Patent Application
20230331683
Sphingosine 1-phosphate (S1P) is a simple lipid that is chemotactic when present extracellularly, but which is also a second messenger when intracellular. These roles require compartmentalization, which is provided in part by extrusion of S1P from cells. The S1P transporters, SPNS2 (endothelium) and MFSD2B (erythrocytes), release S1P from cells. When this release is coupled with S1P degradation in tissue parenchyma, a differential is generated between the extracellular (high) and intracellular (low) S1P concentrations. Mouse genetic studies indicate that endothelial cells use SPNS2 to provide most of the S1P in lymph as well as about one-third of plasma S1P, whereas erythrocytes provide the remainder of plasma S1P via MFSD2B. The S1P gradient in blood functions both to maintain endothelial barrier integrity and promote migration of lymphocytes from the thymus to the blood.
Investigations of SIP receptor modulators led to the realization that the lymph S1P gradient is particularly important for egress of lymphocytes from secondary lymphoid tissue into efferent lymph. However, on-target activity of S1P receptor modulators at endothelial and cardiac S1P receptors drives adverse events such as first dose bradycardia.
The present disclosure provides, in various embodiments, compounds and their pharmaceutically acceptable salts conforming to Formula IA as SPNS2 inhibitors that avoid on-target adverse activity:
X is a C6-C10-aryl or 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl ring members are independently selected from N, O, and S).
R1 and R2 are independently selected from the group consisting of H, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C3-C8-cycloalkyl, C1-C6-haloalkyl, CN, and halo.
W is a bond, O, NH, —NHC(O)—, or —O—(N═)C(R)— (wherein R is H or C1-C6-alkyl).
V is selected from the group consisting of H, C1-C14-alkyl, C2-C12-alkenyl, (C6-C10)aryl, (C6-C10)heteroaryl, —C1-C10-alkyl-(C6-C10)aryl, —C2-C12-alkenyl-(C6-C10)aryl, —C1-C10-alkyl-(C3-C8)cycloalkyl, -(3- to 14-membered heterocycloalkyl) (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S), —(C1-C10)alkyl-(3- to 14-membered heterocycloalkyl) (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S).
T is selected from the group consisting of a bond, —C(O)—, —C(O)NRx—, —C(S)NRx—, —NRxC(O)—, —NRx—, —NRxC(O)NRx—, —NRxC(O)O—, and —OC(O)NRx—.
Rx in each instance is independently selected from H and C1-C6-alkyl.
Subscript m is an integer selected from 0, 1, 2, 3, 4, 5, and 6.
Subscript n is an integer selected from 1 and 2, wherein the sum of n and o is greater than 0.
Each “---” is a single bond that is optionally present. It should be understood that all bonds “---” are either simultaneously present or absent. When “---” is present, then o is selected from 1, 2, and 3. Further, in one embodiment, p is 0, (N)pR6 represents a bond, and U is —CH— or N, or, in another embodiment, p is 1 and U is —CH—. When “---” is not present, per another embodiment, then o is 0 and U is —CH2— or NH.
Subscript q is an integer selected from 1, 2, and 3.
R3 is selected from the group consisting of, H, C1-C6-alkyl, and —C(NH)NH2.
R4 is absent when “---” is present. When “---” is absent, then R4 is H or C1-C6-alkyl.
Each R5 is independently selected from the group consisting of H, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C3-C8-cycloalkyl, C1-C6-haloalkyl, CN, NH2, and halo.
R6 is H or C1-C6-alkyl.
In Formula IA, each alkyl, alkoxy, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl is optionally substituted with 1 - 5 substituents independently selected from the group consisting of hydroxy, halo, C1-C6-haloalkoxy, C1-C6-haloalkyl, —NR′2, —NHC(O)(OC1—C6—alkyl), —NO2, —CN, oxo, —C(O)OH, —C(O)O(C1—C6—alkyl), —C1—C6—alkyl(C1—C6—alkoxy), —C(O)NH2, C1-C6-alkyl, —C(O)C1—C6—alkyl, —OC1—C6—alkyl, —Si(C1—C6—alkyl)3, —S(O)0-2—(C1—C6—alkyl), C6-C10-aryl, —(C1-C6-alkyl)(C6-C10-aryl), 3- to 14-membered heterocycloalkyl, and —(C1-C6-alkyl)-(3- to 14-membered heterocycle) (wherein 1-4 heterocycle members are independently selected from N, O, and S), and —O(C6-C14-aryl).
Each R′ is independently selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C6-C10-aryl, 3- to 14-membered heterocycloalkyl and —(C1-C6-alkyl)-(3- to 14-membered heterocycloalkyl) (wherein 1-4 ring members are independently selected from N, O, and S), and 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S.
The present disclosure also provides, in various embodiments, compounds and their pharmaceutically acceptable salts conforming to Formula I as SPNS2 inhibitors that avoid on-target adverse activity:
X is a C6-C10-aryl or 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl ring members are independently selected from N, O, and S).
R1 and R2 are independently selected from the group consisting of H, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C3-C8-cycloalkyl, C1-C6-haloalkyl, CN, and halo.
W is a bond, O, NH, —NHC(O)—, or —O—(N═)C(R)— (wherein R is H or C1-C6-alkyl).
V is selected from the group consisting of H, C1-C14-alkyl, C2-C12-alkenyl, (C6-C10)aryl, (C6-C10)heteroaryl, —C1-C10-alkyl-(C6-C10)aryl, —C2-C12-alkenyl-(C6-C10)aryl, —C1-C10-alkyl-(C3-C8)cycloalkyl, -(3- to 14-membered heterocycloalkyl) (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S), —(C1-C10)alkyl-(3- to 14-membered heterocycloalkyl) (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S).
Y is —C(O)— and Z is —NH—, or Y is —NH— and Z is —C(O)—.
Each dashed line represented as “
” is a single bond that is optionally present.
R3 is selected from the group consisting of, H, C1-C6-alkyl, and —C(NH)NH2.
R4 is absent when “
” is present, and when “
” is absent, then R4 is H or C1-C6-alkyl.
Subscript m is an integer selected from 0, 1, 2, 3, 4, 5, and 6; n is an integer selected from 1 and 2; o is an integer selected from 0 and, when “
” is present, is selected from 2, and 3; and the sum of n and o is greater than 2.
Each alkyl, alkoxy, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl in Formula I is optionally substituted with 1 - 5 substituents independently selected from the group consisting of hydroxy, halo, C1-C6-haloalkoxy, C1-C6-haloalkyl, —NR′2, —NHC(O)(OC1—C6—alkyl), —NO2, —CN, oxo, —C(O)OH, —C(O)O(C1—C6—alkyl), —C1-C6-alkyl(C1-C6-alkoxy), —C(O)NH2, C1-C6-alkyl, —C(O)C1—C6—alkyl, —OC1—C6—alkyl, —Si(C1—C6—alkyl)3, —S(O)0-1—(C1—C6—alkyl), C6-C10-aryl, —(C1—C6—alkyl)(C6—C10—aryl), 3- to 14-membered heterocycloalkyl, and -(C1-C6-alkyl)-(3- to 14-membered heterocycle) (wherein 1-4 heterocycle members are independently selected from N, O, and S), and -O(C6-C14-aryl).
Each R′ is independently selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C6-C10-aryl, 3- to 14-membered heterocycloalkyl and —(C1-C6-alkyl)-(3- to 14-membered heterocycloalkyl) (wherein 1-4 ring members are independently selected from N, O, and S), and 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S.
Another embodiment of the disclosure is a pharmaceutical composition comprising a compound of Formula IA or Formula I or a pharmaceutically acceptable salt thereof.
The disclosure also provides, in an embodiment, a method of inhibiting spinster homolog 2 (SPNS2), comprising contacting SPNS2 with an effective amount of a compound of Formula IA or Formula I or a pharmaceutically acceptable salt thereof.
Still another embodiment is a method of treating a patient afflicted by a neoplastic disease, comprising administering to the patient a therapeutically effective amount of a compound of Formula IA or Formula I or a pharmaceutically acceptable salt thereof.
In an embodiment, the disclosure provides a method of treating a patient afflicted with an allergic disease, comprising administering to the patient a therapeutically effective amount of a compound of Formula IA or Formula I or a pharmaceutically acceptable salt thereof.
In another embodiment, the disclosure provides a method of treating a patient afflicted with an autoimmune disease, comprising administering to the patient a therapeutically effective amount of a compound of Formula IA or Formula I or a pharmaceutically acceptable salt thereof.
In a properly functioning immune system, the right cells get to the right places at the right times. Gradients of the chemotactic lipid, sphingosine 1-phosphate (S1P), enable correct positioning of immune cells. Lymphocyte egress from secondary lymphoid tissues is particularly dependent on S1P signaling. S1P’s role in lymphocyte trafficking was discovered when the mechanism of action of the immunosuppressive drug fingolimod (FTY720) was investigated. Fingolimod’s active metabolite, phospho-FTY720, desensitizes lymphocyte S1P1 receptors; thereby, rendering these cells unable to detect the S1P-rich environment of efferent lymph1. The resulting lymphopenia is now recognized as a general property of S1P1 receptor agonists. Although fingolimod and other S1P receptor modulators eventually became medicines for treating relapsing remitting multiple sclerosis2, S1P1 receptor agonists have several on target liabilities including initial dose bradycardia and compromised endothelial barrier function2. Therefore, alternative strategies to achieve immunosuppression by modulating S1P signaling without undesirable on-target activity are needed.
S1P is synthesized ubiquitously, but its intracellular accumulation is limited by degradation and export. In lymph nodes (LN), brisk catabolic activity by S1P lyase keeps S1P3 low while lymph endothelial cells extrude S1P into lymph via a transporter, SPNS24, resulting in a lymph - LN S1P gradient. Vascular (blood) S1P gradients are likewise maintained by prominent S1P catabolic activity in tissue parenchyma coupled with the extrusion of S1P into plasma. About ⅓ of plasma S1P is provided by vascular endothelial cells via SPNS24, with the remainder being released from red blood cells (RBCs) by a different S1P transporter. The RBC transporter is known now to be MFSD2B, which is an erythroid lineage-specific major facilitator superfamily member that is distantly related to SPNS25,6. Germ line deletion of Mfsd2b results in a 50% decrease in plasma S1P but an astonishing 60-fold increase in RBC S1P; however, these animals are not lymphopenic5 RBCs lack S1P catabolic enzymes but express sphingosine kinase type 1 (SphK1), which accounts for the high levels of S1P in whole blood. Blood S1P gradients are necessary to maintain endothelial barrier integrity7. Indeed, Hla has proposed that vascular S1P gradients are a fundamental property of the closed circulatory systems of vertebrates9.
The role of the catabolic enzyme S1P lyase in maintaining low LN S1P predicts that S1P lyase inhibitors will eliminate the S1P gradient, which will modulate the immune system by disrupting lymphocyte trafficking analogous to S1P1 agonists. Indeed, S1P lyase deficiency, whether accomplished through genetic manipulation of mice or S1P lyase inhibitor administration, raises S1P levels in tissues, including lymph nodes, with a resulting lymphopenia3,10. However, administering a selective S1P lyase inhibitor to rats and inducing global deletion of the gene (Sgpl1) in mice were both found to be nephrotoxic10. Furthermore, humans deficient in S1P lyase activity because of SGPL1 alleles encoding catalytically deficient S1P lyase exhibit multiple pathologies including steroid resistant nephrosis, adrenal insufficiency, and ichthyosis11,12. Such observations appear to eliminate S1P lyase as a therapeutic target.
Mice rendered deficient in Spns2 either through germ line or endothelium-specific deletion of Spns2, have a 10-fold decrease in S1P levels in thoracic duct lymph and are lymphopenic but the vascular S1P gradient is less affected (30% reduction in plasma S1P)4. These results validate the data disclosed herein that SPNS2 inhibitors of this disclosure, by preventing the formation of the lymph S1P gradient, recapitulate the therapeutic efficacy of S1P1 receptor agonists without their adverse events.
Application of an SPNS2 inhibitor in immuno-oncology comes from another mouse genetics study. In a screen of 810 mouse strains with different germ line gene deletions, Spns2-/- mice were found to have remarkably low metastatic colonization of the lungs when injected with B16-F10 melanoma cells13. This effect was observed with other lung metastatic colonization models and in similar models in liver. As expected, the total number of immune cells in the lung was reduced in the lymphopenic Spns2-/- mice, but the lung resident population was proportionally enriched in natural killer and CD8+ effector cells13.
Thus, results from the study of mice rendered deficient in Spns2 indicate that SPNS2 inhibitors are immunomodulatory. The SPNS2 inhibitors of the disclosure recapitulate the SPNS2 null phenotype, and they and enable S1P transport inhibition as a viable therapeutic strategy as well as providing heretofore unavailable chemical biology tools to explore S1P physiology in vivo.
“Alkyl” refers to straight or branched chain hydrocarbyl including from 1 to about 20 carbon atoms. For instance, an alkyl can have from 1 to 10 carbon atoms or 1 to 6 carbon atoms. Exemplary alkyl includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like, and also includes branched chain isomers of straight chain alkyl groups, for example without limitation, —CH(CH3)2, —CH(CH3)(CH2CH3), —CH(CH2CH3)2, —C(CH3)3, —C(CH2CH3)3, —CH2CH(CH3)2, —CH2CH(CH3)(CH2CH3), —CH2CH(CH2CH3)2, —CH2 C(CH3)3, —CH2C(CH2CH3)3, —CH(CH3)CH(CH3)(CH2CH3), —CH2CH2CH(CH3)2, —CH2CH2C H(CH3)(CH2CH3), —CH2CH2CH(CH2CH3)2, —CH2CH2C(CH3)3, —CH2CH2C(CH2CH3)3, —CH( CH3)CH2CH(CH3)2, —CH(CH3)CH(CH3)CH(CH3)2, and the like. Thus, alkyl groups include primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. An alkyl group can be unsubstituted or optionally substituted with one or more substituents as described herein below.
The phrase “substituted alkyl” refers to alkyl substituted at one or more positions, for example, 1, 2, 3, 4, 5, or even 6 positions, which substituents are attached at any available atom to produce a stable compound, with substitution as described herein. “Optionally substituted alkyl” refers to alkyl or substituted alkyl.
A “haloalkyl” is an alkyl, as defined herein, that is substituted with at least one, such as 1 - 8, halo substituents.
Each of the terms “halogen,” “halide,” and “halo” refers to —F, —Cl, —Br, or —I.
The term “alkenyl” refers to straight or branched chain hydrocarbyl groups including from 2 to about 20 carbon atoms having 1-3, 1-2, or at least one carbon to carbon double bond. An alkenyl group can be unsubstituted or optionally substituted with one or more substituents as described herein below.
“Substituted alkenyl” refers to alkenyl substituted at 1 or more, e.g., 1, 2, 3, 4, 5, or even 6 positions, which substituents are attached at any available atom to produce a stable compound, with substitution as described herein. “Optionally substituted alkenyl” refers to alkenyl or substituted alkenyl.
“Alkyne or “alkynyl” refers to a straight or branched chain unsaturated hydrocarbon having the indicated number of carbon atoms and at least one triple bond. Examples of a (C2-C8)alkynyl group include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, 1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne, 3-hexyne, 1-heptyne, 2-heptyne, 3-heptyne, 1-octyne, 2-octyne, 3-octyne and 4-octyne. An alkynyl group can be unsubstituted or optionally substituted with one or more substituents as described herein below.
“Substituted alkynyl” refers to an alkynyl substituted at 1 or more, e.g., 1, 2, 3, 4, 5, or even 6 positions, which substituents are attached at any available atom to produce a stable compound, with substitution as described herein. “Optionally substituted alkynyl” refers to alkynyl or substituted alkynyl.
