)pyr¡m¡d¡n-5-carbon¡l]amino]3-(sulfamoylam¡no)propan¡l]-methylámino]-3,17-b¡s [(2R)-3-amino-2-hydroxy¡propoxy]-18-hydroxy¡-11 —methyl—1 0,13dioxo-9,12-diazatricycle[13.3.1.12,6]cosa1 (18),2(20),3,5,15( 19), 16-hexaen-8carboxylic ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ φ Ό o z üT Structure Designation 70 oh H?N HCñ η ΟΗ°Ύ^ ^íf Ξ iT = 0 NH2 0 X 1 o = NH 1 O = S — NH¿ II 0 acid (8S,11S,14S)—18— hydroxy—11—methyl— 14-[methyl-[(2S)-2-[[4-amino-2-(4-hydroxy¡- 1,1—dimethyl—indan—5—yl)—6—methyl —pyrimid in— 5-carbonyl]amino]-3- (sulfamoylamino)propanoyl]amino]-10,13dioxo-3,17-bis[(2R)-3-amino-2-hydrox ¡propoxy¡]-9,12- diazatric¡cyclo[13.3.1.12,6]icosa- 1 (18),2(20),3,5,15( 19), 16-hexaen-8carboxylic 71 oh H?N i Η0'' ι OH°XX χ% XX Ί Η Η ] Η Ηϊ 1Γ 0 X 1 0 ΝΗ 1 0 = S—ΝΗ? II 0 acid (8S, 11S, 14S)-3,17-bis[(2R)-3- amino-2-hydroxy¡-propoxy]-14-[[(2S)-2-[[2(4-ter - butylph en¡l)pyrimidin- 5carbonyl]amino]-3- (sulfamoylamino)propanoyl]-methyl-amino]18-hydroxy-11-methyl-10,13-d ioxo-9,12diazatricyclo[ 13.3.1.12,6]icosa- 1 (18),2(20),3,5,15(19),16-hexaen-8carboxylic 72 ο / =ο . > XX..... οηχ / —\ τζ °ι / Ί / Χ° θΧΧΧχ i ,— Ο 0=7 ζ—ώ=Ο Γ-ζ >..... / ί ζ 'ο τζ £ 1 \ Χ° __ / τ acid (8S, 11S, 14S)-3,17-b ¡s[ (2R )-3- amino-2-hydroxy¡-propoxy¡]-14-[[(2S)-2-[ [4(am i no m et i 1)-2-(4-ter-b uti If eni l)-6-met i 1pyrimidín-5-carbon¡l]amino]-3(sulfamoylam¡no)propanoyl ]-methyl-amino]18-hydroxy-11-methyl-10,13-dioxo-9,12diazatricyclo[13.3.1.12,6]icosa1(18),2(20),3,5,15(19) , 16-hexaen-8carboxylic 73 τ ο / =° \ / =χΧ° = / \ / / .......... °*\ / —\ ζζ °=χχΧ° ο—\ / --\ 7==^ ζ-- / —ο °=\ / —Ζ y----7 \......... Ζ Ο ιζ ξ \=ο acid (8S,11S,14S)-3, 17-bis[(2S)-3amino-2-hydroxy¡-propoxy]-14-[[(2S)-4amino-2-[[4-methyl-2-[4-(1methylcyclopropyl)phenyl]pyrimidin— 5— carbonyl]amino]butanoyl]-methyl-amino]-18hydroxy—11—m ethyl—10,13—dioxo—9,12—diazatricyclo[13.3.1.12,6]icose— 1 (19 ),2(20),3,5,15,17-hexaen-8carboxylic IVIA / t / ZUZZ / U I 0 / O I ω o o z üT Structure Denomination 74 ° \ I T ZI Q Z / II....... / y------' z— / / =° °— / HA0 ° \ x \ / ZI / .... .... II......... c / \ °=\ o acid (8S, 11S, 14S)-3,17-bis[(2R)-3- amino-2-hydroxy¡-propoxy ]-14-[[(2S)-4amino-2-[[4-methyl-2-[4-(1- methylcyclopropyl)phenyl]pyrimidin—5—carbonyl]amino]butano¡l]-methyl-am ¡no]-18methoxy-11-methyl-10,13-dioxo-9,12diazatric¡cyclo[13.3.1.12,6]icosa- 1 (18),2(20),3,5,15(19),16 -hexaen-8carboxylic 75 o / =O = ) \ ) / .......... o.......ς y—Y iz °o ~ χ Χχ-. r / --O o=< Z—<n=C )........ / ¿ z o iz , \=o 4^ acid (8S, 11S, 14S)-14-[[(2S) -2-[[4-amino-2-(4-tert-butylphenyl)-6-met¡lpyr¡m¡din-5-carbon¡l]amino]-3(sulfamoylamino)propanoyl]-met¡l-am ¡no]3,17-bis[(2 R)-3-amino-2-hydroxy¡propoxy]-18-methoxy-11-methyl-10,13-dioxo-9,12-diazatricyclo[13.3.1.12 ,6]thing- 1 (18),2(20),3,5,15( 19),16-hexaen-8carboxylic 76 oh A. ,NH? Ί. í 1 1 “ 11 11 „ . I J ’ 1 o„ X I r I J r II ' r γ « γ γ -0 NHZ O 1 O Ί o HN. / / •s. A NIU O ¿ acid (8S, 11S, 14S)-14-[[ (2S)-2-[[4-amino-2-(4-tert-butylphen¡l)-6-methylpyrimidín-5 -carbon¡l]amino]-4- (sulfamoylamino)butanoyl]-methyl-amino]- 3,17-bis[(2 R)-3-amino-2-hydroxy¡propoxy]-18-hydrox ¡-11 —methyl—10,13dioxo-9,12-diazatricyclo[13.3.1.12,6]icosa- 1(18),2(20),3,5,15(19),16-hexaen-8- carboxylic In some embodiments, the compound of formula (I), (la) or (Ib) is a compound, or a ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ salt, a pharmaceutically acceptable solvate or stereoisomer thereof, wherein the compound is acidic (8S,11S,14S)-18-hydroxy¡-11-methyl-14 -[methyl-[(2S)-2-[[4-amino-2-(4-terbutylphenyl)-6-methyl-pyrimidin-5-carbonyl] am¡no]-3-(sulfamoylam¡no)propan¡l]am¡no]-10,13-dioxo-3,17b¡s[(2R)-3-amino-2-hydroxy¡-propoxy]-9 ,12-d¡azatr¡cyclic[13.3.1.12,6]¡cosa-1(18),2(20),3,5,15(19), 16hexaen-8-carboxylic. In some embodiments, the compound of formula (I), (la) or (Ib) is a compound, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound is acidic ( 8S,11S,14S)—18—hydroxy—11—methyl—14—[methyl—[(2S)—2—[[4—methyl—2—[4—(1 — methylcyclop royl )phenyl] p¡r ¡m¡d¡n-5-carbonyl]amino]-3-(sulfamo¡lamino)propan¡l]amino]-10,13-d ioxo-3,17b¡s[(2R)-3-amino -2-hydroxy¡-propoxy]-9,12-diazatr¡cyclic[13.3.1.12,6]cosa-1(18),2(20),3,5,15(19),16hexaen -8-carboxylic. In some embodiments, the compound of formula (I), (la) or (Ib) is a compound, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound is acidic ( 8S,11S,14S)-18-hydroxy¡-11-methyl-14-[methyl-[(2S)-4-amino-2-[[4-amino-2-(4ter-b utilf enyl)—6—methyl—pyrimid in-5-carbonyl]amino]butanoíl]amino]-10,13-d ioxo-3,17-bis[(2R)-3-amí no2—hid roxy—propoxy]9,12—d iazatricyclo[13.3.1.12,6]icose—1(18),2(20),3,5,15(19),16-hexaen-8-carboxylic. In some embodiments, the compound of formula (I), (la) or (Ib) is a compound, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound is acidic ( 8S, 11S,14S)—18—hydroxy—11-methyl-14-[methyl-[(2S)-4-amino-2-[[4-methyl-2-[4-( 1met¡lc¡cloprop¡l)phen¡l]pyrimid¡n-5-carbon¡l]am¡no]butane¡l]am¡no]-10,13-dioxo-3,17 -b¡s[(2R)-3-am¡no-2hidrox¡-propoxy¡]-9,12-d¡azatr¡cyclic[13.3.1.12,6]¡cosa-1(18),2( 20),3,5,15(19),16-hexaen-8-carboxylic. In some embodiments, the compound of formula (I), (la) or (Ib) is a compound, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound is acidic ( 8S,11S,14S)-18-hydroxy¡-11-methyl-14-[methyl-[(2S)-4-amino-2-[[2-(4-terb utilf en¡l)-4- amino-6-difluoromethyl-pyrimidin-5-carbon-10,13-dioxo-3,17b-s[( 2R)-3-amino-2-hydroxy¡-propoxy¡]-9,12-d¡azatr¡cyclic[13.3.1.12,6]cosa-1(18),2(20),3 ,5,15(19), 16hexaen-8-carboxylic. In some embodiments, the compound of formula (I), (la) or (Ib) is a compound, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound is acidic ( 8S, 11S, 14S) —14—[[(2S)—2—[[4—amino—2—(4—tert—butylphenyl)—6—(dif luoromethyl)pyrimid in— 5-carbon¡l]amino ]-3-(sulfamo¡lano)propan¡l]-methyl-am¡no]-3,17-b¡s[(2R)-3-am¡no-2-hydroxy¡propoxy]— 18—hydroxy—11—m ethyl—10,13-dioxo-9,12-diazatricycle[13.3.1.12,6]cosa1 (18),2(20),3,5,15( 19) , 16-hexaen-8-carboxylic. In some embodiments, the compound of formula (I), (la) or (Ib) is presented in the form of a prodrug. Some embodiments include a prodrug of the compound of formula (I), (la) or (Ib), which is converted to an active form through other mechanisms in vivo. In some embodiments, the compounds of the invention are prodrugs of any of the formulas herein. Other forms of compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (opposite) (E) and zusammen (Z) isomers, as well as corresponding mixtures of these. In some situations, the compounds described herein possess one or more chiral centers, and each center exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric and epimeric forms, as well as corresponding mixtures. of this. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. . In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these differences. In some embodiments, diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent. Labeled compounds In some embodiments, the compounds described herein exist in their isotopically labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds as pharmaceutical compositions. Therefore, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to those mentioned herein, except for the fact that one or more atoms are replaced by an atom having a mass atomic mass or a mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that may be incorporated into the compounds described herein, or a solvate or stereoisomer thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chloride, such as 2H, 3H, 13C, 14C,15N,18O,17O,31P,32P,35S,18F and36CI, respectively. Certain isotopically labeled compounds, for example, those in which radioactive isotopes such as 3H and 14C are incorporated, are useful in substrate and / or drug tissue distribution assays. The trite isotopes, i.e. 3H and carbon-14, i.e. 14C, are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with heavy isotopes such as deuterium, i.e., 2H, produces certain therapeutic advantages resulting from increased metabolic stability, for example, increased half-life in vivo or reduced dosage requirements. In some embodiments, the isotopically labeled compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is prepared by any suitable method. In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent tags, or chemiluminescent tags. Pharmaceutically acceptable salts In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such IVIA / t / ZUZZ / U I O / Ο I pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions. In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form an acceptable salt. pharmaceutical view. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and the isolation of the salt thus formed. Examples of pharmaceutically acceptable salts include those salts prepared by reacting the compounds described herein with a mineral, organic acid or an inorganic base; such salts include acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanpropionate, decanoate , digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexin-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, iodide, 2-hydroxyethanesulfonate , iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate , picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylatoundeconate and xylenesulfonate. Additionally, the compounds described herein may be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, acid trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-acid -naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-en-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3hydroxy-2-en-1-carboxylic acid), 3—phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, those compounds described herein comprising IVIA / t / ZUZZ / U I O / O I a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia or with an acceptable organic amine from a primary, secondary, tertiary or quaternary pharmaceutical point of view. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(Ci-4 alkyl)4 and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups they contain. In some embodiments, products soluble or dispersible in water or oil are obtained by such quaternization. Solvates In some embodiments, the compounds described herein exist as solvates. The disclosure provides methods for treating diseases by administering such solvates. The disclosure further provides methods for treating diseases by administering such solvates as pharmaceutical compositions. Solvates contain stoichiometric or non-stoichiometric amounts of a solvent and, in some embodiments, are formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein may conveniently be prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can conveniently be prepared by recrystallization from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofurac or methanol. Furthermore, the compounds provided herein may exist in unsolvated as well as solvated forms. In general, solvated forms are considered equivalent to unsolvated forms, for the purposes of the compounds and methods provided herein. Tautomers In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can be interconverted by the migration of a hydrogen atom, accompanied by an exchange of a single bond and an adjacent double bond. In bond arrangements where tautomerization is possible, there will be a chemical equilibrium of the tautomers. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, soil, and pH. In another aspect, hydrates or metabolites of any of the aforementioned compounds are described. In another aspect, pharmaceutical compositions are described comprising any of the above-mentioned compounds together with a pharmaceutically acceptable excipient. In another aspect, the use of a compound described herein in the manufacture of a medicament for the treatment of a bacterial infection in a patient is described herein. In another aspect, methods are described for treating a mammal in need of such treatment, comprising administering to the mammal an antibacterial effective amount of any of the aforementioned compounds, with a frequency and for a time sufficient to provide a beneficial effect to the mammal. In one embodiment, the mammal has a bacteria-related infection that is resistant to arylomycin A2 treatment. In a further embodiment, the bacteria species causing the bacterial infection is an infection involving Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholdería cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii , Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteríae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxitoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticous, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus paral nfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 34 52A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Coryne bacterium diphtheriae , Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis or Staphylococcus saccharolyticus. In another embodiment, the bacterial infection is an infection involving a Gram-negative bacteria. In such embodiments, the gram-negative bacteria may be, for example, IVIA / t / ZUZZ / U I O / Ο I Escheria coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumanii, Neisseria gonorrhoeae, Neisseria meningitidis, Chlamydia trachomatis, Moraxella catarrhalis, Haemophilus influenzae, Proteus mirabilis, Enterobacter cloacae, Serrada marcescens, Helicobacter pylori, Salmonella enteritidis, Salmonella typhi, Legionella pneumophila, Haemophil us influenzae , Vibrio cholerae, Pseudomonas stutzeri, Ralstonia solanacearum or Xylella fastidiosa. In certain embodiments, the bacterial infection is an infection involving non-termentatory bacteria. Such non-termentatory bacteria may be, for example, Acinetobacter baumannii, Achromobacter xylosoxidans, Bordetella pertussis, Burkholderia cepacia (also known as Pseudomonas cepacia), Burkholderia pseudomallei (also known as Pseudomonas pseudomallei), Elizabethkingia meningoseptica (also known as Chryseobacterium meningosepticum), Moraxella catarrhalis (also known as Branhamella catarrhalis), Pseudomonas aeruginosa or Stenotrophomonas maltophilia (also known as Pseudomonas maltophilia). In another embodiment, the bacterial infection is a lepB-mediated infection. In a further embodiment, the bacterial infection is an infection involving a Gram-positive bacteria. In a further embodiment, methods of treating a mammal in need of such treatment are described, comprising administering to the mammal a second therapeutic agent to any of the above-mentioned treatment methods. In another embodiment, the second therapeutic agent is not an inhibitor of SpsB or LepB. In another embodiment, the second therapeutic agent is an aminoglycoside antibiotic, fluoroquinolone antibiotic, β-lactam antibiotic, macrolide antibiotic, glycopeptide antibiotic, rifampin, chloramphenicol, fluoramphenicol, colistin, mupirocin, bacitracin, daptomycin, or linezolid. In some embodiments, a method of treating a bacterial infection in a patient, preferably a human, is described, wherein the treatment includes administering a therapeutically or pharmacologically effective amount of a combination of 1) a β-lactam antibiotic; and 2) a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; and 3) a pharmaceutically acceptable carrier. In embodiments in which a β-lactam antibiotic is used in combination with a compound disclosed herein, the β-lactam antibiotic may be a carbapenem, cephalosporin, cephamycin, monobactam or penicillin. Exemplary carbapenem antibiotics useful in the methods of the invention include ertapenem, imipenem, biapenem and meropenem. Exemplary cephalosporin antibiotics useful in the methods of the invention include ceftobiprole, ceftaroline, Cefiprome, Cefozopran, cefepime, Cefotaxime and ceftriazone. Exemplary penicillin antibiotics useful in the methods of the invention include ampicillin, amoxicillin, piperacillin, oxacillin, cloxacillin, methicillin and nafcillin. In some embodiments of the invention, the β-lactam may be administered with a β-lactamase inhibitor. In some embodiments of the invention, the carbapenem may be administered with a DHP inhibitor, for example, cilastatin. IVIA / t / ZUZZ / U I O / Ο I In various embodiments of the invention in which a compound disclosed herein and a β-lactam antibiotic are used in combination, the β-lactam antibiotic and the compound disclosed herein may be administered sequentially or concurrently. Preferably, the β-lactam antibiotic and the compound disclosed herein are administered together. When administered concurrently, the β-lactam antibiotic and the compound disclosed herein may be administered in the same formulation or in separate formulations. When administered sequentially, the β-lactam or the compound disclosed herein may be administered first. After administration of the first compound, the other compound is administered, for example, within 1 to 60 minutes, for example, within 1, 2, 3, 4, 5, 10, 15, 30 or 60 minutes. In one aspect of the invention, when a β-lactamase inhibitor is used, it may be administered separately, or in a formulation with the compound disclosed herein and / or β-lactam antibiotic. In one aspect of the invention, when a DHP inhibitor is used to improve the stability of a carbapenem, it may be administered separately, or in a formulation with the compound disclosed herein and / or carbapenem. Further described herein are pharmaceutical compositions comprising a compound disclosed herein, a pharmaceutically acceptable carrier and, optionally, a β-lactam antibiotic. In embodiments in which a combination is used, the β-lactam antibiotic and the compound disclosed herein are present in amounts such that their combination constitutes a therapeutically effective amount. Due to the potentiating effects of the compound disclosed herein, the amount of β-lactam antibiotic present in a combination may be less than that of a β-lactam antibiotic used alone. In certain embodiments, the composition further comprises a β-lactamase antibiotic. In additional embodiments wherein the β-lactam antibiotic is a carbapenem, there is provided a pharmaceutical composition comprising a carbapenem antibiotic, a DHP inhibitor, a compound disclosed herein and a pharmaceutically acceptable carrier. . In some embodiments where the β-lactam antibiotic is a carbepenem, the carbapenem antibiotic is preferably selected from the group consisting of ertapenem, imipenem and meropenem. In some embodiments, a compound disclosed herein is described for use in the treatment of a bacterial infection. In some embodiments, a compound disclosed herein, in combination with one or more additional therapeutic agents including a β-lactam antibiotic, is described for use in the treatment of a bacterial infection. In some embodiments, a compound disclosed herein is described for use as a medicament to treat a bacterial infection. In some embodiments, a compound disclosed herein is described, in combination with one or more additional therapeutic agents including a β-lactam antibiotic, for use as a medicament to treat a bacterial infection. In some embodiments, a compound disclosed herein is described for use in the preparation of a medicament for treating a bacterial infection. In some embodiments, a compound disclosed herein, in combination with one or more additional therapeutic agents including a β-lactam antibiotic, is described for use in the preparation of a medicament for treating a bacterial infection. In some embodiments described herein, a compound disclosed herein can improve the activity of a β-lactam antibacterial agent by inducing sensitivity to the antibacterial agent in a drug-resistant strain such as MRSA (resistant S. aureus). methylcin, according to its acronym in English). In some embodiments, a compound disclosed herein can improve the activity of a β-lactam antibacterial agent by reducing the dosage requirement of the antibacterial agent for a therapeutic effect in a drug-sensitive strain. For example, if a compound disclosed herein reduces the minimum inhibitory concentration (MIC) of an antibacterial agent (where the MIC is the minimum concentration of antibacterial agent that will completely inhibit growth) in a susceptible strain , then such treatment may be advantageous to allow a reduction in the amount of antibacterial agent administered (it could reduce the side effects of an antibiotic) or decrease the frequency of administration. In some embodiments, the compounds disclosed herein can improve the activity of an antibacterial agent such as a carbapenem to prevent the emergence of a resistant subpopulation in a bacterial population heterogeneous with a resistant subpopulation. Enhancers can be used to enhance the activity of antibacterial agents whose clinical efficacy has been limited by the increasing prevalence of resistant strains. In some embodiments described herein, a compound disclosed herein is used as an enhancer wherein a compound disclosed herein may be administered concomitantly with a β-lactam antibiotic (either concurrently or sequentially) to allow the effective treatment of an infection involving resistant bacteria, or to reduce the amount of antibacterial agent needed to treat an infection. In one embodiment, a compound disclosed herein is described that exhibits antibiotic activity useful in the treatment of bacterial infections, such as, by way of example only, various strains of S. aureus, S. pneumoniae, E. faecalis, E. faecium, B. subtilis and E. coli, including species that are resistant to many known antibiotics, such as methylcin-resistant S. aureus (MRSA), vancomycin-resistant Enterococcus species (VRE). ), multidrug-resistant E. faecium, macrolide-resistant S. aureus and S. epidermidis, and linezolid-resistant S. aureus and E. faecium. Methicillin-resistant Staphylococcus aureus Staphylococcus aureus (S. aureus), a spherical bacteria, is the most common cause of staph infections. S. aureus is known to cause a range of diseases, from minor skin infections such as pimples, impetigo, boils, cellulitis, folliculitis, boils, carbuncles, scalded skin syndrome, abscesses, to life-threatening diseases. life, such as pneumonia, meningitis, osteomyelitis, endocarditis, toxic shock syndrome and septicemia. Furthermore, S. aureus is ΜΛ / Ε / ΖυΖΖ / υΊ Oí ΟΊ one of the most common causes of nosocomial infections, often causing post-surgical wound infections. Methicillin was introduced in the late 1950s to treat infections caused by penicillin-resistant S. aureus. It has been previously reported that S. aureus isolates had acquired resistance to methicillin (methicillin-resistant S. aureus, MRSA). The methicillin resistance gene (mecA) encodes a methicillin-resistant penicillin-binding protein that is not present in susceptible strains. mecA is carried on a mobile genetic element, the staphylococcal cassette chromosome mee (SCCmec), of which four forms have been described that differ in size and genetic composition. Methicillin-resistant penicillin-binding protein enables resistance to β-lactam antibiotics, preventing their clinical use during MRSA infections. In one aspect, a method of treating a subject having a resistant bacteria is described, comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In one embodiment, the bacteria is a Gram-positive bacteria. In another embodiment, the Gram-positive bacteria is S. aureus. In a further embodiment, S. aureus is resistant or refractory to a beta-lactam antibiotic. In yet a further embodiment, the beta-lactam antibiotic belongs to the penicillin class. In a further embodiment, the beta-lactam antibiotic is methicillin. In yet a further embodiment, the subject has a methicillin-resistant S. aureus bacteria. In one embodiment, the beta-lactam antibiotic is flucloxacillin. In another embodiment, a method of treating a subject having a dicloxacillin-resistant bacteria is described, comprising administering to the subject a compound disclosed herein or an acceptable salt, solvate or stereoisomer. pharmacist of this, where the subject is refractory to dicloxacillin. Also disclosed herein is a method of treating a subject having methicillin-resistant bacteria, comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, in where it has been determined that the subject has bacteria resistant to methicillin. In one embodiment, the subject is screened for methicillin-resistant bacteria. In another embodiment, screening of the subject is performed through a nasal culture. In a further embodiment, methicillin-resistant bacteria are detected by swabbing the subject's nasal passages and isolating the bacteria. In another embodiment, real-time PCR (polymerase chain reaction) and / or quantitative PCR are used to determine whether the subject has methicillin-resistant bacteria. In one embodiment, a method of treating a subject having first-generation cephalosporin-resistant bacteria is described, comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer. of this, where the subject is refractory to a first generation cephalosporin. In one embodiment, the bacteria is resistant to a first generation cephalosporin. In a further embodiment, the bacteria is resistant to cefacetril. In another embodiment, the bacteria is resistant to cefadroxil. In yet another embodiment, the bacteria is resistant to cephalexin. In a IVIA / t / ZUZZ / U I O / Ο I embodiment, the bacteria is resistant to cephaloglycin. In another embodiment, the bacteria is resistant to cephalonium. In another embodiment, the bacteria is resistant to cephaloridin. In yet another embodiment, the bacteria is resistant to cephalothin. In a further embodiment, the bacteria is resistant to cephapirin. In yet a further embodiment, the bacteria is resistant to cefatrizine. In one embodiment, the bacteria is resistant to cefazaflur. In another embodiment, the bacteria is resistant to cefazedone. In yet another embodiment, the bacteria is resistant to cefazolin. In a further embodiment, the bacteria is resistant to cephradine. In yet another embodiment, the bacteria is resistant to cefroxadine. In one embodiment, the bacteria is resistant to ceftezole. In one embodiment, a method for treating a subject having second-generation cephalosporin-resistant bacteria is described, comprising administering a compound disclosed herein or a technically acceptable salt, solvate or stereoisomer. pharmacist of this, where the subject is refractory to a second generation cephalosporin. In another embodiment, the bacteria is resistant to a second generation cephalosporin. In a further embodiment, the bacteria is resistant to cefaclor. In another embodiment, the bacteria is resistant to cefonicid. In yet another embodiment, the bacteria is resistant to cefprozil. In one embodiment, the bacteria is resistant to cefuroxime. In another embodiment, the bacteria is resistant to cefuzonam. In another embodiment, the bacteria is resistant to cefmetazole. In yet another embodiment, the bacteria is resistant to cefotetan. In a further embodiment, the bacteria is resistant to cefoxitin. In one embodiment, a method