The term “alkoxy” refers to an —O—alkyl group having the indicated number of carbon atoms. For example, a (C1-C6)alkoxy group includes —O—methyl, —O—ethyl, —O—propyl, —O—isopropyl, —O—butyl, —O—sec-butyl, —O—tert-butyl, —O—pentyl, —O—isopentyl, —O—neopentyl, —O—hexyl, —O—isohexyl, and —O—neohexyl.
A “haloalkoxy” is an alkoxy, as defined herein, that is substituted with at least one, such as 1 - 8, halo substituents.
The term “cycloalkyl” refers to a monocyclic, bicyclic, tricyclic, or polycyclic, 3- to 14-membered ring system, which is either saturated, such as “cycloalkyl,” or unsaturated, such as “cycloalkenyl.” The term “cycloalkenyl” refers specifically to cyclic alkenyl, such as C3-C6-cycloalkenyl. The cycloalkyl may be attached via any atom. Cycloalkyl, for instance, also contemplates fused rings wherein, for instance, a cycloalkyl is fused to an aryl or heteroaryl ring as defined herein. Representative examples of cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl. A cycloalkyl group can be unsubstituted or optionally substituted with one or more substituents as described herein.
“Substituted cycloalkyl” refers to cycloalkyl substituted at 1 or more, e.g., 1, 2, 3, 4, 5, or even 6 positions, which substituents are attached at any available atom to produce a stable compound, with substitution as described herein. “Optionally substituted cycloalkyl” refers to cycloalkyl or substituted cycloalkyl.
“Aryl” when used alone or as part of another term means a carbocyclic aromatic group whether or not fused having the number of carbon atoms designated or if no number is designated, up to 14 carbon atoms, such as a C6-C14-aryl. Particular aryl groups are phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, and the like (see e.g. Lang’s Handbook of Chemistry (Dean, J. A., ed) 13th ed. Table 7-2 [1985]). A particular aryl is phenyl. “Aryl” also includes aromatic ring systems that are optionally fused with a cycloalkyl ring, as herein defined. An aryl group can be unsubstituted or optionally substituted with one or more substituents as described herein below.
A “substituted aryl” is an aryl that is independently substituted with one or more substituents attached at any available atom to produce a stable compound, wherein the substituents are as described herein. “Optionally substituted aryl” refers to aryl or substituted aryl.
The term “heteroatom” refers to N, O, and S. Disclosed compounds that contain N or S atoms can be optionally oxidized to the corresponding N-oxide, sulfoxide, or sulfone compounds.
“Heteroaryl,” alone or in combination with any other moiety described herein, refers to a monocyclic aromatic ring structure containing 5 to 10, such as 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, such as 1-4, 1-3, or 1-2, heteroatoms independently selected from the group consisting of O, S, and N. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or heteroatom is the point of attachment of the heteroaryl ring structure such that a stable compound is produced. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrazinyl, quinaoxalyl, indolizinyl, benzo[b]thienyl, benzimidazolyl, benzisoimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, and indolyl. A heteroaryl group can be unsubstituted or optionally substituted with one or more substituents as described herein below.
A “substituted heteroaryl” is a heteroaryl that is independently substituted, unless indicated otherwise, with one or more, e.g., 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, also 1 substituent, attached at any available atom to produce a stable compound, wherein the substituents are as described herein. “Optionally substituted heteroaryl” refers to heteroaryl or substituted heteroaryl.
“Heterocycloalkyl” means a saturated or unsaturated non-aromatic monocyclic, bicyclic, tricyclic or polycyclic ring system that has from 3 to 14, such as 3 to 6, atoms in which from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S or N. A heterocycloalkyl is optionally fused with aryl or heteroaryl of 5-6 ring members, and includes oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. The point of attachment of the heterocycloalkyl ring is at a carbon or heteroatom such that a stable ring is retained. Examples of heterocycloalkyl groups include without limitation morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl, dihydrobenzofuryl, and dihydroindolyl. A hetercycloalkyl group can be unsubstituted or optionally substituted with one or more substituents as described herein below.
“Optionally substituted heterocycloalkyl” denotes a heterocycloalkyl that is substituted with 1 to 3 substituents, e.g., 1, 2 or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are as described herein.
The term “nitrile” or “cyano” can be used interchangeably and refer to a —CN group which is bound to a carbon atom of a heteroaryl ring, aryl ring and a heterocycloalkyl ring.
The term “oxo” refers to a ═O atom attached to a saturated or unsaturated moiety. The ═O atom can be attached to a carbon, sulfur, or nitrogen atom that is part of a cyclic or acyclic moiety.
A “hydroxyl” or “hydroxy” refers to an —OH group.
The substituent —CO2H may be replaced with bioisosteric replacements such as:
and the like, wherein R has the same definition as RA as defined herein. See, e.g., THE PRACTICE OF MEDICINAL CHEMISTRY (Academic Press: New York, 1996), at page 203.
Compounds described herein can exist in various isomeric forms, including configurational, geometric, and conformational isomers, including, for example, cis- or trans-conformations. The compounds may also exist in one or more tautomeric forms, including both single tautomers and mixtures of tautomers. The term “isomer” is intended to encompass all isomeric forms of a compound of this disclosure, including tautomeric forms of the compound. The compounds of the present disclosure may also exist in open-chain or cyclized forms. In some cases one or more of the cyclized forms may result from the loss of water. The specific composition of the open-chain and cyclized forms may be dependent on how the compound is isolated, stored or administered. For example, the compound may exist primarily in an open-chained form under acidic conditions but cyclize under neutral conditions. All forms are included in the disclosure.
Some compounds described herein can have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. A compound as described herein can be in the form of an optical isomer or a diastereomer. Accordingly, the disclosure encompasses compounds and their uses as described herein in the form of their optical isomers, diastereoisomers and mixtures thereof, including a racemic mixture. Optical isomers of the compounds of the disclosure can be obtained by known techniques such as asymmetric synthesis, chiral chromatography, simulated moving bed technology or via chemical separation of stereoisomers through the employment of optically active resolving agents.
Unless otherwise indicated, the term “stereoisomer” means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. Thus, a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, for example greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, or greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of the other stereoisomers of the compound. The stereoisomer as described above can be viewed as composition comprising two stereoisomers that are present in their respective weight percentages described herein.
If there is a discrepancy between a depicted structure and a name given to that structure, then the depicted structure controls. Additionally, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. In some cases, however, where more than one chiral center exists, the structures and names may be represented as single enantiomers to help describe the relative stereochemistry. Those skilled in the art of organic synthesis will know if the compounds are prepared as single enantiomers from the methods used to prepare them.
As used herein, and unless otherwise specified to the contrary, the term “compound” is inclusive in that it encompasses a compound or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof. Thus, for instance, a compound of Formula I includes a pharmaceutically acceptable salt of the compound.
In this description, a “pharmaceutically acceptable salt” is a pharmaceutically acceptable, organic or inorganic acid or base salt of a compound described herein. Representative pharmaceutically acceptable salts include, e.g., alkali metal salts, alkali earth salts, ammonium salts, water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2, 2 -disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts. A pharmaceutically acceptable salt can have more than one charged atom in its structure. In this instance the pharmaceutically acceptable salt can have multiple counterions. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counterions.
The terms “treat”, “treating” and “treatment” refer to the amelioration or eradication of a disease or symptoms associated with a disease. In certain embodiments, such terms refer to minimizing the spread or worsening of the disease resulting from the administration of one or more prophylactic or therapeutic agents to a patient with such a disease.
The terms “prevent,” “preventing,” and “prevention” refer to the prevention of the onset, recurrence, or spread of the disease in a patient resulting from the administration of a prophylactic or therapeutic agent.
The term “effective amount” refers to an amount of a compound as described herein or other active ingredient sufficient to provide a therapeutic or prophylactic benefit in the treatment or prevention of a disease or to delay or minimize symptoms associated with a disease. Further, a therapeutically effective amount with respect to a compound as described herein means that amount of therapeutic agent alone, or in combination with other therapies, that provides a therapeutic benefit in the treatment or prevention of a disease. Used in connection with a compound as described herein, the term can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease, or enhances the therapeutic efficacy of or synergies with another therapeutic agent.
A “patient” or “subject” includes an animal, such as a human, cow, horse, sheep, lamb, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig. In accordance with some embodiments, the animal is a mammal such as a non-primate and a primate (e.g., monkey and human). In one embodiment, a patient is a human, such as a human infant, child, adolescent or adult.
“Inhibitor” means a compound that induces dose dependent lymphopenia and a modest decrease in plasma S1P. In an embodiment, an inhibitor binds to SPNS2.
As described generally above, the present disclosure provides compounds, pharmaceutically acceptable salts, and/or tautomers thereof, wherein the compounds conform to Formula IA:
X is a C6-C10-aryl or 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl ring members are independently selected from N, O, and S).
R1 and R2 are independently selected from the group consisting of H, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C3-C8-cycloalkyl, C1-C6-haloalkyl, CN, and halo.
W is a bond, O, NH, —NHC(O)—, or —O—(N═)C(R)— (wherein R is H or C1-C6-alkyl).
V is selected from the group consisting of H, C1-C14-alkyl, C2-C12-alkenyl, (C6-C10)aryl, (C6-C10)heteroaryl, —C1-C10-alkyl-(C6-C10)aryl, —C2-C12-alkenyl-(C6-C10)aryl, —C1-C10-alkyl-(C3-C8)cycloalkyl, -(3- to 14-membered heterocycloalkyl) (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S), —(C1-C10)alkyl-(3- to 14-membered heterocycloalkyl) (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S).
T is selected from the group consisting of a bond, —C(O)— —C(O)NRx, —C(S)NRx—, —NRxC(O)—, —NRx—, —NRxC(O)NRx—, and —NRxC(O)O—.
Rx in each instance is independently selected from H and C1-C6-alkyl.
Subscript m is an integer selected from 0, 1, 2, 3, 4, 5, and 6.
Subscript n is an integer selected from 1 and 2, wherein the sum of n and o is greater than 0.
Each “
” is a single bond that is optionally present. It should be understood that all bonds “
” are simultaneously present or absent. When “
” is present, then o is selected from 1, 2, and 3. Further, in one embodiment, p is 0, (N)pR6 represents a bond, and U is —CH—or N, or, in another embodiment, p is 1 and U is —CH—. When “
” is not present, per another embodiment, then o is 0 and U is —CH2— or NH.
Subscript q is an integer selected from 1, 2, and 3.
R3 is selected from the group consisting of, H, C1-C6-alkyl, and —C(NH)NH2.
R4 is absent when “
” is present. When “
” is absent, then R4 is H or C1-C6-alkyl.
Each R5 is independently selected from the group consisting of H, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C3-C8-cycloalkyl, C1-C6-haloalkyl, CN, NH2, and halo.
R6 is H or C1-C6-alkyl.
In Formula IA, each alkyl, alkoxy, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl is optionally substituted with 1 - 5 substituents independently selected from the group consisting of hydroxy, halo, C1-C6-haloalkoxy, C1-C6-haloalkyl, —NR′2, —NHC(O)(OC1—C6—alkyl), —NO2, —CN, oxo, —C(O)OH, —C(O)O(C1—C6—alkyl), –C1-C6-alkyl(C1-C6-alkoxy), —C(O)NH2, C1-C6-alkyl, —C(O)C1—C6—alkyl, —OC1—C6—alkyl, —Si(C1—C6—alkyl)3, —S(O)0-2—(C1—C6—alkyl), C6-C10-aryl, –(C1-C6-alkyl)(C6-C10-aryl), 3- to 14-membered heterocycloalkyl, and –(C1-C6-alkyl)-(3- to 14-membered heterocycle) (wherein 1-4 heterocycle members are independently selected from N, O, and S), and —O(C6—C14—aryl).
Each R′ is independently selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C6-C10-aryl, 3- to 14-membered heterocycloalkyl and —(C1-C6-alkyl)-(3- to 14-membered heterocycloalkyl) (wherein 1-4 ring members are independently selected from N, O, and S), and 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S.
In some embodiments, T is a bond; “
” is absent; U is —CH2— or —NH; and m is an integer selected from 1, 2, 3, 4, 5, and 6.
In other embodiments, T is —NRx—; “
” is absent; and U is —CH2— or —NH. In some embodiments, Rx is H.
In still additional embodiments, T is —NRxC(O)NRx—; “
” is absent; and U is —CH2—or —NH. In various embodiments, each instance of Rx is H.
In some embodiments, “
” is present; and m is 0, 1, 2, or 3. In illustrative embodiments, m is 0.
In further embodiments, optionally in combination with any other embodiment described herein, p is 0, (N)pR6 represents a bond, and U is —CH— or N. In other embodiments, p is 1 and U is —CH—.
In various embodiments, optionally in combination with any other embodiment described herein, T is selected from the group consisting of —C(O)NRx, —NRxC(O)—, —NRx—, —NRxC(O)NRx—, and —NRxC(O)O—. In other embodiments, T is a bond. In still further embodiments, T is —C(O)—.
Another embodiment of the present disclosure is a Formula IA compound or pharmaceutically acceptable salt thereof wherein X is C6-C10-aryl. Examples of X include phenyl and naphthyl.
In other embodiments, X is a 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl ring members are independently selected from N, O, and S). In illustrative embodiments, X is benzoxazolyl, benzothiazolyl, and benzimidazolyl.
In various embodiments, the present disclosure provides Formula IA compounds wherein X is a 10-membered heteroaryl (wherein 2 heteroaryl ring members are independently selected from N and O), T is —NRx—, m is 0; and “
” is present.
Various embodiments contemplate Formula IA compounds wherein the moiety:
represents many combinations, as illustrated by the following non-limiting examples:
In various embodiments, the compound of Formula IA is a compound of Formula I, as described in summary above:
X is a C6-C10-aryl or 5- to 10-membered heteroaryl (wherein 1 to 4 heteroaryl ring members are independently selected from N, O, and S).
R1 and R2 are independently selected from the group consisting of H, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C3-C8-cycloalkyl, C1-C6-haloalkyl, CN, and halo.
W is a bond, O, NH, —NHC(O)—, or —O—(N═)C(R)— (wherein R is H or C1-C6-alkyl).
V is selected from the group consisting of H, C1-C14-alkyl, C2-C12-alkenyl, (C6-C10)aryl, (C6-C10)heteroaryl, —C1-C10-alkyl-(C6-C10)aryl, —C2-C12-alkenyl-(C6-C10)aryl, —C1-C10-alkyl-(C3-C8)cycloalkyl, -(3- to 14-membered heterocycloalkyl) (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S), —(C1-C10)alkyl-(3- to 14-membered heterocycloalkyl) (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S).
Y is —C(O)— and Z is —NH—, or Y is —NH— and Z is —C(O)—.
Each dashed line represented as
is a single bond that is optionally present.
R3 is selected from the group consisting of, H, C1-C6-alkyl, and —C(NH)NH2.
In an embodiment, R4 is absent when
is present. In another embodiment, R4 is H or C1-C6-alkyl when
is absent.
Subscript m is an integer selected from 0, 1, 2, 3, 4, 5, and 6; n is an integer selected from 1 and 2; o is an integer selected from 0 and, when
is present, is selected from 2, and 3; and the sum of n and o is greater than 2.
Each alkyl, alkoxy, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl in Formula I is optionally substituted with 1 - 5 substituents independently selected from the group consisting of hydroxy, halo, C1-C6-haloalkoxy, C1-C6-haloalkyl, —NR′2, —NHC(O)(OC1—C6—alkyl), —NO2, —CN, oxo, —C(O)OH, —C(O)O(C1-C6-alkyl), —C1-C6-alkyl(C1-C6-alkoxy), —C(O)NH2, C1-C6-alkyl, —C(O)C1—C6—alkyl, —OC1—C6—alkyl, —Si(C1—C6—alkyl)3, —S(O)0-2—(C1—C6—alkyl), C6-C10-aryl, —(C1-C6-alkyl)(C6-C10-aryl), 3- to 14-membered heterocycloalkyl, and -(C1-C6-alkyl)-(3- to 14-membered heterocycle) (wherein 1-4 heterocycle members are independently selected from N, O, and S), and —O(C6—C14—aryl).