for treating a subject having third-generation cephalosporin-resistant bacteria is described, comprising administering a compound disclosed herein or an acceptable salt, solvate or stereoisomer. pharmacist of this, where the subject is refractory to a third generation cephalosporin. In another embodiment, the bacteria is resistant to a third generation cephalosporin. In a further embodiment, the bacteria is resistant to cefcapene. In another embodiment, the bacteria is resistant to cefdaloxime. In yet another embodiment, the bacteria is resistant to cefdinir. In one embodiment, the bacteria is resistant to cefditorene. In another embodiment, the bacteria is resistant to cefixime. In another embodiment, the bacteria is resistant to cefmenoxime. In yet another embodiment, the bacteria is resistant to cefodizyme. In a further embodiment, the bacteria is resistant to cefotaxime. In yet a further embodiment, the bacteria is resistant to cefpimizole. In one embodiment, the bacteria is resistant to cefpodoxime. In a further embodiment, the bacteria is resistant to cefteram. In yet another embodiment, the bacteria is resistant to ceftibuten. In a further embodiment, the bacteria is resistant to ceftiofur. In yet a further embodiment, the bacteria is resistant to ceftiolene. In one embodiment, the bacteria is resistant to ceftizoxime. In another embodiment, the bacteria is resistant to ceftriaxone. In yet another embodiment, the bacteria is resistant to cefoperazone. In yet a further embodiment, the bacteria is resistant to ceftazidime. IVIA / t / ZUZZ / U I O / Ο I In one embodiment, a method for treating a subject having bacteria resistant to a fourth-generation cephalosporin is described, comprising administering a compound disclosed herein or a commercially acceptable salt, solvate or stereoisomer. pharmaceutical view of this, where the subject is refractory to a fourth generation cephalosporin. In another embodiment, the bacteria is resistant to a fourth generation cephalosporin. In a further embodiment, the bacteria is resistant to cefclidin. In another embodiment, the bacteria is resistant to cefepime. In yet another embodiment, the bacteria is resistant to cefluprenam. In one embodiment, the bacteria is resistant to cefoselis. In another embodiment, the bacteria is resistant to cefozoprane. In another embodiment, the bacteria is acefpirome resistant. In yet another embodiment, the bacteria are acefquinome refractory. In one embodiment, a method for treating a subject having carbapenem-resistant bacteria is described, comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. , where the subject is refractory to a carbapenem. In another embodiment, the bacteria is resistant to a carbapenem. In a further embodiment, the bacteria is resistant to imipenem. In another embodiment, the bacteria is resistant to meropenem. In yet another embodiment, the bacteria is resistant to ertapenem. In one embodiment, the bacteria is resistant to faropenem. In another embodiment, the bacteria is resistant to doripenem. In another embodiment, the bacteria is resistant to panipenem. In yet another embodiment, the bacteria is resistant to biapenem. Staphylococcus aureus resistant to avancomycin and with intermediate resistance to avancomycin Vancomycin-resistant Staphylococcus aureus and intermediate vancomycin-resistant Staphylococcus aureus are specific types of antimicrobial-resistant staphylococcal bacteria that are refractory to vancomycin treatment. S. aureus isolates for which vancomycin MICs are 4-8 pg / mL are classified as having intermediate vancomycin resistance, and isolates for which vancomycin MICs are >16 pg / mL are classified as resistant. to vancomycin (Clinical and Laboratory Standards Institute / NCCLS. Performance Standards for Antimicrobial Susceptibility Testing. Sixteenth informational supplement. M100-S16. Wayne, PA: CLSI, 2006). As used herein, the term minimum inhibitory concentration (MIC) refers to the lowest concentration of an antibiotic that is needed to inhibit the growth of a bacterial isolate in vitro. A common method for determining the MIC of an antibiotic is to prepare several tubes containing serial dilutions of the antibiotic, which are then inoculated with the bacterial isolate of interest. The MIC of an antibiotic is determined from the tube with the lowest concentration that shows no turbidity (no growth). In one aspect, a method of treating a subject having a bacterial infection is described, comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein The bacterial infection comprises a Staphylococcus aureus bacteria with intermediate resistance to vancomycin. In a way IVIA / t / ZUZZ / U I O / Ο I embodiment, Staphylococcus aureus bacteria with intermediate vancomycin resistance have an MIC of between about 4 and about 8 pg / mL. In another embodiment, Staphylococcus aureus bacteria with intermediate vancomycin resistance have an MIC of about 4 pg / mL. In yet another embodiment, Staphylococcus aureus bacteria with intermediate vancomycin resistance have an MIC of about 5 pg / mL. In a further embodiment, Staphylococcus aureus bacteria with intermediate vancomycin resistance have an MIC of about 6 pg / mL. In yet another embodiment, Staphylococcus aureus bacteria with intermediate vancomycin resistance have an MIC of about 7 pg / mL. In one embodiment, Staphylococcus aureus bacteria with intermediate vancomycin resistance have an MIC of about 8 pg / mL. In another aspect, a method of treating a subject having a bacterial infection is described, comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein The bacterial infection comprises vancomycin-resistant Staphylococcus aureus bacteria. In one embodiment, vancomycin-resistant Staphylococcus aureus bacteria have an MIC of about 16 pg / mL. In another embodiment, vancomycin-resistant Staphylococcus aureus bacteria have an MIC of about >16 pg / mL. In yet another embodiment, vancomycin-resistant Staphylococcus aureus bacteria have an MIC of about 20 pg / mL. In a further embodiment, vancomycin-resistant Staphylococcus aureus bacteria have an MIC of about 25 pg / mL. In one embodiment, conditions treated by the compounds described herein include, but are not limited to, endocarditis, osteomyelitis, meningitis, skin and skin structure infections, genitourinary tract infections, abscesses, and necrotizing infections. In another embodiment, the compounds disclosed herein are used to treat conditions, such as, but not limited to, diabetic foot infections, pressure ulcers, burn infections, animal or human bite wound infections, synergistic-necrotizing gangrene. , necrotizing fasciitis, intra-abdominal infection associated with intestinal barrier detachment, pelvic infection associated with intestinal barrier detachment, aspiration pneumonia, and postoperative wound infections. In another embodiment, the conditions listed herein are caused by, contain or result in the presence of VISA (Vancomycin Intermediate Resistance Staphylocpccus aureus) and / or VRSA (Vancomycin Intermediate Resistance Staphylocpccus aureus). vancomycin, according to its acronym in English). Vancomycin-resistant enterococci Enterococci are bacteria that are normally present in the human intestine and female genital tract, and are frequently found in the environment. These bacteria sometimes cause infections. In some cases, enterococci have become resistant to vancomycin (also known as vancomycin-resistant enterococci, or VRE). Common forms of vancomycin resistance occur in enterococcal strains that involve the acquisition of a set of genes encoding proteins that direct peptidoglycan precursors to incorporate D-Ala-D-Lac instead of D-Ala-D- To the. The six different types of vancomycin resistance displayed by enterococci are: Van-A, Van-B, Van-C, Van-D, Van-E and Van-F. In some cases, VRE Van-A is resistant to both vancomycin and teicoplanin, while in other cases, VRE Van-B is resistant to vancomycin, but sensitive to teicoplanin; In other cases, Van-C is partially resistant to vancomycin, and sensitive to teicoplanin. In one aspect, a method of treating a subject having a vancomycin-resistant enterococcus is described, comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, where the enterococcus has developed resistance to vancomycin. In one embodiment, the subject has been previously treated with vancomycin for a sustained period of time. In another embodiment, the subject has been hospitalized. In yet another embodiment, the subject has a weakened immune system, such as patients in Intensive Care Units or in cancer or transplant wards. In a further embodiment, the subject has undergone surgical procedures such as, for example, abdominal or thoracic surgery. In yet another embodiment, the subject has been colonized with VRE. In one embodiment, the subject has a medical device, such that an infection has developed. In another embodiment, the medical device is a urinary catheter or a central intravenous (IV) catheter. In another embodiment, a method of treating a subject having a vancomycin-resistant enterococcus is described, comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer of this, where the enterococcus has resistance to Van-A. In another embodiment, a method of treating a subject having a vancomycin-resistant enterococcus is described, comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer of this, where the enterococcus has resistance to Van-B. In another embodiment, a method of treating a subject having a vancomycin-resistant enterococcus is described, comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer of this, where the enterococcus has resistance to Van-C. Pharmaceutical administration and composition The pharmaceutical compositions described herein comprise a therapeutically effective amount of a compound described herein (i.e., a compound disclosed herein) formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid or liquid filling agent, diluent, encapsulating material or auxiliary formulation of any type. Some examples of materials that can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth gum powder; malt; ΜΛ / Ε / ZUZZ / Ul 0 / 01 gelatin; talcum powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; Sesame oil; olive oil; corn oil and soybean oil; glycols, such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar, buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; osotonic saline solution; Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other compatible non-toxic lubricants such as sodium lauryl sulfate and magnesium stearate; as well as coloring agents, release agents, coating agents, sweetening agents, flavoring and perfuming agents, preservatives and antioxidants, according to the formulator's criteria, may also be present in the composition. The pharmaceutical compositions described herein can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (such as by powders, ointments or drops), buccally, or as an oral spray. or nasal, or a liquid aerosol or dry powder formulation for inhalation. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms optionally contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, acetate ethyl, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular cottonseed, peanut, corn, germ, olive, castor and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters sorbitan fatty acids and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavorings and perfuming agents. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, are optionally formulated according to the known art by using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation is optionally a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3butanediol. Acceptable vehicles and solvents optionally used include water, Ringer's solution, isotonic sodium chloride solution, and U.S.P. Furthermore, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any soft fixed oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectable products. Injectable formulations may be sterilized, for example, by filtration through a bacterial retention filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ use. To prolong the effect of a drug, it is often desirable to delay absorption of the drug from subcutaneous or intramuscular injection. This is optionally achieved by using a liquid suspension of crystalline or amorphous material with poor solubility in water. The absorption rate of the drug depends on its dissolution rate which, in turn, may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parentally administered form of drug is optionally achieved by dissolving or suspending the drug in an oil vehicle. Injectable extended-release forms are prepared by forming microcapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Extended release injectable formulations are optionally prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues. Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compound described herein (i.e., a compound disclosed herein) with suitable non-irritant excipients or carriers such as cocoa butter, polyethylene glycol or a wax. for suppositories, which are solid at room temperature, but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, carbonate of calcium, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents such as , for example, acetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form optionally comprises buffering agents. Solid compositions of a similar type are optionally employed as filling agents in soft and hard gelatin capsules through the use of excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and layers such as enteric coatings and other coatings known in the art of pharmaceutical formulation. They optionally contain opacifying agents, and MA / E / ZUZZ / U1 Oí ΟΊ may also be of a composition that releases the active ingredient(s) only, or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of fixative compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type are optionally employed as filling agents in soft and hard gelatin capsules through the use of excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. The active compounds may also be in microencapsulated form with one or more excipients as indicated above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and layers such as enteric coatings, release control coatings and other coatings known in the art of pharmaceutical formulation. In such solid dosage forms, the active compound is optionally mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms optionally comprise, as is common practice, additional substances other than inert diluents, for example, compression lubricants and other compression aids for tableting, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms optionally comprise buffering agents. They optionally contain opacifying agents, and may also be of a composition such that they release the active ingredient(s) only, or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of fixative compositions that can be used include polymeric substances and waxes. Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers as optionally required. Ophthalmic formulations, ear drops and the like are also contemplated. Ointments, pastes, creams and gels may contain, in addition to an active compound described herein, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, gum tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures of these. The compositions described herein are optionally formulated for administration as a liquid aerosol or an inhalable dry powder. Liquid aerosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles where bacteria reside in patients with bronchial infections, such as chronic bronchitis and pneumonia. Pathogenic bacteria are commonly present in all respiratory tracts up to the bronchi, bronchioles, and lung parenchyma, particularly in the terminal and respiratory bronchioles. During exacerbation of the infection, bacteria may also be present in the alveoli. Liquid aerosol formulations and IVIA / t / ZUZZ / U I 0 / Ο I inhalable dry powder are preferentially administered through the endobronchial tree to the terminal bronchioles, and finally, to the parenchymal tissue. The aerosolized formulations described herein are optionally administered by an aerosol deformation device, such as a jet, vibrating porous plate nebulizer, or an ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having an average diameter of mass medium predominantly between 1 and 5 micrometers. Furthermore, the formulation preferably has a balanced ionic concentration of osmolarity and chloride concentration, and the smallest aerosolizable volume is capable of delivering an effective dose of the compounds described herein (i.e., a compound disclosed herein) in the site of infection. Furthermore, the aerosolized formulation preferably does not negatively impair the functionality of the airways, and does not cause undesirable side effects. Aerosolization devices suitable for administration of the aerosol formulations described herein include, for example, jet nebulizers, vibrating porous plate nebulizers, ultrasonic nebulizers, and powered dry powder inhalers, which can nebulize the formulation to the particle size of aerosol predominantly in the size range of 1-5 μ. Predominantly in this application it means that at least 70% but preferably more than 90% of all aerosol particles generated are within the range of 1-5 μ. A jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a droplet of solvent through a porous plate. An ultrasonic nebulizer works by using a piezoelectric crystal that cuts a liquid into small aerosol droplets. A variety of suitable devices are available, including, for example, AeroNebTM and AeroDoseTM vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream® nebulizers (Medic-Aid Ltd., West Sussex, England), nebulizers Parí LC® and Parí LC Star® jets (Parí Respiratory Equipment, Inc., Richmond, Virginia), and AerosonicTM (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire® ultrasonic nebulizers (Omron Healthcare, Inc., Vernon Hills, Illinois). In some embodiments, the compounds described herein (i.e., a compound disclosed herein) are formulated for use as topical powders and sprays containing, in addition to the compounds described herein, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide in pok / o, or mixtures of these substances. The sprays optionally contain common propellants, such as chlorofluorohydrocarbides. Transdermal patches have the additional advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the appropriate medium. Additionally, absorption enhancers can be used to increase the flow of the compound through the skin. The rate can be controlled by providing a rate-controlling membrane, or by dispersing the compound in a polymer matrix or gel. IVIA / t / ZUZZ / U 1 O / 01 According to the treatment methods described herein, bacterial infections are treated or prevented in a patient such as a human or a lower mammal by administering to the patient a therapeutically effective amount of a compound described herein, in quantities and for a period of time necessary to achieve the desired result. By therapeutically effective amount of a compound described herein is meant a sufficient amount of the compound to treat bacterial infections, in a reasonable benefit / risk ratio applicable to any medical treatment. However, it will be understood that the total daily use of the compounds and compositions described herein will be decided by the treating physician within the scope of medical judgment. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, body weight, general health, sex, and diet; the time of administration, the route of administration and the excretion rate of the specific compound used; the duration of treatment; drugs used in combination or coincident with the specific compound used; and similar factors known in the medical art. The total daily dose of the compounds described herein (i.e., a compound disclosed herein) administered to a human or other mammal in single or divided doses may be in amounts, for example, from 0.01 to 50 mg / kg of body weight, or more commonly, 0.1 to 25 mg / kg of body weight. Single dose compositions may contain such amounts or submultiples thereof to complete the daily dose. In general, the treatment regimens described herein comprise administering to a patient in need of such treatment, about 10 mg to about 2000 mg of the compounds described herein, per day, in single or multiple doses. Examples The compounds disclosed herein are prepared by the methods represented in the reaction schemes shown below. Provided herein are procedures that, in combination with the person's knowledge of the mid-level craft in synthetic organic chemistry, are used in some embodiments to prepare the full range of compounds as disclosed and claimed herein. ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ General Procedure A: Step 1: To a solution of compound 1 (51.0 g, 78.3 mmol), Ag2SO4 (17.1 g, 54.8 mmol) in MeOH (250 mL) and THF (250 mL) I2 (21.8 g, 86.1 mmol) was added at 25° c. The reaction mixture was stirred for 2 h at 25°C and filtered. The filtrate was concentrated until dry. The residue was partitioned into ethyl acetate (300 mL) and saturated aqueous Na2S2Ü3 solution (300 mL). The organic phase was separated and washed with brine (2 x 300 mL), dried over Na2SO4 and concentrated to dryness to obtain crude compound 2 (60.0 g, 98.6% yield) as a yellow solid. Step 2: To a solution of compound 2 (60.0 g, 77.2 mmol) and DIEA (38.3 mL, 231.0 mmol) in CH2CI2 (600 mL) SEMCI (27.1 mL, 154.0 mmol) was added. The reaction was stirred at 25°C for 2 h and concentrated to dryness. The residue was diluted with ethyl acetate (500 mL), washed with water (2 x 500 mL) and brine (2 x 500 mL), dried over Na2SO4 and concentrated to dryness. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 10-40% ethyl acetate in petroleum ether) to obtain compound 3 (65.0 g, 92.8% yield) as a yellow solid. . Step 3: A mixture of compound 3 (20.00 g, 22.0 mmol), bis(pinacolato)d¡boiO (8.39 g, 33.0 mmol), triphenylphosphine (1.16 g, 4.4 mmol), tricyclohexylphosphine (1.24 g, 4.4 mmol), Pd (OAc)2 (0.49 g, 2.2 mmol) and K2OAC (8.65 g, 88.1 mmol) in DMSO (200 mL) and water (20 mL) were stirred at 80 °C for 1 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 mL) and filtered. The filtrate was washed with water (2 x 200 mL) and brine (200 mL), dried over Na2SO4 and concentrated to obtain crude compound 4 (20.00 g, 97% yield) as a gray solid (three parallel batches were combined at this stage). Step 4: To a solution of compound 4 (60.0 g, 66.0 mmol) in MeOH (600 mL) H2O2 (135 mL, 1.3 mol) was added. The mixture was stirred at 0°C for 2 h and diluted with ethyl acetate (700 mL). The mixture was washed with saturated aqueous NaHCOs (2 x 200 mL), saturated aqueous Na2S2Os (500 mL), brine (2 x 200 mL), dried over N2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 10-50% ethyl acetate in petroleum ether) to obtain a crude product, which was further purified by preparative HPLC (water (0.04% NH3H2O ​​+ NH4HCO3 10mM) - ACN) to obtain compound 5 (37.0 g, 70.1% yield) as a white solid. Step 5: To a solution of compound 5 (50.0 g, 62.7 mmol) in ethanol (700 mL), 10% Pd / C (14.7 g, 13.8 mmol) and a drop of ammonia were added. The mixture was stirred in hydrogen (0.34 MPa (50 psi)) at 40°C for 5 h and filtered. The filtrate was concentrated to obtain crude compound 6 (35.0 g, 97.4% yield) as a white solid. Step 6: To a solution of compound 6 (35.0 g, 61.0 mmol) in DMA (400 mL) CbzOSu (15.2 g, 60.9 mmol) in DMA (20.0 mL) was added dropwise at 0°C. After addition, the mixture was stirred at 15°C for 14 h and then diluted with ethyl acetate (500 mL). The separated organic phase was washed with brine (3 x 200 mL), dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 55% ethyl acetate in petroleum ether) to obtain compound 7 (21.0 g, 97.0% yield) as a white solid. Step 7: To a solution of compound 7 (21.0 g, 29.7 mmol) in DMF (84.0 mL) compound 8 (23.1 g, 89.0 mmol) and K2CO3 (24.6 g, 178.0 mmol) were added. The mixture was stirred at 50°C for 16 h, and another portion of compound 8 (23.1 g, 89.0 mmol) and K2CO3 (24.6 g, 178 mmol) were added. The reaction mixture was stirred at 50°C for 1 h, diluted with ethyl acetate (500 mL) and filtered. The filtrate was washed with brine (2 x 300 mL), dried in N2SO4 and concentrated to dryness. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 55% ethyl acetate in petroleum ether) to obtain compound 9 (20.0 g, 83.3% yield) as a white solid. Step 8: To a solution of compound 9 (24.0 g, 29.3 mmol) in MeCN (200 mL) and water (100 mL) NaNs (27.3 g, 420 mmol) and CeCIs (3.6 g, 14.6 mmol) were added. The mixture was stirred at 75°C for 16 h. The reaction mixture was diluted with ethyl acetate (700 mL) and filtered. The filtrate was washed with brine (2 x 200 mL), dried over NazSCk and concentrated to dryness. The residue was dissolved in DMF (200 mL), K2CO3 (16.2 g, 117 mmol) and Mel (12.5 g, 87.8 mmol) were added. The reaction was stirred at 25°C for 1 h, diluted with ethyl acetate (600 mL) and filtered. The filtrate was washed with brine (3 x 300 mL), dried over Na2SO4 and concentrated to dryness. The residue was dissolved in THF (480 mL), and PPh3 (46.1 g, 176 mmol) and H2O (6.33 g, ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ 351 mmol). The solution was stirred at 35°C for 16 h. BocsO (14.7 g, 67.3 mmol) was added to the above-mentioned reaction mixture. The reaction was stirred at 30°C for another 1 h and concentrated to dryness. The residue was diluted with ethyl acetate (700 mL), washed with brine (2 x 300 mL), dried over Na2SO4 and concentrated. The product MA / E / ZUZZ / UI Crude Oí ΟΊ was purified by column chromatography (silica gel, 100-200 mesh, 17% acetone in petroleum ether, then 85% ethyl acetate in petroleum ether) to obtain compound 10 (24.4 g, 79.2% yield) as a white solid. General procedure B: 14 Step 1: A mixture of compound 10 (5.00 g, 4.74 mmol) and 10% palladium on carbon (1.51 g, 1.42 mmol) in ethanol (100 mL) was stirred in hydrogen (0.34 MPa (50 psi)) at 35 °C for 2 h and filtered. The filtrate was concentrated to obtain crude compound 11 (4.30 g, 98.5% yield) as a white solid. Step 2: To a solution of compound 11 (4.30 g, 4.67 mmol) and compound 12 (2.54 g, 6.08 mmol) in THF (43 mL) DIEA and HATU (2.13 g, 5.61 mmol) were added at 0°C. After addition, the reaction mixture was stirred at 25°C for 3 h and quenched by the addition of methanol (1 mL). The reaction mixture was concentrated and then diluted with ethyl acetate (100 mL). The solution was washed with saturated aqueous Na2C0s (150 mL), brine (150 mL x 2), dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 50-70% ethyl acetate in petroleum ether) to obtain compound 13 (6.00 g, 97.3% yield) as a white solid. Step 3: To a solution of compound 13 (150 mg, 0.11 mmol) and a drop of NH3H2O ​​in ethanol (15.0 mL) 10% of Pd / C (36.3 mg, 0.03 mmol) was added. The reaction was stirred at 30°C under H2 atmosphere (0.10 MPa (15 psi)) for 2 h and filtered. The filtrate was concentrated to obtain compound 14 (135 mg, 63.0% yield) as a white solid. The methods for LCMS analysis are as follows: LCMS (Method 5-95 AB, ESI): ESI, compounds were eluted with a gradient of 5% AcCN / H2Q over 0.7 min to 95% AcCN / FW. This concentration was maintained for 0.4 min. Flow rate, 1.5 mL / min, with a Merck RP-18e column, 2 x 25 mm. TFA was present at 0.05% in all chromatographic solvents; LCMS (Method 5-100 AB, 7 min): Instrument: Waters Acquity UPLC with a 2.1 x 30 mm CSH 1.8 um C18 column maintained at 40°C and ESI ionization. Compounds were eluted with a gradient of 5% B in eluent A over 5.2 min to 100% B. This concentration was maintained for 1.8 min, and the total run time was 7 min. The flow rate was 0.9 mUmin, and the eluents were: (A) Milli-Q water + 10 mM ammonium formate at pH = 3.8, and (B) MeCN. Example 1: IVIA / t / ZUZZ / U I O / Ο I Step 1: To a solution of 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid (46.5 mg, 0.17 mmol) (synthesis given in example 17) DIEA (159 uL, 0.91 mmol) and HATU (104 mg, 0.27 mmol) were added to DMF (1.00 mL) and dichloromethane (8.00 mL) at 0°C. After 5 min, compound 14 (135 mg, 0.11 mmol) was added. The reaction was stirred at 20°C for 2 h and quenched by the addition of methanol (0.50 mL). The reaction mixture was concentrated to dryness. The residue was partitioned between ethyl acetate (30 mL) and water (20 mL). The aqueous phase was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (3 x 80 mL), dried in NasSO, and concentrated to dryness. The crude product was purified by preparative TLC (10% methanol in dichloromethane) to obtain compound 16 (80.0 mg, 48.8% yield) as a yellow solid. Step 5: To a solution of compound 16 (80.0 mg, 0.06 mmol) in methanol (1.00 mL) was added HCl (4 N in methanol, 0.08 mL, 0.32 mmol). The mixture was stirred at 30°C for 0.5 h and quenched by the addition of NaHCOs (70.0 mg, 0.83 mmol). The mixture was concentrated, and then THF (5 mL), water (1 mL), and ΒοοςΟ (0.01 mL, 0.06 mmol) were added. The mixture was stirred at 30°C for 0.5 h and diluted with water (10 mL) and ethyl acetate (20 mL). The separated aqueous phase was washed with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (60 mL), dried over Na2SÜ4, and concentrated. The residue was purified by preparative TLC (10% methanol in dichloromethane) to obtain compound 17 (50.0 mg, 68.7% yield) as a yellow solid. Step 6: To a solution of compound 17 (50.0 mg, 0.04 mmol) in THF (4.00 mL) was added a solution of LiOHXO (4.8 mg, 0.11 mmol) in water (1 mL). The reaction was stirred at 20°C for 1 h and concentrated. The residue was diluted with water (20 mL) and adjusted to pH = 4 by adding 5% aqueous KHSO4. The mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over Na2SO4 and concentrated to obtain crude compound 18 (49.0 mg, 99.1% yield) as a white solid. Step 7: A mixture of compound 18 (49 mg, 0.04 mmol) in 5% TEA in HFIP (3 mL, 2.01 mmol) was stirred at 35°C for 3 h and concentrated. The residue was diluted with methanol (5 mL) and neutralized with NaHCOa. After filtration, the filtrate was purified by preparative HPLC (1929% acetonitrile / 0.2% formic acid in water) to obtain the title compound (12.6 mg, 32.9% yield) as a white solid. 1H NMR (400 MHz , DMSO - de) δ (ppm) 9.39 (s, 1 H), 8.47 - 8.30 (m, 2H), 7.57 - 7.50 (m, 5H), 7.05 - 6.73 (m, 5H), 6.36 - 6.22 (m, 2H), 5.13 - 5.01 (m, 1H), 4.64 (s, 1H), 4.22 - 3.99 (m, 10H), 3.25 - 2.67 (m, 12H), 1.32 - 1.06 (m, 12H). LCMS (Method 5-95 AB, ESI): Rt = IVIA / t / ZUZZ / U I O / Ο I 0.789 min, [M+H]+= 995.8. Example 2: Step 1: A solution of diethyl malonate (8.00 g, 50.00 mmol), triethylorthoacetate (24.30 g, 150.00 mmol), ZnCl2 (2.01 mg, 0.01 mmol) and AC2O (1.00 mL, 4.32 mmol) was heated to 135°C for 6 h, while adding an additional amount of AC2O (1.00 mL, 4.32 mmol) every 30 min. The reaction mixture was cooled to room temperature and partitioned into (200 mL) and ethyl acetate (200 mL). The organic layer was dried with Na2SO4 and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 10-20% ethyl acetate in petroleum ether) to obtain diethyl 2-(1-ethoxyethylidene)malonate (9.00 g, 78.3% performance) as a yellow solid. Step 2: LHMDS (1N in THF, 50.2 mL, 50.2 mmol) was added to a solution of 4-(tert-butyl)benzonitrile (4.00 g, 25.1 mmol) in THF (30 mL) at 0°C. The reaction was stirred for 16 h at 20°C. The mixture was quenched by the addition of aqueous HCl (4 M, 20 mL) at 0°C, and then adjusted to pH >8 by the addition of aqueous NaOH (4 M). The separated aqueous layer was extracted with dichloromethane (3 x 30 mL). The combined organic layers were dried with Na2SO4 and concentrated to dryness to obtain crude 4-(tert-butyl)benzimidamide (3.30 g, 74.5% yield) as a brown solid. Step 3: Sodium (470 mg, 20.4 mmol) was added to ethanol (10 mL) and stirred for 30 min. This freshly prepared sodium ethoxide solution was added to a solution of diethyl 2-(1-ethoxyethylidene)malonate (4.23 g, 18.4 mmol) and 4-(tert-butyl)benzimidamide (1.80 g, 10.2 mmol) in ethanol. (30 mL). The reaction mixture was stirred at 50°C for 16 h and quenched with saturated aqueous NH4CI (30 mL). The mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (30 mL) and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum ether) to obtain ethyl 2-(4-(tert-butyl)phenyl)-4-methyl -6-oxo-1,6dihydropyrimidine-5-carboxylate (1.00 g, 31.1% yield) as a white solid. Step 4: A mixture of POCh (5.00 mL, 50.6 mmol) and ethyl 2-(4-(tert-butyl)phenyl)-4-methyl-6-oxo1,6—dihydropyrimidine—5—carboxylate (1.00 g, 3.2 mmol ) was stirred at 110°C for 2 h. The mixture was concentrated in vacuo and diluted with ethyl acetate (100 mL). The solution was washed with saturated aqueous NaHCOs (50 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum) to obtain ethyl 2-(4-(tert-butyl)phenyl)-4-chloro -6-methylpyrmidin-5-carboxylate (0.90 g, 85.0% yield) as a pale yellow solid. Step 5: A mixture of ethyl 2-(4-(tert-butyl)phenyl)-4-chloro-6-methylpyrimidine-5-carboxylate (1.00 g, 3.00 mmol) and ammonia (4 M in MeOH, 25.0 mL, 100.0 mmol) was stirred for 16 h at 70°C. The reaction was concentrated to dryness and diluted with ethyl acetate (100 mL). The solution was washed with water (2 x 30 mL), brine (30 mL), dried with Na2SO4 and concentrated to dryness. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum ether) to obtain methyl 4—amino—2—(4—(tert-butyl)phenyl )—6—methylpyrimidine—5—carboxylate (900 mg, 95.6% yield) as a white solid. Step 6: A mixture of methyl 4-amino-2-(4-(tert-butyl)phenyl)-6-methylpyrimidine-5-carboxylate (900 mg, 3.0 mmol) and NaOH (601 mg, 15.0 mmol) in water (5 mL) and MeOH (15 mL) was stirred at 80°C for 3 h IVIA / t / ZUZZ / U I O / O I and concentrated under reduced pressure. The residue was acidified to pH <5 by adding 1 M HCl and extracted with ethyl acetate (2 x 80 mL). The combined organic layers were concentrated under reduced pressure to obtain crude 4-amino-2-(4-(tert-butyl)phenyl)-6-methylpyrimidine-5-carboxylic acid (850 mg, 99.1% yield) as a white solid. . (formic acid salt) was prepared as described in Example 1, replacing 1(4—(tert—butyl)ph enyl)—6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4—amino —2—(4—(tert—butyl)ph enyl)—6— methylpyrimidine-5-carboxylic in the first stage.1H NMR (400MHz, MeOH - d4) δ (ppm) 8.36 - 8.10 (m, 3H), 7.63 - 7.34 (m, 2H), 7.27 - 6.28 (m, 6H), 5.28 - 5.1 0 (m, 1H), 4.74 - 4.45 (m, 2H), 4.42 - 3.90 (m, 6H), 3.87 - 3.35 (m , 3H), 3.29 - 2.89 (m, 8H), 2.87 - 2.37 (m, 3H), 1.49 - 1.15 (m, 12H). LCMS (Method 5-95 AB, ESI): Rt = 0.610 min, [M+H]+ = 1008.4. Example 3: OH H2N. γ\^<ΝΗ·' y HO* η OH |] CX^ u X Y O Y HN II h II h I II N, .N. -Y .N, or γ |f N || 0 ΝΗ, O k । O 1 NH 0=4=0 1 NH, X t K;CO- T LilIMDS | O» “ T Y T„r- NH 1 3 4 γγ nJCo N-X^OLt T Y T Π NH, O Cl O 7 8 OH 'Ύ EtONa _ POCI E:OH T [1 .. JH2 XX ΙΙΝ,ΧΟΜ O O 6 7 Na OH ° Ύγ. MwOH H;,0 LO. N N^^k^OH NH, O 9 Step 1: A mixture of 4-hydroxybenzonithlo (5.0 g, 42.0 mmol), 1-bromo-3,3-dimethylbutane MA / E / ZUZZ / U1 Oí ΟΊ (10.4 g, 63.0 mmol) and K2CO3 (17.4 g, 126 mmol) in DMF (20 mL) were stirred at 80°C for 2 h. After cooling to room temperature, the reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with water (2 x 300 mL), brine (200 mL), dried over MgSO4 and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 10% ethyl acetate in petroleum ether) to obtain 4-(3,3-dimethylbutoxy)benzonitrich (8.0 g, 93.8 % yield) as a colorless oil. Step 2: LHMDS (1 N in THF, 30.0 mL, 30.0 mmol) was added to 4-(3,3-dimethylbutoxy¡)benzonitrile (3.0 g, 14.8 mmol) in THF (30 mL) at 0°C. The reaction was stirred for 16 h at 20°C and quenched by the addition of 4 M HCl until pH = 2. The mixture was then adjusted to pH = 12 by the addition of 4 M NaOH and extracted with chloroform (3 x 100 mL). The combined organic layers were dried over Na2SO4 and concentrated to dryness to obtain crude 4-(3,3-dimethylbutoxy)benzimidamide (3.0 g, 92.3% yield) as a yellow solid. Step 3: To a solution of 4-(3,3-dimethylbutoxy)benzimidamide (4.70 g, 20.4 mmol) and EtONa (1.85 g, 27.2 mmol) in ethanol (20 mL) was added 2- (1-ethoxyethylidene)malonate (3.00 g, 13.6 mmol). The reaction mixture was stirred for 3 h at 50°C and concentrated to dryness. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The separated organic layer was washed with brine (50 mL), dried over MgSO4 and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 30% ethyl acetate in petroleum ether) to obtain ethyl 2-(4-(3,3dimethylbutoxy)phenyl)-4-methyl-6 -oxo-1,6-dihydropyrimidine—5—carboxylate (1.70 g, 34.8% yield) as a white solid. Step 4: A mixture of ethyl 2—(4—(3,3—dimethylbutoxy)phenyl)—4—methyl—6—oxo—1,6—dihydropyrimidine—5—carboxylate (1.70 g, 4.74 mmol) in POCl3 (30.0 mL, 325 mmol) was stirred at 110°C for 3 h and concentrated to dryness. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to obtain ethyl 4-chloro-2-(4-(3,3dimethylbutoxy)phenyl )—6-methylpyrimidine-5-carboxylate (1.40 g, 78.3% yield) as a white solid. Step 5: A mixture of ethyl 4-chloro-2-(4-(3,3-dimethylbutox¡)phen¡l)-6-methyl¡r¡m¡d¡n-5-carboxylate (1.20 g, 3.18 mmol) and ammonia (4 M in MeOH, 30.0 mL, 120 mmol) were stirred for 16 h at 70°C and concentrated to dryness. The residue was partitioned between ethyl acetate (200 mL) and water (100 mL). The separated organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated to dryness. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to obtain ethyl 4-amino-2-(4-(3,3-dimethylbutoxy )phenyl)—6—methylpyrimidine—5—carboxylate (1.00 g, 87.9% yield) as a white solid. Step 6: A mixture of ethyl 4-amino-2-(4-(3,3-dimethylbutoxy)phenyl)-6-methylpyrimidine-5-carboxylate (1.00 g, 2.80 mmol) and NaOH (560 mg, 14.0 mmol) in MeOH (15 mL) and water (10 mL) were stirred at 80 °C for 22 h and concentrated. The residue was adjusted to pH = 5 by adding 1M HCl. The solid was collected by filtration and dried to obtain 4-amino-2-(4-(3,3-dimethylbutoxy)phenyl)-6methylpyrimidine-5-carboxylic acid (800 mg, 86.8% yield) as a white solid. ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ The title compound was prepared as described in Example 1, replacing 1—(4—(tert—butyljf enyl)—6—oxo—1,6—d ihyd ropyridazine—4—carboxylic acid with 4-amino-2 -(4-(3,3dimethylbutoxyphenyl)—6—methylpyrimidine—5—carboxylic.1H NMR (400MHz, DMSO - de} δ (ppm) 8.34 (s, 1H), 8.20 (d, J = 8.4 Hz, 2H), 7.12-7.04 (m, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.92 -6.84 (m 1 H), 6.84- 6.74 (m, 2H), 8.56 (s, 1H), 6.44 (s, 1H), 5.23 - 5.13(m, 1H), 4.83 - 4.79 (m, 2H), 4.54 - 4.42 (m, 1H), 4.26 - 4.20 (m, 1H), 4.18 - 3.97 (m, 7H), 3.65 - 3.56 (m, 1H), 3.40 - 3.33 (m, 4H), 3.28 -3.13 (m, 3H), 3.12 - 2.94 (m, 5H), 2.45 (s, 3H), 1.80 - 1.68 (m, 3H) , 1.34 (d, J = 6.0 Hz, 3H), 1.01 (s, 9H); LCMS (Method 5-95 AB): μλ / ε / zuzz / u i gold i Rt = 0.823 min, [Μ + H]+= 1052.4. Example 4: Step 1: To a solution of 4-bromophenol (7.16 g, 43.4 mmol) in DMF (30.0 mL), 1-bromo-3,3-dimethylbutane (5.00 g, 28.9 mmol) and K2CO3 (10.0 g, 72.2 mmol) were added. The reaction mixture was stirred at 50°C for 16 h and cooled to room temperature. The mixture was filtered, and the filtrate was diluted with ethyl acetate (80 mL) and water (80 mL). The separated organic layer was washed with brine (3 x 80 mL), dried in N2SO4 and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 5% methanol in dichloromethane) to obtain 1-bromo^4-(3,3dimethylbutox¡)benzene (6.10 g, 82.1% yield) as a white solid. Step 2: A mixture of 1-bromo-4—(3,3-dimethylbutoxy)benzene (6.10 g, 23.7 mmol), Pd(dppf)CI2 (1.74 g, 2.37 mmol), bis(pinacolato)diboron (9.04 g, 35.6 mmol) and potassium acetate (7.00 g, 71.2 mmol) in DMF (60 mL) was heated at 80°C for 4 h under N2 atmosphere and then filtered. The filtrate was partitioned into ethyl acetate (100 mL) and water (100 mL). The separated organic layer was washed with brine (3 x 150 mL), dried over NasSO and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 2% ethyl acetate in petroleum ether) to obtain 2-(4-(3,3dimethylbutoxy¡)phenyl)-4,4,5 ,5-tetramethyl-1,3,2-dioxaborolane (6.30 g, 87.3% yield) as a white solid. Step 3: To a solution of 2-(4-(3,3-dimethylbutoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.30 g, 20.7 mmol) in acetone (60 mL) ammonium acetate (83 mL, 82.7 mmol) and NalÜ4 (13.3 g, 62.0 mmol) were added. The reaction was stirred at 40°C for 16 h and concentrated to dryness. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 2% methanol in dichloromethane to obtain (4-(3,3-dimethylbutoxy¡)phenyl)boronic acid (4.50 g, 20.3 mmol, 98.0% yield) as a yellow solid. Step 4: A mixture of (4—(3,3—dimethylbutoxy)phenyl)boronic acid (200 mg, 0.90 mmol), copper diacetate (32.7 mg, 0.18 mmol) and methyl 6-oxo-1,6-dih¡ Dropyridazin-4-carboxylate (146 mg, 0.95 mmol) in dichloromethane (6 mL) and pyridine (1 mL) was stirred at 20°C for 16 h. The reaction mixture was diluted with ethyl acetate (80 mL) and filtered. The filtrate was washed with brine (50 mL) and concentrated to dryness. The residue was purified by preparative TLC (33% ethyl acetate in petroleum ether, Rf = 0.3) to obtain methyl 1-(4-(3,3-dimethylbutoxy)phenyl)-6-oxo-1,6 -dih¡drop¡r¡dazín-4-carboxylate (235 mg, 79.0% yield) as a green solid. Step 5: A mixture of methyl 1-(4-(3,3-dimethylbutoxy)phenyl)-6-oxo-1,6-dihydropyridazin-4carboxylate (235 mg, 0.71 mmol) and NaOH (71.1 mg, 1.78 mmol) in MeOH (10 mL) and water (3 mL) was stirred for 1 h at 80°C. The reaction mixture was adjusted to pH = 5 with HCl (1M in water) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated to dryness to obtain crude 1-(4-(3,3-dimethylbutoxy¡)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid (220 mg , 97.8% yield) as a yellow solid. The title compound was prepared as described in Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 1-(4 -(3,3—dimethylbutoxy)phenyl)—6—oxo— ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ 1,6-dihydropyridazine—4-carboxylic.1H NMR (400 MHz, DMSO - de)', δ (ppm) 9.33 (s, 1 H), 8.46 (s, 1H), 8.35 - 8.34 (m, 2H), 8.02 (s, 1H), 7.57 (s, 1H), 7.50 - 7.47 (m, 2H), 7.07 - 7.05 (m, 3H), 6.90 - 6.66 (m, 8H), 6.36 (s, 1H), 6.22 ( s, 1H), 5.05 - 5.02 (m, 2H), 4.67 - 4.64 (m, 2H), 4.10 - 3.92 (m, 8H),3.25 - 3.23 (m, 6H), 3.08 - 3.07 (m, 3H), 2.97 - 2.95 (m, 3H), 2.85 - 2.83 (m, 4H), 2.68 (s, 1H), 1.68 (t, J = 6.8 Hz, 2H), 1.16 (d, J = 6.4 Hz, 3H), 0.98 (s, 9H). LCMS (Method 5-95 AB, ESI), Rt = 0.830 min, [M + H]+= ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ 1039.3. Example 5: Step 1: To a solution of PhsP+MeBr (201 g, 563 mmol) in THF (500 mL) was added n-BuLi (2.5 N in hexanes, 225 mL, 563 mmol) in N2 at 0°C. The mixture was stirred at room temperature until the solution became clear; then, a solution of 1-(4-bromophenyl)ethan-1-one (70 g, 352 mmol) in THF (200 mL) was added dropwise. After addition, the mixture was heated to 70°C for 20 h and quenched by the addition of saturated aqueous NH4CI (1000 mL). The resulting solution was extracted with ethyl acetate (2 x 1000 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, petroleum ether) to obtain 1-bromo-4-(prop-1-en-2-yl)benzene (50 g, 72.1% yield ) as a colorless oil. Step 2: To a solution of 1-bromo-4-(prop-1-en-2-yl)benzene (20.0 g, 101 mmol) in dichloromethane (100 mL) ZnEt2 (1 M in toluene, 507 mL, 507 mmol) and CH2I2 (81.9 mL, 1010 mmol) at 0°C in a N2 atmosphere. The mixture was heated to 70°C for 72 h and concentrated to dryness. The residue was partitioned between water (500 mL) and petroleum ether (500 mL). The organic layer was washed with brine (3 x 100 mL), dried over Na2SO4 and concentrated to dryness. The residue was then purified by preparative HPLC (55-85% acetonitrile / 0.225% FA in water) to obtain 1-bromo-4-(1methylcyclopropyl)benzene (201 g, 60.7% yield) as an oil. colorless. Step 3: A mixture of 1-bromo^l-(1-methylcyclopropyljbenzene (28.8 g, 136 mmol), bis(pinacholate)diboron (36.3 g, 143 mmol), KOAc (40.1 g, 408 mmol) and Pd( dppf)2Cl2 (9.97 g, 13.6 mmol) in DMF (200 mL) was heated at 80°C for 6 h under N2 atmosphere. The reaction was diluted with ethyl acetate (600 mL) and filtered. The filtrate was washed with water (2 x 200 mL), brine (3 x 200 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0% - 10% of ethyl acetate in petroleum ether) to obtain 4,4,5,5-tetramethyl2-(4~(1-methylcyclopropyl)phenyl)-1,3,2-dioxaborolane (30 g, 85.2%) as a white solid. Step 4: A mixture of 4,4,5,5-tetramethyl-2-(4-(1-methylcyclopropyl)phenyl)-1,3,2-dioxaborolane (20.0 g, 77.5 mmol), ethyl 2-chloro-4-methylpyrimidin-5-carboxylate (15.4 g, 77.5 mmol), Na2CO3 (24.6 g, 232 mmol) and Pd(dppf)2Cl2 (5.67 g, 7.75 mmol) in 1,4-dioxane (400 mL) and water (20.0 mL) were heated to 100°C for 16 h in N2 and filtered. The filtrate was concentrated until dry. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0% - 5% ethyl acetate in petroleum) to obtain ethyl 4—methyl—2—(4—(1—methylcyclopropyl)phenyl)pyrimidin —5—carboxylate (26.0 g, 56.4% yield) as a white solid. Step 5: A mixture of ethyl 4-methyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidin-5-carboxylate (26.0 g, 79.0 mmol) and NaOH (9.47 g, 237 mmol) in MeOH (260 mL) and water (26 mL) was stirred at 80°C for 16 h and concentrated. The residue was diluted with water (100 mL) and adjusted to pH = 4 with HCl (1M). The mixture was filtered, and the filtrate was concentrated to dryness to obtain crude 4-methi 1-2-(4-(1 methylcycloproyl)phenyl)pyrimidine-5-carboxylic acid (28.0g, 100% yield) as a white solid. The title compound was prepared as described in Example 1, replacing 1-(4(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with the acid compound 4-methy 1- 2-(4-(1 methylcyclopropyl)phenyl)pyrimidine—5—carboxylic.1H NMR (400 MHz, MeOH - Λ) δ (ppm) 8.86 (s, 1H), 8.18 (d, J = 8.4 Hz, 2H ), 7.32 (d, J = 8.4 Hz, 2H), 6.90 - 6.87 (m, 2H), 6.78 (m, 2H), 6.39 (s, 2H), 5.29 - 5.26 (m, 1H), 4.80 - 4.75 ( m, 1H), 4.60 (d, J = 9.2 Hz, 1H), 4.36 - 4.32 (m, 1H), 4.27-4.19 (m, 2H), 4.11 - 4.05 (m, 3H), 3.65 - 3.60 (m, 1H), 3.45 - 3.34 (m, 1H), 3.28 - 3.13 (m, 4H), 3.06 (s, 3H), 3.00 - 2.86 (m, 1H), 2.77- 2.72 (m, 10H) 2.65 (m, 3H) ), 1.48 (s, 3H), 1.37 (d, J = 6.8 Hz, 3H), 0.97- 0.95 (m, 2H), 0.89-0.88 (m, 2H). LCMS (Method 5-95 AB, ESI), Rt = 0.802 min, [M + H]+= 991.2. ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ Step 1: A mixture of 1-bromo-4—(1-methylcyclopropyl)benzene (5.20 g, 24.6 mmol), Pd(PPh3)4 (2.80 g, 2.46 mmol) and Zn(CN)2 (6.47 g, 55.1 mmol) in DMF (50 mL) was heated at 120°C for 16 h in a Ns atmosphere. After cooling to room temperature, the mixture was diluted with ethyl acetate (500 mL) and filtered. The filtrate was washed with brine (2 x 200 mL), dried over NasSO4 and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-0.5% ethyl acetate in petroleum ether) to obtain 4-(1-methylcyclopropyl)benzonitrich (14.0 g, 92.1 % yield) as a light yellow oil. Step 2: A mixture of 4-(1-methylcyclopropyl)benzonitrile (5.00 g, 31.8 mmol) and LHMDS (1 N in THF, 63.6 mL, 63.6 mmol) in THF (50 mL) was stirred at 30°. C for 16 h and inactivated by adding 1M HCl (50 mL). The separated aqueous layer was adjusted to pH = 8 by adding 1M NaOH and extracted with ethyl acetate (5 x 100 mL). The combined organic layers were dried and concentrated to obtain crude 4-(1-methylcyclopropyl)benzimidamide (4.80 g, 86.6% yield) as a yellow solid. Step 3: A mixture of 4-(1-methylcyclopropyl)benzimide (1.80 g, 10.3 mmol), 2-(1-ethoxyethylidene)malonate (12.0 mL, 18.6 mmol), and freshly prepared sodium ethoxide ( 20.7 mmol) in ethanol (40 mL) was heated at 50°C for 16 h. After cooling to room temperature, the reaction mixture was quenched with HCl (1 M, 100 mL) and extracted with ethyl acetate (4 x 100 mL). The combined organic layers were washed with brine (100 mL), dried, and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 30% ethyl acetate in petroleum ether) to obtain ethyl 4—methyl—2—(4—(1—methylcyclopropyl)phenyl)—6 —oxo—1,6—dihydropyrimidine—5—carboxylate (2.50 g, 77.5% yield) as a yellow solid. Step 4: A mixture of ethyl 4—methyl—2—(4—(1 —methylcycloprc>pyl)pheniI)—6—oxo—1,6—dihydropyrimidine—5-carboxylate (6.5 g, 20.8 mmol) in POCh (69.3 mL, 743 mmol) was heated at 110°C for 2 h and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 5% ethyl acetate in petroleum ether) to obtain ethyl 4-chloro-6-methyl-2-(4-(1methyl) cloprop¡l)phen¡l)pyrimide¡n-5-carboxylate (6.1 g, 88.6% yield) as a yellow oil. Step 5: A mixture of ethyl 4-chloro-6-methyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidine-5carboxylate (6.10 g, 18.4 mmol) in ammonia (10 N in MeOH, 60 mL, 600 mmol) was heated at 50°C for 16 h and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 20% ethyl acetate in petroleum ether) to obtain ethyl 4-amino-6-methyl2-(4-(1-methylcyclopropyl)phen. l)pyrimidín-5-carboxylate (3.00 g, 52.2% yield) as a white solid. Step 6: A mixture of ethyl 4-amino-6-methyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidin-5-carboxylate (1.85 g, 5.94 mmol) and NaOH (0.95 g, 23.8 mmol) in MeOH (20 mL) and water (10 mL) was heated at 80°C for 2 h. After cooling to room temperature, the mixture was filtered. The filter cake was dried to obtain crude 4-amino-6-methyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidine-5-carboxylic acid (1.68 g, 100% yield) as a white solid. . The title compound was prepared as described in Example 1, replacing 1—(4—(tert-butyl)phenyl)—6—oxo—1,6-dihydropyridazine-4-carboxylic acid with 4 -amino-6-methyl-2-(4-(1methylcyclopropyl)phenyl)pyrimidine—5—carboxylic.1H NMR (400 MHz, MeOH - efe) δ (ppm) 8.12 (d, J= 8.4 Hz, 2H) , 7.47 (d, J = 8.4 Hz, 2H), 7.21 - 7.15 (m, 1 H), 7.02 (d, J = 8.4 Hz, 1H), 6.93 - 6.86 (m, 1H), 6.85 6.80 (m, 1H ), 6.5 (s, 1H), 6.4 (s, 1H), 5.25-5.17 (m, 1 H), 4.85-4.77 (m, 2H), 4.32 -4.25 (m, 1H), 4.244.14 (m, 3H), 4.12 - 4.04 (m, 2H), 3.66 - 3.59 (m 1H), 3.58 - 3.43 (m, 1H), 3.41 - 3.38 (m, 1 H), 3.37 3.31 (m, 2H), 3.29 - 3.28 (m, 1H), 3.28 - 3.20 (m, 1H), 3.19 - 3.14 (m, 1H), 3.13 - 3.07 (m, 2H), 3.1 (s, 3H), 2.75 (s, 1H), 2.7 (s, 12H), 2.63 (s, 3H), 1.48 (s, 3H), 1.42- 1.28 (m, 3H), 1.03- 0.97 (m, 2H), 0.940 .90 (m, 2H). LCMS (Method 10-80 AB, ELSD), Rt = 1.412 min, [M + H]+= 1006.7. IVIA / t / ZUZZ / U I 0 / 0 I Example 7: IVIA / t / ZUZZ / UΊ O / 01 The title compound was prepared as described in Example 1, replacing 1-(4(tert-butyl)phenyl)-6-oxo-1,6-d ihyd ropyridazine-4-carboxylic acid with 2-(4- (tert-butyl)phenyl)-4,6-dimethylpyrimidine-5-carboxylic.1H NMR (400 MHz, MeOH - d4) δ (ppm) 8.89 (d, J = 7.6 Hz, 1H), 8.55 (d, J = 8.8 Hz, 1H), 8.21 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.05 - 6.97 (m, 2H), 6.77 (s, 1 H), 6.45 ( s, 1H), 5.43 - 5.39 (m, 1H), 4.81 - 4.76 (m, 2H), 4.27 - 4.21 (m, 3H), 4.10 - 4.05 (m, 3H), 3.63-3.59 (m, 1H), 3.37-3.33 (m, 1H), 3.28-3.20 (m, 2H), 3.12 -3.07 (m, 6H), 2.97-2.90 (m, 1H), 2.46 (s, 6H), 1.38 (s, 9H) , 1.37 (s, 3H). LCMS (Method 10-80 AB, ELSD), Rt = 0.652 min, [M + H]+ = 1007.5. Example 8: The title compound was prepared as described in Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 2-(4- (tert-butyl)phenyl)-4-methylpyrimidine-5-carboxylic.1H NMR (400 MHz, MeOH - d4) δ (ppm) 8.84 (s, 1H), 8.381 (s, 1H), 8.34 8.25 (m, 2H), 7.55-7.47 (m, 1H), 7.07 - 6.93 (m, 1H), 6.89 - 6.74 (m, 2H), 6.66-6.56 (m, 1H), 6.51 (s, 1H) ), 5.33-5.03 (m, 1H), 4.83-4.81 (m, 2H), 4.47 (s, 1H), 4.37 -3.95 (m, 6H), 3.65 - 3.50 (m, 1H), 3.49 -3.34 ( m, 1H), 3.28-3.07 (m,4H), 3.07-2.94 (m, 4H), 2.66 (s, 3H), 1.40 -1.32 (m,12H). LCMS (Method 5-95 AB, ELSD), Rt = 0.667 min, [M + H]+= 993.4. Example 9: Step 1: To a solution of 4-bromophenol (5.00 g, 28.9 mmol), PPh3 (22.7 g, 86.7 mmol) and cyclohexanol (8.68 g, 86.7 mmol) in THF (75.0 mL) DIAD (17.2 mL, 86.7 mmol) was added ) slowly, at 0°C. The reaction mixture was stirred for 3 h at 20°C and concentrated. The residue was diluted with water (70 mL) and then extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 100% petroleum ether to obtain 1-bromo^t-(cyclohexyloxy¡)benzene (6.24 g, 85.0% yield) as a white solid. This was then converted to 1-(4-(cyclohexyloxy)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid by procedures analogous to those used in Example 4. The title compound was prepared as described in Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 1- (4-(cyclohexyloxy)phenyl)-6-oxo-1,6dihydropyridazine—4—carboxylic acid.1H NMR (400 MHz, DMSO - de)', δ (ppm) 9.33 (s, 1H), 8.44- 8.34 ( m, 2H), 8.06 (s, 1H), 7.55 (d, J = 1.6 HZ, 1H), 7.47 -7.43 (m, 1H), 7.06- 7.04 (m, 2H), 6.89 -6.67 (m, 6H) , 6.36 (s, 1H), 6.22 (s, 1H), 5.02 (s, 1H), 4.66 (s, 1H), 4.40 (s, 1H), 4.05 -3.98 (m, 7H), 3.25 (s, 2H) ), 3.12-2.97 (m, 6H), 2.83 (s, 3H), 1.98- 1.93 (m, 2H), 1.73 - 1.72 (m, 2H), 1.53 - 1.15 (m, 9H). LCMS (Method 5-95 AB, ELSD), Rt = 0.815 min, [M + H]+= 1037.5. Example 10: Step 1: A mixture of compound 1 (2.50 g, 11.0 mmol) and compound 2 (4.20 g, 26.0 mmol) was stirred at 50°C for 48 h. The reaction mixture was heated to 70°C for another 1 h to complete the reaction. The mixture was then poured into ice water (100 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with water (50 mL), dried with Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0% - 5% ethyl acetate in petroleum ether) to obtain compound 3 (177 mg, 5.8% yield) as a yellow oil. . Step 2: A mixture of bis(pinacolato)diboron (177 mg, 0.70 mmol), potassium acetate (125 mg, 1.27 mmol) and compound 3 (158 mg, 0.63 mmol) in DMF (3.00 mL) was stirred at 80°C for 14 h in a N2 atmosphere. The reaction mixture was diluted with ethyl acetate (20 mL) and filtered. The filtrate was concentrated in vacuo to obtain crude compound 4 (138 mg, 0.47 mmol) as a brown oil. Step 3: A mixture of compound 4 (138 mg, 0.47 mmol), compound 5 (102 mg, 0.51 mmol), sodium carbonate (98.8 mg, 0.93 mmol) and 1,1bis(diphenylphosphino)ferrocene palladium