Each R′ is independently selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C6-C10-aryl, 3- to 14-membered heterocycloalkyl and —(C1-C6-alkyl)-(3- to 14-membered heterocycloalkyl) (wherein 1-4 ring members are independently selected from N, O, and S), and 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S.
Additional embodiments, optionally in combination with any other embodiment described herein, provide for Formula I compounds wherein
is present.
In various embodiments, o is 2. In further embodiments, o is 3, or o is 0.
In other embodiments, optionally in combination with any other embodiment described herein m is 0.
The present disclosure also provides Formula I compounds, or their pharmaceutically acceptable salts, wherein X is C6-C10-aryl. For example, in an embodiment X is phenyl.
Additional embodiments provide Formula I compounds wherein R3 and R4, if present, are independently selected from H and C1-C6-alkyl. In an illustrative embodiment, each of R3 and R4, if present, is H.
In other embodiments, R3 is C(NH)NH2.
The present disclosure also provides Formula I compounds, in embodiments, wherein W is a bond or O, and V is C1-C14-alkyl or -C1-C10-alkyl-(C6-C10)aryl.
One embodiment, optionally in combination with any other embodiment described herein, provides for a Formula I compound or pharmaceutically acceptable salt thereof wherein each of R1 and R2 is H.
In various embodiments, X is phenyl; each of R1 and R2 is H; W is a bond or O; V is C1-C14-alkyl; o is 0; R3 is selected from the group consisting of, H, C1-C6-alkyl, and —C(NH)NH2; and R4 is H or C1-C6-alkyl.
The present disclosure provides specific examples of Formula I and Formula IA compounds, and their pharmaceutically acceptable salts, and/or tautomers thereof as set forth in Table 1 below.
The disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds disclosed herein or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof in admixture with a pharmaceutically acceptable carrier. In some embodiments, the composition further contains, in accordance with accepted practices of pharmaceutical compounding, one or more additional therapeutic agents, pharmaceutically acceptable excipients, diluents, adjuvants, stabilizers, emulsifiers, preservatives, colorants, buffers, flavor imparting agents.
In one embodiment, the pharmaceutical composition comprises a compound selected from those illustrated in Table 1 or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, and a pharmaceutically acceptable carrier.
The pharmaceutical composition of the present disclosure is formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular subject being treated, the clinical condition of the subject, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
The “therapeutically effective amount” of a compound (or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof that is administered is governed by such considerations, and is the minimum amount necessary to induce dose dependent lymphopenia and a modest decrease in plasma S1P, or to inhibit SPNS2 activity, or both. Such amount may be below the amount that is toxic to normal cells, or the subject as a whole. Generally, the initial therapeutically effective amount of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure that is administered is in the range of about 0.01 to about 200 mg/kg or about 0.1 to about 20 mg/kg of patient body weight per day, with the typical initial range being about 0.3 to about 15 mg/kg/day. Oral unit dosage forms, such as tablets and capsules, may contain from about 1 mg to about 1000 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure. In another embodiment, such dosage forms contain from about 50 mg to about 500 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure. In yet another embodiment, such dosage forms contain from about 25 mg to about 200 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure. In still another embodiment, such dosage forms contain from about 10 mg to about 100 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure. In a further embodiment such dosage forms contain from about 5 mg to about 50 mg of a compound (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof) of the present disclosure.
The disclosed compositions can be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
Suitable oral compositions as described herein include without limitation tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, syrups or elixirs.
Also encompassed by the present disclosure are pharmaceutical compositions suitable for single unit dosages that comprise a compound of the disclosure or its pharmaceutically acceptable stereoisomer, salt, or tautomer and a pharmaceutically acceptable carrier.
Compositions suitable for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. For instance, liquid formulations of the inventive compounds contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically palatable preparations of the SPNS2 inhibitor.
For tablet compositions, a compound of the present disclosure in admixture with non-toxic pharmaceutically acceptable excipients is used for the manufacture of tablets. Examples of such excipients include without limitation inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known coating techniques to delay disintegration and absorption in the gastrointestinal tract and thereby to provide a sustained therapeutic action over a desired time period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
For aqueous suspensions, a compound of the present disclosure is admixed with excipients suitable for maintaining a stable suspension. Examples of such excipients include without limitation are sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia.
Oral suspensions can also contain dispersing or wetting agents, such as naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending a compound of the present disclosure in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide a compound of the present disclosure in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation reaction products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable, an aqueous suspension or an oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of inj ectables.
The compounds disclosed herein may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compositions for parenteral administrations are administered in a sterile medium. Depending on the vehicle used and concentration the concentration of the drug in the formulation, the parenteral formulation can either be a suspension or a solution containing dissolved drug. Adjuvants such as local anesthetics, preservatives and buffering agents can also be added to parenteral compositions.
S1P gradients are chemotactic, a property that enables correct positioning of immune cells, and they help to maintain endothelial barrier integrity. Accordingly, S1P gradients are manipulated for therapeutic benefit using Formula I compounds because they target the endothelial S1P exporter, SPNS2.
Thus, in one embodiment, the disclosure provides a method of inhibiting spinster homolog 2 (SPNS2). The method comprises contacting SPNS2 with an effective amount of a compound as described herein. In some embodiments, the contacting occurs in vitro. In other embodiments, the contacting occurs ex vivo or in vivo.
Another embodiment is a method of treating a patient afflicted by a neoplastic disease, comprising administering to the patient a therapeutically effective amount a compound as described herein. In some embodiments, the neoplastic disease is metastatic neoplasms.
An additional embodiment is a method of treating a patient afflicted with an allergic disease, comprising administering to the patient a therapeutically effective amount of a compound as described herein. An illustrative allergic disease is asthma.
The compounds disclosed herein also are useful in a method of treating a patient afflicted with an autoimmune disease, comprising administering to the patient a therapeutically effective amount of the compound. In various embodiments, the autoimmune disease is chosen from multiple sclerosis, type I diabetes, inflammatory bowel diseases, Crohn’s disease, ulcerative colitis, Grave’s disease, Addison’s disease, dermatomyositis, myasthenia gravis, systemic lupus erythematosus, scleroderma, and psoriasis. An exemplary autoimmune disease is multiple sclerosis. In accordance with some embodiments, multiple sclerosis comprises one or more progressive forms of multiple sclerosis as well as the remitting relapsing form of the disease.
Additional embodiments include a method of treating a patient afflicted with atherosclerosis or pulmonary arterial hypertension. The method comprises administering to the patient a therapeutically effective amount of a compound as described herein.
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The present disclosure will be more fully understood by reference to the following examples. The examples should not, however, be construed as limiting the scope of the present disclosure.
To a 6-dram vial containing N-boc-amino acid (1.1 equiv) was added DMF (0.2 M), DIEA (1.8 equiv) and HCTU (1.1 equiv). The resulting mixture was allowed to stir at rt for 5 minutes, followed by addition of aniline derivative (1 equiv). The resulting mixture was allowed to stir at rt until consumption of aniline as monitored by TLC (1 - 4 hours). The resulting reaction mixture was diluted in ethyl acetate and washed with a saturated lithium bromide solution. The organic layer was then dried over anhydrous sodium sulfate and concentrated in vacuo to afford an orange oil which was then subjected to flash chromatography with an appropriate ethyl acetate in dichloromethane solvent system to afford the pure product.
To a 6-dram vial containing 4-iodobenzoic acid derivative (1.1 equiv) was added DCM (0.2 M), DIEA (1.8 equiv) and HCTU (1.1 equiv). The resulting mixture was allowed to stir at room temperature for 5 minutes, followed by addition of a mono-N-Boc protected diamine derivative (1.0 equiv). The resulting mixture was allowed to stir at room temperature for 18 hours at which time starting material was completely consumed on TLC. The resulting reaction mixture concentrated in vacuo to afford a yellow oil which was then subjected to flash chromatography with an appropriate ethyl acetate in hexanes solvent system to afford the pure product.
To a 6-dram vial containing a Boc-protected amine (1.0 equiv) was added hydrogen chloride (30-100 equiv, 4 M in dioxane). The resulting mixture was allowed to stir until consumption of starting material as monitored by TLC (0.5 - 6 hours). A thick white precipitate forms during the course of the reaction. This precipitate was either vacuum filtered over a filter frit and washed with diethyl ether or triturated with diethyl ether and/or ethyl acetate to afford the pure product as an HCl salt.
To a round bottom flask containing Boc-protected amine or diboc protceted guanidine compounds (1 equiv) dissolved in dichloromethane was added TFA (30 equiv). The resulting solution was allowed to stir until consumption of starting material as monitored by TLC (1-6 hours). Concentration in vacuo and filtration of the resulting off-white solid, followed by washing with diethyl ether afforded the corresponding TFA salts.
TFA salt or HCl amine salt (1 equiv), DIEA (15 equiv), and (Z)-tert-butyl (((tert-butoxycarbonyl)imino)(1H-pyrazol-1-yl)methyl)carbamate (1 equiv) were added to a microwave vial containing MeCN at room temperature. The resulting solution was then placed in a CEM microwave synthesized and heated to 50° C. for 3 hours. After cooling down to room temperature, the solution was concentrated in vacuo to afford the crude mixture as a yellow oil, which was then purified by column chromatography using the appropriate ethyl acetate and hexanes solvent system to afford the diboc protected guanidino compounds.
To a pressure-sealed tube purged with nitrogen was added 1-decene and 0.5 M 9-BBN in THF (2.2 equiv). The resulting mixture was allowed to stir at 70° C. for 1-2 hours. Upon completion of the hydroboration step, sequential addition of an aryl iodide or aryl bromide (1.0 equiv), Pd(dppf)Cl2*CH2Cl2 (0.075 equiv), and 3 M KOH (3.0 equiv) was performed. The resulting mixture was allowed to stir at 70° C. for 16 hours or until complete consumption of the starting material was observed on TLC. The resulting mixture was concentrated in vacuo to afford a brown oil which was then subjected to flash chromatography with an appropriate ethyl acetate and hexane solvent system to afford the purified product.
To a pressure-sealed tube purged with nitrogen was added 1-decene (1.0 equiv) and 0.5 M 9-BBN in THF (1.5 equiv). The resulting mixture was allowed to stir at 70° C. for 2 hours. Upon completion of the hydroboration step, sequential addition of an aryl iodide (1.0 equiv), Pd(dppf)Cl2*CH2Cl2 (0.05 equiv), and 3 M KOH (3.0 equiv) was performed. The resulting mixture was allowed to stir at 70° C. for 4 hours until complete consumption of the starting material was observed on TLC. The resulting mixture was concentrated in vacuo to afford a brown oil which was then subjected to flash chromatography with an appropriate ethyl acetate and hexane solvent system to afford the purified product.
To a 6-dram vial containing an N-Boc-amino acid (1.3 equiv) was added DCM and CDI (1.3 equiv). The resulting mixture was allowed to stir at room temperature for 2 hours, followed by addition of phenol (1.0 equiv) and DIEA (1.6 equiv). The resulting mixture was allowed to stir at room temperature for an additional 16 hours at which point the starting material was determined to be completely consumed by TLC. The resulting mixture was concentrated in vacuo to afford a brown oil which was then subjected to flash chromatography with an appropriate ethyl acetate and hexane solvent system to afford the purified product.
To a pressure-sealed tube containing PPh3 (2.0 equiv) was added THF and a Boc protected amine (1.0 equiv) under inert atmosphere. The resulting mixture was allowed to stir at 0° C. for 20 minutes, followed by the addition of DIAD (2.0 equiv). The resulting mixture was heated 70° C. for 4 hours, where starting material was determined to be completely consumed by TLC. The crude reaction mixture was diluted in ethyl acetate and washed with water. The organic layer was then dried over anhydrous sodium sulfate and concentrated in vacuo to afford an orange oil which was then subjected to flash chromatography with an appropriate ethyl acetate and hexanes solvent system to afford the purified product.
To a pressure-sealed tube containing 2-amino-4-bromo-phenol (1.0 equiv) was added EtOH/H2O (5:1), K2CO3 (1.2 equiv), and CS2 (1.2 equiv). The resulting mixture was allowed to stir at 80° C. for 3 hours, where starting material was determined to be completely consumed based of TLC. The resulting mixture was diluted in water, and acetic acid was added in dropwise until a white solid was precipitated. This solid was solubilized by ethyl acetate, which was then subjected to flash chromatography with an appropriate ethyl acetate in hexane solvent system to afford the pure product.
To a round bottom flask containing 5-bromobenzo[d]oxazole-2-thiol (1.0 equiv) was sequentially added DCM, SOCl2 (2.5 equiv), and DMF (0.04 equiv) under inert atmosphere. The resulting mixture was allowed to stir at rt for 1 hour, where starting material was determined to be completely consumed based of TLC. The result mixture was diluted in ethyl acetate and washed with water. The organic layer was then dried over anhydrous sodium sulfate and concentrated in vacuo to afford a light pink oil which was then subjected to flash chromatography with an appropriate ethyl acetate in hexanes solvent system to afford the pure product.
To a seal-pressured tube containing 6-bromobenzo[d]thiazol-2(3H)-one (1.0 equiv) was sequentially added POCl3 (30 equiv). The resulting mixture was allowed to stir at 98° C. for 16 hours, where starting material was determined to be completely consumed based of TLC. The resulting mixture was poured over ice. The solution was neutralized to pH 9 by addition of NH4OH, and the resulting solid collected by filtration.
To a pressure-sealed tube containing benzoxazole (1.0 equiv) was added DMF, N-boc-amine (1.2 equiv), and K2CO3 (2.0 equiv). The resulting mixture was allowed to stir at 120° C. for 2 hours, where starting material was determined to be completely consumed based of TLC. The resulting reaction mixture was diluted in ethyl acetate and washed with a saturated lithium bromide solution. The organic layer was then dried over anhydrous sodium sulfate and concentrated in vacuo to afford a clear oil which was then subjected to flash chromatography with an appropriate ethyl acetate in hexanes solvent system to afford the pure product.
1-iodo-4-isocyanatobenzene (1.0 equiv) was added to an oven dried 6-dram vial containing a stir bar and purged with nitrogen. Anhydrous DCM was added to the vial and the solution was cooled to 0° C. with an ice bath. A mono-N-Boc protected diamine (1.05 equiv) was dissolved in DCM and added dropwise to the 1-iodo-4-isocyanatobenzene solution. The reaction mixture was then allowed to warm to room temperature slowly over the course of 16 hours. After complete consumption of starting material was observed by TLC, the crude reaction mixture was concentrated under reduced pressure and subjected to flash chromatography with an appropriate ethyl acetate and hexanes mobile phase to yield purified product.
1-iodo-4-isocyanatobenzene (1.0 equiv) was added to an oven dried 6-dram vial containing a stir bar and purged with nitrogen. Anhydrous DCM was added to the vial and the solution was cooled to 0° C. with an ice bath. An N-Boc protected amino-alcohol (1.05 equiv) was dissolved in DCM and added dropwise to the 1-iodo-4-isocyanatobenzene solution. The reaction mixture was then allowed to warm to room temperature slowly over the course of 16 hours. After complete consumption of starting material was observed by TLC, the crude reaction mixture was concentrated under reduced pressure and subjected to flash chromatography with an appropriate ethyl acetate and hexanes mobile phase to yield purified product.
To a dry pressure tube containing nitroaniline (1.0 equiv) dissolved in 200 proof ethanol was added tin (II) chloride (5.0 equiv). After, 12.1 M hydrochloric acid (10 equiv) was added. This was then refluxed for one hour, where starting material was determined to be completely consumed based off TLC. The resulting mixture was diluted with 3 M aq. NaOH. This was allowed to stir for five minutes and then extracted three times with ethyl acetate.