dichloride (34.1 mg, 0.05 mmol) in water (0.5 mL) and 1,4-dioxane (5 mL) was heated at 100°C in N2 for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (80 mL). The solution was washed with water (40 mL), brine (40 mL), dried and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to obtain compound 6 (60.0 mg, 38.5% yield) as a pale oil. Step 4: A mixture of compound 6 (60.0 mg, 0.18 mmol) and sodium hydroxide (14.4 mg, 0.36 mmol) in methanol (1.5 mL) and water (1.5 mL) was stirred at 80°C for 2 h and concentrated. The aqueous residue was adjusted to pH = 5 with 5% KHSO4 and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (40 mL), dried, and concentrated to obtain crude compound 7 (45.8 mg, 83.3% yield) as a white solid. The title compound was prepared as described in Example 1, replacing 1—(4—(tert-butyl)phenyl)—6—oxo—1,6—dihydropyridazine—4—carboxylic acid with the compound 7.1H NMR (400 MHz, MeOH - d4) δ (ppm) 8.88 (s, 1H), 8.50 - 8.43 (m, 2H), 8.40 (s, 1H), 7.58 - 7.52 (m, 2H), 7.02 (s, 1H), 6.89 - 6.79 (m, 2H), 6.60 - 6.48 (m, 2H), 5.29 - 5.16 (m, 1H), 4.81 - 4.75 (m, 3H), 4.46 (s, 1H), 4.28 - 3.91 (m, 6H) , 3.69 - 3.53 (m, 1H), 3.43 - 3.35 (m, 1H), 3.28 - 3.11 (m, 4H), 3.07 (s, 3H), 3.01 - 2.98 (m, 1H), 2.81 2.60 (m, 4H), 2.49 - 2.34 (m, 1H), 1.41 - 1.30 (m, 3H), 1.04 - 1.00 (m, 6H), LCMS (Method 5-95 AB, ESI), Rt = 0.771 min, [M + H ]+= 1029.7. Example 11: ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ Step 1: A solution of methyl 3-aminopyrazine-2-carboxylate (5.0 g, 32.7 mmol) and m-CPBA (10.6 g, 49.0 mmol) in dichloromethane (50 mL) was stirred at 60°C for 16 h. After cooling to room temperature, the reaction mixture was diluted with dichloromethane (250 mL) and filtered. The filtrate was concentrated to dryness, and the residue was taken up in 10% ethyl acetate in petroleum ether (200 mL). The resulting mixture was stirred at 25°C for 1 h and filtered. The solid was collected and dried to obtain crude 2-amino-3-(methoxycarbonyl)pyrazine 1-oxide (5.5 g, 99.6% yield) as a yellow solid. Step 2: A mixture of 2-amino-3-(methoxycarbon¡l)pyrazine 1-oxide (5.50 g, 32.5 mmol) and POCI3 (15.2 mL, 163 mmol) in DMF (30 mL) was heated at 100°C for 16 h. After cooling to room temperature, the mixture was diluted with H2O (300 mL) and adjusted to pH = 7 with solid NaHCOs. The resulting mixture was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine (100 mL), dried, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 10% ethyl acetate in petroleum ether) to obtain methyl 3-amino-5-chloropyrazín-2-carboxylate (940 mg, 15.4 % performance). Step 3: A mixture of (4-(tert-butyl)phenyl)boronic acid (937 mg, 5.26 mmol), methyl 3-amino-5chloropyrazine-2-carboxylate (940 mg, 5.01 mmol), K3PO4 (2.08 g, 15.0 mmol) and Pd(dppf)Cl2 (367 mg, 0.50 mmol) in DMF (10.0 mL) was heated at 90°C for 16 h in N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and filtered. The filtrate was washed with brine (2 x 100 mL), dried, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 15% ethyl acetate in petroleum ether) to obtain the crude product (two isomers). The crude product was further separated by SFC (supercritical fluid chromatography) to obtain methyl 3-amino-5-(4(tert-butyl)phenyl)pyrazin-2-carboxylate (120 mg, 8.4% yield) as a yellow solid. Step 4: A mixture of methyl 3-amino-5-(4-(tert-butyl)phenyl)pyrazine-2-carboxylate (120 mg, 0.42 mmol) and NaOH (42.1 mg, 1.05 mmol) in methanol (5 mL) and water (1 mL) was heated to 80°C for 16 h. The mixture was concentrated, and the aqueous residue was adjusted to pH = 2 by the addition of 1 M HCl. The resulting mixture was extracted with ethyl acetate (3x10 mL). The combined organic layers were dried and concentrated to obtain crude 3-amino-5-(4-(tert-butyl)phenyl)pyrazin-2-carboxylic acid (110 mg, 96.4% yield). ) as a yellow solid. The title compound was prepared as described in Example 1, replacing 1-(4(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 3-amino acid. -5-(4-(tert-butyl)phen¡l)pyraz¡n2-carboxylic.1H NMR (400MHz, DMSO - de) δ (ppm) 8.55 - 8.42 (m, 1 H), 8.37 (br s , 1H), 8.09 - 7.91 (m, 2H), 7.63 - 7.46 (m, 2H), 7.12 - 6.99 (m, 1 H), 6.95 - 6.62 (m, 3H), 6.48 - 5.93 (m, 2H), 5.19 - 4.89 (m, 1H), 4.70 - 4.51 (m, 1H), 4.32 - 3.85 (m, 5H), 3.41 - 3.12 (m, 5H), 3.07 -2.63 (m, 8H), 1.39 - 1.25 (m , 9H), 1.24 - 1.04 (m, 3H). (Method 5-95 AB, ESI): Rt = 0.689 min, [M + H]+= 994.4. Example 12: IVIA / t / ZUZZ / U 1 O / 01 Step 1: A mixture of 4-(tert-butyl)piperidine hydrochloride (1.00 g, 5.60 mmol), 1H-pyrazole-1-carboximidine hydrochloride (0.82 g, 5.63 mmol) and DIEA (1.45 g, 11.3 mmol) in DMF (5.00 mL) was stirred at 60°C for 16 h and diluted with MTBE (60 mL). The resulting suspension was stirred for 10 min and filtered. The solid was collected to obtain crude 4-(tert-butyl)piperidine—1-carboximidamide (1.00 g, 97.0% yield) as a white solid. Step 2: A mixture of 4-(tert-butyl)piperidine-1-carboximidamide (1.00 g, 5.46 mmol), NaOEt (742 mg, 10.9 mmol) and diethyl 2-(1-ethoxyethylidene)malonate (1.88 g, 8.18 mmol) in ethanol (20.0 mL) was heated at 50°C for 20 h and concentrated to dryness. The residue was diluted with ethyl acetate (50 mL), washed with brine (2 x 30 mL), dried and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to obtain ethyl 2-(4-(tert-butyl)piperidin1yl)^4-methyl 6—oxo- 1,6-dihydropyrimidine-5-carboxylate (350 mg, 20.0% yield) as a light yellow solid. Step 3: A mixture of ethyl 2—(4—(tert—butyl)piperldin—1—yl)—4—methyl—6—oxo—1,6—dihydropyrimidin—5-carboxylate (350 mg, 1.09 mmol) and POCh (10 mL, 108 mmol) was heated at 90°C for 20 h and concentrated to dryness. The residue was purified by preparative TLC (20% ethyl acetate in petroleum ether, Rf = 0.8) to obtain ethyl 2—(4—(tert-butyl)piperidin—1—¡I)—4—chloro—6— methylpyrimidine—5— carboxylate (270 mg, 73.0% yield) as a pale oil. Step 4: A mixture of ethyl 2-(4-(tert-butyl)piperidin-1-yl)-4-chloro-6-methylpyrimidine-5-carboxylate (170 mg, 0.50 mmol) and NH3H2O ​​(2.00 mL, 55.1 mmol ) in MeOH (5 mL) was heated at 60°C for 60 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (40 mL), washed with brine (20 mL), dried and concentrated. The residue was purified by preparative TLC (10% ethyl acetate in petroleum ether, Rf = 0.4) to obtain ethyl 4-amino-2-(4-(tert-butyl)pyridin—1—yl)—6 —methylpyrimidine-5-carboxylate (130 mg, 81.1% yield) as a pale yellow solid. Step 5: A mixture of ethyl 4-amino-2-(4-(tert-butyl)pyperidin-1-yl)-6-m ethylpyrimid in-5-carboxylate (130 mg, 0.41 mmol) and NaOH (40.6 mg, 1.01 mmol) in MeOH (5 mL) and water (1 mL) was heated at 80 °C for 16 h and concentrated. The aqueous residue was adjusted to pH = 2 with 1 M HCl and extracted with ethyl acetate (3x10 mL). The combined organic layers were concentrated to obtain crude 4-amino-2-(4-(tert-butyl)p-per-din-1-yl)-6-methylpyrimidin-5-carboxylic acid (100 mg, 84.3% performance) as a white solid. The title compound was prepared as a white solid by the procedure of Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2 acid. —(4—(tert—butyl)piperidin—1 —yl)—6—methylpyrimidine—5—carboxylic.1H NMR (400 MHz, MeOH - d4) δ (ppm) = 8.30 (s, 1H), 7.1 7 - 7.14 (m, 1 H), 6.95 (s, 1 H), 6.89 - 6.76 (m, 2H), 6.64 - 6.54 (m, 1 H), 6.50 (s, 1H), 5.12-5.22 (m, 1 H) , 4.75-4.71 (m, 2H), 4.55(s, 1H), 4.28 - 4.04 (m, 5H), 3.62 - 3.57 (m, 1H), 3.41 -3.33 (m, 2H), 3.32-3.35 (m, 2H), 3.21 - 3.10 (m, 2H), 3.10-3.04 (m, 3H), 3.01 (s, 1 H), 2.94-2.82 (m, 1H), 2.81 - 2.74 (m, 2H), 2.74 - 2.64 (m, 1H), 2.42 - 2.33 (m, 3H), 1.85 - 1.73 (m, 2H), 1.40 - 1.28 (m, 4H), 1.26 - 1.13 (m, 2H), 0.91 (s, 9H). LCMS (Method 5-95 AB, ESI): Rt = 0.747 min, [M / 2+H]+= 508.5. Example 13: ΜΛ / Ε / ZUZZ / U1 Heard 1 IVIA / t / ZUZZ / U I O / Ο I Step 1: A mixture of 4-isopropoxyphenylboronic acid (29.6 g, 164 mmol), methyl 2-chloro-4,6dimethylpyrimidine-5-carboxylate (30.0 g, 150 mmol), Na2CO3 (31.7 g, 299 mmol) and Pd(dppf)Cl2 (10.9 g, 15.0 mmol) in water (15 mL) and 1,4-dioxane (150 mL) was heated at 100 °C for 16 h under a nitrogen atmosphere and then filtered. The filtrate was concentrated until dry. The residue was partitioned between ethyl acetate (500 mL) and water (500 mL). The aqueous layer was extracted with ethyl acetate (500 mL). The combined organic layers were washed with brine (3 x 500 mL), dried, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum ether) to obtain methyl 2-(4-isopropoxyphenyl)-4,6- dimethylp¡hm¡din-5-carboxylate (42.0 g, 93.5% yield) as a white solid. Step 2: A mixture of methyl 2-(4-isopropoxyphenyl)-4,6-dimethylpharmin-5-carboxylate (21.0 g, 69.9 mmol) and NaOH (8.39 g, 210 mmol) in MeOH (100 mL) and water (10 mL) was heated at 80°C for 22 h and concentrated. The aqueous residue was adjusted to pH = 5 by adding 1 M HCl and filtered. The collected solid was dried to obtain crude 2-(4-isopropoxyphenyl)-4,6-dimethylpyrmidine-5-carboxylic acid (19.0 g, 95.0% yield) as a white solid. . The title compound was prepared as a white solid by the procedure of Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydro¡r¡dazín-acid. 4-carboxylic with 2—(4—isopropoxyphenyl)—4,6—dimethylpyrimidine—5—carboxylic acid.1H NMR (400 MHz, MeOH - d4): δ (ppm) 8.47 (s, 1H), 8.30 - 8.28 (m , 2H), 7.02 - 6.94 (m, 2H), 6.82 - 6.70 (m, 4H), 6.57 (s, 1H), 6.43 (s, 1H), 5.33 - 5.32 (m, 1H), 4.69 - 4.66 (m , 2H), 4.35 - 4.09(m, 6H), 3.57 - 3.56 (m, 1H), 3.39 - 3.37 (m, 1 H), 3.25 - 3.00 (m, 9H), 2.54 (s, 6H), 1.35 - 1.33 (m, 9H), LCMS (Method 5-95 AB, ESI): Rt= 0.608 min, [M + H]+= 1009.5. Step 1: A mixture of ethyl 2-chloro-4-methylpyridine-5-carboxylate (30.0 g, 150 mmol), (4-sopropoxyphenyl)boionic acid (28.3 g, 157 mmol), sodium carbonate (31.7 g, 299 mmol) and Pd(dppf)Cl2 (10.9 g, 15.0 mmol) in water (30 mL) and 1,4-dioxane (300 mL) were heated at 100°C for 16 h in a nitrogen atmosphere. The reaction was cooled to room temperature, and the mixture was diluted with ethyl acetate (300 mL) and filtered. The filtrate was washed with brine (100 mL), dried, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 2% ethyl acetate in petroleum ether) to obtain ethyl 2—(4—isopropoxyphenyl)—4—methylpyrimidine—5-carboxylate (32.5 g , 72.4% yield) as a white solid. Step 2: A mixture of ethyl 2-(4-isopropoxyphenylHl-methylpharmidin-5-carboxylate (32.5 g, 108 mmol) and sodium hydroxide (21.6 g, 541 mmol) in MeOH (150 mL) and water (15 mL) was stirred at 80°C for 3 h and concentrated. The aqueous residue was adjusted to pH = 5 with 2M HCl and filtered. The filter cake was washed with water (3 x 50 mL) and dried to obtain 2—(4—isopropoxyphenyl)—4—methylpyrimidine—5—carboxylic acid (28.0 g, 95.0% yield) as a white solid. The title compound was prepared by the procedure of Example 1, replacing 1—(4—(tert-butyl)ph enyl)—6—oxo—1,6—dihydropyridazine—4—carboxylic acid with 2-(4-isopropoxyph enyl)-4methylpyrimidine-5-carboxylic.1H NMR (400 MHz, MeOH - di)·. δ (ppm) 8.82 (brs, 1H), 8.35 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 6.90 (d , J = 8.0 Hz, 1H), 6.86 - 6.76 (m, 2H), 6.59 (br s, 1H), 6.45 (s, 1H), 5.27 - 5.16 (m, 1H), 4.75-4.66 (m, 2H ), 4.65-4.45 (m, 2H), 4.37 -4.19 (m, 1H), 4.17 - 4.00 (m, 5H), 3.71 - 3.54 (m, 1H), 3.50 - 3.44 (m, 1H), 3.42 - 3.35 (m, 1H), 3.29 - 3.09 (m, 5H), 3.06 (s, 3H), 2.69 (s, 3H), 1.33 - 1.38 (m, 9H), LCMS (Method 5-95 AB, ESI): Rt = 0.609 min, [M+H]+= 996.7. Example 15: IVIA / t / ZUZZ / U I O / □ I Step 1: A mixture of 4,4,5,5-tetramethyl-2-(4-(1-methylcyclopropyl)phenyl)-1,3,2-dioxaborolane (4.67 g, 18.1 mmol), ethyl 2-chloro ^4-methylpyrimidin-5-carboxylate (3.30 g, 16.5 mmol), sodium carbonate (3.49 g, 32.9 mmol) and Pd(dppf)Cl2 (1.20 g, 1.64 mmol) in water (3 mL ) and 1,4-dioxane (30 mL) was heated at 100°C for 16 h in a nitrogen atmosphere. The reaction was cooled to room temperature, and the reaction mixture was diluted with ethyl acetate (300 mL) and filtered. The filtrate was washed with water (100 mL), brine (50 mL), dried and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to obtain ethyl 4,6-dimethyl-2-(4-(1-methyl). lcyclopropyl)phenyl)pyrimidin-5-carboxylate (2.10 g, 43.1% yield) as a white solid. Step 2: A mixture of ethyl 4,6-dimethyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidine-5-carboxylate (2.10 g, 7.09 mmol) and sodium hydroxide (567 mg, 14.2 mmol) in MeOH (30 mL) and water (3 mL) was stirred at 80°C for 4 h and concentrated. The aqueous residue was adjusted to pH = 5 with 1M HCl and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried, and concentrated. The crude product was recrystallized with 10% ethyl acetate in petroleum ether (10 mL) to obtain 4,6—dimethyl-2-(4-(1-methylcylclopropyl)phenyl)pyrim acid. ¡din¡n-5-carboxylic (1.10 g, 55% yield) as a white solid. The title compound was prepared by the procedure of Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine—4-carboxylic acid with 4,6—dimethyl— 2-(4-(1methylcyclopropyl)phenyl)pyrimidine—5-carboxylic.1H NMR (400 MHz, DMSO-cfe): δ (ppm) 8.27 (d, J = 8.4H, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.17-7.06 (m, 1H), 7.04 - 6.90 (m, 1H), 6.87 -6.70 (m, 2H), 6.44 (s, 1H), 6.30 (m, 1H), 5.39 - 5.05 (m, 1H), 4.75 - 4.58 (m, 1H), 4.48 - 4.35 (m, 1H), 4.18 - 3.90 (m, 6H), 3.31 3.13 (m, 3H) ), 3.06- 2.95 (m, 5H), 2.93 -2.64 (m, 3H), 2.44 (s, 6H), 1.42 (s, 3H), 1.21 (d, J = 6.4 Hz, 3H), 0.93 - 0.86 ( m, 2H), 0.85 - 0.77 (m, 2H), LCMS (Method 5-95 AB, ESI): Rt = 0.631 min, [M+H]+= 1006.3. Example 16: IVIA / t / ZUZZ / U I 0 / 0 I 3 5 Step 1: To a solution of 4-bromophenol (14.3 g, 86.7 mmol) in DMF (100 mL), 1-bromo-3,3-dimethylbutane (10.0 g, 57.8 mmol) and potassium carbonate (20.0 g, 145 mmol) were added. . The reaction mixture was stirred at 50°C for 16 h. The reaction was cooled to room temperature, and the mixture was diluted with ethyl acetate (500 mL) and filtered. The filtrate was washed with brine (400 mL) and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0%-2% ethyl acetate in petroleum ether) to obtain 1-bromo^t-(3,3-dimethylbutoxy)benzene (14.5 g, 97.5% yield) as a white solid. Step 2: A mixture of 1-bromo-4-(3,3-dimethylbutoxy)benzene (10.0 g, 38.9 mmol), bis(pinacolato)diboron (10.4 g, 40.8 mmol), potassium acetate (11.5 g, 116.7 mmol ) and Pd(dppf)2Cl2 (2.85 g, 3.89 mmol) in DMF (100 mL) was heated at 80°C for 16 h under a nitrogen atmosphere and filtered. The filtrate was diluted with water (500 mL) and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (500 mL), dried, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 2% ethyl acetate in petroleum ether) to obtain 2—(4—(3,3—dimethylbutoxyphenyl)—4,4,5, 5-tetramethyl—1,3,2— dioxaborolane (16.0 g, 52.6 mmol) as a colorless oil. Step 3: A mixture of 2-(4-(3,3-dimethylbutox¡)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.00 g, 3.29 mmol), ethyl 2- chloro-4-methylpyrmidin-5-carboxylate (692 mg, 3.45 mmol), sodium carbonate (697 mg, 6.57 mmol) and Pd(dppf) Ola (240 mg, 0.33 mmol) in water (1 mL) and 1,4-dioxane (10 mL) was heated at 100°C for 16 h under a nitrogen atmosphere, and diluted with ethyl acetate (100 mL). The resulting mixture was filtered, and the filtrate was washed with water (2 x 40 mL), brine (50 mL), dried, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-2% ethyl acetate in petroleum ether) to obtain ethyl 2-(4-(3,3-dimethylbutoxy¡)phenyl )^4methylpyrimidine-5-carboxylate (460 mg, 40.9% yield) as a colorless oil. Step 4: A mixture of ethyl 2-(4-(3,3-dimethylbutoxyphenyl)-4-methylpyrimidine-5-carboxylate (460 mg, 1.34 mmol) and sodium hydroxide (269 mg, 6.72 mmol) in MeOH (10 mL ) and water (10 mL) was stirred at 80°C for 16 h and concentrated. The aqueous residue was adjusted to pH = 5 with 1M HCl and filtered. The filter cake was dried to obtain 2-(4-( Crude 3,3-dimethylbutoxyphenyl)-4-methylpyrmidine-5-carboxylic acid (400 mg, 94.7% yield) as a white solid. The title compound was prepared by the procedure of Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazin-4-carboxylic acid with 2 -(4-(3,3—dimethylb utoxy)phenyl)— 4-methylp¡r¡m¡dine-5-carboxylic.1H NMR (400 MHz, MeOH-ck): δ (ppm) 8.80 (s, 1H), 8.27 (d, J = 8.8 Hz, 2H), 7.06 - 7.05 (m, 1 H), 6.93 (d, J= 8.8 Hz, 2H), 6.85 - 6.86 (m, 1H), 6.69 -6.66 ( m, 2H), 6.49 (s, 1H), 6.37 (s, 1H), 5.23 - 5.21 (m, 1H), 4.55 - 4.50 (m, 2H), 4.23 - 4.05 (m, 1H), 3.60 - 3.58 (m, 1H), 3.50 3.38 (m, 1H), 3.26 -3.24 (m, 2H), 3.17 - 3.11 (m, 2H), 3.18-2.99 (m, 4H), 2.64 (s, 3H), 1.76 - 1.70 (m, 2H), 1.35 (d, J = 6.4 Hz, 3H), 0.99 (s, 9H). LCMS (Method 5-95 AB, ESI): Rt = 0.844 min, [M+H]+= ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ 1037.4. IVIA / t / ZUZZ / U I O / Ο I Step 1: To a solution of compound 10 (200 mg, 0.19 mmol) and a drop of NH3H2O ​​in ethanol (15 mL), 10% of Pd / C (60.6 mg, 0.06 mmol) was added. The reaction mixture was stirred at 30°C under H2 atmosphere (0.10 MPa (15 psi)) for 2 h, and filtered. The filtrate was concentrated to obtain crude compound 11 (174 mg, 100% yield) as a white solid. Step 2: To a solution of compound 11 (174 mg, 0.19 mmol) in dichloromethane (10 mL), DIEA (0.13 mL, 0.76 mmol) and acid (S)-2-(((benzyloxy)carbon¡l)am were added. ¡no)^l-((tertbutoxycarbonyl)amino)butano¡co (134 mg, 0.38 mmol) at 0°C, followed by a solution of HATU (86.8 mg, 0.23 mmol) in DMF (1 mL). The mixture was stirred at 20°C for 2 h and quenched with MeOH (0.5 mL). The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried, and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 5% MeOH in dichloromethane) to obtain compound 19 (200 mg, 83.8% yield) as a white solid. Step 3: To a solution of compound 19 (200 mg, 0.16 mmol) and a drop of ammonium hydroxide in ethanol (15 mL) 10% of Pd / C (76.4 mg, 0.07 mmol) was added. The reaction mixture was stirred at 40°C under H2 atmosphere (0.10 MPa (15 psi)) for 6 h and filtered. The filtrate was concentrated to obtain crude compound 20 (178 mg, 100% yield) as a white solid. ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ Step 1: A mixture of 6-oxo-1,6-dihydropyridazine-4-carboxylic acid (2.00 g, 14.3 mmol) and HCl (4 M in MeOH, 15.0 mL, 60.0 mmol) was stirred at 25°C for 24 h and he concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 30%-60% ethyl acetate in petroleum ether) to obtain methyl 6-oxo-1,6-dihydro¡ridaz n-4-carboxylate (1.00 g, 45.5% yield) as a white solid. Step 2: A mixture of (4-(tert-butyl)phenyl)boronic acid (118 mg, 0.65 mmol), methyl 6-oxo-1,6d¡hydro¡r¡dazín-4-carboxylate (500 mg, 3.24 mmol), copper(II) acetate (24 mg, 0.13 mmol)) and pyridine (2 mL) in dichloromethane (10 mL) were stirred at 25°C for 24 h and concentrated. The residue was diluted with ethyl acetate (80 mL) and washed with brine (2 x 30 mL), dried and concentrated. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 33% ethyl acetate in petroleum ether) to obtain methyl 1-(4-(tert-butyl)phenyl)—6-oxo- 1,6-dihydropyridazine—4-carboxylate (770 mg, 82.9% yield) as a white solid. Step 3: A mixture of methyl 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylate (770 mg, 2.69 mmol) and lithium hydroxide hydrate (247 mg, 10.8 mmol) in THF (10 mL) and water (2 mL) was stirred for 2 h at 25°C and concentrated. The residue was adjusted to pH = 3 with 1M HCl and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried and concentrated to obtain 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid (730 mg, 99.7% yield) as a solid. white. The title compound was prepared by the procedure of Example 1, replacing compound 14 with compound 20.1H NMR (400 MHz, DMSO-de): δ (ppm) 8.43 (s, 1H), 8.38 - 8.28 (m, 2H ), 8.14 - 8.07 (m, 1H), 7.60 - 7.44 (m, 5H), 7.10 - 7.04 (m, 1H), 6.93 - 6.91 (m, 1H), 6.78 (s, 2H), 6.35 (s, 1H ), 6.24 (s, 1H), 5.05-4.94 (m, 1 H), 4.67-4.65 (m, 3H), 4.35 (s, 1H), 4.12 -3.93 (m, 11 H), 3.3 -3.27 (m , 2H), 3.17-3.10 (m, 3H), 2.99 - 2.97 (m, 4H), 2.80 (s, 4H), 2.67-2.64 (m, 1 H), 2.12-2.03 (m, 2H), 1.33 - 1.28 (m, 9H), 1.17-1.00 (m, 3H). LCMS (Method 5-95 AB, ESI): Rt = 0.797 min, [M+H]+= 929.4. MA / E / ZUZZ / UI Heard ΟΊ Example 18: The title compound was prepared from compound 20 by the procedure of Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dih¡drop¡r¡dazin-4 acid -carboxylic with 4-amino-2-(4-(isopentylox¡)phen¡l)-6-methylpyr¡mid¡n-5-carboxylic acid.1H NMR (400 MHz, ΜβΟΗ-04) δ (ppm) 8.41 (s, 1H), 8.23 ​​(d, J = 8.8 Hz, 2H), 7.18 - 7.04 (m, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.93 - 6.87 (m, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.60 (s, 1H), 6.46 (s, 1H), 4.87 - 4.73 (m, 2H), 4.52 - 4.41 (m, 1H) , 4.24 - 4.01 (m, 8H), 3.27 - 2.97 (m, 11H), 2.45 (s, 3H), 2.31 -2.11 (m, 2H), 1.75 (t, J = 6.8 Hz, 2H), 1.34 (d , J = 6.8 Hz, 3H), 1.02 (s, 9H). LCMS (Method 5-95 AB, ESI): Rt = 0.767 min, [M+H]+= 987.8. Example 19: The title compound was prepared from compound 20 by the procedure of Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine—4-carboxylic acid with 2— (4—(tert-butyl)phenyl)—4,6—dimethylpyrimidine—5—carboxylic.1H NMR (400 MHz, MeOH-ck) δ (ppm) 8.34 (s, 1H), 8.28 (d, J= 8.4 Hz , 2H), 7.48 (d, J= 8.8 Hz, 2H), 7.02 (d, J=8.0 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.81 -6.80 (m, 1 H), 6.66 (s, 1H), 6.55 (s, 1H), 6.56 (s, 1H), 5.21 -5.18 (m, 1H), 4.81 -4.76 (m, 1H), 4.41 -4.39 (m, 1H), 4.24- 4.06 (m, 6H), 3.27-3.22 (m, 2H), 3.19-3.12 (m, 4H), 3.10-3.07 (m, 1H), 3.03 (s, 3H), 2.99 - 2.95 (m, 1H) , 2.51 (s, 6H), 2.30 - 2.17 (m, 2H), 1.37 (s, 9H), 1.34 (d, J = 6.8 Hz, 3H). LCMS (Method 5-95 AB, ESI): Rt= 0.622 min, [M+H]+= 942.4. Example 20: OH NH2 The title compound was prepared from compound 20 by the procedure of Example 1 by replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 2—(4—isopropoxyphenyl)—4—methylpyrimidine—5—carboxylic.1H NMR (400 MHz, MeOH-ck): δ (ppm) 8.89 (s, 1H), 8.23 ​​(d, J = 8.8 Hz, 2H), 7.05 -6.92 (m, 4H), 6.87-6.82 (m, 1 H), 6.66 (s, 1 H), 6.51 (s, 1 H), 6.42 (s, 1 H), 5.20-5.11 (m, 1H) ), 4.83-4.72 (m, 2H), 4.69 - 4.59 (m, 1H), 4.40 - 4.03 (m, 6H), 3.40-3.32 (m, 1H), 3.29 - 3.07 (m, 6H), 2.99 (s, 3H), 2.97 - 2.80 (m, 1H), 2.70 (s, 12H), 2.68 (s, 3H), 2.39 - 2.15 (m, 2H), 1.47 - 1.30 (m, 9H), LCMS ( Method 5-95 AB, ESI): Rt = 0.732 min, [M+H]+= 930.7. Example 21: MA / E / ZUZZ / U1D / O1 The title compound was prepared from compound 20 by the procedure of Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4- amino-6-methyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidin-5-carboxylic.1H NMR (400 MHz, ΜβΟΗ-Λ): δ (ppm) 8.36 (s, 1H), 8.18-8.1 5 (m, 2H), 7.33-7.31 (m, 2H), 7.11 (s, 1H), 6.93-6.91 (m, 1 H), 6.86-6.81 ( m, 2H), 6.58 - 6.46 (m, 3H), 5.04 - 5.03 (m, 1H), 4.82 (s, 2H), 4.54 (s, 1H), 4.22 - 4.05 (m, 6H), 3.18 2.98 (m , 10H), 2.46 (s, 3H), 2.25 - 2.18 (m, 2H), 1.44 (s, 3H), 1.34 (d, J = 6.4 HZ, 2H), 0.93 - 0.91 (m, 2H), 0.82 - 0.80 (m, 2H). LCMS (Method 5-95 AB, ESI): Rt = 0.58 min, [M+H]+= 941.5. Example 22: The title compound was prepared from compound 20 by the procedure of Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazin-4 acid -carboxylic acid with 1-(4-(3,3dimethylbutoxyphenyl)—6—oxo—1,6—dihydropyridazine—4—carboxylic acid.1H NMR (400 MHz, MeOH-ck): δ (ppm) 8.08 (s, 1H), 7.45 -6.85 (m, 9H), 6.60 (s, 1H), 6.31 (s, 1H), 5.03 -5.01 (m, 1H), 4.74 -4.71 (m, 1H), 4.37 (s, 1H) , 4.25 (s, 1H), 4.11 - 4.06 (m, 4H), 3.91 - 3.90 (m, 1H), 3.38 - 3.31 (m, 3H), 3.30 - 3.12 (m, 3H), 2.99 - 2.90 (m, 7H), 2.18 (s, 2H), 1.76 - 1.73 (m, 2H), 1.37 - 1.35 (m, 3H), 1.02 (s, 2H), LCMS (Method 5-95 AB, ESI): Rt = 0.660 min , [M+H]+= 974.6. ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ Example 23: The title compound was prepared from compound 20 by the procedure of Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 2— (4—(tert—butyl)f enyl)^4—methylpyrimidine—5—carboxylic.1H NMR (400 MHz, MeOH-ck): δ (ppm) 8.72 (s, 1H), 8.34 (m, 1H), 8.26 -8.24 (d, J = 8.0Hz, 1H), 7.47-7.45 (d, J = 8.0Hz, 2H), 6.92-6.91 (d, J= 4.0Hz, 1H), 6.81 - 6.79 (d, J = 8.0 Hz, 2H), 6.61 (s, 1 H), 6.47 (s, 2H), 5.10 - 5.09 (m, 1 H), 4.80 - 4.76 (m, 2H), 4.48 4.46 (m, 1H), 4.29- 4.27 (d, J = 8.0 Hz, 1H), 4.18-4.12 (m, 4H), 4.03- 4.02 (d, J= 4.0Hz, 1H), 3.26 (s, 1H), 3.20 - 3.15 (m, 4H), 3.10 - 3.14 (m, 1H), 2.97 (s, 3H), 2.92 - 2.89 (d, J = 12.0Hz, 1H), 2.76 - 2.67 (m, 1H), 2.62-2.60 (m, 3H), 2.29 - 2.23 (m, 3H), 1.35- 1.32 (m, 12H). LCMS (Method 5-95 AB, ESI): Rt = 0.769 min, [M+H]+ = 928.8. Example 24: 100 The title compound was prepared from compound 20 by the procedure of Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4- amino-2-(4-(tert-butyl)phenyl)-6-methylpyrimidine-5-carboxylic acid.1H NMR (400 MHz, MeOH-oú): δ (ppm) 8.24 ( s, 1H), 8.23 ​​- 8.17 (m, 2H), 7.54 - 7.48 (m, 1H), 7.21 - 7.14 (m, 1H), 7.02 - 6.92 (m, 1H), 6.88 (s, 1H), 6.85 ( s, 1H), 6.59 (s, 1H), 6.45 (s, 1H), 5.30-5.01 (m, 1 H), 4.83-4.79 (m, 2H), 4.66-4.52 (m, 1H), 4.25- 4.04 (m, 6H), 3.25 -2.99 (m, 10H), 2.52-2.43 (m, 3H), 2.33 -2.08 (m, 2H), 1.40 - 1.33 (s, 12H). LCMS (Method 5-95 AB, ESI): Rt = 0.592 min, [M+H]+ = 943.4. ΜΛ / Ε / ZUZZ / Ul 0 / Ol Example 25: The title compound was prepared from compound 20 by the procedure of Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4- ami no-2- (4-(tert-butyl)piper¡din-1 -yl)- 6-methylpyrimidine-5-carboxylic.1H NMR (400 MHz, MeOH-c / 4): δ (ppm) 7.27 - 7.21 (m, 1H), 7.04 (d, J = 8 Hz, 1H), 6.92 - 6.87 (m, 2H), 6.55 (m, 1H), 6.38 (s, 1H), 5.04 5.01 (m, 1H) , 4.72 (m, 2H), 4.28 - 4.07 (m, 6H), 3.52 - 3.34 (m, 2H), 3.31 - 3.04 (m, 8H), 2.99 (s, 3H), 2.95 -2.86 (m, 2H) , 2.40 (s, 3H), 2.28 - 2.12 (m, 2H), 1.85 (m, 2H), 1.44 - 1.33 (m, 4H), 1.30 - 1.19 (m, 2H), 0.92 (s, 9H). LCMS (Method 5-95 AB, ESI): Rt = 0.731 min, [M / 2 + H]+= 479.5. Example 26: 101 The title compound was prepared from compound 20 by the procedure of Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 1- (4—(cylohexyloxyXenyl)—6—oxo—1,6—dihydropyridazine—4—carboxylic.1H NMR (400 MHz, MeOH-ck): δ (ppm) 8.34 - 8.14 (m, 1H), 7.48 -7.33 (m , 1H), 7.19-6.62 (m, 9H), 6.35 -6.30 (m, 1H), 5.01 -4.90 (m, 1H), 4.73 - 4.71 (m, 1H), 4.37 - 3.92 (m, 7H), 3.36 - 3.30 (m, 4H), 3.18 - 2.91 (m, 9H), 2.28 - 2.18 (m, 2H), 2.18-1.98 (m, 2H), 1.82 - 1.80 (m, 2H), 1.55- 1.43 (m, 6H), 1.36 - 1.35 (m, 3H).LCMS (Method 595 AB, ESI): Rt = 0.696 min, [M / 2 + H]+= 485.9. Example 27: The title compound was prepared from compound 20 by the procedure of Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 2- (4-(3,3-dimethylbutoxy)phenyl)-4-methylpyrimidine-5-carboxylic.1H NMR (400 MHz, MeOH-ck): δ (ppm) 8.79 (s, 1 H), 8.37 (d, J = 8.4 Hz, 2H), 7.07 - 7.00 (m, 3H), 6.87 - 6.83 (m, 2H), 6.72 (s, 1H), 6.58 (s, 1H), 6.47 (s, 1H), 4.84- 4.83 (m, 2H), 4.41 (s, 1H), 4.27- 4.03 (m, 8H), 3.32- 2.99 (m, 11H), 2.74 -2.68 (m, 3H), 2.32-2.19 (m, 2H), 1.78- 1.75 (m, 2H), 1.39-1.34 (m, 3H), 1.04 (s, 9H). LCMS (Method 5-95 AB, ESI): Rt = 0.825 min, [M+H]+= 973.0. Example 28: 102 The title compound was prepared from compound 20 by the procedure of Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4- methyl-2-(4-(1-methylcyclopropyl)phenyl)pyrimidine-5-carboxylic.1H NMR (400 MHz, MeOH-ck): δ (ppm) 8.79 (s, 1H), 8.20 ( d, J= 8.4 Hz, 2H), 7.31 (d, J= 8.4 Hz, 2 H), 7.00- 6.80 (m, 3 H), 6.88 (s, 1H), 6.44 (s, 1 H), 6.40 ( s, 1H), 5.18 - 5.10 (m, 1H), 4.84 - 4.71 (m, 1H), 4.65 - 4.53 (m, 1H), 4.37 - 4.30 (m, 1H), 4.28 - 4.17(m, 2H) ), 4.16 - 3.97 (m, 3H), 3.27 - 3.08 (m, 6H), 3.06 - 2.73 (m, 5H), 2.70 (s, 12H), 2.62 (s, IVIA / t / ZUZZ / U I 0 / 0 I 3H), 2.37 - 2.15 (m, 2H), 1.47 (s, 3H), 1.37 (d, J = 6.8 Hz, 3H), 1.02 - 0.92 (m, 2H), 0.91 - 0.82 (m, 2H), LCMS (Method 5-95 AB, ESI): Rt = 0.763 min, [M+H]+ = 926.3. Step 1: A mixture of 4,4,5,5-tetramethyl-2-(4-(1-methylcyclopropyl)phenyl)-1,3,2-dioxaborolane (8.0 g, 31.0 mmol ), sodium periodate (33.1 g, 155 mmol) and ammonium acetate (11.9 g, 155 mmol) in acetone (80 mL) and water (80 mL) were stirred at 25°C for 16 h and filtered. The filtrate was concentrated, and the aqueous residue was extracted with ethyl acetate (2 x 150 mL). The combined organic layers were concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 103 25% ethyl acetate in petroleum ether) to obtain (4-(1-methylcyclopropyl)phenyl)boronic acid (5.4 g, 99.0% yield) as a white solid. Step 2: A mixture of (4-(1-methylcyclopropyl)phenyl)boronic acid (1.00 g, 5.68 mmol), copper (II) acetate (0.21 g, 1.14 mmol), methyl 6-oxo-1,6-d Hydropyridazin-4-carboxylate (0.92 g, 5.97 mmol) in dichloromethane (10 mL) and pyridine (1 mL) was stirred at 25°C for 16 h. The mixture was diluted with 1M HCl (50 mL) and then extracted with dichloromethane (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried, and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-25% ethyl acetate in petroleum ether) to obtain methyl 1-(4-(1-methylcyclopropyl)phen. l)-6-oxo-1,6-d¡hydro¡r¡dazín-4-carboxylate (1.00 g, 61.7%) as a yellow solid. Step 3: A mixture of methyl 1-(4-(1-methylcyclopropyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylate (6.0 g, 21.1 mmol) and sodium hydroxide (2.1 g, 52.76 mmol ) in MeOH (50 mL) and water (20 mL) was heated at 80°C for 2 h and concentrated. The aqueous residue was adjusted to pH = 5 with 1N HCl and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (200 mL), dried and concentrated to obtain 1-(4-(1-methylcyclopropyl)phenyl)-6-oxo-1,6dihydropyridazine-4-carboxylic acid (5.30 g). , 92.9% yield) as a light yellow solid. The title compound was prepared from compound 20 by the procedure of Example 1, replacing 1-(4-(tert-butyl)phenyl)—6-oxo-1,6-dihydropyridazine—4-carboxylic acid with 1- (4-(1-methylcyclopropyl)phenyl)-6-oxo-1,6-dihydropyridazin-4-carboxylic.1H NMR (400 MHz, MeOH-Ó4): δ (ppm)8.32 (d, J= 2.0 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1 H), 7.39-7.32 (m, 4H), 7.15-7.13 (m, 1H), 7.027.00 (m, 1H), 6.90 (s, 1H), 6.68 (s, 1H), 6.50 (s, 1H), 6.41 (s, 1H), 4.87 -4.78 (m, 2H), 4.36 - 4.34 (m, 1H), 4.20-4.04 (m, 6H), 3.37-3.30 (m, 3H), 3.21 -3.05 (m, 5H), 2.87 (s, 3H), 2.71 (s, 12H), 3.33 -3.21 (m, 2H), 1.43 (s, 3H) , 1.37 (d, J = 6.8 Hz, 3H), 0.91 - 0.88 (m, 2H), 0.81 - 0.78 (m, 2H). LCMS (Method 5-95 AB, ESI): Rt = 0.739 min, [M+H]+= 928.4. ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ Example 30: The title compound was prepared by the procedure of Example 22, replacing (S)-2-(((benzylox¡)carbon¡l)amino)-4-((tert-butoxycarbon¡l)amino acid) butanoic acid with (S)-2(((benzyloxy¡)carbon¡l)amino)-3-((tert-butoxy¡carbon¡l)amino)propanoic acid and then by the Procedure 104 general B, replacing 1—(4—(tert—butyl)phenyl)—6—oxo—1,6—dihydropyridazine—4—carboxylic acid with 2—(4—(tert—butyl)phenyl)^4,6 acid —dimethylpyrimidine—5—carboxylic.1H NMR (400 MHz, MeOH-ck): δ (ppm) 8.43 (s, 1H), 8.33 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.0 Hz, 1H), 6.88 (d, J= 8.4 Hz, 1H), 6.83 (s, 1H), 6.76 (s, 1H), 6.61 (s, 1H), 6.39 ( s, 1H), 5.33 -5.30 (m, 1H), 4.38-4.36 (m, 2H), 4.21 - 4.03 (m, 2H), 3.49 - 3.44 (m, 6H), 3.26 - 2.96 (m, 10H) , 2.57 (s, 6H), 1.38 (s, 9H), 1.34 (d, J = 6.8 Hz, 3H). LCMS (Method 5-95 AB, ESI), Rt = 0.611 min, [M+H]+= 928.5. Example 31: The title compound was prepared by the procedure of Example 22, replacing acid (S)-2-(((benzylox¡)carbon¡l)amino)-4-((tert-butoxy¡carbon¡l)am¡ no)butanoic acid with (S)-2(((benzyloxy¡)carbon¡l)amino)-3-((tert-butoxy¡carbon¡l)amino)propanoic acid and then by General Procedure B, replacing 1-(4-(tert-butyl)phen¡l)-6-oxo-1,6-d¡hydro¡r¡dazín-4-carboxylic acid with 2-(4-( tert-butyl)phenyl)—4-methylpyrimidine-5-carboxylic.1H NMR (400 MHz, MeOH - da): δ (ppm) 8.91 (s, 1H), 8.35 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.08 - 7.00 (m, 1H), 6.96 - 6.80 (m, 2H), 6.71 6.60 (m, 1H), 6.54 (s, 1H), 6.41 - 6.27 (m , 1 H), 5.50 - 5.25 (m, 1 H), 4.76 - 4.58 (m, 1 H), 4.54 - 4.41 (m, 1H), 4.26 - 3.95 (m, 6H), 3.57 - 3.48 (m, 1H), 3.41 - 3.35 (m, 1H), 3.28 - 2.84 (m, 9H), 2.71 - 2.66 (m, 3H), 1.42 -1.30 (m, 12H). LCMS (Method 5-95 AB, ESI): Rt = 0.770 min, [M+H]+= 914.8. Example 32: 105 ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ the synthesis of 4-amino-2-(4-tert-butylphen¡l)-6The general procedure for (difluoromethyl)pyrimidine-5-carbonitrile was carried out by the procedures of Chem. Eur. J. 2018, 24, 1311-1316. Step 1: A solution of boron trifluoride diethyl etherate (2.68 mL, 21.71 mmol, 1.05 equiv) in acetonitrile (19.2 mL) was stirred for 15 min in N2 at -30°C. 1,1,2,2-Tetrafluoro-N,N-dimethylethanamine (3.0 g, 20.68 mmol, 1.0 equiv) in acetonitrile (27 mL) was added, and the mixture was stirred for 5 min. The reaction was brought back to room temperature. A solution of malononitrile (1.37 g, 20.68 mmol, 1.0 equiv) in dry acetonitrile (19.2 mL) was added to the solution under an inert atmosphere at 25°C, quickly followed by Ν,Ν-diisopropylethylamine (5.4 mL, 31.01 mmol, 1.5 equiv). The mixture was stirred for 2 h. The reaction was quenched by the addition of silica gel. The solution was concentrated under reduced pressure to obtain a yellow solid residue, which was purified by column chromatography (silica gel, 100-200 mesh, 10-50% EtOAc in heptanes) to obtain 2-[1(dimethylam ¡no)-2,2-difluoro-ethylidene]propandinitrile (1.68 g, 9.816 mmol, 48% yield) as a yellow solid. Step 2: 2-[1-(dimethylamino)-2,2-difluoro—ethylidene]propandinitrile (150 mg, 0.8800 mmol, 1.0 equiv) and (4-tert-butylbenzenecarboxydoyl)ammonium chloride (372.87 mg, 1.75 mmol, 2.0 equiv) were dissolved in absolute ethanol (2.9214 mL, 0.3 M) and capped in a microwave vial. The reaction was heated to 70°C under microwave irradiation, and stirred for 30 minutes. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude reaction mixture was then purified by flash chromatography (silica gel, 100-200 mesh, 0-50% EtOAc in heptanes) to obtain 4—amino—2—(4—tert—butylphenyl)—6—( difluoromethyl)pyrimidin—5—carbonitrile (175 mg, 0.5789 mmol, 66% yield) as a white solid. Step 3: 4—amino—2—(4—tert—butylphenyl)—6—(difluoromethyl)pyrimidin—5—carbonitrile (160 mg, 0.5300 mmol, 1.0 equiv) was dissolved in absolute EtOH (2.6 mL). A 4 M aqueous potassium hydroxide solution (0.66 mL, 2.65 mmol, 5.0 equiv) was added, and the reaction mixture was heated to 70 °C for 18 h. 106 The reaction mixture was cooled to room temperature, a 1 N KHSO4 solution was added, and the reaction mixture was diluted with EtOAc (20 mL). The phases were separated, and the aqueous layer was extracted with EtOAc (2 x 20 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain 4-amino-2-(4(tert-butyl)phenyl)-6 acid. —(difluoromethyl)pyrimidine-5-carboxylic acid as a yellow solid (170 mg, 0.53 mmol, 99% crude yield), which was used without further purification. The title compound was prepared from compound 20 by the procedure of Example 1, replacing 1-(4-(tert-butyl)phen¡l)-6-oxo-1,6-dihydrop¡r acid dazín-4-carboxylic acid with 4-amino-2-(4-(tert-butyl)phenyl)-6-(difluoroDmethyl)pyramidal acid 5-carboxylic.1H NMR (400MHz, DMSO - de) δ (ppm) 9.25 (d, 5.6 Hz, 1 H), 8.85 (d, J=8.1 Hz, 1 H), 8.32 (d, J=7 .Q Hz, 1H), 8.21 (d, J=8.6 Hz, 2H), 7.52 (d, J=8.7 Hz, 2H), 7.19 (dd, J=8.6, 2.2 Hz, 1H), 7.01 (d, J =8.6 Hz, 1H), 6.83 (s, 1H), 6.73 (s, 1H), 6.66-6.75 (m, 2H), 6.26-6.33 (m, 2H), 4.80 (m, 1H), 4.73-4.60 ( m, 2H), 4.08-3.88 (m, 6H), 3.28 (d, J=15.1 Hz, 1H), 3.03-2.78 (m, 11H), 2.35 (s, 3H), 2.09-1.99 (m, 1H) , 1.97-1.86 (m, 1H), 1.29 (s, 9H), 1.17 (d, J=6.7 Hz, 3H). LCMS (Method 5-100 AB, 6 min): Rt=1.66 min, [M+H]+= 979.3. Example 33: ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ The title compound was prepared as described in Example 1, replacing 1—(4—(tert—butyl)phenyl)—6—oxo—1,6—d ihyd ropyridazine—4—carboxylic acid with 4-amino acid -2-(2-fluoro-4-(terpentyl)phenyl)—6—methylpyrimidine—5—carboxylic.1H NMR (400MHz, MeOH - d4) δ (ppm) 8.49 (s, 1 H), 7.77 7.73 (m, 1H), 7.29 - 7.27 (m, 1H), 7.20 - 7.05 (m, 3H), 6.86 - 6.77 (m, 2H), 6.61 - 6.48 (m, 2H), 5.30 5.20 (m, 1H), 4.36- 4.14 (m, 8H), 3.63 - 3.60 (m, 1H), 3.40 - 3.36 (m, 1H), 3.21 - 3.01 (m, 9H), 2.48 (s, 3H), 1.74 - 1.71 (m, 2H), 1.33 (s, 9H), 0.74 - 0.70 (m, 3H). LCMS (Method 5-95 AB, ESI): Rt = 0.752 min, [M+H]+= 1040.5. 107 Example 34 nh2 ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ 4-Amino-2-(4-(cyclopropylmethyl)phenyl)-6-methylpyrmidin-5-carboxylic acid was prepared as described in Example 54, replacing 2-(3,3-dimethylbutoxy)-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyridine with 2-(4 -(cyclopropylmethyl)phenyl)—4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The title compound was prepared as described in Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2- (4—(cyclopropylmethyl)phenyl)—6—methylpyrimidine-5-carboxylic.1H NMR (400MHz, MeOH - ck) δ (ppm) 8.18 (d, J = 7.6 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.12 - 7.04 (m, 1H), 6.90 - 6.74 (m, 3H), 6.59 (s, 1H), 6.52 -6.42 (m, 1H), 5.22 - 5.13 (m, 1H), 4.82 - 4.80 (m, 2H), 4.27-3.91 (m, 6H), 3.63 -3.54 (m, 1 H), 3.25-3.14 (m, 3H), 3.06 (s, 3H), 3.03 -2.95 (m, 2H ), 2.59 (d, J= 6.8 Hz, 2H), 2.47 (s, 3H), 1.40 - 1.29 (m, 3H), 1.07 -0.95 (s, 1H), 0.57-0.50 (m, 2H), 0.26- 0.19 (m, 2H) ppm, LCMS (Method 5-95 AB, ESI): Rt = 0.750 min, [M+H]+= 1006.3. Example 35 2-Amino-6-(4-(tert-butyl)-2-fluorophenyl)-4-methylnicotinic acid was produced by an approach similar to the procedure used to prepare 2-amino-6 acid. —(4-(tert-butyl)phenyl)-4-methylnicotinic acid described in WO2017084630, the contents of which are incorporated herein by reference in 108 its entirety. The title compound was prepared as a salt of formic acid as described in Example 1, replacing 1-(4-(fer-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 2—amino—6—(4—(fer—butyl)—2—fluorophenyl)—4—methylnicotinic.1H NMR (400MHz, MeOH - d4) δ (ppm) 8.38 (s, 2H), 7.70 - 7.68 (m, 1H), 7.30 - 7.18 (m, 2H), 7.03 - 6.55 (m, 6H), 5.21 (m, 1H), 4.39 - 3.99 (m, 8H), 3.62 - 3.38 (m, 3H), 3.18 - 2.86 (m, 9H), 2.32 - 2.28 (m, 3H), 1.35 (s, 12H), LCMS (Method 5-95 AB, ESI): Rt = 0.783 min, [M+H]+ = 1025.5. Example 36 ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ The title compound was prepared as described in Example 1, replacing 1—(4—(tert-butyl)phenyl)-6-oxo-1,6-d ihyd ropyridazine^t-carboxylic acid with 4-amino acid -2-(4-butylphenyl)-6methylpyrimidine-5-carboxylic.1H NMR (400MHz, MeOH -Ó4) 8.45 (s, 1H), 8.14 (d, J = 8.4 Hz 1 H), 7.28 (d, J = 8.4 Hz 1H), 7.12 - 7.10 (m, 1H), 6.91 - 6.86 (m, 2H), 6.79 (s, 1H), 6.59 (s, 1H), 6.44 (s, 1H), 5.19 5.16 (m, 1H) ), 4.32 - 4.04 (m, 7H), 3.64 - 3.59 (m, 1 H), 3.23 - 3.07 (m, 1 OH), 2.69 - 2.65 (m, 3H), 2.47 (s, 3H), 1.38 - 1.35 (m, 5H), 0.97 - 0.93 (m, 3H), LCMS (Method 5-95 AB, ESI): Rt =0.781 min, [M+H]+= 1008.5. Example 37 109 The general procedure for the synthesis of methyl 6—(4—(fer—butyl)phenyl)—4—chloronicotinate was carried out using the procedures of J. Med. Chem. 2013, 56, 1023-1040. Step 1: Methyl 4,6-dichloropyridine-3-carboxylate (3072 mg, 14.91 mmol, 1.05 equiv) and Pd(PPh3)4 (820 mg, 0.71 mmol, 0.05 mmol) were stirred in diglyme ( 13 mL) at room temperature for 15 min. To this suspension were then added 4-ίθ / ·-όυΙίΙόβηοβηόθΓ0ηίοο acid (2528 mg, 14.2 mmol, 1.0 equiv) in IPA (15 mL) and a 2.0 M aqueous solution of K2CO3 (13.14 mL, 26.27 mmol, 1.85 equiv). The mixture was stirred at 95°C for 2 h. The reaction was cooled to room temperature and concentrated under reduced pressure. NaHCOs were added aq. sat. and DCM to the crude reaction mixture. The phases were separated, the aqueous layer was extracted with an additional amount of DCM (2 x 40 mL), and the organic layers were combined. The organic layer was then washed with brine (2 x 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The solid was then redissolved in DCM, and silica gel (20 g) was added, and the obtained mixture was concentrated under reduced pressure to obtain a dry packet of yellow solid. The crude reaction mixture was then purified by flash chromatography (silica gel, 100-200 mesh, 0-30% EtOAc in heptanes) to obtain methyl 6-(4-tert-butylphenyl)-4-chloro-pyridin—3 -carboxylate (2950 mg, 9.711 mmol, 68.4% yield) as a clear oil. Step 2: Methyl 6—(4—butylphenyl)—4—chloro—pyridine—3—carboxylate (5000 mg, 16.46 mmol, 1.0 equiv) was dissolved in DCM (54.8 mL), and 70% by weight of 3-chloroperbenzoic acid (m-CPBA) (8521 mg, 24.69 mmol, 1.5 equiv). The reaction mixture was stirred at t. to. for 36 hours. The reaction mixture was diluted with sat. of NaHCOs and extracted with DCM (3 x 40 mL). The organics were combined, washed with water (1 x 40 mL), brine (1 x 40 mL), dried with Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was then purified by flash chromatography (silica gel, 100-200 mesh, 10-80% EtOAc in heptanes) to obtain methyl 6(4-tert-butylphenyl)-4-chloro-1-oxo- pyridine-3-carboxylate (3100 mg, 9.6942 mmol, 59% yield) 110 as a solid beige. Step 3: Methyl 6-(4-tert-butylphenyl)-4-chloro-1-oxide-pyridine—1-io-3-carboxylate (3100 mg, 9.69 mmol, 1.0 equiv) was dissolved in DMSO (19.4 mL) , and sodium azide (1891 mg, 29.08 mmol, 3.0 equiv) was added. The reaction mixture was stirred at 50°C for 30 min. The reaction mixture was cooled to t. a., poured into water and extracted with EtOAc (3 x 40 mL). The organics were combined, washed with water (1 x 40 mL), brine (1 x 40 mL), dried with anhydrous NazSO4, filtered over a sintered funnel, and concentrated under reduced pressure to obtain methyl 4—azido—6 —(4-tert-butylphenyl)—1 —oxide-pyridine-l-io-3-carboxylate (2052 mg, 6.29 mmol, 64.9% yield) as a pale orange solid which was taken to the next step without purification. The general procedure for the synthesis of methyl 6-(4-(tert-butyl)phenyl)-4-chloronicotinate was carried out using the procedures of Org. Lett. 2015, 17, 2948-2951. Step 4: To a nitrogen-flooded, flame-dried flask, methyl 4-azido-6(4-tert-butylphenyl)-1-oxide-pyridin-1—io—3-carboxylate (500 mg, 1.53 mmol, 1.0 equiv) and DCM (4.7 mL). The reaction mixture was cooled to -70°C, and EtsN (0.43 mL, 3.06 mmol, 2.0 equiv) was added followed by oxalyl chloride (0.26 mL, 3.06 mmol, 2.0 equiv). The reaction was then stirred from -70°C to t. to. during 3 hours. NaHCOs aq. was added. sat., and the reaction was diluted with EtOAc (30 mL). The phases were separated, and the aqueous layer was extracted with more EtOAc (2x10 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over Na2SO4, filtered over a sintered funnel, and concentrated under reduced pressure. The crude reaction mixture was then purified by flash chromatography (silica gel, 100-200 mesh, 0-50% EtOAc in heptanes) to obtain methyl 4-azido-6-(4-ferbutylphenyl)—2—chloro—pyridin —3—carboxylate (280 mg, 0.812 mmol, 53% yield) as a yellow solid. Step 5: Triphenylphosphine (197.8 mg, 0.750 mmol, 1.0 equiv) was added to a stirring solution of methyl 4-azido-6-(4-fer-butylphenyl)-2-chloro-pihdin-3 -carboxylate (260 mg, 0.750 mmol) in THF (7.54 mL). The reaction was stirred at. to. for 2 hours, after which H2O (2 mL) was added. The reaction was stirred at t. to. for 12 hours. NaHCOs were added aq. sat. and EtOAc (20 mL), and the phases were separated. The aqueous layer was extracted with more EtOAc (2 x 10 mL). The organic layers were combined, the layer was washed with brine (2 x 20 mL), dried over Na2S©4, filtered, and the filtrate was concentrated under reduced pressure. The crude reaction mixture was then purified by flash chromatography (silica gel, 100-200 mesh, 0-100% EtOAc in heptanes) to obtain methyl 4-amino-6-(4-tert-butylphenyl)-2-cyopyridin. -3-carboxylate (180 mg, 0.565 mmol, 74.9% yield) as a white powder. Step 6: Methyl 4-amino-6-(4-tert-butylphenyl)-2-chloro-pyridine-3-carboxylate (180 mg, 0.5600 mmol) was dissolved in THF (5.65 mL) , and a 1.0 M aqueous solution of lithium hydroxide (0.62 mL, 0.620 mmol, 1.1 equiv) was added, and the reaction was stirred at t. to. for 24 hours. 1N KHSCU (40 mL) and EtOAc (40 mL) were added, and the phases were separated. The aqueous layer was extracted with EtOAc (2 x 40 mL). The organic layers were combined, washed with brine (3 x 40 mL), dried in Na2SO4, filtered over a sintered funnel, and the filtrate was concentrated under reduced pressure to obtain 4-amino-6-(4ter-butylphenyl acid )-2-chloro-pyridine-3-carboxylic acid (180 mg, 0.5906 mmol, 104% yield) isolated as MA / E / ZUZZ / UI Heard ΟΊ 111 a white solid, which was taken to the next stage without purification. The title compound was prepared as described in Example 1, replacing 1—(4—(tert-butyl)phenyl)-6-oxo-1,6—dihydropyridazine—4—carboxylic acid with 4—amino—6— (4—tert—butylphenyl)—2—chloro—pyridine—3—carboxylic.1H NMR (400 MHz, DMSO-Ó6+D2O) δ 8.31 (s, 1H), 7.79 (d, J = 8.6 Hz, 2H) , 7.47 (d, J= 8.6 Hz, 2H), 7.08 (s, 1H), 7.09-7.04 (m, 1H), 6.89 (d, J= 7.8 Hz, 1H), 6.74-6.64 (m, 2H), 6.34 (s, 1H), 6.24 (s, 1H), 4.94^.85 (m, 1H), 4.60-4.58 (m, 1H), 4.18-3.87 (m, 7H), 3.34-3.31 (m, 1H) , 3.273.19 (m, 1H), 3.17-3.09 (m, 1H), 3.05-2.76 (m, 8H), 1.27 (s, 9H), 1.16 (d, J = 7.0 Hz, 3H). LCMS (Method 5-100 AB, 7 min): Rt = 1.85 min, [M+H] + = 1027.5. Example 38 ΜΛ / Ε / ZUZZ / U1 Heard 1 The title compound was prepared as described in Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2 -(4-(1,1-difluoro-2methylpropyl)phenyl)-6-methylpharmidin-5-carboxylic.1H NMR (400MHz, MeOH - d4) δ (ppm) 8.42 - 8.34 (m, 3H), 7.61 - 7.49 (m, 2H), 7.21 -7.03 (m, 1H), 6.97 -6.72 (m, 3H), 6.68- 6.56 (m, 1H), 6.47 ( s, 1H), 5.20 -5.10 (m, 1H), 4.84-4.73 (m, 2H), 4.41 - 4.00 (m, 6H), 3.75- 3.32 (m, 3H), 3.27-2.91 (m, 8H), 2.642.30 (m, 4H), 1.45 - 1.25 (m, 3H), 1.00 (d, J = 6.8 Hz, 6H), LCMS (Method 5-95 AB, ESI): Rt = 0.645 min, [M+H ]+= 1045.0. Example 39 112 ΝΗΡΜΒ ΝΗΡΜΒ ΝΗ2 To a solution of ethyl 2-(4-(tert-butyl)-2-formylphenyl)-4-((4-methoxybenzyl)amino)-6-methylpyrimidine-5-carboxylate (140 mg, 0.30 mmol) in THF (2.00 mL) and ΝΗ3Ή2Ο (4.00 mL, 0.30 mmol) I2 (84.7 mg, 0.33 mmol) was added. The reaction was stirred at 20°C for 2 h. The solution was concentrated to dryness. The residue was partitioned between ethyl acetate (40 mL) and water (40 mL). The organic phase was washed with saturated Na2S2O3 solution (2 x 30 mL) and brine (30 mL). The organic phase was dried over Na2SO4 and concentrated to dryness. The residue was purified by preparative TLC (ethyl acetate: petroleum ether = 1:10) to obtain ethyl 2-(4-(tert-butyl)-2-cyanophenyl)-4-((4-methoxybenc ¡l)amino)-6methylpyrimidine-5-carboxylate (135 mg, 97.1% yield) as a yellow solid. To a solution of ethyl 2-(4-(tert-butyl)-2-cyanophenyl)-4-((4-methoxybenzyl)amino)-6methylpyrimidine-5-carboxylate (135 mg, 0.29 mmol) in acetonitrile (6.0 mL) and water (3.0 mL) CAN (646 mg, 1.18 mmol) was added. The reaction mixture was stirred at 20°C for 30 min. The reaction mixture was partitioned into ethyl acetate (40.0 mL) and water (40.0 mL). The organic phase was washed with brine (2 x 40 mL), dried with Na2SO4 and concentrated to dryness. The residue was purified by preparative TLC (ethyl acetate: petroleum ether = 2:10) to obtain ethyl 4-amino-2-(4-(tert-butyl)-2-cyanophenyl)-6methylpyrimidin-5- carboxylate (80.0 mg, 80.3% yield) as a yellow solid. Step 3: To a solution of ethyl 4-amino-2-(4-(tert-butyl)-2-cyanophenyl)-6-methylpyramidan-5carboxylate (80.0 mg , 0.23 mmol) in THF (6.0 mL) and water (2.0 mL) LYOH-H2O (24.4 mg, 0.58 mmol) was added. The reaction was stirred at 80°C for 1 h. The mixture was concentrated to remove methanol, and then water (20 mL) was added to the reaction mixture. The mixture was adjusted to pH=2 with 1M HCl. The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were concentrated to dryness to obtain 4-amino-2-(4-(tert-butyl)-2-cyanophenyl)-6-methylpyrimidine-5-carboxylic acid (50 mg, 69.2% yield ) as a white solid. The title compound was prepared as described in Example 1, replacing 1—(4—(tert—butyl)phenyl)—6—oxo—1,6—d ihyd ropyridazine—4—carboxylic acid with 4-amino- 2-(4-(tert-butyl)-2cyanophen¡l)-6-methylpyr¡mid¡n-5-carboxylic.1H NMR (400MHz, MeOH - cty 8.53 (s, 1 H), 8.15 - 8.13 (m, 1H), 7.85- 7.75 (m, 2H), 7.07 (br, 1 H), 7.00-6.84 (m, 2H), 8.60 (s, 1H), 8.48 (s, 1 H), 5.20 ( s, 1H), 4.38 4.01 (m, 5H), 3.63- 3.60 (m, 1H), 3.38-2.94 (m, 5H), 2.50 - 2.45 (m, 3H), 1.38 (s, 12H), LCMS (Method 5-100 AB, 1.5 min): Rt = 0.633 min, [M+H]+= 1033.7. 113 Example 40 IVIA / t / ZUZZ / U I 0 / 0 I Step 1: To a mixture of 4-tert-butylbenzeneboronic acid (500 mg, 2.81 mmol) in 1,4-dioxane (25 mL), methyl 2-amino-4,6-dichloro-pyrid was added. ¡n-3-carboxylate (745 mg, 3.37 mmol), Pd(PPh3)4 (162 mg, 0.140 mmol), K3PO4 (894 mg, 4.21 mmol) and H2O (3 mL). The reaction mixture was degassed with N2 gas, then stirred at 60°C for 18 h. The reaction was quenched with saturated aqueous NaHCOa (25 mL) then extracted with EtOAc (3 x 75 mL). The organic layers were combined, washed with brine, dried over Na2SÜ4, filtered over Celite and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% EtOAc in heptanes) to obtain methyl 2-amino-6-(4-tert-butylphenylHt-chloro-pyridin). -3-carboxylate (565 mg, 1.77 mmol) as a yellow solid. Step 2: To a mixture of methyl 2-amino-6-(4-tert-butylphenyl)-4-chloro-pyridine-3-carboxylate (679 mg, 2.13 mmol) in 1,4-dioxane (5.6 mL) 1M aqueous LiOH (4.26 mL, 4.26 mmol) was added. The reaction mixture was stirred at 60°C for 15 h, then cooled to room temperature. Diethyl ether was added, and the precipitate was collected by filtration to obtain 2-amino-6-(4-tert-butylphenyl)-4-chloropindine-3-carboxylic acid (502 mg, 77.3% yield) as a solid. pale yellow. The title compound was prepared as described in Example 1, replacing 1—(4—(fe / ^butyl)phenyl)—6—oxo—1,6—d ihyd ropyridazine—4—carboxylic acid with 2- amino-6-(4-fer-butylphen¡l)-4chloro-pyridine-3-carboxylic.1H NMR (400MHz, DMSO+D2O) δ 8.35 (s, 2H), 7.93 (d, J = 8.5Hz, 2H) , 7.48 (d, J = 8.6Hz, 2H), 7.19 (s, 1 H), 7.07 (d, J = 9.7Hz, 1H), 6.89 (d, J = 8.6Hz, 1H), 6.75 (s, 1 H), 6.71 (s, 1H), 6.37 (s, 1H), 6.27 (s, 1H), 4.94 - 4.87 (m, 1 H), 4.67 - 4.58 (m, 1H), 4.17-4.10 (m, 1H ), 4.08 - 3.90 (m, 6H), 3.41 - 3.09 (m, 4H), 3.07 -2.76 (m, 7H), 1.29 (s, 9H), 1.17 (d, J = 6.7Hz, 3H), LCMS ( Method 5-100 AB, 7 min): Rt = 1.97 min, [M+H] + = 1027.5. 114 Example 41 nh2 MA / E / ZUZZ / U1 I heard ΟΊ The title compound was prepared as described in Example 1, replacing 1—(4—(tert—butyl)phenyl)—β—oxo—1,6—d ihyd ropyridazine—4—carboxylic acid with 4-amino acid -2-(4-cyclobutylphenyl)-6methylpyrimidine—5—carboxylic.1H NMR (400MHz, MeOH - d4) 8.48 (s, 1H), 8.15 (d, J= 8.0 Hz2H), 7.35 (d, J = 8.0 Hz 2H), 7.18 - 7.16 (m, 1H), 6.97 - 6.95 (m, 2H), 6.89 (s, 1H), 6.82 (s, 1H), 6.61 (s, 1H), 6.43 (s, 1H) ), 5.23 - 5.19 (m, 1H), 4.47 - 4.44 (m, 2H), 4.33 - 4.08 (m, 6H), 3.67 - 3.59 (m, 2H), 3.42 - 3.36 (m, 1H), 3.29-3.16 (m, 4H), 3.09-3.04 (m, 5H), 2.50 (s, 3H), 2.40 -2.38 (m, 2H), 2.21 - 2.08 (m, 3H), 1.94 -1.89 (m, 1H), 1.39 (d, J=7.2 Hz, 3H), LCMS (Method 5-95 AB, ESI): Rt = 0.737 min, [M+H]+= 1006.6. Example 42 The title compound was prepared as described in Example 1, replacing 1-(4(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-6 -met¡l-2-(4neopent¡lfen¡l)primidine-5-carboxylic.1H NMR (400MHz, MeOH - d4) δ (ppm) 8.40 (br s, 1H), 8.15 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.15 - 7.06 (m, 1H), 6.85 - 6.78 (m, 3H), 6.60 (br, s, 1H), 6.48 (s, 1H), 5.18 (s, 1H), 4.50-4.22 (m, 6H), 4.22-4.01 (m, 6H), 3.62 -3.34 (m, 2H), 3.24 - 2.99 (m, 8H), 2.58 - 2.34 (m, 5H), 1.38 - 1.35 (m, 3H), 0.94 (s, 9H), LCMS (Method 5-95 AB, ESI): Rt = 0.798 min, [M+H]+= 1022.3. 115 Example 43 ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ The title compound was prepared from compound 20 by the procedure of Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4- amino-2-(4-(tert-butyl)-2-hydroxyphenyl)-6-methylpyrimidin-5-carboxylic acid.1H NMR (400MHz, DMSO ) δ 8.87 (d, J = 8.1Hz, 1H), 8.33 (d, J= 7.8Hz, 1H), 8.17 (d, J = 8.4Hz, 1H), 7.21 (d, J= 8.7Hz, 1H) , 7.02 (d, J = 8.6Hz, 1H), 6.97 (dd, J= 8.5, 1.9 Hz, 1H), 6.87 (d, J = 1.9Hz, 1H), 6.75 (s, 1H), 6.69 (d, J = 1.5Hz, 1H), 6.33 (s, 1H), 6.30 (s, 1H), 4.84 (dd, J = 9.6, 4.1Hz, 1H), 4.74 - 4.63 (m, 2H), 4.11 - 3.90 (m , 6H), 3.34 3.25 (m, 1H), 3.12-2.79 (m, 10H), 2.37 (s, 3H), 2.36 (s, 15H), 2.10-1.89 (m, 2H), 1.27 (s, 9H) , 1.18 (d, J= 6.7Hz, 3H), LCMS (Method 5-100 AB, 7 min): Rt = 1.64 min, [M+H]+= 959.7. Example 44 4-Amino-2-(4-(tert-butyl)-2-hydroxyphenyl)-6-methylpyrimidine-5-carboxylic acid was prepared as described in Example 54, replacing 2-(3,3-dimethylbutox ¡)-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan—2—yl)pyridine with 2—(2—(benzyloxy)—4—(tert—butyl)phenyl)—4,4 ,5,5-tetramethyl—1,3,2—dioxaborolane. The title compound was prepared as described in Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(4 —(tert—butyl)—2—hydroxyphenyl)— 6-methylpyrimidine-5-carboxylic.1H NMR (400MHz, MeOH - άή δ (ppm) 8.45 (s, 1H), 8.29 - 8.19 (m , 1 HOUR), 116 7.11 - 7.00 (m, 1H), 6.99 - 6.71 (m, 5H), 6.66 - 6.56 (m, 1H), 6.50 (s, 1H), 5.23 - 5.09 (m, 1H), 4.83 4.52 (m, 1H) , 4.41(s, 1H), 4.31 - 3.94 (m, 6H), 3.66 - 3.54 (m, 1H), 3.42 -3.34 (m, 1H), 3.29 - 2.93 (m, 9H), 2.51 -2.36 (m, 3H), 1.40 - 1.27 (m, 12H), LCMS (Method 5-95 AB, ESI): Rt = 0.791 min, [M+H]+ = 1024.9. Example 45 Step 1: To an ice-cold stirred solution of DCM (50 mL) of 4-(1,1-dimethylpropyl)phenol (1.00 g, 6.09 mmol, 1.0 equiv) in nitrogen was added pyridine (981 uL, 12.18 mmol, 2.0 equiv) followed by dropwise addition of trifluoromethanesulfonic anhydride (1.23 mL, 7.31 mmol, 1.2 equiv). The mixture was stirred for 30 minutes at 0°C, then allowed to warm to room temperature. The reaction was washed with aq KHSO4. 1.0 M (30 mL), then with aq. NaHCOs. sat. (2 x 30 mL), aq. brine. sat. (30 mL). The solution was dried over anhydrous MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The crude reaction mixture was then purified by flash chromatography (silica gel, 100-200 mesh, 0-100% EtOAc in heptanes) to obtain [4—(1,1 —dimethylpropyl)phenyl]trifluoromethanesulfonate (1800 mg, 6,075 mmol, 99.7% yield) as a clear oil. Step 2: To a stirred solution of [4-(1,1-dimethylpropyl)phenyl]trifluoromethanesulfonate (400 mg, 1.35 mmol, 1.0 equiv) in anhydrous DMSO (6 mL) was added bis(pinacolato)diboron (377 mg, 1.48 mmol, 1.1 equiv) followed by KOAc (132 mg, 1.35 mmol, 1.0 equiv). The mixture was stirred and purged with a flow of argon for 1 hour. PdCl2(dppf)’CH2Cl2 (49 mg, 0.067 mmol, 0.05 equiv) was then added, and argon stripping continued for 15 min. The mixture was kept in argon and heated to 80°C for 3 h. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (75 mL), washed with water (50 mL) and aq. brine. sat. (4 x 25 mL). The organic layer was dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The crude reaction mixture was then purified by flash chromatography (silica gel, 100-200 mesh, 0-100% EtOAc in heptanes) to obtain 2—[4—(1,1—dimethylpropyl)phenyl]—4,4 ,5,5—tetramethyl—1,3,2—dioxaborolane (310 mg, 1.13 mmol, 83.7% yield) as a white solid. Step 3: To a flame-dried, nitrogen-flooded vial, 2—[4—(1,1—dimethylpropyl)phenyl]—4,4,5,5—tetramethyl—1,3,2—dioxaborolane (336) was added. mg, 1.23 mmol, 1.3 equiv), K2CO3 (261 117 mg, 1.88 mmol, 2.0 equiv), methyl 4-amino-2-chloro-6-methyl-pyrimide-5-carboxylate (190 mg, 0.9400 mmol, 1.0 equiv) and PdCl2«( dppf)CH2Cl2 (77 mg, 0.0900 mmol, 0.1 equiv). The solids were suspended in a mixture of 1,4-dioxane (2.36 mL) and water (0.24 mL) and degassed with nitrogen for 5 min. The vial was sealed and heated to 100°C for 2 hours. The reaction was cooled to t. a., and NaHCOa sat. ac. and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (2x10 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was then purified by flash chromatography (silica gel, 100-200 mesh, 0-60% EtOAc in heptanes) to obtain methyl 4amino-2-[4-(1,1-dimet lpropyl)phenyl]-6-methyl-pyrimidin-5-carboxylate (80 mg, 0.255 mmol, 27% yield) as a white solid. Step 4: Methyl 4-amino-6-chloro-2-[4-(1,1-dimethylpropyl)phenyl]pyrimidine-5-carboxylate (70 mg, 0.21 mmol) was added to a scintillation vial equipped with a magnetic stir bar. , 1.0 equiv), THF (2.1 mL) and a 1.0 M aqueous solution of lithium hydroxide (0.23 mL, 0.2300 mmol, 1.1 equiv). The reaction mixture was stirred at t. to. for 12 hours. The reaction was concentrated under reduced pressure to obtain lithium 4-amino-6-chloro-2-[4-(1,1-dimethylpropyl)phenyl]pyrimidine-5-carboxylate (67 mg, 0.2095 mmol, 99.9% yield) as a bright yellow solid, which was used directly without purification. The title compound was prepared as described in Example 1, replacing 1—(4—(tert-butyl)phenyl)-6-oxo-1,6—d ihydropyridazine—4—carboxylic acid with 4-amino- Lithium 6-chloro-2-[4-(1,1dimethylpropyl)phenyl]pyrimídine—5—carboxylate.1H NMR (400 MHz, DMSO-ds+DzO) δ 8.11 (d, J= 7.9 Hz, 2H) , 7.51 (d, J= 8.0 Hz, 2H), 7.19 (d, J = 10.0 Hz, 1H), 6.99 (d, J= 8.8 Hz, 1H), 6.70 (s, 2H), 6.28 (s, 1H) , 6.20 (s, 1H), 5.00-4.88 (m, 1H), 4.73-4.55 (m, 2H), 4.11-3.90 (m, 6H), 3.37-3.23 (m, 2H), 3.16-2.90 (m , 4H), 2.91-2.75 (m, 4H), 2.67-2.62 (m, 1H), 2.42 (s, 3H), 2.36 (s, 12H), 1.63 (q, J= 7.9 Hz, 2H), 1.25 ( s, 6H), 1.16 (d, J = 6.7 Hz, 3H), 0.60 (t, J = 7.4 Hz, 3H). LCMS (Method 5-100 AB, 7 min): Rt = 1.83 min, [M+H]+= 1022.7. Example 46 EITHER The title compound was prepared as described in Example 1, replacing acid 1—(4— 118 (fer-butyl)phenyl)-6-oxo-1,6-d ihyd ropyridazine—4-carboxylic acid with 4-amino-2-(4-(tert-butyl)phenyl)pyrimidine—5—carboxylic acid.1H NMR ( 400MHz, MeOH - d4) 8.81 - 8.72 (m, 1H), 8.47 (s, 1H), 8.17 (d, J = 6.8 Hz, 2H), 7.47 (d, J = 6.8 Hz, 2H), 7.06 (s, 1 H), 6.78 - 6.67 (m, 2H), 6.48 -6.40 (m, 2H), 4.773.48 (m, 12H), 3.13 -2.69 (m, 6H), 1.49- 1.22 (m, 12H). LCMS (Method 5-95 AB, ESI): Rt = 0.778 min, [M+H]+ = 994.4. Example 47 MA / E / ZUZZ / U1 I heard ΟΊ The title compound was prepared from compound 20 by the procedure of Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4- am¡no-2-(1,1-dimet¡lindan-5-¡l)-6-met¡l-pyr¡m¡dine-5-carboxylic¡co.1H NMR (400MHz, DMSO+ D2O) δ 8.32 (S, 3H), 8.07-8.05 (m, 2H), 7.22 (d, J = 8.8Hz, 1H), 7.08 (d, J = 9.6Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 6.72 (s, 1H), 6.69 (s, 1H), 6.37 (s, 1H), 6.24 (s, 1H), 4.85-4.79 (m, 1H), 4.62-4.55 (m, 1H) , 4.11-4.06 (m, 1H), 4.06-3.96 (m, 4H), 3.95-3.91 (m, 2H), 3.26-3.19 (m, 1 H), 3.02-2.80 (m, 12H), 2.32 (s , 3H), 2.09 1.83 (m, 4H), 1.20 (s, 6H), 1.16 (d, J = 7.0Hz, 3H). LCMS (Method 5-100 AB, 7 min): Rt = 1.59 min, [M+H] + = 962.5. Example 48 119 ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ To a mixture of 4-(tert-butyl)-2-methylphenol (400 mg, 2.44 mmol) in dichloromethane (5.0 mL) were added pyridine (0.39 mL, 4.87 mmol) and TI2O (0.61 mL, 3.65 mmol) at 0° c. The reaction mixture was stirred at 0°C for 2 h. The reaction mixture was diluted with dichloromethane (30 mL). The organic layer was washed with 1M HCl (10 mL), saturated NaHCOs (20 mL), brine (2 x50 mL). The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was purified by column (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum) to obtain 4-(er-butyl)-2-methyl phenyl trif luoromethanesulfonate (710 mg, 98.4% yield). like a colorless oil. A mixture of 4—(fer—butyl)—2—methylphenyl trifluoromethanesulfonate (710.0 mg, 2.4 mmol), potassium acetate (705 mg, 7.19 mmol), Pd(dppf)Cl2 (178 mg, 0.24 mmol), and bls(pinacolato )diboron (791 mg, 3.11 mmol) in DMF (10.0 mL) was stirred in nitrogen at 80°C for 16 h. The mixture was diluted with ethyl acetate (80 mL), which was filtered, and the filtrate was washed with brine (3 x 80 mL). The organic layer was concentrated in vacuo. The residue was purified by column (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum) to obtain 2—(4—(fer—butyl)—2—methylphenyl)—4,4,5 ,5—tetramethyl—1,3,2— dioxaborolane (530 mg, 80.7% yield) as a white solid. A mixture of 2-(4-(tert-butyl)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (530 mg, 1.93 mmol), ethyl 2-chloro^l -((4-methoxybenzyl)amino)-6-methylpyrimín-5-carboxylate (681 mg, 2.03 mmol), Pd(dppf)Cl2 (70.7 mg, 0.10 mmol) and NasCOs ( 615 mg, 5.80 mmol) was suspended in 1,4-dioxane (6.0 mL) and water (0.60 mL), purged with N2 (0.10 MPa (15 psi)), and heated at 100°C for 16 h. The reaction mixture was diluted with ethyl acetate (20 mL). The reaction mixture was washed with brine (2 x 20 mL), dried with Na2SO4 and concentrated. The residue was purified by column (silica gel, 100200 mesh, 0-5% ethyl acetate in petroleum) to obtain ethyl 2—(4—(tert-butyl)—2—methylphenyl)—4—((4— methoxybenzylamino)-6-methylpyrimidin-5-carboxylate (500 mg, 57.8% yield) as a colorless oil. Step 4: A solution of ethyl 2-(4-(tert-butyl)-2-methylphenyl)-4-((4-methoxybenzyl)amino)-6methylpyrimidine-5-carboxylate (200 mg , 0.45 mmol), (diacetoxyiodo)benzene (216 mg, 0.67 mmol), Cu(OTFA)2 (12.9 mg, 0.04 mmol) and Pd(OAc)2 (5.02 mg, 0.02 mmol) in acetic acid (0.30 mL) and Acetic anhydride (4.50 mL) was stirred at 80°C in air for 24 h. The solvent was removed in vacuo. The residue was diluted with saturated NaHCOs solution (15.0 mL), extracted with ethyl acetate (3x30 mL). All organic layers were combined and washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 100 120 mesh 200, 0 - 20% ethyl acetate in petroleum) to obtain ethyl 2-(2-acetoxl-4-(tert-butyl)-6-methylphenyl)-4((4-methoxybenzyl)amino)- 6-methylpyrimidine-5-carboxylate (110 mg, 48.7% yield) as a light yellow oil. Step 5: A solution of ethyl 2—(2—acetoxy—4—(fer—butyl)—6—methyl phenyl)—4—((4—methoxybenzyl)amino)-6-methylpyr Imdin-5-carboxylate (110 mg, 0.22 mmol) in trifluoroacetic acid (3.0 mL, 0.22 mmol) was stirred at 75°C for 16 h. The mixture was concentrated to dryness and purified by column (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to obtain ethyl 4-amino-2-(4-(ter). -but¡l)-2-hydroxy¡-6-methylphen¡l)-6-met¡lp¡hm¡din-5-carbox¡late (74.0 mg, 99% yield) as a white solid. Step 6: To a solution of ethyl 4-amino-2-(4-(yer-butyl)-2-hydroxy-6-methylphenyl)-6-methylpyrimiden-5-carbox Tolate (74.0 mg, 0.22 mmol) in methanol (5.00 mL) was added NaOH (34.5 mg, 0.86 mmol) in water (1.00 mL). The reaction was stirred at 80°C for 1 h. The mixture was concentrated to dryness and diluted with water (30 mL). The mixture was adjusted to pH=5 with 1M HCl, and the aqueous layer was extracted with ethyl acetate (2 x 60 mL). The combined organic layers were dried in Na2SO4, concentrated in vacuo to obtain 4-amino-2-(4-(tert-butyl)-2-hydroxy¡-6-methylphen¡l)-6methylpyrimidine-5-carboxylic acid (65.0 mg, 95.7% yield) as a white solid. The title compound was prepared as described in Example 1, replacing 1—(4—(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(4-(tert-butyl)-2-hydroxy6-methylphenyl)-6-methylpyrimidine-5-carboxylic acid.1H NMR (400MHz, MeOH-di) 8.46 (s, 1H), 7.10 - 7.00 (m, 1H), 6.87 -6.76 (m, 5H), 6.61 (s, 1H), 6.47 (s, 1H), 5.19-5.16 (m, 1H), 4.37 -3.90 (m, 8H ), 3.63-3.58 (m, 3H), 3.19-2.99 (m, 10H), 2.51 (s, 3H), 2.46 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H), 1.30 (s, 9H). LCMS (Method 5-95 AB, ESI): Rt= 0.670 min, [M+H]+=1009.6. Example 49 IVIA / t / ZUZZ / U I Ο / Ο I The title compound was prepared as described in Example 1, replacing 1—(4—(tert-butyl)phenyl)-6-oxo-1,6—dihydropyridazine—4—carboxylic acid with 2—amino—6— (4—(tert—butyl)phenyl)—4—methylnicotinic.1H NMR (400MHz, DMSO+D2O) δ 8.93 (d, J = 9.3Hz, 1 H), 8.37 (d, J = 9.2Hz, 1 H) , 7.81 (d, J = 8.5Hz, 2H), 7.60 (d, J = 8.5Hz, 2H), 7.24 - 7.15 (m, 2H), 7.02 (d, J = 8.9Hz, 1H), 6.76 - 6.65 ( m, 121 2Η), 6.31 (s, 1H), 6.23 (s, 1 H), 5.02 -4.92 (m, 1H), 4.77- 4.60 (m, 2H), 4.14-3.86 (m, 6H), 3.42-3.23 (m , 2H), 3.18 - 2.76 (m, 9H), 2.37 (s, 12H), 1.31 (s, 9H), 1.17 (d, J = 6.7Hz, 3H). LCMS (Method 5-100 AB, 7 min): Rt = 1.77 min, [M+H] + = 1007.5. General procedure C: ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ Step 1: To a solution of compound 5 (2.0 g, 2.5 mmol) (synthesized as in General procedure A), tert-butyl (5S)-5-[(3-nitrophenyl)sulfonyloxymethyl]-2oxo-oxazolidine-3-carboxylate (1.36 g, 3.38 mmol) was added to DMF (12 mL) (synthesized as in General procedure D starting from (S)-3-amino-1,2-propanediol) and potassium carbonate (1.04 g, 7.52 mmol) at 25°C in an inert atmosphere. The reaction mixture was stirred for 16 h at 25°C. The reaction mixture was poured into aq. water / NaHCOa. sat. (1:1) drip with stirring. A beige solid precipitated, which was recovered by filtration. The solid was purified by column chromatography (silica gel, 100-200 mesh, 25-100% EtOAc in mixture (1:1) DCM / heptanes) to obtain compound 6 (1.99 g, 79.6% yield) as a white solid. Step 2: Compound 6 (1.99 g, 2 mmol) was dissolved in methanol (12.7 mL), and the reaction flask was purged with nitrogen before the addition of the 10 wt% palladium-on-carbon catalyst (159 mg , 0.15 mmol). The reaction mixture was purged with hydrogen and stirred in 1 atm of hydrogen at 25 °C for 3 h. The reaction flask was purged with nitrogen by bubbling into solution for 15 minutes, before the addition of Cbz-O-succinimide (0.5 g, 2 mmol). The reaction was stirred at 25°C for 16 h. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), washed with water (2 x 100 mL) and brine (2 x 100 mL), dried over Na2SO4 and concentrated to dryness to obtain compound 7 (1.81 g, 99.8% yield) as an off-white solid. 122 Step 4: To a solution of compound 8 (1.72 g, 1.55 mmol) in methanol (17 mL) p-toluenesulfonic acid (29 mg, 0.155 mmol) was added. The reaction mixture was stirred at 25°C for 16 h. The reaction mixture was poured into sat. aqueous NaHCOs / water. (1:1) drip with stirring. A beige solid precipitated, which was recovered by filtration. The solid was dissolved in DCM, dried with Na2SO4, filtered and concentrated under reduced pressure to obtain crude compound 9 (1.52 g, 100% yield) as an off-white solid. Step 5: A solution of compound 9 (1.52 g, 1.55 mmol) in DMF (15 mL) and methanol (0.565 mL) in an inert atmosphere (N2) was cooled to -15°C. Cesium carbonate (1.07 g, 3.28 mmol) was added to the cold solution, and the reaction mixture was stirred at -20 to -15°C for 6 h. The filtrate was concentrated to obtain crude compound 6 (35.0 g, 97.4% yield) as a white solid. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL) at −15 °C. The phases were separated, and the organic phase was washed with water (2 x 30 mL) and brine (2 x 30 mL), then dried over Na2SO4 and concentrated under reduced pressure. The solid was purified by column chromatography (silica gel, 100-200 mesh, 2-10% MeOH in DCM) to obtain compound 10 (1.07 g, 75% yield) as a white solid. General procedure D: Cl o2n.^.sl 1.2 eq. CbzCl l ^;l θ 1.5 eq. l.2 eq.K;CO51.1 eq. t-BuOK OH 10 v H2O / 10 v THF0H15 v THF °a 6vACN, S.Oeq.PiR2 θ H * CbzHN.Á *HNCYoH ” ήE,np¡» 12 Stage¡) 2 3E,apn 3 ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ ,S eq. Boc:O 0.1 eq. DMAP 6vACN Stage 4 Step 1: A 5 L flask was charged with (phy)-3-amino-1,2-propanediol (107 mL, 1.38 mol), and 10 volumes of both THF (1260 mL) and water ( 1260 mL). The reaction material was stirred at room temperature until complete dissolution (20 minutes). Then, the solution was cooled to 0°C, and potassium carbonate (229.4 g, 1.66 mol) was added. Finally, benzyl chloroformate (237 mL, 1.66 mol) was loaded into an addition funnel, and added dropwise to the reaction mixture while maintaining the internal temperature below 8°C (over a period of 60 minutes). . After completion of the reaction (2 h), the layers were separated. The organic layer was concentrated under reduced pressure (half), while the aqueous phase was extracted 3 times with EtOAc (3 x 1260 mL). All organics were combined, washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated to 2-3 volumes. Heptanes (1260 mL) were added to the residue, which was stirred at 10-20°C for 2-3 hours. The white solid formed was filtered and washed with heptanes. The solid was transferred to a flask and placed under high vacuum for drying, so as to obtain compound 2 (325 123 g, 104% yield) as a white solid. Compound 2 (175 g, 779 mmol) was loaded into a 5 L, 3-neck round-bottom flask equipped with a thermometer and dissolved in THF (2631 mL). The solution was cooled to 0°C, and potassium tert-butoxide (96.13 g, 857 mmol) was added portionwise, while maintaining the temperature between 0-10°C. After reagent addition was complete, the reaction mixture was allowed to warm to 25°C and stirred for 3 h. At the end, the reaction mixture was cooled again with an ice bath to maintain the internal temperature at around 10°C, while 4M HCl endioxane was added to the reaction mixture until reaching a pH of 5-6. The reaction mixture was then stirred at 25°C for 30 minutes. The precipitate was filtered and washed with MeCN (700 mL) twice. The filter cake was loaded into a 2 L Erlenmeyer flask, and shaken with 1.5 L of MeCN for 30 min. The solid was filtered again and washed with MeCN (700 mL) twice. All organics were combined and concentrated under reduced pressure at 2-3 V, below 45°C. MTBE (1.5 L) was added to the resulting suspension, and the suspension was again concentrated under reduced pressure to 2-3 V, below 45°C. 1-1.5 L of MTBE was added to the suspension, which was stirred at room temperature for 30 minutes. The solid was then collected by filtration, and washed with MTBE (1 L). The solid was dried under vacuum to obtain compound 3 (85.5 g, 93.8% yield) as an off-white solid. Compound 3 (75 g, 640 mmol) was loaded into a 2 L round-bottom flask, and 6 V of MeCN (450 mL) was added followed by pyridine (155 mL, 1.92 mol). The resulting solution was cooled to 0°C. Then, 3-nitrobenzenesulfonyl chloride (149 g, 673 mmol) was added portionwise, while maintaining the temperature below 10°C. The reaction mixture was stirred at 0°C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to 2-3 V. MTBE (10 V, 750 mL) was then added to the flask, and the resulting mixture was concentrated under reduced pressure to 2-3 V. 1.5 L of sat solution. of NaHCOs (20 V). The mixture was stirred vigorously at 10-20°C for 30 minutes. The resulting mixture was filtered and washed with water twice (1000 mL x 2). The wet cake was collected and loaded again into a round bottom flask. 1.5 L of sat solution was added. of NaHCOs (20 V). The mixture was stirred vigorously at 10-20°C for 30 minutes. The resulting mixture was filtered and washed with water twice (1000 mL x 2). The wet cake was collected and loaded again into a round bottom flask. Water (10 V, 750 mL) and MTBE (5 V, 375 mL) were added, and the resulting biphasic suspension was stirred vigorously for 30 min. The solids were filtered, washed twice with MTBE (400 mL x 2). The cake was dried under high vacuum to obtain compound 4 (178 g, 92% yield) as an off-white solid. Compound 4 (182.7 g, 604 mmol) was added to a 5 L round-bottom flask with 4-dimethylaminopyridine (7.38 g, 60.4 mmol), and MeCN (1.1 L) was added. The reaction mixture was cooled to 0°C, and di-tert-butyl dicarbonate (237.5 g, 1.1 mol) was added, maintaining the reaction temperature below 0°C. The reaction mixture was stirred at 0°C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure. MeOH (500 mL) was added to the mixture, and concentrated under reduced pressure until a thick orange gum was obtained. 700 mL of MeOH was added to the mixture. The reaction flask was placed under sonication for three minutes. A precipitate formed IVIA / t / ZUZZ / U I O / Ο I 124 white, which was stirred at room temperature for 30 minutes. The solid was recovered by filtration and washed with cold MeOH to obtain compound 5 (191.4 g, 78.7% yield) as a white solid. 98.95% ee.1H NMR (400 MHz, CDCh) δ 8.77 (t, J = 1.9 Hz, 1H), 8.56 (ddd, J = 8.3, 2.2, 1.0 Hz, 1H), 8.25 (ddd, J = 7.9, 1.7 , 1.1 Hz, 1H), 7.85 (t, J = 8.0 Hz, 1H), 4.75 -4.67 (m, 1H), 4.36 (dd, J = 11.5, 3.5 Hz, 1H), 4.30 (dd, J = 11.5, 4.2 Hz, 1H), 4.05 (dd, J = 10.6, 9.2 Hz, 1H), 3.82 (dd, J = 10.6, 6.2 Hz, 1H), 1.53 (s, 9H). Example 50 ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ The title compound was prepared as described in Example 1, replacing 1-(4(tert-butyl)phenyl)-6-oxo-1,6-dUnidropyridazine-4-carboxylic acid with 4-amlno-2-( 4-(tert-butyl)phenyl)-6methylpinmidine-5-carboxylic acid, and compound 14 by compound 10 described in the C.1H NMR procedure (400 MHz, DMSO - de + D2O) δ (ppm) δ 9.28 (d, J = 3.9 Hz, 1H), 8.91 (d, J= 6.7 Hz, 1H), 8.31 (d, J = 5.0 Hz, 1H), 8.06 (d, J = 7.9 Hz, 2H), 7.63 (d , J= 8.2 Hz, 2H), 7.19 (d, J= 7.8 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.69 (d, J= 6.2 Hz, 2H), 6.28 (s, 1H ), 6.17 (s, 1 H), 5.06 -4.93 (m, 1 H), 4.73-4.59 (m, 2H), 4.17 - 3.94 (m, 8H), 3.41 - 3.33 (m, 1H), 3.32 - 3.22 (m, 1H), 3.17 - 3.06 (m, 1H), 3.05 - 2.95 (m, 2H), 2.92 - 2.76 (m, 1H), 2.85 (s, 3H), 2.42 (s, 3H), 2.39 (s , 9H), 1.29 (s, 9H), 1.16 (d, J = 6.4 Hz, 3H). LCMS (Method 5-100 AB, 7 min): Rt = 1.62 min, [M+H]+= 1008.5. Example 51 125 The title compound was prepared from compound 20 by the procedure of Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4- amino-6-(4-tert-butylphenyl)-2-chloro-pyridine-3-carboxylic acid, prepared as described in example 37.1H NMR (400 MHz, DMSO-C / 6+ D2O) δ 8.34 (s, 3H), 7.80 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.09 (s, 1H), 7.06 (d, J= 8.8 Hz, 1H), 6.87 (d, J = 8.6 Hz, 1H), 6.74 (s, 1H), 6.67 (s, 1H), 6.37 (s, 1H), 6.24 (s, 1H), 4.86-4.80 (m, 1H), 4.65 -4.55 (m, 1H), 4.13 - 3.94 (m, 7H), 3.26-3.21 (m, 1H), 3.09 - 2.76 (m, 10H), 2.03-1.92 (m, 2H), 1.28 ( s, 9H), 1.15 (d, J = 6.7 Hz, 3H). LCMS (Method 5-100 AB, 7 min): Rt = 1.59 min, [M+H]+= 962.5. Example 52 IVIA / t / ZUZZ / U I O / Ο I Step 1: T1CI4 (14.3 mL, 127 mmol) was added to DCM (45.0 mL) in an RB three-neck flask, and the temperature was maintained at -78°C in a nitrogen atmosphere. Then, the addition of 1M Zn(CH3)2 in toluene (127 mL, 127 mmol) was performed while maintaining the temperature. The orange-brown solution obtained was stirred vigorously at -78°C for one hour. A solution of 5-bromo-2,3dihydro-1H-inden-1-one (4.50 g, 21.3 mmol) in DCM (45.0 mL) was added dropwise to the above mixture. The reaction solution was allowed to stir for 2 h at -78°C, then warmed to -10°C and stirred for 16 h. The reaction mixture was quenched by adding ice-cold saturated NH4Cl solution dropwise. The organics were separated, and the aqueous layer was extracted with ethyl acetate (3 x 126 100 mL); The organic layers were washed with brine (3 x 100 mL). The organics were combined and dried over NaSO4, before being concentrated to dryness. The crude product was then purified by flash column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum) to obtain 5-bromo-1,1-dimethyl-2,3-dihydro- 1 / - / -índene (4.80 g, 99.8% yield) as a yellow oil. Step 2: A mixture of 5-bromo-1,1-dimethyl-2,3-dihydro-1 / - / -indene (5.7 g, 25.3 mmol), Pd(dppf)Cl2 (926 mg, 1.27 mmol), KOAc (7.45 g, 75.9 mmol) and pinacol diboronate (9.64 g, 37.9 mmol) in DMF (57.0 mL) was stirred in N2 at 80°C for 3 h. The solvent was removed, and the residue was purified by flash column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum) to obtain 2-(1,1-dimethyl-2,3 -dihid ro-1H-inden-5-¡I)-4,4,5,5-tetramethyl-1,3,2dioxaborolane (6.5 g, 94.3% yield) as a white solid. Step 3: A mixture of 2—(1,1—dimethyl—2,3—dihydro—1 / - / -inden—5—yl)—4,4,5,5—tetramethyl—1,3,2— dioxaborolane (1.95 g, 7.15 mmol), ethyl 2-chloro-4-((4-methoxy¡benzyl)amino)-6-methylpyrimidín-5-carboxylate ethyl 2-chloro- 4-((4-methoxy¡benzyl)amino)-6-met¡lp¡rímidín-5-carboxylate (2.00 g, 5.96 mmol), Pd(dppf)Cl2 (0.22 g, 0.30 mmol) and Na2COs (1.89 g, 17.8 mmol) in a solvent mixture of water (2.00 mL) and 1,4dioxane (40.0 mL) was purged with N2 (0.10 MPa (15 psi)) and heated to 100°C for 4 p.m. After filtration, 50.0 mL of ethyl acetate was added to the mixture. The mixture was washed with brine (2 x 50.0 mL). The organics were combined and dried with Na2SO4 and concentrated to dryness. The crude product was purified by column (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum) to obtain ethyl 2-(6-acetoxy-1,1-dimethyl-2,3-d¡ hydro-1 / - / -inden-5-yl)-4-((4methoxybenzyl)amino)-6-methylpyrmidin-5-carboxylate (2.50 g, 94.2% performance) as a colorless oil. Step 4: A solution of ethyl 2-(6-acetoxy-1,1-dimethyl-2,3-dihydro-1 / - / -inden-5-yl)- 4-((4methoxybenz) l)amino)-6-methylpyrimidin-5-carboxylate (1.00 g, 2.24 mmol), Phl(OAc)2 (1.08 g, 3.37 mmol), Cu(OTFA)2 (64.9 mg, 0.22 mmol) and Pd(OAc)2 (25.1 mg, 0.11 mmol) in HOAc (1.00 mL) and AC2O (15 mL) were stirred at 80°C in air for 16 h. The solvent was removed in vacuo. The residue was diluted with saturated NaHCOs solution (30.0 mL), extracted with ethyl acetate (3x100 mL), washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The crude product obtained was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum) to obtain 5—(5—(ethoxycarbonyl)^4—((4—) diacetate. methoxybenzyljamine)—6—methylpyrimidin—2—ii)—1,1—dimethyl—2,3—dihydro—1 / - / —inden—4,6—diyl (300 mg, 0.5957 mmol, 26.5% performance), ethyl 2-(6-acetoxy¡-1,1d¡methyl-2,3-dihydro-1H-¡nden-5-¡l)^4-((4-methoxy¡benzyl )amino)-6-methyl¡r¡m¡din-5-carbox¡late (300 mg, 0.5957 mmol, 26.5% yield), ethyl 2-(4-acetoxy-1,1-d¡ methyl-2,3-d¡hydro-1 / - / -inden-5—¡I)—4-((4methoxy¡benzyl)amino)-6-methyl¡lp¡rim¡n- 5-carboxylate (330 mg), as a light yellow oil. Step 5: A solution of 5-(5-(ethoxycarbonyl)-4-((4-methoxybenzyl)amino)-6methylpyrimidin—2—yl)—1,1 —dimethyl—2,3 diacetate —dihydro—1 / - / —inden—4,6—diyl (330 mg, 0.590 mmol) in TFA (5.00 mL) was stirred at 75°C for 16 h. The mixture was concentrated. Ethyl acetate (40 mL) was added. The organic layer was washed with NaHCOs (aq., 30.0 mL), brine (30.0 mL), dried over Na2SO4 and concentrated. He ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ 127 Crude material was purified by silica gel column (16% ethyl acetate in petroleum ether) to obtain ethyl 4-amino-2-(4,6-dihydroxy-1,1-dimethyl-2, 3-dihydro—1H-inden-5-yl)-6-methylpyrimidine-5carboxylate (160 mg, 76.2% yield) as a yellow solid. Step 6: To a solution of ethyl 4-amino-2-(4,6-dihydroxy-1,1—dimethyl—2,3-dihydro- 1 / - / -inden-5yl)—6—methylpyrimidine—5—carboxylate (160 mg, 0.450 mmol) in MeOH (5.00 mL) and water (1.00 mL) NaOH (71.6 mg, 1.79 mmol) was added. The reaction was stirred at 80°C for 3 h. The mixture was adjusted to pH = 2 with 1 M HCl (aq.). The mixture was partitioned into ethyl acetate (50.0 mL) and water (30.0 mL). The organic layer was washed with brine (40.0 mL), dried over Na2SO4 and filtered. The filtrate was concentrated to obtain 4amino-2-(4,6-dihydroxy-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)-6-methylpyryl acid. m¡d¡n-5-carboxylic¡ (100 mg, 67.8% yield) as a yellow solid. The title compound was prepared as described in Example 1, replacing 1—(4—(tert—butyl)phenyl)—6—oxo—1,6—d ihyd ropyridazine—4—carboxylic acid with 4-am ¡no-2-(4,6-dih¡droxy¡-1,1dimethyl—2,3—dihydro—1 / - / —inden—5—¡I)—6—methylpyrimidine—5—carboxylic.1H NMR (400MHz , MeOH - d4) δ (ppm) 8.42 (br s, 1H), 7.25 - 6.95 (m, 1H), 6.91 - 6.45 (m, 5H), 6.21 (s, 1H), 5.26 - 5.08 (m, 1H) , 4.64 3.88 (m, 8H), 3.68 -3.34 (m, 2H), 3.26 - 2.93 (m, 9H), 2.79 - 2.70 (m, 2H), 2.43 (s, 3H), 1.95 - 1.83 (m, 2H ), 1.36 (d, J = 6.4 Hz, 3H), 1.23 (s, 6H), LCMS (Method 5-95AB, ESI): Rt = 0.799 min, [M+H]+= 1052.5. ΜΛ / Ε / ZUZZ / Ul O / Ol Example 53 Step 1: Sodium methoxide (25% by weight in methanol, 16.4 mL, 71.5 mmol) was added to a solution of 4-fer-butylbenzamidine (4.20 g, 23.8 mmol) in methanol (11.9 mL). The reaction mixture was stirred at room temperature for 10 min, then diethyl malonate (3.62 mL, 23.8 mmol) was added. The reaction mixture was stirred at room temperature for 16 h, then concentrated under reduced pressure. H2O was added followed by concentrated HCl, to obtain an acidic pH. The resulting mixture was extracted with EtOAc (3x). The organic layers were combined, washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain 2-(4-tert-butylphenyl)pyrimidin—4,6-diol (4.08 g, 70.1% performance) as a whitish solid. The raw material was used in the 128 next stage without additional purification. Step 2: DMF (1.33 mL, 17.2 mmol) was added to POCI3 (21.5 mL, 230 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 h. This solution was then added to 2-(4-tert-butylphenyl)pyrimidin-4,6-dloI (4.01 g, 16.4 mmol), and the reaction mixture was stirred at room temperature for 30 min, then at 100°C for 4 p.m. The mixture was then cooled to room temperature and poured into ice / water. The resulting mixture was extracted with EtOAc (3x). The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% EtOAc in heptanes) to obtain 2-(4-tert-butylphenyl)-4,6-dichloro-p ¡r¡m¡d¡n-5-carbaldehyde (2.94 g, 57.9% yield) as an off-white solid. Step 3: A solution of sodium chlorite (1.20 g, 13.3 mmol) in water (4.2 mL) was added to a solution of 2-(4-fer-butylphen¡l)-4,6-dichloro-p¡ r¡m¡d¡n-5-carbaldehyde (2.94 g, 9.51 mmol) and sulfamic acid (1.29 g, 13.3 mmol) in fer-butanol (21 mL) and water (8.4 mL). The reaction mixture was stirred at room temperature for 5 h, then additional portions of sulfamic acid (260 mg, 2.68 mmol) and sodium chlorite (240 mg, 2.65 mmol) were added. The reaction mixture was stirred at room temperature for an additional 2 h. Water was added, and the mixture was extracted with EtOAc (3x). The organic layers were combined, washed with brine, dried over N2SO4, filtered and concentrated under reduced pressure to obtain 2-(4-er-butylphenyl)-4,6-dichloro-pyrimidine-5-carboxylic acid (3.09 g, 99.9% yield) as an off-white solid. The crude material was used in the next step without any further purification. Step 4: Potassium carbonate (3.28 g, 23.8 mmol) was added to a solution of 2-(4-tert-butylphenyl)-4,6-dichloro-pyrimidine-5-carboxylic acid (3.09 g, 9.50 mmol) in DMF (47.5 mL). The reaction mixture was stirred at room temperature for 15 min; then, iodoethane (1.91 mL, 23.8 mmol) was added. The reaction mixture was stirred at room temperature for 16 h, then diluted with EtOAc. The resulting mixture was washed with water (2x) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 100-200 mesh, 0-10% EtOAc in heptanes) to obtain ethyl 2-(4-yer-butylphenyl)-4,6-dichloro-pyrimidine-5carboxylate. (2.95 g, 87.9% yield) as an off-white solid. Step 5: A solution of ethyl 2-(4-tert-butylphenyl)-4,6-dichloro-pyrimidine-5-carboxylate (800 mg, 2.26 mmol) and 2M ammonia in ¡PrOH (24.0 mL, 48.0 mmol) was stirred. at room temperature for 16 h. H2O was then added, and the mixture was extracted with EtOAc (3x). The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain ethyl 4-amino-2-(4-te / '-butylphenyl)-6-chloro-pyrimidin. -5-carboxylate (765 mg, quantitative) as a colorless oil. The crude material was used in the next step without any further purification. Step 6: 1N aqueous lithium hydroxide (2.40 mL, 2.40 mmol) was added to a solution of ethyl 4amino-2-(4-tert-butylphenyl)-6-chloro-pyrimidine-5-carboxylate (200 mg , 0.599 mmol) in THF (6.0 mL). The reaction mixture was stirred at 50°C for 16 h, then cooled to room temperature. 