To a 6-dram vial containing aryl amide derivatives, 13.7 M acetic acid (70 equiv) was added and the reaction was allowed to stir at 65° C. for 3 hours. The resulting mixture was diluted with ethyl acetate and washed with brine in triplicate. The combined organic layer was then dried over anhydrous sodium sulfate, concentrated in vacuo, and subjected to flash chromatography with an appropriate ethyl acetate in hexanes solvent system to yield purified product.
(a) N-boc-amino acid (1.1 equiv), HCTU (1.1 equiv), DIEA (1.8 equiv), DMF, rt; (b) HCl, dioxane, rt; (c) N,N′-Di-Boc-1H-pyrazole-1-carboxamidine (1 equiv), DIEA (15 equiv), MeCN, 50° C. µw; (d) HCl, dioxane, rt.
Synthesized according to General Procedure 1. White solid (92%, 298 mg). 1H NMR (400 MHz, CDCl3) δ 9.00 (brs, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.5 Hz, 2H), 4.07 (dd, J= 13.5, 3.9 Hz, 1H), 3.85 (brs, 1H), 3.18 (t, J= 11.7 Hz, 1H), 3.03 - 2.79 (m, 1H), 2.59 - 2.40 (m, 3H), 1.99 - 1.76 (m, 2H), 1.69 - 1.60 (m, 1H), 1.60 - 1.49 (m, 2H), 1.49 -1.33 (m, 10H), 1.32 - 1.18 (m, 14H), 0.86 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 171.7, 154.9, 138.6, 136.1, 128.6, 119.8, 79.9, 46, 44.7, 43.8, 35.3, 31.9, 31.5, 29.6, 29.6, 29.5, 29.3, 29.2, 28.4, 27.9, 24.3, 22.7, 14.1. HRMS: (ESI) [M+Na]+ calc. for C27H44N2O3Na, 467.3250, observed, 467.3233.
Synthesized according to General Procedure 1. White solid (95%, 316 mg). 1H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8 Hz, 2H), 3.70 - 3.45 (m, 3H), 3.28 (dt, J= 10.6, 7.8, 1H), 3.11 - 2.97 (m, 1H), 2.52 (t, J= 7.7 Hz, 2H), 2.26 - 1.99 (m, 2H), 1.63 - 1.50 (m, 2H), 1.45 (s, 9H), 1.34 - 1.20 (m, 14H), 0.88 (t, J= 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 171.1, 154.4, 139.0, 135.7, 128.6, 120.2, 79.5, 48.9, 45.7, 45.2, 45.2, 44.3, 35.3, 31.5, 29.6, 29.6, 29.5, 29.3, 29.3, 28.5, 22.7, 14.1. HRMS: (ESI) [M+Na]+ calc. for C26H42N2O3Na, 453.3093, observed, 453.3082.
Synthesized according to General Procedure 1. White solid (90%, 252 mg). 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J= 8.4 Hz, 2H), 7.10 (d, J= 8.5 Hz, 2H), 3.12 (t, J= 6.8 hz, 2H), 2.56 (t, J= 7.6 Hz, 2H), 2.37 (t, J= 7.5 Hz, 2H), 1.83 (p, J= 7.1 Hz, 2H), 1.58 (t, J = 6.9 Hz, 2H), 1.42 (s, 9H), 1.37 - 1.19 (m, 14H), 0.89 (t, J= 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 173.8, 158.6, 139.9, 137.5, 129.6, 121.3, 80.0, 40.9, 36.3, 35.2, 33.1, 32.8, 30.7, 30.7, 30.6, 30.5, 30.3, 28.8, 27.3, 23.7, 14.5. HRMS: (ESI) [M+H]+ calc. for C25H43N2O3, 419.3268, observed, 419.3257.
Synthesized according to General Procedure 1. White solid (100%, 360 mg). 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.41 (d, J= 8.4 Hz, 2H), 7.12 (d, J= 8.4 Hz, 2H), 5.21 (s, 1H), 3.48 (q, J= 6.1 Hz, 2H), 2.63 - 2.49 (m, 4H), 1.57 (p, J = 7.4 Hz, 2H), 1.43 (s, 9H), 1.36 - 1.17 (m, 14H), 0.87 (d, J= 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 169.7, 156.4, 139.3, 135.5, 129.0, 120.0, 79.7, 37.6, 36.6, 35.5, 32.0, 31.7, 29.8, 29.7, 29.6, 29.5, 29.4, 28.5, 22.8, 14.3. HRMS: (ESI) [M-boc+H]+ calc. for C19H33N2O, 305.2587, observed, 305.2573.
Synthesized according to General Procedure 1. White solid (95%, 258 mg). 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.42 (d, J= 8.4 Hz, 2H), 7.10 (d, J= 8.4 Hz, 2H), 4.68 (s, 1H), 3.16 (q, J= 6.6 Hz, 2H), 2.54 (dd, J= 8.7, 6.7 Hz, 2H), 2.37 (t, J= 7.5 Hz, 2H), 1.80 - 1.69 (m, 2H), 1.55 (p, J= 6.9 Hz, 4H), 1.43 (s, 9H), 1.34 - 1.20 (m, 14H), 0.86 (t, J= 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 171.3, 156.4, 139.0, 135.8, 128.9, 120.0, 79.4, 39.7, 37.0, 35.5, 32.0, 31.7, 29.8, 29.7, 29.6, 29.5, 29.4, 28.6, 22.8, 22.7, 14.3. HRMS: (ESI) [M+H]+ calc. for C26H45N2O3, 433.3425, observed, 433.3405.
Synthesized according to General Procedure 1. Light brown solid (96%, 310 mg). 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J= 8.4 Hz, 2H), 7.10 (d, J= 8.4 Hz, 2H), 4.60 (s, 1H), 3.11 (q, J= 6.7 Hz, 2H), 2.55 (d, J= 7.6 Hz, 2H), 2.33 (t, J= 7.5 Hz, 2H), 1.73 (p, J= 7.5 Hz, 2H), 1.60 - 1.34 (m, 15H), 1.35 - 1.20 (m, 14H), 0.88 (t, J= 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 171.2, 156.2, 139.0, 135.7, 128.9, 120.0, 79.3, 40.4, 37.6, 35.5, 32.0, 31.7, 29.9, 29.8, 29.7, 29.6, 29.5, 29.4, 28.6, 26.4, 25.3, 22.8, 14.3. HRMS: (ESI) [M+H]+ calc. for C27H47N2O3, 447.3581, observed, 447.3573.
Synthesized according to General Procedure 1. White solid (71%, 178 mg). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.49 (d, J= 8.0 Hz, 2H), 7.11 (d, J= 8.4 Hz, 2H), 4.83 (t, J= 5.1 Hz, 1H), 3.24 (q, J= 6.3 Hz, 2H), 2.55 (d, J= 7.8 Hz, 2H), 2.36 (d, J= 7.8 Hz, 2H), 1.92 - 1.81 (m, 2H), 1.58 (q, J= 8.0 Hz, 2H), 1.45 (s, 9H), 1.25 (s, 12H), 0.88 (t, J = 6.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 171.2, 157.3, 138.8, 136.1, 128.9, 119.9, 79.9, 39.4, 35.5, 34.8, 32.0, 31.7, 29.7, 29.7, 29.5, 29.4, 28.5, 27.4, 22.8, 14.3. HRMS: (ESI) [M+H]+ calc. for C24H41N2O3, 405.3112, observed, 405.3110.
Synthesized according to General Procedure 1. Yellow solid (71%, 172 mg). 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.49 (d, J= 8.0 Hz, 2H), 7.11 (d, J= 8.4 Hz, 2H), 4.82 (t, J= 6.9 Hz, 1H), 3.24 (q, J= 6.3 Hz, 2H), 2.54 (d, J= 7.8 Hz, 2H), 2.37 (d, J= 6.6 Hz, 2H), 1.87 (tt, J= 8.2, 5.7 Hz, 2H), 1.57 (p, J= 7.6 Hz, 2H), 1.45 (s, 9H), 1.28 (s, 10H), 0.86 (t, J= 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 171.2, 157.3, 138.8, 136.1, 128.9, 119.9, 79.9, 39.4, 35.5, 34.8, 32.0, 31.7, 29.6, 29.4, 29.4, 28.5, 27.4, 22.8, 14.3. HRMS: (ESI) [M+H]+ calc. for C23H39N2O3, 391.2955, observed, 391.2932.
Synthesized according to General Procedure 1. White solid (68%, 240 mg). 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.40 (d, J= 7.9 Hz, 2H), 7.11 (d, J= 6.2 Hz, 2H), 3.61 (dd, J= 10.8, 7.2 Hz, 1H), 3.51 - 3.39 (m, 1H), 3.37 - 3.21 (m, 1H), 3.06 - 2.95 (m, 1H), 2.76 - 2.64 (m, 1H), 2.55 (t, J= 7.7 Hz, 2H), 2.50 - 2.29 (m, 3H), 2.18 - 2.04 (m, 1H), 1.57 (q, J= 7.8 Hz, 3H), 1.45 (s, 9H), 1.36 - 1.18 (m, 14H), 0.87 (d, J= 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 169.6, 154.8, 139.3, 135.4, 129.0, 120.1, 79.4, 51.1, 45.3, 40.8, 35.8, 35.5, 32.0, 31.7, 31.0, 29.8, 29.7, 29.6, 29.5, 29.4, 28.7, 22.8, 14.3. HRMS: (ESI) [M+H]+ calc. for C27H45N2O3, 445.3425, observed, 445.3424.
Synthesized according to General Procedure 1. Crude mixture dried in vacuo and carried forward to the next reaction without purification.
Synthesized according to General Procedure 1. White solid (71%, 280 mg). 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.26 (s, 1H), 7.70 (d, J= 8.5 Hz, 2H), 7.55 - 7.48 (m, 2H), 7.29 (dd, J= 8.4, 1.7 Hz, 1H), 4.87 (t, J= 6.5 Hz, 1H), 3.27 (q, J= 6.3 Hz, 2H), 2.73 (t, J= 7.7 Hz, 2H), 2.43 (t, J= 6.7 Hz, 2H), 1.94 - 1.86 (m, 2H), 1.68 (p, J=7.5 Hz, 2H), 1.47 (s, 9H), 1.41 - 1.22 (m, 10H), 0.87 (t, 3H). 13C NMR (101 MHz, CDCl3) δ 171.5, 157.4, 139.5, 135.3, 132.4, 130.8, 128.1, 128.1, 127.6, 126.0, 120.1, 116.4, 79.9, 39.4, 36.2, 34.8, 32.0, 31.5, 29.6, 29.5, 29.4, 28.5, 27.4, 22.8, 14.3. HRMS: (ESI) [M+H]+ calc. for C27H41N2O3, 441.3112, observed, 441.3133.
Synthesized according to General Procedure 1. Yellow solid (82%, 190 mg). 1H NMR (400 MHz, CDCl3) δ 8.09 (t, J= 8.4 Hz, 1H), 7.93 (s, 1H), 6.93 - 6.86 (m, 2H), 4.79 (s, 1H), 3.23 (q, J= 6.4 Hz, 2H), 2.57 - 2.51 (m, 2H), 2.43 (t, J= 7.0 Hz, 2H), 1.90 (p, J = 6.9 Hz, 2H), 1.56 (p, J= 7.2 Hz, 2H), 1.42 (s, 9H), 1.34 - 1.19 (m, 14H), 0.87 (t, J= 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 171.2, 156.7, 151.6, 140.1 (d, J= 6.5 Hz), 123.8 (d, J= 10.2 Hz), 123.3 (d, J= 213.0 Hz), 114.8 (d, J= 18.9 Hz), 79.6, 39.8, 35.4, 34.8, 32.0, 31.3, 29.7, 29.7, 29.6, 29.5, 29.3, 28.5, 26.6, 22.8, 14.3. HRMS: (ESI) [M+Na]+ calc. for C25H41FN2NaO3, 459.2993, observed, 459.3016.
Synthesized according to General Procedure 1. Yellow solid (86%, 462 mg). 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 7.80 (d, J= 8.8 Hz, 1H), 7.74 (s, 1H), 6.91 (d, J = 8.9 Hz, 1H), 4.88 (t, 1H), 3.99 (t, J= 6.4 Hz, 2H), 3.24 (q, J= 6.3 Hz, 2H), 2.37 (t, 2H), 1.89 - 1.83 (m, 2H), 1.82 - 1.73 (m, 2H), 1.47 - 1.43 (m, 11H), 1.37 - 1.21 (m, 10H), 0.87 (t, J= 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 171.4, 157.5, 153.5, 131.2, 124.9, 123.8 (q, J = 271.5 Hz), 119.2, 119.1 (q, J= 30.9 Hz), 113.5, 80.1, 69.2, 39.4, 34.5, 32.0, 29.6, 29.4, 29.4, 29.2, 28.5, 27.4, 25.9, 22.8, 14.2. HRMS: (ESI) [M+H]+ calc. for C25H40F3N2O4, 489.2935, observed, 489.2930.
Synthesized according to General Procedure 1. Colorless oil (73%, 332 mg). 1H NMR (500 MHz, CDCl3) δ 9.2 (s, 1H), 7.5 (d, J= 7.9 Hz, 1H), 7.4 (s, 1H), 7.1 (d, J= 8.3 Hz, 2H), 3.4 - 3.3 (m, 2H), 2.9 (s, 3H), 2.5 (d, J= 7.7 Hz, 3H), 2.4 - 2.2 (m, 2H), 2.0 - 1.9 (m, 2H), 1.6 (p, J= 7.5 Hz, 2H), 1.5 (s, 9H), 1.3 - 1.2 (m, 14H), 0.9 (t, J= 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 171.3, 157.3, 138.5, 136.5, 128.9, 119.8, 80.2, 47.0, 35.5, 34.5, 34.2, 32.0, 31.7, 29.7, 29.6, 29.5, 29.4, 28.6, 24.4, 22.8, 14.2. HRMS: (ESI) [M+H]+ calc. for C26H45N2O3, 433.3430, observed, 433.3418.
Synthesized according to General Procedure 1. Colorless oil (86%, 380 mg). 1H NMR (500 MHz, CDCl3) δ 7.4 (d, J= 8.5 Hz, 2H), 7.4 (s, 1H), 7.1 (d, J= 8.0 Hz, 2H), 4.2 (s, 1H), 2.8 (s, 2H), 2.5 (t, J= 7.7 Hz, 2H), 2.4 - 2.3 (m, 1H), 1.9 (d, J= 13.2 Hz, 2H), 1.8 -1.7 (m, 3H), 1.6 - 1.5 (m, 2H), 1.5 (s, 9H), 1.3 - 1.2 (m, 14H), 0.9 (t, J= 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 172.7, 154.8, 139.3, 135.5, 129.0, 120.1, 79.8, 44.4, 43.3, 35.5, 32.0, 31.6, 29.7, 29.7, 29.6, 29.5, 29.4, 28.8, 28.6, 22.8, 14.2. HRMS: (ESI) [M+H]+ calc. for C27H45N2O3, 445.3425, observed, 445.3420.
Synthesized according to General Procedure 4. White solid (28%, 83 mg). 1H NMR (400 MHz, CD3OD) δ 7.44 (d, J= 8.4 Hz, 2H), 7.11 (d, J= 8.4 Hz, 2H), 2.55 (t, J= 7.6 Hz, 2H), 2.13 - 2.04 (m, 1H), 2.01 - 1.77 (m, 3H), 1.62 - 1.50 (m, 2H), 1.36 - 1.19 (m, 14H), 0.88 (t, J= 6.7 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 172.8, 140.3, 137.1, 129.7, 121.4, 46.2, 45.1, 40.5, 36.3, 33.1, 32.7, 30.7, 30.7, 30.6, 30.5, 30.3, 27.4, 23.7, 22.0, 14.5. HRMS: (ESI) [M+H]+ calc. for C22H37N2O, 345.2906, observed, 345.2906.
Synthesized according to General Procedure 4. White solid (77%, 250 mg). 1H NMR (400 MHz, CD3OD) δ 7.45 (d, J= 8.4 Hz, 2H), 7.12 (d, J= 8.5 Hz, 2H), 3.59 (dd, J= 11.8, 5.5 Hz, 1H), 3.50 - 3.31 (m, 4H), 2.56 (t, J= 7.6 Hz, 2H), 2.44 - 2.33 (m, 1H), 2.28 -2.17 (m, 1H), 1.58 (p, J= 6.8 Hz, 2H), 1.36 - 1.21 (m, 14H), 0.89 (t, J= 6.7 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 172.2, 140.3, 137.2, 129.7, 121.3, 48.9, 46.5, 44.7, 36.3, 33.1, 32.7, 30.7, 30.7, 30.6, 30.5, 30.5, 30.3, 23.7, 14.5. HRMS: (ESI) [M+H]+ calc. for C21H35N2O, 331.2744, observed, 331.2760.
Synthesized according to General Procedure 3. White solid (64%, 125 mg). 1H NMR (400 MHz, CD3OD) δ 7.45 (d, J= 8.5 Hz, 2H), 7.12 (d, J= 8.7 Hz, 2H), 3.03 (t, J= 7.5 Hz, 2H), 2.59 - 2.52 (m, 4H), 2.05 - 1.96 (m, 2H), 1.59 (p, J= 7.0 Hz, 2H), 1.36 - 1.23 (m, 14H), 0.89 (t, J= 6.7 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 172.6, 140.1, 137.3, 129.7, 121.3, 40.4, 36.3, 34.4, 33.1, 32.8, 30.7, 30.7, 30.6, 30.5, 30.3, 24.3, 23.7, 14.5. HRMS: (ESI) [M+H]+ calc. for C20H35N2O, 319.2749, observed, 319.2733.
Synthesized according to General Procedure 3. White solid (79%, 226 mg). 1H NMR (400 MHz, CD3OD) δ 7.47 (d, J= 8.5 Hz, 2H), 7.12 (d, J= 8.5 Hz, 2H), 3.26 (t, J= 6.4 Hz, 2H), 2.80 (t, J= 6.3 Hz, 2H), 2.57 (t, J= 7.6 Hz, 2H), 1.60 (p, J= 7.1 Hz, 2H), 1.39 -1.20 (m, 14H), 0.90 (t, J= 6.6 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 170.3, 140.2, 137.2, 129.7, 121.2, 37.0, 36.3, 33.6, 33.1, 32.8, 30.7, 30.7, 30.6, 30.5, 30.3, 23.7, 14.5. HRMS: (ESI) [M+H]+ calc. for C19H33N2O, 305.2587, observed, 305.2599.
Synthesized according to General Procedure 3. White solid (90%, 54 mg). 1H NMR (400 MHz, CD3OD) δ 7.45 (d, J = 8.5 Hz, 2H), 7.11 (d, J= 8.4 Hz, 2H), 2.97 (t, J= 7.1 Hz, 2H), 2.56 (t, J= 7.6 Hz, 2H), 2.45 (t, J = 6.7 Hz, 2H), 1.82 - 1.68 (m, 4H), 1.59 (p, J = 7.3 Hz, 2H), 1.37 - 1.21 (m, 14H), 0.90 (t, J= 6.8 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 173.6, 140.1, 137.4, 129.7, 121.3, 40.4, 36.8, 36.3, 33.1, 32.8, 30.7, 30.7, 30.6, 30.5, 30.3, 28.0, 23.7, 23.4, 14.5. HRMS: (ESI) [M+H]+ calc. for C21H40N3O, 350.3166, observed, 350.3171.
Synthesized according to General Procedure 3. White solid (81%, 209 mg). 1H NMR (400 MHz, CD3OD) δ 7.45 (d, J= 8.5 Hz, 2H), 7.11 (d, J= 8.8 Hz, 2H), 2.94 (t, J= 7.6 Hz, 2H), 2.56 (t, J= 7.6 Hz, 2H), 2.41 (t, J= 7.3 Hz, 2H), 1.79 - 1.65 (m, 4H), 1.58 (p, J = 7.0 Hz, 2H), 1.52 - 1.42 (m, 2H), 1.37 - 1.21 (m, 14H), 0.89 (t, J= 6.8 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 174.1, 140.0, 137.4, 129.6, 121.3, 40.5, 37.4, 36.3, 33.1, 32.8, 30.7, 30.7, 30.7, 30.6, 30.5, 30.3, 28.3, 27.0, 26.2, 23.7, 14.5. HRMS: (ESI) [M+H]+ calc. for C22H39N2O, 347.3057, observed, 347.3050.
Synthesized according to General Procedure 3. White solid (62%, 84 mg). 1H NMR (400 MHz, CD3OD) δ 7.45 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 3.02 (t, J = 7.5 Hz, 2H), 2.60 - 2.51 (m, 4H), 2.01 (p, J = 7.0 Hz, 2H), 1.59 (p, J = 7.2 Hz, 2H), 1.36 -1.23 (m, 12H), 0.88 (t, J= 6.8 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 172.7, 140.1, 137.3, 129.7, 121.3, 40.4, 36.3, 34.4, 33.1, 32.8, 30.7, 30.6, 30.4, 30.3, 24.3, 23.7, 14.5. HRMS: (ESI) [M+H]+ calc. for C19H33N2O, 305.2587, observed, 305.2564.
Synthesized according to General Procedure 3. White solid (67%, 90 mg). 1H NMR (400 MHz, CD3OD) δ 7.45 (d, J = 8.5 Hz, 2H), 7.12 (d, J= 8.5 Hz, 2H), 3.02 (t, J = 7.6 Hz, 2H), 2.60 - 2.51 (m, 4H), 2.05 - 1.96 (m, 2H), 1.59 (p, J= 7.3 Hz, 2H), 1.37 - 1.22 (m, 10H), 0.88 (t, J= 6.8 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 172.7, 140.1, 137.3, 129.7, 121.3, 40.4, 36.3, 34.4, 33.0, 34.8, 30.6, 30.4, 30.3, 24.3, 23.7, 14.4. HRMS: (ESI) [M+H]+ calc. for C18H31N2O, 291.2431, observed, 291.2421.
Synthesized according to General Procedure 3. White solid (100%, 213 mg). 1H NMR (400 MHz, CD3OD) δ 7.43 (d, J= 8.5 Hz, 2H), 7.12 (d, J= 8.8 Hz, 2H), 3.55 (dd, J = 11.7, 7.7 Hz, 1H), 3.45 - 3.37 (m, 1H), 3.30 - 3.20 (m, 1H), 3.00 (dd, J= 11.7, 9.0 Hz, 1H), 2.80 - 2.69 (m, 1H), 2.66 - 2.50 (m, 4H), 2.32 - 2.22 (m, 1H), 1.80 - 1.70 (m, 1H), 1.58 (p, J= 7.5 Hz, 2H), 1.36 - 1.21 (m, 14H), 0.88 (t, J= 6.8 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 170.2, 138.8, 135.8, 128.3, 119.9, 49.6, 44.8, 38.4, 34.9, 34.8, 31.6, 31.3, 29.6, 29.3, 29.3, 29.2, 29.0, 28.8, 22.3, 13.0. HRMS: (ESI) [M+H]+ calc. for C22H37N2O, 345.2900, observed, 345.2872.
Synthesized according to General Procedure 3. White solid (91%, 167 mg). 1H NMR (400 MHz, CD3OD) δ 7.44 (d, J= 8.5 Hz, 2H), 7.12 (d, J= 8.5 Hz, 2H), 3.55 (dd, J= 11.7, 7.7 Hz, 1H), 3.47 - 3.37 (m, 1H), 3.30 - 3.20 (m, 1H), 3.01 (dd, J= 11.7, 9.0 Hz, 1H), 2.81 - 2.69 (m, 1H), 2.68 - 2.50 (m, 4H), 2.32 - 2.22 (m, 1H), 1.82 - 1.70 (m, 1H), 1.59 (p, J = 7.2 Hz, 2H), 1.38 - 1.20 (m, 14H), 0.89 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 171.7, 140.2, 137.2, 129.7, 121.3, 51.0, 46.2, 39.9, 36.3, 36.2, 33.1, 32.8, 31.1, 30.8, 30.7, 30.6, 30.5, 30.3, 23.7, 14.5. HRMS: (ESI) [M+H]+ calc. for C22H37N2O, 345.2900, observed, 345.2878.
Synthesized according to General Procedure 3. White solid (83%, 185 mg). 1H NMR (400 MHz, CD3OD) δ 8.17 (d, J= 2.2 Hz, 1H), 7.73 (d, J= 8.8 Hz, 1H), 7.68 (d, J= 8.4 Hz, 1H), 7.56 - 7.51 (m, 2H), 7.31 (dd, J= 8.4, 1.7 Hz, 1H), 3.06 (t, J= 7.6 Hz, 2H), 2.73 (t, J= 7.6 Hz, 2H), 2.61 (t, J= 7.0 Hz, 2H), 2.10 - 2.00 (m, 2H), 1.68 (p, J= 7.5 Hz, 2H), 1.41 - 1.19 (m, 10H), 0.87 (t, J= 6.8 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 172.9, 140.8, 136.5, 133.6, 132.3, 129.1, 129.0, 128.4, 127.1, 121.2, 117.7, 40.4, 37.0, 34.5, 33.0, 32.6, 30.6, 30.4, 30.4, 24.3, 23.7, 14.5. HRMS: (ESI) [M+H]+ calc. for C22H33N2O, 341.2587, observed, 341.2603.
Synthesized according to General Procedure 3. White solid (66%, 101 mg). 1H NMR (400 MHz, CD3OD) δ 7.68 (t, J= 8.3 Hz, 1H), 7.02 - 6.91 (m, 2H), 3.03 (t, J= 7.8 Hz, 2H), 2.59 (t, J= 7.3 Hz, 4H), 2.02 (p, J= 7.2 Hz, 2H), 1.59 (p, J= 7.1 Hz, 2H), 1.40 -1.20 (m, 14H), 0.90 (t, J= 6.7 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 173.2, 155.9 (d, J= 246 Hz), 143.2, 125.9, 125.2, 124.1 (d J= 12 Hz), 116.2 (d, J= 19.5 Hz), 40.4, 36.2, 33.9, 33.1, 32.4, 30.7, 30.6, 30.5, 30.2, 24.3, 23.7, 14.5. HRMS: (ESI) [M+H]+ calc. for C20H34FN2O, 337.2650, observed, 337.2649.
Synthesized according to General Procedure 3. Light yellow solid (46%, 140 mg). 1H NMR (400 MHz, CD3OD) δ 7.89 (d, J= 2.6 Hz, 1H), 7.69 (dd, J= 8.9, 2.7 Hz, 1H), 7.09 (d, J= 8.9 Hz, 1H), 4.04 (t, J= 6.2 Hz, 2H), 3.03 (t, J= 7.5 Hz, 2H), 2.56 (t, J= 7.1 Hz, 2H), 2.02 (p, J= 7.1 Hz, 2H), 1.82 - 1.72 (m, 2H), 1.55 (p, J= 7.7 Hz, 2H), 1.40 - 1.24 (m, 10H), 0.88 (t, J= 6.8 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 172.7, 154.8, 132.3, 126.3, 124.9 (q, J= 267 Hz), 120.1 (q, J= 6 Hz), 119.5 (q, J= 31 Hz), 114.6, 70.0, 40.4, 34.3, 33.0, 30.6, 30.3, 30.3, 30.2, 26.9, 24.2, 23.7, 14.4. HRMS: (ESI) [M+H]+ calc. for C20H32F3N2O2, 389.2410, observed, 389.2415.
Synthesized according to General Procedure 3. White solid (53%, 148 mg). 1H NMR (400 MHz, CD3OD) δ 7.45 (d, J= 8.4 Hz, 2H), 7.12 (d, J= 8.4 Hz, 2H), 3.09 (t, J= 7.4 Hz, 2H), 2.72 (s, 3H), 2.56 (t, J= 7.5 Hz, 4H), 2.03 (p, J= 7.0 Hz, 2H), 1.58 (p, J= 7.4 Hz, 2H), 1.38 - 1.21 (m, 14H), 0.89 (t, J= 6.8 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 172.6, 140.1, 137.3, 129.7, 121.3, 50.1, 36.3, 34.4, 33.6, 33.1, 32.7, 30.7, 30.7, 30.6, 30.5, 30.3, 23.7, 22.9, 14.5. HRMS: (ESI) [M+H]+ calc. for C21H37N2O, 333.2900, observed, 333.2897.
Synthesized according to General Procedure 3. White solid (84%, 260 mg). 1H NMR (400 MHz, CD3OD) δ 7.46 (d, J= 8.5 Hz, 2H), 7.12 (d, J= 8.5 Hz, 2H), 3.47 (dt, J= 13.0, 3.8 Hz, 2H), 3.09 (td, J= 12.6, 3.4 Hz, 2H), 2.80 - 2.70 (m, 1H), 2.56 (t, J= 7.8 Hz, 2H), 2.14 - 2.05 (m, 2H), 2.04 - 1.91 (m, 2H), 1.59 (p, J= 8.0 Hz, 2H), 1.36 - 1.20 (m, 14H), 0.88 (t, J= 6.8 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 174.0, 140.2, 137.2, 129.7, 121.4, 44.3, 41.6, 36.3, 33.1, 32.7, 30.7, 30.7, 30.6, 30.5, 30.3, 26.7, 23.7, 14.5. HRMS: (ESI) [M+H]+ calc. for C22H37N2O, 345.2900, observed, 345.2902.
Amine free base of the title compound was synthesized according to General Procedure 11. The title compound was produced by dissolving the amine free base in methanolic HCl, followed by concentration in vacuo. White solid (30%, 123 mg). 1H NMR (400 MHz, CD3OD) δ 7.44 (d, J= 8.4 Hz, 2H), 7.12 (d, J= 8.4 Hz, 2H), 3.24 - 3.17 (m, 2H), 2.91 (s, 6H), 2.60 - 2.51 (m, 4H), 2.06 (p, J= 7.0 Hz, 2H), 1.59 (p, J= 7.2 Hz, 2H), 1.38 -1.21 (m, 14H), 0.89 (t, J= 6.7 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 172.6, 140.2, 137.2, 129.7, 121.4, 58.8, 43.5, 36.3, 34.1, 33.1, 32.7, 30.7, 30.7, 30.6, 30.4, 30.3, 23.7. HRMS: (ESI) [M+H]+ calc. for C22H39N2O, 347.3057, observed, 347.3054.
Synthesized according to General Procedure 5. Purified by silica chromatography (40% ethyl acetate in hexanes). White solid (53%, 58 mg). 1H NMR (400 MHz, CDCl3) δ 10.23 (brs, 1H), 7.55 (d, J= 8.0 Hz, 2H), 7.08 (d, J= 8.2 Hz, 2H), 4.32 (brs, 1H), 3.78 - 3.42 (m, 1H), 3.41 - 3.13 (m, 1H), 2.76 (p, J= 5.4 Hz, 1H), 2.54 (t, J= 7.6 Hz, 2H), 2.41 - 2.12 (m, 1H), 1.91 - 1.78 (m, 1H), 1.70 - 1.39 (m, 24H), 1.36 - 1.60 (m, 14H), 0.87 (t, J= 0.87, 3H). 13C NMR (101 MHz, CDCl3) δ 170.7, 162.3, 156.0, 150.6, 138.9, 136.1, 128.7, 120.4, 82.4, 79.8, 48.6, 43.0, 35.5, 32.0, 31.7, 29.7, 29.6, 29.4, 29.3, 28.3, 28.1, 27.6, 23.9, 22.8, 14.1. HRMS: (ESI) [M+H]+ calc. for C33H55N4O5, 587.4172, observed, 587.4184.