1N aqueous HCl was added, and the resulting mixture was extracted with a 4:1 solution of CHCls / iPrOH (3x). The layers MA / E / ZUZZ / U1 I heard ΟΊ 129 organic compounds were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 4-amino-2-(4-tert-butylphenyl)-6-chloro-pyrimidin-5 acid. -carboxylic acid (190 mg, quantitative) as an off-white solid. The title compound was prepared as described in Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-d ihydropyridazine-4-carboxylic acid with 4~amino- 2-(4-tert-butylphenyl)-6chloro-pyrimidine-5-carboxylic.1H NMR (400MHz, DMSO+D2O) δ 8.34 (s, 1H), 8.16 (d, J = 8.5Hz, 2H) , 7.52 (d, J = 8.6Hz, 2H), 7.07 (d, J = 8.9Hz, 1H), 6.89 (d, J = 8.4Hz, 1H), 6.72 (s, 1H), 6.70 (s, 1H ), 6.35 (s, 1H), 6.25 (s, 1H), 4.94-4.88 (m, 1 H), 4.66-4.56 (m, 1 H), 4.19-4.11 (m, 1H), 4.08 -3.99 (m , 3H), 3,993.93 (m, 3H), 3.40 - 3.29 (m, 1 H), 3.25 - 3.10 (m, 2H), 3.07 - 2.98 (m, 2H), 2.97 - 2.79 (m, 6H), 1.28 (s, 9H), 1.17 (d,J = 6.8Hz, 3H). LCMS (Method 5-100 AB, 7 min): Rt = 1.88 min, [M+H]+= 1028.2. ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ Example 54 Step 1: To a solution of 5-bromopyridin-2-ol (2.00 g, 11.49 mmol) in DMF (10.0 mL) were added 1-bromo-3,3-dimethylbutane (2.85 g, 17.2 mmol) and AgzCOs ( 9.51 g, 34.5 mmol). The reaction mixture was stirred at 110°C for 2 h. The reaction mixture was diluted with ethyl acetate (40 mL). After filtration, the filtrate was washed with brine (3 x 40 mL), and dried in NaaSO. After filtration, the filtrate was concentrated to dryness. The residue was purified by column (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum) to obtain 5-bromo-2-(3,3dimethylbutoxy)pyridine (1.00 g, 33.7% performance) as a yellow oil. 130 Step 2: A mixture of 5-bromo-2-(3,3-dimethylbutox¡)pyr¡dine (1.20 g, 4.65 mmol), KOAc (1.37 g, 14.0 mmol), Pd(dppf) Cl2 (345 mg, 0.46 mmol), bis(pinacolato)diboron (1.77 g, 6.97 mmol) in DMF (10.0 mL) was stirred under nitrogen at 80°C for 16 h. The reaction mixture was diluted with ethyl acetate (20 mL), then filtered, and the filtrate was washed with brine (3 x 20 mL). The organic layer was concentrated in vacuo until dry. The residue was purified by column chromatography (silica gel, 100-200 mesh, 50-100% ethyl acetate in petroleum) to obtain 2—(3,3—dimethylbutoxy)—5—(4,4,5, 5—tetramethyl—1,3,2— dioxaborolan-2-¡l)pyr¡dine (480 mg, 33.8% yield) as a yellow oil. Step 3: A mixture of 2-(3,3-dimethylbutox¡)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2¡l)pyri¡ dna (300 mg, 0.98 mmol), ethyl 2-chloro-4-((4-methoxybenzyl)amino)-6-methylpyrimidin-5-carboxylate (347 mg, 1.03 mmol), Pd(dppf)Cl2 (36.0 mg, 0.05 mmol) and Na2CO3 (312 mg, 2.95 mmol) in a mixture of 1,4-dioxane (6.0 mL) and water (0.60 mL) was purged with N2(0.10 MPa (15 psi)) and heated at 100°C for 16 h. After filtration, 20 mL of ethyl acetate was added to the mixture. The mixture was washed with brine (2 x 20 mL). The organic layer was dried with N2SO4 and concentrated to dryness. The crude material was purified by column (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum) to obtain ethyl 2-(6-(3,3-dimethylbutoxy)pyridin-3-yl )—4—((4—methoxybenzyl)amino)—6—methylpyrimidine-5carboxylate (370 mg, 78.7% yield) as a yellow solid. Step 4: To a solution of ethyl 2-(6-(3,3-dimethylbutoxy)pyridin-3-l)-4-((4-methoxybenzyl) )amino)6-methylpyrimidine-5-carboxylate (175.0 mg, 0.37 mmol) in acetonitrile (4.00 mL) and water (2.00 mL) ceric ammonium nitrate (802 mg, 1.46 mmol) was added. The reaction was stirred at 20°C for 30 min. The reaction mixture was partitioned into ethyl acetate (20 mL) and water (20 mL). The organic layer was washed with brine (2 x 20 mL), dried with Na2SO4 and concentrated to dryness. The crude product was purified by preparative TLC (ethyl acetate: petroleum ether = 1:10, Rf = 0.3) to obtain ethyl 4-amino2-(6-(3,3—dimethylbutoxy)pyridin—3—yl)—6 —methylpyrimidine-5-carboxylate (100 mg, 76.3% yield) as a yellow solid. Step 5: To a solution of ethyl 4-amino-2-(6-(3,3-dimethylbutoxy)pyridin-3-yl)-6-methylpyrimidin-5-carboxylate (100 mg, 0.28 mmol) in methanol ( 5.00 mL) and water (1.00 mL) NaOH (44.6 mg, 1.12 mmol) was added. The reaction mixture was stirred at 80°C for 1 h. The mixture was concentrated to dryness. The mixture was adjusted to pH 2 with HCl (1 M). The aqueous layer was extracted with ethyl acetate (2 x 60 mL), and the combined organic layers were concentrated to obtain 4-amino-2-(6-(3,3dimethylbutoxy)pyridin—3—yl)—6—methylpyrimidin acid. —5—carboxylic (80 mg, 86.8% yield) as a white solid. The title compound was prepared as described in Example 1, replacing 1-(4(tert-butyl)phenyl)-6-oxo-1,6-d ihydropyridazineA-carboxylic acid with 4-am i no-2 -(6-(3,3dimethylbutoxy)pyridin—3—I)—6—methylpyrimidine—5—carboxylic.1H NMR (400MHz, MeOH - d4) 9.04 (s, 1H), 8.51 - 8.42 (m, 2H ), 7.12 - 6.99 (m, 1H), 6.89 - 6.69 (m, 3H), 6.55 (s, 1H), 5.27 - 5.10 (m, 1H), 4.83 4.73 (m, 2H), 4.53 - 4.29 (m , 3H), 4.18 - 4.07 (m, 3H), 4.05 - 3.92 (m, 1H), 3.67 - 3.52 (m, 1H), 3.44 3.37 (m, 1H), 3.36 -3.33 (m, 1H), 3.29 - 3.19 (m, 2H), 3.18-3.09 (m, 2H), 3.07 (s, 3H), 3.00-2.91 (m, 1H), 2.45 (s, 3H), 1.79 - 1.67 (m, 2H), 1.41 - 1.28 (m, 2H), 1.00 (s, 9H). LCMS (Method 10-80 AB, ESI): ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ 131 Rt = 1.868 min, [M+H]+= 1054.6. Example 55 MA / E / ZUZZ / U1 I heard ΟΊ The title compound was prepared by the procedure of Example 1, replacing compound 14 with compound 20 and replacing 1-(4-(er-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(4-tert-butphenyl)-6-chloro-pyrimidine-5-carboxylic acid described in example 53.1H NMR (400MHz, DMSO+D2O) δ 8.87 (d, J = 8.0Hz, 1H), 8.30 (d, J = 7.7Hz, 1H), 8.15 (d, J= 8.1 Hz, 2H), 7.52 (d, J= 8.2Hz, 2H), 7.19 ( d, J = 8.5Hz, 1H), 7.00 (d, J = 8.6Hz, 1H), 6.71 (s, 2H), 6.30 (s, 1H), 6.25 (s, 1H), 4.86 - 4.80 (m, 1H), 4.73 - 4.58 (m, 2H), 4.20 - 3.96 (m, 5H), 3.85 3.64 (m, 3H), 3.35- 3.23 (m, 1H), 3.15-2.77 (m, 11 H), 2.74- 2.55 (m, 1H), 2.46 -2.36 (m, 2H), 2.40 (s, 12H), 2.38 -2.20 (m, 1 H), 2.13-1.86 (m, 2H), 1.28 (s, 9H), 1.18 (d,J = 7.1Hz, 3H) LCMS (Method 5-100 AB, 7 min): Rt = 1.63 min, [M+H]+= 963.6. Example 56 132 Ethyl 2-(4-(tert-butyl)phenyl)-4-chloro-6-methylpyrimidine-5-carboxylate (150 mg, 0.45 mmol), TEA (188 uL, 1.35 mmol) and methylamine (33.4 mg, 0.50 mmol) in ethanol (5.00 mL) they were shaken at 60°C for 1 h. The reaction mixture was diluted with ethyl acetate (40 mL). The organic layer was washed with brine (2 x 30 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified by preparative TLC (10% ethyl acetate in petroleum ether, Rf = 0.4) to obtain ethyl 4-amino-2-(4-(tert-butyl)-2methylphenyl)-6-methylpyrimidin-5- carboxylate (125 mg, 85.0% yield) as a white solid. Step 5: Ethyl 4-amino-2-(4-(tert-butyl)-2-methylphenyl)-6-methylpyrimidin-5-carboxylate (120 mg, 0.37 mmol ) was dissolved in MeOH (10.0 mL) and water (2.0 mL). NaOH (58.6 mg, 1.47 mmol) was added, and the mixture was stirred at 80°C for 2 h. The reaction mixture was concentrated, and the pH was adjusted to pH=3 with 1M HCl. The reaction mixture was partitioned into ethyl acetate (50.0 mL) and water (50.0 mL). Then the aqueous layer was extracted with ethyl acetate (50.0 mL*2). The combined organic layers were dried over Na2SO4 and concentrated to obtain 2-(4-(tert-butyl)phenyl)-4-methyl-6-(methylamino)pyrmide acid. n-5carboxylic (100 mg, 91% yield) as a white solid. The title compound was prepared as described in Example 1, replacing 1-(4(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 2-(4 - (tert-butyl)phenyl)-4-methyl-6(methylamino)pyrimidine-5-carboxylic acid.1H NMR (400MHz, MeOH - d4) 8.38 (s, 1 H), 8.24 (d , J = 7.6 Hz, 2H), 7.50 (d, J = 8.4Hz, 2H), 7.10-7.04 (m, 1 H), 6.50 - 6.77 (m, 2H), 6.59 (s, 1H), 6.48 (s , 1H), 5.20-5.16 (m, 1H), 4.37 -3.97 (m, 8H), 3.61 -3.58 (m, 1H), 3.38 -3.35 (m, 1H), 3.19-2.98 (m, 12H), 2.44 (s, 3H), 1.36 - 1.34 (m, 12H), LCMS (Method 5-95 AB, ESI): Rt = 0.794 min, [M+H]+= 1022.5. Example 57 ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ EITHER The title compound was prepared as described in Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2- (6-hydroxy¡-1,1-dimethyl2,3-dihydro—1 H-inden-5-¡I)-6-methylpyrimidine-5-carboxylic acid, which was prepared by the procedures described in example 52.1H NMR (400MHz, MeOH - d4) δ (ppm) 8.47 (br s, 1H), 8.11 (s, 1H), 7.02 (brs, 1H), 6.88-6.70 (m, 3H), 6.65 (s, 1H), 6.59 (brs, 1H), 6.52 (brs, 1H), 5.18 (brd, J = 8 Hz 1H), 133 4.44-3.95 (m, 8H), 3.6 (brd, J = 10.4 Hz, 1H), 3.43 -3.32 (m, 1H), 3.26 -2.96 (m, 9H), 2.86- 2.79 (m, 2H), 2.44 ( s, 3H), 1.96 - 1.88 (m, 2H), 1.35 (br d, J= 6.4 Hz, 3H), 1.25 (br s, 6H), LCMS (Method 5-95 AB, ESI): Rt = 0.783 min, [M+H]+= 1036.5. Example 58 OH Step 1: To a mixture of 5-(tert-butyl)-2-hydroxybenzaldehyde (4.30 g, 24.1 mmol) in DCM (60 mL) at 0°C, pyridine (3.89 mL, 48.3 mmol) and triflic anhydride were added. (6.09 mL, 36.2 mmol). The reaction mixture was stirred at 0°C for 2 h. The reaction mixture was diluted with ethyl acetate (100 mL). The organic layer was washed successively with 1M HCl (50 mL), saturated NaHCOs (50 mL), and brine (50 mL). The organic layer was dried over N2SO4 and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum) to obtain 4-(tert-butyl)-2-formylphenyl trifluoromethanesulfonate (4.50 g, 60.1% performance) as a yellow oil. Step 2: A mixture of 4-(tert-butyl)-2-formylphenyl trifluoromethanesulfonate (3.90 g, 12.6 mmol), bis(pinacolato)diboron (4.78 g, 18.85 mmol), potassium acetate (3.75 g, 37.7 mmol), Pd(PPh3)CÍ2 (882 mg, 1.26 mmol) in DMF (40.0 mL) was stirred for 16 h in N2 (0.10 MPa (15 psi)) at 80°C. The mixture was filtered and diluted with ethyl acetate (80 mL). The organic layers were washed with brine (2 134 χ 100 mL), were dried in Na2SO4 and concentrated to dryness. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum) to obtain the crude product. The crude product was purified by preparative HPLC (with a gradient of acetonitrile and water (with 0.225% formic acid)) to obtain 5—(fer—butyl)—2—(4,4,5,5—tetramethyl—1, 3,2—dioxaborolan-2-yl)benzaldehyde (1.30 g, 35.9% yield) as a yellow solid. Step 3: A mixture of 5-(tert-butyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzaldehyde (300 mg, 1.04 mmol), ethyl 2-chloro -4-((4-methoxy¡benzyl)amino)-6-met¡lp¡rímidín-5carboxylate (402 mg, 1.2 mmol), Pd(dppf)Cl2 (76.2 mg, 0.10 mmol ) and Na2CO3 (331 mg, 3.12 mmol) in a mixed solvent of 1,4-dioxane (10.0 mL) and water (1.0 mL) was purged with N2 (0.10 MPa (15.0 psi)) and heated to 100°C for 4 p.m. After filtration, 20 mL of ethyl acetate was added to the reaction mixture. The mixture was washed with brine (2 x 30 mL), dried over N2SO4 and concentrated to dryness. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum) to obtain ethyl 2—(4—(fer—butyl)—2—formylphenyl) —4—((4—methoxy¡benzyl)amino)-6-methyl¡lp¡r¡m¡d¡n-5-carbox¡late (220 mg, 45.8% yield) as a white solid. Step 4: To a solution of ethyl 2-(4-(tert-butyl)-2-formylphenyl)-4-((4-methoxybenzyl)amino)-6methylpyrimidine-5-carboxylate (220 mg, 0.48 mmol) in methanol (10.0 mL), 10% Pd / C (101 mg, 0.10 mmol) was added. The mixture was stirred in hydrogen (0.34 MPa (50 psi)) at 40°C for 6 h. The mixture was filtered, and the filtrate was concentrated to obtain ethyl 2-(4-(tert-but¡l)-2-(hydroxy¡methyl)phen¡l)-4-((4methoxy¡benzyl) amino)-6-methyl!rim!din-5-carboxylate (180 mg, 81.5% yield) as a white solid. Step 5: To a solution of ethyl 2-(4-(tert-butyl)-2-(hydroxymethyl)phenyl)-4-((4-methoxybenzyl)amino)6 -methylpyrimidine-5-carboxylate (180 mg, 0.39 mmol) in acetonitrile (8.0 mL) and water (4.0 mL) ceric ammonium nitrate (851 mg, 1.55 mmol) was added. The reaction was stirred at 20°C for 30 min. The reaction mixture was partitioned into ethyl acetate (40 mL) and water (40 mL). The organic phase was washed with brine (2 x 40 mL), dried with Na2SO4 and concentrated to dryness. The crude product was purified by preparative TLC (ethyl acetate: petroleum ether = 1:10, TLC: 15% EtOAc in petroleum, Rf = 0.3) to obtain ethyl 4-amino-2-(4-(tert-but ¡l)-2-(hydroxy¡methyl)phen¡l)-6-methylpyramidan-5-carboxylate (100 mg, 75% yield) as a yellow solid. Step 6: To a solution of ethyl 4-amino-2-(4-(tert-butyl)-2-(hydroxymethyl)phenyl)-6-methylpyrimidin5 -carboxylate (100 mg, 0.29 mmol) in methanol (10.0 mL) and water (3.0 mL) NaOH (46.59 mg, 1.16 mmol) was added. The reaction was stirred at 80°C for 1 h. The mixture was concentrated to remove methanol. Water (20 mL) was added to the mixture, and the mixture was adjusted to pH = 2 with 1M HCl. The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were concentrated to obtain 4-amino-2-(4-(fer-butyl)-2-(hydroxymethyl)phenyl)-6-methylpyrimidin-5-acid. carboxylic (80.0 mg, 87.1% yield) as a white solid. Step 7: The title compound was prepared as described in Example 1, replacing 1-(4-(yer-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino acid. -2-(4-(ter ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ 135 butyl)-2-(hydroxymethyl)phenyl)-6-methylpyrimidine—5-carboxylic.1H NMR (400MHz, MeOH - d4) 8.42 (s, 2H), 7.90 (d, J= 8.4 Hz, 2H), 7.55- 7.48 (m, 1 H), 7.46 (br, 1H), 7.09-7.82 (m, 3H), 6.63 (s, 1 H), 6.50 (s, 1H), 5.22 - 5.19 (m, 1 H), 4.96 - 4.26 (m, 1H), 4.25 (br, 1H), 4.24 - 4.15 (m, 4H), 3.22 - 3.05 (m, 4H), 2.45 2.44 (m, 3H), 1.39 (s, 12H), LCMS ( Method 5-95 AB, ESI): Rt = 0.713 min, [M+H]+= 1038.5. Example 59 The title compound was prepared as described in Example 1, replacing 1—(4—(tert-butyl)phenyl)-6-oxo-1,6-d ihydropyridazinY-carboxylic acid with 4-amino-2 -(4-(tert-butyl)-2methylphenyl)—6—methylpyrimidine—5—carboxylic.1H NMR (400MHz, MeOH - d4) 8.41 (s, 1H), 7.49 - 7.39 (m, 1H), 7.36 - 7.26 (m, 2H), 7.18 - 7.01 (m, 1H), 6.94 - 6.73 (m, 3H), 6.67 - 6.57 (m, 1H), 6.49 - 6.28 (m, 1H), 5.23 - 5.10 (m, 1H), 4.74 - 4.50 (m, 2H), 4.45 - 3.91 (m, 6H), 3.66 - 3.31 (m, 3H), 3.26 - 2.70 (m, 8H), 2.52 - 2.29 (m, 6H), 1.42 - 1.25 (m, 12H). LCMS (Method 5-95 AB, ESI): Rt = 0.627 min, [M+H]+= 1022.8. Example 60 136 The title compound was prepared as described in Example 1, replacing 1—(4—(tert—butyl)phenyl)—6—oxo—1,6—d ihyd ropyridazine—4—carboxylic acid with 4-amino acid -2-(4-(tert-butyl)-3f luorofenyl)—6—methylpyrimidine—5—carboxylic.1H NMR (400MHz, MeOH - d4) δ (ppm) 8.42 (br s, 1 H), 7.46 7.36 ( m, 1H), 7.18 - 7.00 (m, 1H), 6.95 -6.72 (m, 3H), 6.59 (s, 1H), 6.46 (s, 1H), 5.23 - 5.08 (m, 1H), 4.80 - 4.77 (m, 2H), 4.50 - 3.94 (m, 6H), 3.68 - 3.33 (m, 3H), 3.29 - 2.95 (m, 8H), 2.47 (s, 3H), 1.45 1.31 (m, 12H), LCMS (Method 5-95 AB, ESI): Rt = 0.774 min, [M+H]+= 1026.6. ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ Example 61 Step 1: In a nitrogen-flooded, flame-dried flask, DIPEA (16.4 mL, 94.17 mmol, 2.0 equiv) was added, followed by chloromethyl methyl ether (MOMO) (5.4 mL, 70.6 mmol, 1.5 equiv) to a solution of 5-tert-butyl-2-iodo4enol (13.0 g, 47.08 mmol, 1.0 equiv) in DCM (157 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. A saturated aqueous solution of NaHCOs was added to the reaction mixture (40 mL) at 0°C. The mixture was then extracted with DCM (3 x 40 mL). The organic layers were combined, dried over Na2SO4, filtered over a sintered funnel, and the filtrate was concentrated under reduced pressure. The crude material was purified by filtration over a silica gel pad (800 g) with elution of 20% EtOAc in heptanes to obtain 4-tert-butyl-1-iodo-2-(methoxymethoxy)benzene (13.8 g, 43.1 mmol, 91.5% yield) as a yellow oil. To a flame-dried, nitrogen-flooded flask, 4-tert-butyl-1-iodo-2(methoxymethoxy)benzene (13.0 g, 40.6 mmol, 1.0 equiv) and 2-isopropoxy-4,4,5.5- were added. tetramethyl-1,3,2dioxaborolane (28.9 mL, 142.11 mmol, 3.5 equiv) and anhydrous THF (203 mL). The solution was cooled to 78°C, and a 2.5 M solution of n-BuLI in heptanes (48.7 mL, 121.8 mmol, 3.0 equiv) was added dropwise, and the reaction was stirred for 3 hours. NaHCOs sat was added. ac. at -78°C, heating the flask to t. a., and with dilution with EtOAc (300 mL). The phases were separated, and the aqueous layer was extracted with additional EtOAc (2 x 100 mL). The organic layers were then washed with brine (2 x 200 mL), dried in N2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 100-200 mesh, 0-30% EtOAc in heptanes) to obtain 2-[4-tert-butyl-2-(methoxymethoxy)phenyl]-4,4, 5,5-tetramethyl-1,3,2-dioxaborolane (3542 mg, 11,061 mmol, 27% 137 performance) as a white solid. The title compound was prepared as described in Example 17, replacing 1(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-6-( (4-tert-butyl)-2hydroxyphenyl)-2-chloro-pyridine-3-carboxylic acid, prepared as in example 37, replacing 4-tert-butylbenzeneboronic acid with 2-[4-tert-butyl-2-(methoxymethoxy) phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.1H NMR (400 MHz, DMSO-ob+DsO) δ 8 8.32 (s, 2H), 7.65 (d, J = 8.7 Hz , 1H), 7.21 (s, 1H), 7.07 (d, J = 8.0 Hz, 1 H), 6.95 (dd, J = 8.4, 1.9 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.85 (d, J = 1.9 Hz, 1H), 6.73 (s, 1H), 6.70 (s, 1H), 6.36 (s, 1H), 6.25 (s, 1H), 4.92-4.88 (m, 1H), 4.64 - 4.53 (m, 1H), 4.11 (dd, J= 5.6, 4.7 Hz, 1H), 4.05-3.91 (m, 6H), 3.37-3.30 (m, 1 H), 3.26-3.18 (m, 1H), 3.19 -3.09 (m, 1H), 3.02-2.88 (m, 6H), 2.86-2.75 (m, 2H), 1.24 (s, 9H), 1.16 (d, J = 6.8 Hz, 3H), LCMS (Method 5-100 AB, 7 min): Rt = 2.03 min, [M+H]+= 1043.5. Example 62 ΜΛ / Ε / ΖυΖΖ / υΊ I heard ΟΊ o=s—NH2 II or 4-Amino-2-(4-(tert-butyl)-2-fluorophenyl)-6-methylpyrimidine-5-carboxylic acid was prepared as described in Example 54, replacing 2- (3,3-dimethylbutox¡)-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyr¡dine with 2-(4-(ter- butyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The title compound was prepared as described in Example 1, replacing 1-(4-(tert-butyl)phenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylic acid with 4-amino-2-(4 -(tert-butyl)-2-fluorophen¡l)6-methylpyr¡midine-5-carboxylic.1H NMR (400MHz, MeOH - ch) δ (ppm) 7.75 - 7.69 (m, 1H), 7.34 - 7.26 (m, 1H), 7.25 - 7.17 (m, 1H), 7.12 - 7.01 (m, 1H), 6.96 - 6.73 (m, 3H), 6.63 - 6.54 (m, 1H), 6.44 (s, 1H) , 5.21 - 5.10 (m, 1H), 4.82 - 4.65 (m, 4H), 4.44 (s, 1H), 4.32 - 3.87 (m, 6H), 3.66 - 3.48 (m, 1H), 3.42 3.32 (m, 1H) ), 3.25 - 2.87 (m, 8H), 2.49 -2.32 (m, 3H), 1.39 - 1.29 (m, 12H). LCMS (Method 5-95 AB, ESI): Rt = 0.769 min, [M+H]+= 1026.5. Example 63 138 ΜΛ / Ε / ΖυΖΖ / υΊ Ο / ΟΊ The general procedure for the synthesis of ethyl 6—(4—(fer—butyl)phenyl)—4—chloro—2—methylnicotinate was performed using the procedures of J. Med. Chem. 2013, 56, 1023-1040. Step 1: Ethyl 4,6-dichloro-2-methyl-pyridin-3-carboxylate (966 mg, 4.13 mmol, 1.05 equiv) and Pd(PPh3)4 (227 mg, 0.2000 mmol, 0.05 equiv ) were stirred in Diglima (3.6 mL) at room temperature for 15...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: ML / E / ZυZZZ / υΊ Oí ΟΊ formula (I); wherein: R1 is H or -(Ci-C6)alkyl optionally substituted with one, two or three R1a; each R1a is independently halogen, -CN, -ORa, -SRa, -NRcRd, -NO2, -C(=O)Rb, NRaC(=O)Rb, -C(=O)ORa, -C(=O)NRcRd, -NRaC(=O)NRcRd, -S(=O)2Rb, -S(=O)Rb, - S(=O)2NRcRd, S(=O)NRcRd, -NRaS(=O)2Rb, -NRaS(=O)2NRcRd, -NRaORa, -NRaC(=O)NRaORa -O(Ci-C6)alkyleneNRcRd, -NRaC(=NRc)Ra, -C(=NRa)NRcRd, -NRaC(=NRa)NRcRd, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R1a on the same carbon are taken together to form an oxo; R2 is H, -NRcRd or -(Ci-Cejalkyl optionally substituted with one, two or three R2a;each R2a is independently halogen, -CN, -ORa, -SRa, -NRcRd, -NO2, -C(=O)Rb, NRaC(=O)Rb, -C(=O)ORa, -C(=O)NRcRd, -NRaC(=O)NRcRd, -S(=O)2Rb, -S(=O)Rb, -S(=O)2NRcRd, S(=O)NRcRd, -NRaS(=O)2Rb, -NRaS(=O)2NRcRd, -NRaORa, -NRaC(=O)NRaORa, -O(C1-C6)alkylenNRcRd, -NRaC(=NRc)Ra, -C(=NRa)NRcRd, -NRaC(=NRa)NRcRd, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; that of R2a on the same carbon comes together to form an oxo; R3 is H, -(C3-C6)cycloalkyl or -(C1-C6)alkyl optionally substituted with one, of the three R3a; each R3a is independently halogen, -CN, -ORa, -SRa, -NRcRd, -NO2, -C(=O)Rb, NRaC(=O)Rb, -C(=O)ORa, -C(=O)NRcRd, -NRaC(=O)NRcRd, -S(=O)2Rb, -S(=O)Rb, -S(=O)2NRcRd, S(=O)NRcRd, -NRaS(=O)2Rb, -NRaS(=O)2NRcRd, -NRaORa, -NRaC(=O)NRaORa, -O(C1-C6)alkylenNRcRd, -NRaC(=NRc)Ra, -C(=NRa)NRcRd, -NRaC(=NRa)NRcRd, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;X is (C1-C2)alkylene, (C2-C6)alkenylene, (C2-C6)alkynylene, (C3-C7)cycloalkylene, (C2-C7)heterocycloalkylene, arylene or heteroarylene; wherein the alkylene, alkenylene, alkynylene, cycloalkylene, heteroacycloalkylene, arylene and heteroarylene are optionally substituted with one, two or three Rx; each Rx is independently halogen, -CN, -ORa, -NRcRd, -NO2, -C(=O)Rb, -C(=O)ORa, C(=O)NRcRd, -(Ci-Csjalkyl, -(Ci-C6)haloalkyl, -(Ci-C6)heteroalkyl, -(Ci-Cejhydroxyalkyl, -(Ci-Cejaminoalkyl, -(C3-C7)cycloalkyl or -(C2-C7)heterocycloalkyl; or two Rx on the same carbon are taken together to form an oxo; and is bonded, -O-, -S-, (Ci-Cs)alkylene, (C2-C6)alkenylene, (C2-C6)alkynylene, (C3C7)cycloalkylene, (C2-C7)heterocycloalkylene, arylene or heteroarylene; wherein the alkylene, alkenylene, alkynylene, cycloalkylene, heteroacycloalkylene, arylene and heteroarylene are optionally substituted with one, two or three RY;each RY is independently halogen, -CN, -ORa, -NRcRd, -NO2, -C(=O)Rb, -C(=O)ORa, C(=O)NRcRd, -(C1-Ce)alkyl, -(C1-Ce)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C3-C7)cycloalkyl or -(C2-C7)heterocycloalkyl; or two RYs on the same carbon are taken together to form an oxo; Z is H, halogen, -CN, -OR10, -SR10, -NR12R13, -C(=O)R11, -C(=O)OR2, -C(=O)NR12R13, -(C1Ci2)alkyl, -(Ci-Ci2)heteroalkyl, -(C1-C12)haloalkyl, -(C1-C12)hydroxyalkyl, -(C1-C12)aminoalkyl, -(C2-C12)alkenyl, -(C2-C12)alkynyl, -(C3-C9)cycloalkyl, -(C2-C7)heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one, two or three Rz;each Rz is independently halogen, -CN, -OR10, -NR12R13, -NO2, -C(=O)R11, C(=O)OR10, -C(=O)NR12R13, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C7)cycloalkyl or -(C2-C7)heterocycloalkyl; or two Rz on the same carbon are taken together to form an oxo; each R10 is independently H, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hyd roxyalkyl, -(C1-C6)aminoalkyl, -(C2-C6)alkenyl, -(C2-C1)alkynyl, -(C3-C7)cycloalkyl, (C2-C7)heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally independently substituted with one, two or three R10a; each R10a is independently halogen, -CN, -ORa, -NRcRd, -C(=O)Rb, -C(=O)ORa, C(=O)NRcRd, -(C1-C6)alkyl or -(C1-C6)haloalkyl; or two R10a on the same carbon are taken together to form an oxo;each R11 is independently -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C2-C6)alkenyl, -(C2-C1)alkynyl, -(C3-C7)cycloalkyl, -(C2-C7)heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, MA / E / ZUZZ / U1 Oí ΟΊ 162 heterocycloalkyl, aryl and heteroaryl are optionally independently substituted with one, two or three R11a; each R11a is independently halogen, -CN, -ORa, -NRcRd, -C(=O)Rb, -C(=O)ORa, C(=O)NRcRd, -(Ci-C6)alkyl or -(Ci-C6)haloalkyl; or two R11a on the same carbon are taken together to form an oxo; each R12 and R13 is independently H, -(Ci-C6)alkyl, -(Ci-C6)haloalkyl, -(Ci-C6)heteroalkyl, -(Ci-C6)hydroxyalkyl, -(Ci-C6)aminoalkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C2-C7)cycloalkyl, -(C2-C7)heterocycloalkyl, aryl or heteroaryl;wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally independently substituted with one, two or three R12a groups; or R12 and R13 are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl group optionally substituted with one, two or three R12b groups; Each R12a is independently a halogen, -CN, -ORa, -NRcRd, -C(=O)Rb, -C(=O)ORa, C(=O)NRcRd, -(Ci-Csjalkyl or -(Ci-C6)haloalkyl; or two R12a on the same carbon are taken together to form an oxo; each R12b is independently a halogen, -CN, -ORa, -NRcRd, -C(=O)Rb, -C(=O)ORa, C(=O)NRcRd, -(Ci-Csjalkyl or -(Ci-C6)haloalkyl; or two R12b on the same carbon are taken together to form an oxo; each Ra is independently H, -(Ci-Csjalkyl, -(C1-C6)haloalkyl, -(Ci-C6)heteroalkyl, -(Ci-C6)hydroxyalkyl, -(Ci-Cejaminoalkyl, -(C2-C6)alkenyl, -(C2-Ce)alkynyl, -(C3-C7)cycloalkyl, (C2-C7)heterocycloalkyl, aryl or heteroaryl;wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally independently substituted with one, two or three halogens, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH2 or -(C1C6)alkyl; each Rb is independently — (C1 —Cj alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, (C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C7)cycloalkyl, (C2-C7)heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally independently substituted with one, two or three halogens, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH2 or -(C1Cj alkyl;and each Rc and Rd is independently H, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C1-C6)heteroalkyl, -(C1-C6)hydroxyalkyl, -(C1-C6)aminoalkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, (C3-C7)cycloalkyl, (C2-C7)heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally independently substituted with one, two or three halogens, -CN, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH2 or -(C1-C6)alkyl; or Rc and Rd are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl optionally substituted with one, two or three oxo, halogen, -CN, -OH, -OMe, -NH2, IVIA / t / ZUZZ / U 1 O / 01 163 C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH2 or -(Ci-C6)alkyl.; 2. The compound according to claim 1, wherein R2 is H or -(Ci-C6)alkyl.