Synthesized according to General Procedure 5. Purified by silica chromatography (40% ethyl acetate in hexanes). Colorless residue (62%, 70 mg). 1H NMR (400 MHz, CDCl3) δ 13C NMR (101 MHz, CDCl3) δ HRMS: (ESI) [M+H]+ calc. for C32H53N4O5, 573.4010, observed, 573.4000.
Synthesized according to General Procedure 5. Purified by silica chromatography (40% ethyl acetate in hexanes). White solid (70%, 218 mg). 1H NMR (400 MHz, CDCl3) δ 11.54 (brs, 1H), 9.45 (brs, 1H), 8.60 (t, J= 6.3 Hz, 2H), 7.47 (d, J= 8.4 Hz, 2H), 7.08 (d, J= 8.6 Hz, 2H), 3.52 (q, J= 6.1 Hz, 2H), 2.54 (t, J= 7.6 Hz, 2H), 2.47 - 2.37 (m, 2H), 1.98 - 1.88 (m, 2H), 1.59 - 1.51 (m, 2H), 1.50 (s, 9H), 1.33 (s, 9H), 1.37 - 1.17 (m, 14H), 0.87 (t, J= 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 171.3, 163.2, 157.2, 153.2, 138.7, 135.9, 128.4, 121.2, 83.5, 79.8, 39.3, 35.4, 34.4, 31.9, 31.6, 29.6, 29.5, 29.3, 29.2, 28.1, 28.0, 28.0, 27.6, 22.7, 14.1. HRMS: (ESI) [M+H]+ calc. for C31H53N4O5, 561.4010, observed, 561.4016.
Synthesized according to General Procedure 4. White solid (70%, 35 mg). 1H NMR (400 MHz, CD3OD) δ 7.42 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 3.95 - 3.85 (m, 1H), 3.84 - 3.73 (m, 1H), 3.39 (dd, J = 13.9, 10.1 Hz, 1H), 3.24 - 3.15 (m, 1H), 2.71 -2.61 (m, 1H), 2.57 (t, J= 7.6 Hz, 2H), 2.18 - 2.08 (m, 1H), 1.94 - 1.82 (m, 2H), 1.77 - 1.53 (m, 3H), 1.38 - 1.20 (m, 14H), 0.90 (t, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 173.3, 157.9, 140.3, 137.2, 48.9, 47.4, 44.0, 36.3, 33.1, 32.8, 30.7, 30.7, 30.6, 30.5, 30.3, 28.8, 25.0, 23.7, 14.5. HRMS: (ESI) [M+H]+ calc. for C23H39N4O, 387.3124, observed, 387.3154.
Synthesized according to General Procedure 4. White solid (70%, 35 mg). 1H NMR (400 MHz, CD3OD) δ 7.42 (d, J= 8.4 Hz, 2H), 7.12 (d, J= 8.5 Hz, 2H), 3.95 - 3.85 (m, 1H), 3.84 - 3.73 (m, 1H), 3.39 (dd, J = 13.9, 10.1 Hz, 1H), 3.24 - 3.15 (m, 1H), 2.71 -2.61 (m, 1H), 2.57 (t, J= 7.6 Hz, 2H), 2.18 - 2.08 (m, 1H), 1.94 - 1.82 (m, 2H), 1.77 - 1.53 (m, 3H), 1.38 - 1.20 (m, 14H), 0.90 (t, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 173.3, 157.9, 140.3, 137.2, 48.9, 47.4, 44.0, 36.3, 33.1, 32.8, 30.7, 30.7, 30.6, 30.5, 30.3, 28.8, 25.0, 23.7, 14.5. HRMS: (ESI) [M+H]+ calc. for C23H39N4O, 387.3124, observed, 387.3154.
Synthesized according to General Procedure 3. White solid (56%, 59 mg). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J= 8.4 Hz, 2H), 7.12 (d, J= 8.5 Hz, 2H), 3.26 (t, J= 7.2 Hz, 2H), 2.57 (t, J = 7.6 Hz, 2H), 2.48 (t, J = 7.0 Hz, 2H), 2.00 - 1.89 (m, 2H), 1.59 (p, J = 8 Hz, 2H), 1.37 - 1.22 (m, 14H), 0.89 (t, J= 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 173.3, 158.7, 140.1, 137.3, 129.7, 121.4, 41.9, 36.3, 34.0, 33.1, 32.8, 30.7, 30.7, 30.6, 30.5, 30.3, 25.8, 23.7, 14.5. HRMS: (ESI) [M+H]+ calc. for C21H37N4O, 361.2962, observed, 361.2952.
(a) N-boc-amino acid (1.3 equiv), CDI (1.3 equiv), DIEA (1.6 equiv), DCM, rt; (b) PPh3 (2.0 equiv), DIAD (2.0 equiv), THF, 70° C.; (c) (i) 9-BBN (2.2 equiv), 1-decene (2.0 equiv), (ii) aryl bromide (1.0 equiv), Pd(dppf)Cl2*CH2Cl2 (0.075 equiv), 3 M KOH (3.0 equiv), THF, 70° C.; (d) 4 M HCl/Dioxane, DCM, rt.
Synthesized according to General Procedure 1. Orange solid (39%, 322 mg). 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.19 (s, 1H), 8.03 (d, J = 2.5 Hz, 1H), 7.03 (dd, J= 8.6, 2.5 Hz, 1H), 6.77 (d, J= 8.5 Hz, 2H), 3.16 (q, J= 6.6 Hz, 2H), 2.49 (t, J= 7.0 Hz, 2H), 1.33 (s, 9H). 13C NMR (400, DMSO) 13C NMR (126 MHz, DMSO-d6) δ 170.6, 156.0, 147.3, 128.4, 127.0, 124.5, 117.3, 110.0, 78.1, 37.1, 37.0, 28.7. HRMS (ESI+) m/z calc’d. for C14H20BrN2O4+ (M+H)+ 359.0601, found 359.0596.
Synthesized according to General Procedure 1. Crude mixture dried in vacuo and carried forward to the next reaction without purification.
Synthesized according to General Procedure 1. Orange solid (50%, 320 mg). 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 9.15 (s, 1H), 8.05 (d, J= 2.5 Hz, 1H), 7.04 (dd, J= 8.6, 2.5 Hz, 1H), 6.78 (d, J= 8.5 Hz, 1H), 6.75 - 6.71 (m, 1H), 2.87 (q, J= 6.8 Hz, 2H), 2.36 (t, J= 7.4 Hz, 2H), 1.52 (p, J= 7.4 Hz, 2H), 1.34 (s, 9H), 1.23 (td, J= 8.4, 4.1 Hz, 2H).
Synthesized according to General Procedure 1. Yellow solid (38%, 228 mg). 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.17 (s, 1H), 7.69 (d, J= 8.6 Hz, 1H), 6.95 (d,J=2.3 Hz, 1H), 6.88 (dd, J= 8.6, 2.2 Hz, 1H), 6.76 (s, 1H), 3.14 (q, J = 6.7 Hz, 2H), 2.47 (t, J= 6.3 Hz, 2H), 1.31 (s, 9H).
Synthesized according to General Procedure 1. Light yellow solid (38%, 228 mg). 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.11 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 6.93 (d, J= 2.3 Hz, 1H), 6.85 (dd, J = 8.6, 2.3 Hz, 1H), 6.75 - 6.70 (m, 1H), 2.87 (q, J = 6.6 Hz, 2H), 2.29 (t, J= 7.4 Hz, 2H), 1.64 - 1.53 (m, 2H), 1.29 (s, 9H). HRMS (ESI+) m/z calc’d. for C15H22BrN2O4+ (M+H)+ 373.0757, found 373.0757.
Synthesized according to General Procedure 9. Pink solid (69%, 230 mg). δ 1H NMR (500 MHz, Chloroform-d) δ 7.81 (d, J = 1.8 Hz, 1H), 7.43 (dd, J= 8.6, 1.9 Hz, 1H), 7.37 (d, J= 8.6 Hz, 1H), 5.21 (t, J= 6.2 Hz, 1H), 3.68 (q, J= 6.2 Hz, 2H), 3.12 (t, J= 6.2 Hz, 2H), 1.42 (s, 9H). HRMS (ESI+) m/z calc’d. for C14H18BrN2O3+ (M+H)+ 341.0495, found 341.0493.
Synthesized according to General Procedure 9. Pink solid (80%, 117 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.84 - 7.75 (m, 1H), 7.42 (ddd, J= 8.6, 1.9, 0.7 Hz, 1H), 7.35 (dt, J= 8.6, 0.7 Hz, 1H), 4.72 (s, 1H), 3.27 (q, J= 6.6 Hz, 2H), 3.02 - 2.94 (m, J= 7.9, 7.5 Hz, 2H), 2.08 (p, J= 7.1 Hz, 2H), 1.42 (s, 9H). HRMS (ESI+) m/z calc’d. for C15H20BrN2O3+ (M+H)+ 355.0652, found 355.0653.
Synthesized according to General Procedure 9. Amber oil (24%, 75 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.80 (d, J = 1.9 Hz, 1H), 7.45 - 7.33 (m, 2H), 4.65 (s, 1H), 3.14 (t, J = 6.8 Hz, 2H), 2.94 (t, J = 7.5 Hz, 2H), 1.90 (p, J = 7.5 Hz, 2H), 1.55 (p, J= 7.1 Hz, 2H), 1.44 (s, 9H), 1.27 - 1.23 (m, 2H). HRMS (ESI+) m/z calc’d. for C17H24BrN2O3+ (M+H)+ 383.0965, found 383.1040.
Synthesized according to General Procedure 9. Pink solid (33%, 70 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.38 (s, 1H), 7.30 - 7.25 (m, 1H), 7.20 (d, J = 8.3 Hz, 2H), 5.95 (s, 1H), 5.00 (s, 1H), 3.58 (t, J= 5.4 Hz, 2H), 3.44 (q, J= 5.9 Hz, 2H), 1.43 (s, 9H).
Synthesized according to General Procedure 9. Light yellow solid (82%, 215 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.37 (d, J= 1.9 Hz, 1H), 7.28 - 7.25 (m, 1H), 7.19 (d, J= 8.3 Hz, 1H), 6.07 (d, J= 6.9 Hz, 1H), 4.89 (t, J = 6.5 Hz, 1H), 3.52 (q, J = 6.3 Hz, 2H), 3.26 (t, J= 6.3 Hz, 2H), 1.84 - 1.77 (m, 2H), 1.46 (s, 9H).
Synthesized according to General Procedure 6. Clear oil (53%, 62 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.46 (d, J = 1.7 Hz, 1H), 7.36 (dd, J= 8.2, 1.4 Hz, 1H), 7.11 (dt, J = 8.4, 1.6 Hz, 1H), 5.33 (s, 1H), 3.66 (t, J = 6.3 Hz, 2H), 3.10 (t, J = 6.2 Hz, 2H), 2.70 (t, J= 7.7 Hz, 2H), 1.68 - 1.60 (m, 2H), 1.43 (d, J= 1.3 Hz, 9H), 1.29 (d, J= 22.9 Hz, 14H), 0.88 (t, J = 6.8 Hz, 3H) HRMS (ESI+) m/z calc’d. for C24H39N2O3+ (M+H)+ 403.2955, found 403.2933.
Synthesized according to General Procedure 6. White solid (28%, 99 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.42 (s, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 4.89 (s, 1H), 3.27 - 3.18 (m, 2H), 2.93 (t, J= 7.3 Hz, 2H), 2.66 (t, J= 7.6 Hz, 2H), 2.08 - 1.99 (m, 2H), 1.87 - 1.72 (m, 1H), 1.39 (s, 10H), 1.31 - 1.15 (m, 14H), 0.84 (t, J= 6.9 Hz, 3H). HRMS (ESI+) m/z calc’d. for C15H20BrN2O3+ (M+H)+ 417.3112, found 417.3106.
Synthesized according to General Procedure 6. Off-white solid (68%, 59 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.45 (d, J= 1.7 Hz, 1H), 7.35 (d, J= 8.3 Hz, 1H), 7.10 (dd, J = 8.3, 1.7 Hz, 1H), 4.63 (d, J= 6.2 Hz, 1H), 3.13 (q, J= 6.7 Hz, 2H), 2.91 (t, J= 7.5 Hz, 2H), 2.69 (t, 2H), 1.89 (p, J = 7.6 Hz, 2H), 1.63 (d, J= 7.5 Hz, 2H), 1.54 (q, J = 7.2 Hz, 2H), 1.43 (s, 11H), 1.35 - 1.22 (m, 14H), 0.88 (t, J= 6.9 Hz, 3H). HRMS (ESI+) m/z calc’d. for C27H45N2O3+ (M+H)+ 445.3425, found 445.3417.
Synthesized according to General Procedure 6. Yellow oil (80%, 66 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.56 (d, J = 8.1 Hz, 1H), 7.30 (s, 1H), 7.14 (d, J = 8.2 Hz, 1H), 5.29 (t, J= 6.2 Hz, 1H), 3.69 (q, J= 6.2 Hz, 2H), 3.11 (t, J = 6.1 Hz, 2H), 2.72 (t, J= 7.7 Hz, 2H), 1.65 (p, J= 7.2 Hz, 2H), 1.44 (s, 8H), 1.36 - 1.23 (m, 14H), 0.89 (t, J= 6.8 Hz, 3H). HRMS (ESI+) m/z calc’d. for C24H39N2O3+ (M+H)+ 403.2955, found 403.2952.
Synthesized according to General Procedure 6. Yellow oil (29%, 27 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.51 (d, J= 8.1 Hz, 1H), 7.26 - 7.23 (m, 1H), 7.09 (dd, J= 8.1, 1.6 Hz, 1H), 4.75 (s, 1H), 3.24 (q, J= 6.6 Hz, 2H), 2.93 (t, J= 7.4 Hz, 2H), 2.68 (dd, J= 8.6, 6.8 Hz, 2H), 2.04 (t, J= 7.1 Hz, 2H), 1.67 - 1.52 (m, 2H), 1.39 (s, 9H), 1.32 - 1.18 (m, 14H), 0.89 - 0.80 (m, 3H). HRMS (ESI+) m/z calc’d. for C25H41N2O3+ (M+H)+ 417.3112, found 417.3111.
Synthesized according to General Procedure 3. White solid (73%, 38 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.50 - 7.47 (m, 2H), 7.22 (dd, J= 8.4, 1.8 Hz, 1H), 3.50 (t, J = 6.7 Hz, 2H), 3.34 (t, J = 6.9, 1.5 Hz, 2H), 2.72 (t, J = 7.6 Hz, 2H), 1.64 (p, J= 7.5 Hz, 2H), 1.34 - 1.24 (m, 15H), 0.88 (t, J = 6.9 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) δ 164.8, 150.7, 142.1, 141.1, 127.1, 119.8, 111.2, 37.6, 36.8, 33.2, 33.1, 30.7, 30.7, 30.6, 30.5, 30.2, 27.1, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C19H31N2O+ (M+H)+ 303.2431, found 303.2422.
Synthesized according to General Procedure 3. White solid (92%, 70 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.48 - 7.42 (m, 2H), 7.21 (dd, J= 8.4, 1.7 Hz, 1H), 3.12 -3.07 (m, 4H), 2.74 - 2.70 (m, 2H), 2.41 - 2.18 (m, 2H), 1.65 (t, J = 7.6 Hz, 2H), 1.34 - 1.24 (m, 14H), 0.89 (t, J= 6.9 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) δ 167.6, 150.5, 142.0, 141.0, 126.9, 119.5, 111.0, 40.0, 36.8, 33.2, 33.1, 30.7, 30.7, 30.6, 30.4, 30.2, 26.3, 25.3, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C20H33N2O+ (M+H)+ 317.2587, found 317.2585.
Synthesized according to General Procedure 3. Off-white solid (59%, 30 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.45 (d, J= 8.4 Hz, 1H), 7.42 (d, J= 1.6 Hz, 1H), 7.20 (dd, J = 8.4, 1.7 Hz, 1H), 2.99 (t, J= 7.4 Hz, 2H), 2.94 (t, J= 7.6 Hz, 2H), 2.75 - 2.69 (m, 2H), 1.94 (p, J= 7.5 Hz, 2H), 1.76 - 1.68 (m, 2H), 1.68 - 1.60 (m, 2H), 1.55 - 1.47 (m, 2H), 1.36 - 1.24 (m, 14H), 0.89 (t, J= 6.9 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) δ 167.6, 149.0, 140.5, 139.6, 125.3, 117.9, 109.6, 39.1, 35.4, 31.8, 31.7, 29.3, 29.3, 29.2, 29.0, 28.8, 27.5, 26.8, 25.7, 25.4, 22.3, 13.0. HRMS (ESI+) m/z calc’d. for C22H37N2O+ (M+H)+ 345.2900, found 345.2879.
Synthesized according to General Procedure 3. White solid (54%, 30 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.57 (d, J = 8.1 Hz, 1H), 7.42 (d, J = 1.5 Hz, 1H), 7.22 (d, J = 8.2, 1H), 3.50 (t, J = 6.7 Hz, 2H), 3.33 (t, J = 6.7 Hz, 2H), 2.75 (t, J = 7.6 Hz, 2H), 1.66 (t, J= 7.5 Hz, 2H), 1.35 - 1.23 (m, 14H), 0.89 (t, J = 6.8 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) δ 164.2, 152.6, 142.5, 139.9, 126.5, 120.0, 111.3, 37.6, 37.0, 33.1, 30.7, 30.7, 30.6, 30.5, 30.2, 27.1, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C19H31N2O+ (M+H)+ 303.2431, found 303.2432.
Synthesized according to General Procedure 3. White solid (79%, 18 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.55 (dd, J= 8.1, 0.6 Hz, 1H), 7.41 (dd, J = 1.5, 0.7 Hz, 1H), 7.22 (dd, J= 8.2, 1.6 Hz, 1H), 3.15 - 3.06 (m, 4H), 2.79 - 2.72 (m, 2H), 2.28 - 2.19 (m, 2H), 1.68 (q, J= 7.0 Hz, 2H), 1.40 - 1.22 (m, 15H), 0.93 - 0.86 (m, 3H). 13C NMR (126 MHz, Methanol-d4) δ 167.0, 152.4, 142.2, 139.8, 126.4, 119.6, 111.1, 40.0, 37.0, 33.1, 30.7, 30.7, 30.6, 30.4, 30.2, 26.3, 25.3, 23.7, 14.4.
(a) CS2 (1.2 equiv), K2CO3 (1.2 equiv), EtOH/H2O, 80° C.; (b) SOCl2 (2.5 equiv), DMF (0.04 equiv), DCM, rt; (c) N-boc-amine (1.2 equiv), K2CO3 (2.0 equiv), DMF, 120° C.; (d) (i) 9-BBN (2.2 equiv), 1-decene (2.0 equiv); (ii) aryl bromide (1.0 equiv), Pd(dppf)Cl2*CH2Cl2 (0.15 equiv), 3 M KOH (3.0 equiv), THF, 70° C.; (e) 4 M HCl/Dioxane, DCM, rt.
Synthesized according to General Procedure 10. Crude mixture dried in vacuo and carried forward to the next reaction without purification.
Synthesized according to General Procedure 11. Crude mixture dried in vacuo and carried forward to the next reaction without purification.
Synthesized according to General Procedure 13. Light pink solid (67%, 92 mg).1H NMR (500 MHz, Chloroform-d) δ 7.46 (d, J= 1.9 Hz, 1H), 7.14 (dd, J= 8.4, 1.9 Hz, 1H), 7.09 (d, J= 8.4 Hz, 1H), 5.96 (s, 1H), 4.99 (s, 1H), 3.59 (q, J = 5.3 Hz, 2H), 3.44 (q, J= 5.8 Hz, 2H), 1.43 (s, 9H). HRMS (ESI+) m/z calc’d. for C14H19BrN3O3+ (M+H)+ 356.0604, found 356.0617.
Synthesized according to General Procedure 13. White solid (91%, 90 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.44 (d, J= 1.9 Hz, 1H), 7.11 (dd, J = 8.4, 1.9 Hz, 1H), 7.08 - 7.06 (m, 1H), 6.24 (s, 1H), 4.96 (s, 1H), 3.52 (q, J = 6.1 Hz, 2H), 3.26 (q, J = 6.3 Hz, 2H), 1.79 (p, J= 6.2 Hz, 2H), 1.45 (s, 9H). HRMS (ESI+) m/z calc’d. for C15H21BrN3O3+ (M+H)+ 370.0761, found 370.0754.
Synthesized according to General Procedure 13. White solid (51%, 170 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.47 (dd, J= 1.9, 0.5 Hz, 1H), 7.14 (dd, J = 8.4, 1.9 Hz, 1H), 7.09 (dd, J= 8.4, 0.5 Hz, 1H), 5.23 (s, 1H), 4.68 (s, 1H), 3.53 - 3.47 (m, 2H), 3.19 (q, J= 6.6 Hz, 2H), 1.76 - 1.67 (m, 3H), 1.66 - 1.57 (m, 2H), 1.45 (s, 9H). HRMS (ESI+) m/z calc’d. for C16H23BrN3O3+ (M+H)+ 384.0917, found 384.0906.
Synthesized according to General Procedure 13. White solid (64%, 68 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.46 (d, J = 1.9 Hz, 1H), 7.12 (s, 1H), 7.08 (d, J = 8.4 Hz, 1H), 5.40 (s, 1H), 4.58 (s, 1H), 3.47 (q, J= 6.6 Hz, 2H), 3.14 (q, J= 6.6 Hz, 2H), 1.71 (p, J= 7.1 Hz, 2H), 1.54 (p, J= 7.0 Hz, 2H), 1.44 (s, 9H), 1.43 (d, J = 8.8 Hz, 2H). HRMS (ESI+) m/z calc’d. for C17H25BrN3O3+ (M+H)+ 398.1074, found 398.1053.
Synthesized according to General Procedure 13. White solid (66%, 90 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.48 (d, J= 2.0 Hz, 1H), 7.18 (dd, J = 8.4, 1.9 Hz, 1H), 7.13 (d, J= 8.4 Hz, 1H), 6.44 (s, 1H), 4.64 (p, J= 6.3, 5.7 Hz, 1H), 4.41 - 4.34 (m, 2H), 3.94 (dd, J= 9.5, 5.0 Hz, 2H), 1.46 (s, 9H). HRMS (ESI+) m/z calc’d. for C15H18BrN3O3+ (M+H)+ 368.0610, found 368.0587.
Synthesized according to General Procedure 13. White solid (73%, 122 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.53 - 7.45 (m, 1H), 7.21 - 7.05 (m, 2H), 5.60 (d, J= 37.4 Hz, 1H), 4.46 (s, 1H), 3.74 (dd, J= 11.6, 5.9 Hz, 1H), 3.58 - 3.31 (m, 3H), 2.35 - 2.20 (m, 1H), 2.18 - 1.96 (m, 1H), 1.47 (s, 9H). HRMS (ESI+) m/z calc’d. for C16H21BrN3O3+ (M+H)+ 3 82.0761, found 382.0763.
Synthesized according to General Procedure 13. White solid (83%, 175 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.50 (d, J = 1.8 Hz, 1H), 7.17 (dd, J = 8.5, 1.9 Hz, 1H), 7.11 (d, J= 8.4 Hz, 1H), 5.04 (s,1H), 4.46 (s, 1H), 3.74 (dd, J= 11.6, 5.9 Hz, 1H), 3.57 -3.28 (m, 3H), 2.33 - 2.23 (m, 1H), 2.04 (s, 1H), 1.47 (s, 9H). HRMS (ESI+) m/z calc’d. for C16H21BrN3O3+ (M+H)+382.0749, found 382.0763.
Synthesized according to General Procedure 13. Off-white solid (77%, 114 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.50 (d, J = 2.4 Hz, 1H), 7.22 - 7.08 (m, 2H), 5.63 (s, 1H), 5.22 (dt, J= 54.0, 3.4 Hz, 1H), 4.58 (d, J = 27.9 Hz, 1H), 4.11 - 4.00 (m, 1H), 3.90 - 3.54 (m, 2H), 3.25 (p, J = 9.0, 8.5 Hz, 1H), 1.48 (s, 9H). 19F NMR (376 MHz, Chloroform-d) δ -195.77 - -196.25 (m). HRMS (ESI+) m/z calc’d. for C16H20BrFN3O3+ (M+H)+ 400.0672, found 400.0656.
Synthesized according to General Procedure 13. White solid (65%). 1H NMR (500 MHz, Chloroform-d) δ 7.47 (t, J= 1.7 Hz, 1H), 7.15 (dt, J= 8.4, 1.8 Hz, 1H), 7.10 (dd, J= 8.5, 1.6 Hz, 1H), 5.14 (d, J= 7.8 Hz, 1H), 4.10 (s, 2H), 3.94 - 3.85 (m, 1H), 2.95 (t, J= 12.9 Hz, 2H), 2.17 - 2.07 (m, 2H), 1.53 - 1.40 (m, 11H). HRMS (ESI+) m/z calc’d. for C16H21BrN3O3+ (M+H)+ 382.0766, found 382.0737.
Synthesized according to General Procedure 13. White solid (49%, 70 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.47 (s, 1H), 7.11 (s, 2H), 4.71 (s, 1H), 4.37 (s, 1H), 3.89 (dd, J= 11.0, 6.0 Hz, 1H), 3.78 - 3.67 (m, 2H), 3.53 (dd, J= 11.1, 4.2 Hz, 1H), 2.37 -2.24 (m, 1H), 2.07 - 1.96 (m, 1H), 1.46 (s, 9H). HRMS (ESI+) m/z calc’d. for C16H21BrN3O3+ (M+H)+ 382.0766, found 382.0737.
Synthesized according to General Procedure 13. White solid (66%, 72 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.48 - 7.45 (m, 1H), 7.12 - 7.11 (m, 2H), 4.71 (s, 1H), 4.37 (s, 1H), 3.89 (dd, J= 11.0, 6.0 Hz, 1H), 3.78 - 3.70 (m, 2H), 3.53 (dd, J= 11.2, 4.2 Hz, 1H), 2.38 - 2.23 (m, 1H), 2.07 - 1.95 (m, 1H), 1.46 (s, 9H). HRMS (ESI+) m/z calc’d. for C16H21BrN3O3+ (M+H)+ 382.0766, found 382.0737.
Synthesized according to General Procedure 13. Off-white solid (71%, 105 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.47 (d, J= 1.8 Hz, 1H), 7.16 - 7.09 (m, 2H), 3.67 (t, J= 6.6 Hz, 4H), 3.57 (t, J= 6.7, 4H), 1.49 (s, 9H). HRMS (ESI+) m/z calc’d. for C16H21BrN3O3+ (M+H)+ 382.0766, found 382.0737.
Synthesized according to General Procedure 13. White solid (87%, 79 mg). 1H NMR (500 MHz, Chloroform-d) δ 1H NMR (500 MHz, Chloroform-d) δ 7.38 (d, J= 1.9 Hz, 1H), 7.30 - 7.25 (m, 1H), 7.20 (d, J = 8.3 Hz, 1H), 5.95 (s, 1H), 5.00 (s, 1H), 3.58 (t, J = 5.4 Hz, 2H), 3.44 (q, J= 5.9 Hz, 2H), 1.43 (s, 9H). HRMS (ESI+) m/z calc’d. for C14H19BrN3O3+ (M+H)+ 356.0604, found 356.0613.
Synthesized according to General Procedure 13. White solid (81%, 63 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.37 (d, J= 1.9 Hz, 1H), 7.28 - 7.23 (m, 1H), 7.19 (d, J= 8.3 Hz, 1H), 6.06 (s, 1H), 4.89 (s, 1H), 3.52 (q, J = 6.2 Hz, 2H), 3.27 (q, J = 6.3 Hz, 2H), 1.82 - 1.76 (m, 2H), 1.46 (s, 9H). HRMS (ESI+) m/z calc’d. for C15H21BrN3O3+ (M+H)+ 370.0761, found 370.0766.
Synthesized according to General Procedure 13. White solid (76%, 83 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.41 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.23 (d, J= 8.3 Hz, 1H), 5.46 (d, J= 19.9 Hz, 1H), 4.46 (s, 1H), 3.74 (dd, J= 11.6, 5.9 Hz, 1H), 3.59 - 3.32 (m, 3H), 2.34 - 2.22 (m, 1H), 2.15 - 1.98 (m, 1H), 1.47 (s, 9H). HRMS (ESI+) m/z calc’d. for C16H21N3O3+ (M+H)+ 382.0761, found 382.0764.
Synthesized according to General Procedure 13. Off-white solid (74%, 112 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.40 (s, 1H), 7.31 - 7.27 (m, 1H), 7.22 (d, J = 8.3, 1.7 Hz, 1H), 5.98 - 5.71 (m, 1H), 4.45 (s, 1H), 3.74 (dd, J= 11.6, 5.9 Hz, 1H), 3.61 - 3.32 (m, 3H), 2.34 - 2.21 (m, 1H), 2.17 - 1.96 (m, 1H), 1.47 (s, 9H). HRMS (ESI+) m/z calc’d. for C16H21N3O3+ (M+H)+ 382.0761, found 382.0766.
Synthesized according to General Procedure 13. White solid (53%, 70 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.28 (s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.04 (td, J= 8.0, 1.7 Hz, 1H), 5.76 (s, 1H), 4.94 (s, 1H), 3.62 (q, J = 5.5 Hz, 2H), 3.45 (q, J= 5.9 Hz, 2H), 1.44 (s, 9H). HRMS (ESI+) m/z calc’d. for C14H19BrN3O3+ (M+H)+ 356.0604, found 356.0607.
Synthesized according to General Procedure 13. White solid (68%, 115 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.31 (d, J= 8.1, 0.9 Hz, 1H), 7.17 (d, J= 7.9, 0.9 Hz, 1H), 6.89 (t, J = 8.0 Hz, 1H), 6.13 (s, 1H), 5.09 (s, 1H), 3.59 (q, J = 6.4 Hz, 2H), 3.26 (q, J = 6.3 Hz, 2H), 1.79 (p, J= 6.2 Hz, 2H), 1.46 (s, 9H). HRMS (ESI+) m/z calc’d. for C15H21BrN3O3+ (M+H)+ 370.0761, found 370.0762.
Synthesized according to General Procedure 13. White solid (86%, 141 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.31 (dd, J= 8.2, 2.3 Hz, 1H), 7.18 (d, J= 8.0 Hz, 1H), 6.94 - 6.87 (m, 1H), 6.56 (s, 1H), 5.08 (s, 1H), 3.69 - 3.60 (m, 2H), 3.47 - 3.40 (m, 2H), 1.41 (s, 9H).
Synthesized according to General Procedure 13. White solid (68%, 115 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.31 (d, J= 8.1, 0.9 Hz, 1H), 7.17 (d, J= 7.9, 0.9 Hz, 1H), 6.89 (t, J = 8.0 Hz, 1H), 6.13 (s, 1H), 5.09 (s, 1H), 3.59 (q, J = 6.4 Hz, 2H), 3.26 (q, J = 6.3 Hz, 2H), 1.79 (p, J= 6.2 Hz, 2H), 1.46 (s, 9H). HRMS (ESI+) m/z calc’d. for C15H21BrN3O3+ (M+H)+ 370.0761, found 370.0762.