3. The compound according to claim 1 or 2, wherein R2 is H.

4. The compound according to any of claims 1-3, wherein R3 is H or -(Ci-C6)alkyl.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R3 is -(CiCejalkyl.

6. The compound according to any of claims 1-4, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R3 is methyl.

7. The compound according to any of claims 1-6, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R4 is H.

8. The compound according to any of claims 1-6, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R4 is methyl.

9. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein the compound has the structure of formula (a): ML / E / ZυZZZ / υΊ Oí ΟΊ formula (a) 10. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof; wherein the compound has the structure of formula (Ib): 164 MLE / E / ZυZZZ / υΊ Oí ΟΊ formula (Ib).

11. The compound according to any of claims 1-10, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R1 is —(Ci— Cejalkyl optionally substituted with one, two or three R1a.

12. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R1 is —(Ci— Cejalkyl substituted with an R1a.

13. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R1a is independently halogen, -CN, -ORa, -NRcRd, -NRcC(=O)Rb, -NRcC(=O)NRcRd, -NRcS(=O)2Rb or -NRcS(=O)2NRcRd.

14. The compound according to any one of claims 1-13, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R1a is independently -NRcRd or -NRcS(=O)2NRcRd.

15. The compound according to any of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1a is independently -NRcRd.

16. The compound according to any of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R1a is independently -NRcS(=O)2NRcRd.

17. The compound according to any of claims 1-14, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R1 is CH2CH2NH2, -CH2CH2NHSO2NH2 or -CH2NHSO2NH2.

18. The compound according to any one of claims 1-15, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R1 is - 165 CH2CH2NH2.

19. The compound according to any of claims 1-14 or 16, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R1 is CH2CH2NHSO2NH2.

20. The compound according to any of claims 1-14 or 16, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R1 is CH2NHSO2NH2.

21. The compound according to any one of claims 1-20, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein X is (C2C7)heterocycloalkylene or heteroarylene; each optionally substituted with one, two or three Rx.

22. The compound according to any of claims 1-21, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein X is (C2C7)heterocycloalkylene optionally substituted with one, two or three Rx.

23. The compound according to any of claims 1-21, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein X is a heteroarylene optionally substituted with one, two or three Rx.

24. The compound according to any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each Rx is independently halogen, -ORa, -NRcRd, -(Ci-C6)alkyl, or -(Ci-C6)haloalkyl; or two Rx on the same carbon are taken together to form an oxo.

25. The compound according to any one of claims 1-24, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each Rx is independently -NRcRd or -(C1-C6)alkyl; or two Rx at the same carbon are taken together to form an oxo.

26. The compound according to any one of claims 1-25, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Y is -(C2C7)heterocycloalkylene or arylene; each optionally substituted with one, two or three RY groups.

27. The compound according to any of claims 1-26, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Y is an arylene optionally substituted with one, two or three RY groups.

28. The compound according to any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each RY is independently halogen, -ORa, -NRcRd, -(C1-C1e)alkyl, or -(C1-C1e)haloalkyl; or two RYs on the same carbon are taken together to form an oxo.

29. The compound according to any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is H, halogen, -CN, -OR10, -SR10, -NR12R13, -C(=O)R11, -C(=O)OR2, -C(=O)NR12R13, -(C1-C12)alkyl, -(C1-C12)heteroalkyl, -(C1-C12)haloalkyl, -(C1-C12)hydroxyalkyl, -(C1-C12)aminoalkyl, -(C2-C12)alkenyl, -(C2-C12)alkynyl, -(C3-C7)cycloalkyl, -(C2-C7)heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroacycloalkyl, aryl and heteroaryl are optionally substituted with one, two or three Rz.

30. The compound according to any one of claims 1-29, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is a halogen, -OR10, -NR12R13, -(Ci-Ci2)alkyl, -(Ci-Ci2)heteroalkyl, -(Ci-Ci2)haloalkyl, -(CiCi2)hydroxyalkyl, -(Ci-Ci2)aminoalkyl, -(C3-C9)cycloalkyl, or -(C2-C7)heterocycloalkyl; wherein the alkyl, cycloalkyl, and heteroacycloalkyl groups are optionally substituted with one, two, or three Rz groups.

31. The compound according to any one of claims 1-30, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Z is -OR10, (Ci-Ci2)alkyl, -(Ci-Ci2)haloalkyl or -(C3-C9)cycloalkyl; wherein the alkyl and cycloalkyl groups are optionally substituted with one, two or three Rz groups.

32. The compound according to any of claims 1-31, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Z is-OR10.

33. The compound according to any of claims 1-31, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Z is —(Ci— Ci2)alkyl optionally substituted with one, two or three Rz.

34. The compound according to any one of claims 1-31, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Z is —(Ci— Ci2)alkyl.

35. The compound according to any one of claims 1-31, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Z is —(Ci— Ci2)haloalkyl optionally substituted with one, two or three Rz.

36. The compound according to any one of claims 1-31, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Z is —(Oí— Ci2)haloalkyl.

37. The compound according to any of claims 1-31, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Z is -(CsCsjcycloalkyl optionally substituted with one, two or three Rz.

38. The compound according to any one of claims 1-31, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Z is -(C3C9)cycloalkyl.

39. The compound according to any of claims 1-31, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Z is -(C3C7)cycloalkyl optionally substituted with one, two or three Rz.

40. The compound according to any one of claims 1-31, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is -(C3C7)cycloalkyl. MLE / E / ZυZZZ / υΊ Oí ΟΊ 167 41. The compound according to any one of claims 1-40, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each Rz is independently halogen,-OR10,-NR12R13 or-(Ci-C6)alkyl.

42. The compound according to any one of claims 1-41, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each Rz is independently —(Ci—C6)alkyl.

43. The compound according to any one of claims 1-42, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R10 is -(C1-C6)alkyl, -(C1-C6)haloalkyl or -(C3-C7)cycloalkyl.

44. The compound according to any one of claims 1-43, or a salt, a solvate or stereoisomer acceptable from the pharmaceutical standpoint hereof, wherein R10 is -(CiCs)alkyl or -(C3-C7)cycloalkyl.

45. The compound according to any one of claims 1-20, or a salt, a solvate or stereoisomer acceptable from the pharmaceutical point of view hereof, wherein-XYZ is ΜΛ / Ε / ΖυΖΖ / υΊ Yes ΟΊ 168 Υγγ· Ύγ Υ Υ\Υ ^ΤΥ' Υύ Ά ! m ΥΎ C ΝΥ ΝΗ„CI Υζς ν^ΥΥ^ΟΗ ^vO-sz^v' Ί] ΟγΧγ^ΝΗζ ΥγΥΥΗ- 'ϊ| OH nYC ΝΫ Ν. < ΎΎ I . CI . I ΗΝbCt^ N, Υ\γ Υ^γ Υ\χ Υ\ίΥΗ· N^Iy HOJ Μγ^ Νγ^ 0Η Νγ^ I ' Nl·, NH¿ NIL CI ^\ς·Y b® =3⁄43⁄4 \γγ ΝΗ; Η.Ν< 46. ​​The compound according to any one of claims 1-20, or a salt, a solvate or stereoisomer acceptable from the pharmaceutical point of view hereof, wherein-XYZ is 169 μλ / ε / zuzz / ui gold i 47. The compound according to any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein -XYZ is . or 48. The compound according to any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein -XYZ is 170 MA / E / ZUZZ / U1 Oí ΟΊ 49. The compound according to any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein-XYZ is 50. A compound, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, selected from the group consisting of: 0 / ΟΊ 174 MA / E / ZUZZ / U1 I hear ΟΊ ΜΛ / Ε / ΖυΖΖ / υΊ 0 / ΟΊ 176 MA / E / ZUZZ / U1 I hear ΟΊ 178 MA / E / ZUZZ / U1O / O1 51. The compound according to claim 50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of: 179 OH 180 MA / E / ZUZZ / U1 Oí ΟΊ 181 ML / E / ZυZZZ / υΊ 0 / ΟΊ 182 52. The compound according to claim 50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of: ML / E / ZUZZ / U1 Oí Oí ML / E / ZUZZ / U1 ...

53. The compound according to claim 50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of: 187 MA / E / ZUZZ / U1 Oí ΟΊ 188 OH OH MA / E / ZUZZ / U1 Oí ΟΊ 54. The compound according to claim 50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from the group consisting of: 189 55. The compound according to claim 50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is (8S,11S,14S)18-hydroxy-11-methyl-14-[methyl-[(2S)-2-[[4-amino-2-(4-tert-butylphenyl)-6-methyl-pyrimidin-5-carbonyl]amino]-3-(sulfamolamino)propanyl]amino]-10,13-dioxo-3,17-bis[(2R)-3-amino-2-hydroxypropoxy]-9,12-diazatricyclo[13.3.1.12.6]cosa-1(18),2(20),3,5,15(19),16-hexaen-8-carboxylic acid.

56. The compound according to claim 50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is (8S,11S,14S)18-hydroxy-11-methyl-14-[methyl-[(2S)-2-[[4-methyl-2-[4-(1-methylcyclopropyl)phenyl]pyrimidin-5-carbonyl]amino]-3-(sulfamolamino)propanyl]amino]-10,13-dioxo-3,17-bis[(2R)-3-amino-2-hyd roxypropoxy]-9,12-diazatricyclo[13.3.1.12,6]icosa-1(18),2(20),3,5,15(19),16-hexaen-8-carboxylic.

57. The compound according to claim 50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is (8S,11S,14S)18-hydroxy-11-methyl-14-[methyl-[(2S)^4-amino-2-[[4-amino-2-(4-tert-butylphenyl)-6-methyl-pyrimidi-5-carbonyl]amino]butanyl]amino]-10,13-dioxo-3,17-bis[(2R)-3-amino-2-hydroxy-propoxy]-9,12d-azatricyclo[13.3.1.12.6]cosa-1(18),2(20),3,5,15(19),16-hexaen-8-carboxylic acid.

58. The compound according to claim 50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is (8S,11S,14S)18-hydroxy-11-methyl-14-[methyl-[(2S)-4-amino-2-{[4-methyl-2-[4-(1-methylcyclopropyl)phenyl]pyrimidine-5-190 carbonyl]amino]butanyl]amino]-10,13-dioxo-3,17-bis[(2R)-3-amino-2-hydroxypropoxy]-9,12d azatricyclo[13.3.1.12.6]cosa-1(18),2(20),3,5,15(19),16-hexaen-8-carboxylic acid.

59. The compound according to claim 50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is (8S,11S,14S)18-hydroxy-11-methyl-14-[methyl-[(2S)^1-amino-24[2-(4-tert-butylphenyl)-4-amino-6-difluoromethylpyrimidin-5-carbonyl]amino]butanoyl]amino]-10,13-dioxixo-3,17-bis[(2R)-3-amino-2-hydroxypropoxy]9,12-diazatrichloro[13.3.1.12.6]cosa-1(18),2(20),3,5,15(19),16-hexaen-8-carboxylic acid.

60. The compound according to claim 50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is (8S,11S,14S)14-[[(2S)-2-[[4-amino-2-(4-tert-butylphenyl)-6-(difluoromethyl)pyrimidin-5-carbonyl]amino]-3-(sulfamoylamino)propanyl]-methyl-amino]-3,17-bis[(2R)-3-amino-2-hydroxypropoxy]-18-hydroxy-11-methyl-10,13-dioxo-9,12-diazatric acid [13.3.1.12.6]cosa-1(18),2(20),3,5,15(19),1 6-hexaen-8-carboxylic.

61. A pharmaceutical composition comprising the compound according to any one of claims 1-60, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient.

62. Use of a compound according to any of claims 1-60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the preparation of a medicament for the treatment of a bacterial infection in a patient.

63. A method of treating a bacterial infection in a mammal, comprising administering to the mammal an effective amount of a compound according to any of claims 1-60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, with a frequency and for a sufficient time to provide a beneficial effect to the mammal.

64. A method of treating a lepB-mediated infection in a mammal, comprising administering to the mammal an effective amount of a compound according to any of claims 1-60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, with a frequency and for a sufficient time to provide a beneficial effect to the mammal.

65. The method according to claim 63 or 64, wherein the bacterial infection is an infection involving Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticous, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis,MA / t / ZUZZ / UlO / Ol 191 Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylorí, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferí, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A grupo de homología, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostrídium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacteríum diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae,Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedias, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis or Staphylococcus saccharolyticus., 66. The method according to any of claims 63-65, wherein the bacterial infection is an infection involving Acinetobacter baumannii, Klebsiella pneumoniae or Pseudomonas aeruginosa.

67. The method according to any of claims 63-66, wherein the bacterial infection is an infection involving Acinetobacter baumannii.

68. The method according to claim 63 or 64, wherein the bacterial infection is an infection involving a Gram-negative bacterium.

69. The method according to any of claims 63-68, further comprising administering a second therapeutic agent.

70. The method according to claim 69, wherein the second therapeutic agent is not an inhibitor of SpsB or LepB.

71. The method according to claim 70, wherein the second therapeutic agent is an aminoglycoside antibiotic, fluoroquinolone antibiotic, β-lactam antibiotic, macrolide antibiotic, glycopeptide antibiotic, rifampicin, chloramphenicol, fluoramphenicol, colistin, mupirocin, bacitracin, daptomycin, or linezolid.

72. The method according to claim 70, wherein the second therapeutic agent is a β-lactam antibiotic.

73. The method according to claim 72, wherein the β-lactam antibiotic is selected from penicillins, monobactams, cephalosporins, cephamycins, and carbapenems.

74. The method according to claim 73, wherein the β-lactam antibiotic is selected from Azlocillin, Amoxicillin, Ampicillin, Doripenem, Meropenem, Biapenem, Cefamandole, Imipenem, Mezlocillin, Cefmetazole, Cefprozil, Piperacillin / tazobactam, Carbenicillin, Cefaclor, Cefalothin, Ertapenem, Cefazolin, Cefepime, Cefonicid, Cefoxitin, Ceftazidime, Oxacillin, Cefdinir, Cefixime, Cefotaxime, Cefotetan, Cefpodoxime, Ceftizoxime, Ceftriaxone, Faropenem, Mecillin, Methicillin, Moxalactam, Ticarcillin, Tomopenem, Ceftobiprole, Ceftaroline, Flomoxef, Cefiprome and Cefozopran.

75. The method according to any of claims 63-74, further comprising administering a β-lactamase inhibitor.