Synthesized according to General Procedure 13. White solid (96%, 186 mg). 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J= 1.9 Hz, 1H), 7.29 - 7.26 (m, 1H), 7.17 (d, J= 8.3 Hz, 1H), 5.12 (s, 2H), 3.66 (t, J = 6.0 Hz, 5H), 3.42 (q, J = 6.1 Hz, 5H), 1.35 (s, 19H). 13C NMR (101 MHz, CDCl3) δ 156.3, 149.3, 142.7, 127.3, 117.1, 112.6, 112.4, 79.6, 49.8, 39.4, 28.4. HRMS (ESI+) m/z calc’d. for C21H32BrN4O5+ (M+H)+ 499.1551, found 499.1601.
Synthesized according to General Procedure 13. White solid (91%, 134 mg). 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 1.8 Hz, 1H), 7.29 - 7.25 (m, 1H), 7.20 (d, J = 8.3 Hz, 1H), 4.71 (d, J = 7.0 Hz, 1H), 4.37 (s, 1H), 3.88 (dd, J= 10.9, 6.0 Hz, 1H), 3.80 - 3.65 (m, 3H), 3.51 (dd, J = 11.0, 4.2 Hz, 1H), 2.30 (m, 1H), 2.01 (m, 1H), 1.45 (s, 11H). 13C NMR (101 MHz, CDCl3) δ 160.9, 155.3, 149.6, 142.7, 127.3, 117.2, 112.6, 112.4, 53.4, 50.6, 45.8, 31.9, 28.5. HRMS (ESI+) m/z calc’d. for C16H21BrN3O3+ (M+H)+ 382.0761, found 382.0764.
Synthesized according to General Procedure 13. Brown solid (84%, 125 mg). 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 1.8 Hz, 1H), 7.29 - 7.26 (m, 1H), 7.20 (d, J = 8.3 Hz, 1H), 4.72 - 4.67 (m, 1H), 4.37 (s, 1H), 3.88 (dd, J= 11.0, 6.0 Hz, 1H), 3.75 - 3.68 (m, 2H), 3.52 (dd, J = 11.0, 4.2 Hz, 1H), 2.30 (dtd, J = 13.5, 7.7, 5.9 Hz, 1H), 2.07 - 1.94 (m, 1H), 1.45 (s, 12H). 13C NMR (101 MHz, CDCl3) δ 160.9, 155.3, 149.6, 142.7, 127.3, 117.2, 112.6, 112.5, 53.4, 50.7, 45.8, 31.9, 28.5. HRMS (ESI+) m/z calc’d. for C16H21BrN3O3+ (M+H)+ 382.0761, found 382.0765.
Synthesized according to General Procedure 13. White solid (96%, 155 mg). 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J= 1.9 Hz, 1H), 7.22 (dt, J = 8.4, 1.9 Hz, 1H), 7.13 (dd, J= 8.3, 1.8 Hz, 1H), 6.15 (d, J = 8.6 Hz, 1H), 4.13 - 3.97 (m, 2H), 3.84 (h, J = 6.7 Hz, 1H), 2.98 - 2.82 (m, 4H), 2.07 (dd, J= 13.4, 3.8 Hz, 3H), 1.42 (d, J= 1.5 Hz, 13H), 1.27 -1.12 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 161.4, 154.8, 148.9, 142.2, 127.2, 117.2, 113.1, 112.4, 80.0, 50.7, 42.6, 32.4, 28.5. HRMS (ESI+) m/z calc’d. for C17H23BrN3O3+ (M+H)+ 396.0917, found 396.0922.
Synthesized according to General Procedure 6. White solid (74%, 58 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.17 (s, 1H), 7.12 (d, J = 8.1 Hz, 1H), 6.84 (dd, J = 8.2, 1.7 Hz, 1H), 5.53 (s, 1H), 4.96 (s, 1H), 3.59 (q, J = 5.3 Hz, 2H), 3.43 (q, J = 5.9 Hz, 2H), 2.63 (t, J = 7.7 Hz, 2H), 1.61 (p, J = 7.4 Hz, 2H), 1.43 (s, 9H), 1.33 - 1.22 (m, 10H), 0.87 (t, J = 6.8 Hz, 3H). HRMS (ESI+) m/z calc’d. for C22H36N3O3+ (M+H)+ 390.2751, found 390.2749.
Synthesized according to General Procedure 6. White solid (86%, 70 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.17 (d, J= 1.7 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 6.84 (dd, J = 8.1, 1.7 Hz, 1H), 5.59 (s, 1H), 5.00 (s, 1H), 3.59 (q, J = 5.2 Hz, 2H), 3.43 (q, J = 5.8 Hz, 2H), 2.66 - 2.60 (m, 2H), 1.60 (dd, J = 10.5, 4.7 Hz, 2H), 1.43 (s, 9H), 1.32 - 1.22 (m, 12H), 0.87 (t, J = 6.9 Hz, 3H). HRMS (ESI+) m/z calc’d. for C23H38N3O3+ (M+H)+ 404.2908, found 404.2904.
Synthesized according to General Procedure 6. White solid (60%, 56 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.15 (d, J= 1.7 Hz, 1H), 7.10 (d, J= 8.1 Hz, 1H), 6.81 (dd, J= 8.1, 1.7 Hz, 1H), 6.22 (d, J= 37.0 Hz, 1H), 5.27 - 5.11 (m, 1H), 3.58 (t, J = 5.6 Hz, 2H), 3.42 (q, J = 5.9 Hz, 2H), 2.61 (t, J = 7.7 Hz, 2H), 1.59 (p, J = 7.3 Hz, 2H), 1.40 (s, 9H), 1.26 (d, J = 19.9 Hz, 14H), 0.87 (t, J = 6.9 Hz, 3H). HRMS (ESI+) m/z calc’d. for C24H40N3O3+ (M+H)+ 418.3064, found 418.3078.
Synthesized according to General Procedure 6. White solid (76%, 66 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.17 (d, J= 1.7 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 6.84 (dd, J = 8.2, 1.7 Hz, 1H), 5.60 (s, 1H), 4.97 (s, 1H), 3.58 (s, 2H), 3.43 (d, J = 5.8 Hz, 2H), 2.63 (t, J= 7.6 Hz, 2H), 1.60 (p, J= 7.4 Hz, 2H), 1.43 (s, 9H), 1.31 - 1.23 (m, 16H), 0.88 (t, J= 6.9 Hz, 3H). HRMS (ESI+) m/z calc’d. for C25H42N3O3+ (M+H)+ 432.3221, found 432.3221.
Synthesized according to General Procedure 6. White solid (64%, 58 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.19 (s, 1H), 7.14 (d, J = 8.1 Hz, 1H), 6.86 (dd, J = 8.1, 1.7 Hz, 1H), 5.65 (s, 1H), 5.00 (s, 1H), 3.60 (s, 2H), 3.45 (q, J = 5.9 Hz, 2H), 2.65 (t, J = 7.6 Hz, 2H), 1.62 (q, J= 7.3 Hz, 2H), 1.45 (s, 9H), 1.35 - 1.23 (m, 18H), 0.90 (t, J = 6.8 Hz, 4H). HRMS (ESI+) m/z calc’d. for C26H44N3O3+ (M+H)+ 446.3372, found 446.3377.
Synthesized according to General Procedure 6. Off-White solid (36%, 99 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.42 (s, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 4.89 (s, 1H), 3.29 - 3.16 (m, 2H), 2.93 (t, J = 7.3 Hz, 2H), 2.66 (t, J = 7.7 Hz, 2H), 2.15 - 2.00 (m, 2H), 1.92 - 1.74 (m, 1H), 1.39 (s, 9H), 1.29 - 1.20 (m, 14H), 0.84 (t, J = 6.9 Hz, 3H). HRMS (ESI+) m/z calc’d. for C25H42N3O3+ (M+H)+ 432.3221, found 432.3227.
Synthesized according to General Procedure 6. Off-White solid (77%). 1H NMR (500 MHz, Chloroform-d) δ 7.15 (s, 1H), 7.11 (d, J = 8.1 Hz, 1H), 6.82 (dd, J = 8.2, 1.7 Hz, 1H), 5.94 (s, 1H), 4.81 (s, 1H), 3.47 (t, J = 7.1 Hz, 2H), 3.16 (q, J = 6.8 Hz, 2H), 2.62 (t, J= 7.7 Hz, 2H), 1.73 - 1.66 (m, 2H), 1.63 - 1.55 (m, 4H), 1.43 (s, 10H), 1.32 - 1.23 (m, 14H), 0.87 (t, J = 6.9 Hz, 3H). HRMS (ESI+) m/z calc’d. for C26H44N3O3+ (M+H)+ 446.3377, found 446.3351.
Synthesized according to General Procedure 6. Off-white solid (65%, 51 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.17 (d, J= 1.7 Hz, 1H), 7.11 (d, J= 8.1 Hz, 1H), 6.83 (dd, J = 8.1, 1.7 Hz, 1H), 5.00 (s, 1H), 4.55 (s, 1H), 3.47 (q, J = 6.6 Hz, 2H), 3.13 (t, J = 6.7 Hz, 2H), 2.67 - 2.58 (m, 2H), 1.70 (p, J = 7.2 Hz, 2H), 1.60 (dd, J = 10.4, 4.6 Hz, 2H), 1.55 -1.49 (m, 2H), 1.44 (s, 10H), 1.42 (d, J= 9.1 Hz, 2H), 1.32 - 1.22 (m, 14H), 0.87 (t, J = 6.9 Hz, 3H). HRMS (ESI+) m/z calc’d. for C27H46N3O3+ (M+H)+ 460.3534, found 460.3529.
Synthesized according to General Procedure 6. Yellow oil (83%, 87 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.19 (d, J= 1.6 Hz, 1H), 7.15 (d, J= 8.2 Hz, 1H), 6.88 (s, 1H), 5.35 (s, 1H), 4.63 (d, J = 5.5 Hz, 1H), 4.42 - 4.31 (m, 2H), 3.90 - 3.85 (m, 2H), 2.68 -2.59 (m, 2H), 1.45 (d, J = 0.7 Hz, 9H), 1.34 - 1.21 (m, 16H), 0.90 - 0.82 (m, 3H). 13C NMR (126 MHz, Chloroform-d) δ 160.7, 156.2, 146.7, 141.9, 139.3, 121.7, 116.4, 108.42, 80.02, 42.7, 36.0, 32.0, 31.9, 29.7, 29.6, 29.6, 29.5, 29.3, 29.2, 28.4, 22.7, 14.1. HRMS (ESI+) m/z calc’d. for C25H39N3O3+ (M+H)+430.3070, found 430.3100.
Synthesized according to General Procedure 6. Off-white solid (77%, 76 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.20 (s, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.17 (s, 1H), 4.45 (s, 1H), 3.74 (dd, J= 11.5, 6.0 Hz, 1H), 3.58 - 3.34 (m, 3H), 2.63 (t, J= 7.7 Hz, 2H), 2.29 - 2.23 (m, 1H), 2.14 - 1.98 (m, 1H), 1.61 (p, J = 7.2 Hz, 2H), 1.46 (s, 9H), 1.34 - 1.20 (m, 14H), 0.88 (t, J = 7.0 Hz, 3H). HRMS (ESI+) m/z calc’d. for C26H42N3O3+ (M+H)+ 444.3321, found 444.3320.
Synthesized according to General Procedure 6. Off-white solid (60%, 122 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.19 (d, J = 1.7 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 6.86 (dd, J= 8.2, 1.7 Hz, 1H), 5.29 (s, 1H), 4.47 (s, 1H), 3.74 (dd, J= 11.5, 6.0 Hz, 1H), 3.57 - 3.31 (m, 3H), 2.68 - 2.60 (m, 2H), 2.34 - 2.21 (m, 1H), 2.14 - 1.95 (m, 1H), 1.61 (p, J = 7.2 Hz, 2H), 1.47 (s, 10H), 1.33 - 1.23 (m, 14H), 0.90 - 0.84 (m, 3H). HRMS (ESI+) m/z calc’d. for C26H42N3O3+ (M+H)+444.3221, found 444.3229.
Synthesized according to General Procedure 6. Yellow oil (75%, 98 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.22 - 7.10 (m, 2H), 6.87 (d, J = 8.2 Hz, 1H), 6.20 (s, 1H), 5.21 (dt, J= 53.9, 3.3 Hz, 1H), 4.58 (d, J = 28.5 Hz, 1H), 4.11 - 3.99 (m, 1H), 3.89 - 3.52 (m, 2H), 3.34 - 3.23 (m, 1H), 2.64 (t, J = 7.7 Hz, 2H), 1.61 (p, J = 7.3 Hz, 2H), 1.47 (s, 9H), 1.32 - 1.23 (m, 14H), 0.88 (t, J = 6.7 Hz, 3H). 19F NMR (376 MHz, Chloroform-d) δ -196.00 - -196.49 (m). HRMS (ESI+) m/z calc’d. for C26H41FN3O3+ (M+H)+ 462.3132, found 462.3139.
Synthesized according to General Procedure 6. Off-white solid (85%, 95 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.22 - 7.09 (m, 2H), 6.87 (dd, J = 8.1, 1.7 Hz, 1H), 4.92 (s, 1H), 4.10 (s, 3H), 3.96 - 3.88 (m, 1H), 2.97 (t, J = 10.2 Hz, 2H), 2.71 - 2.60 (m, 2H), 2.22 - 2.12 (m, 2H), 1.62 (h, J= 7.1, 6.4 Hz, 2H), 1.51 - 1.42 (m, 11H), 1.28 (d, J = 14.1 Hz, 14H), 0.90 (t, J = 6.9 Hz, 3H). HRMS (ESI+) m/z calc’d. for C26H42N3O3+ (M+H)+ 444.3226, found 444.3195.
Synthesized according to General Procedure 6. White solid (70%, 53 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.18 (d, J= 1.6 Hz, 1H), 7.14 (d, J= 8.1 Hz, 1H), 6.82 (dd, J = 8.1, 1.7 Hz, 1H), 4.72 (s, 1H), 4.37 (s, 1H), 3.88 (dd, J = 10.9, 6.0 Hz, 1H), 3.80 -3.68 (m, 2H), 3.58 - 3.47 (m, 1H), 2.63 (t, J = 7.6 Hz, 2H), 2.37 - 2.24 (m, 1H), 2.07 - 1.95 (m, 1H), 1.61 (t, J = 7.4 Hz, 2H), 1.46 (s, 9H), 1.32 - 1.22 (m, 14H), 0.88 (t, J = 6.7 Hz, 3H). HRMS (ESI+) m/z calc’d. for C26H42N3O3+ (M+H)+ 444.3226, found 444.3195.
Synthesized according to General Procedure 6. Off-white solid (77%, 64 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.19 - 7.11 (m, 2H), 6.82 (dd, J = 8.1, 1.7 Hz, 1H), 4.75 (d, J= 7.3 Hz, 1H), 4.37 (s, 1H), 3.87 (dd, J = 10.9, 6.0 Hz, 1H), 3.78 - 3.67 (m, 2H), 3.52 (dd, J = 10.9, 4.1 Hz, 1H), 2.66 - 2.59 (m, 2H), 2.35 - 2.22 (m, 1H), 2.04 - 1.80 (m, 2H), 1.60 (p, J = 7.1 Hz, 2H), 1.45 (s, 9H), 1.33 - 1.21 (m, 14H), 0.87 (t, J = 6.9 Hz, 3H). HRMS (ESI+) m/z calc’d. for C26H42N3O3+ (M+H)+ 444.3226, found 444.3195.
Synthesized according to General Procedure 6. White solid (79%, 84 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.18 (s, 1H), 7.15 (d, J = 8.1 Hz, 1H), 6.85 (dd, J = 8.1, 1.7 Hz, 1H), 3.69 - 3.62 (m, 4H), 3.58 - 3.53 (m, 4H), 2.64 (t, J = 7.6 Hz, 2H), 1.65 - 1.56 (m, 2H), 1.49 (s, 9H), 1.34 - 1.19 (m, 14H), 0.87 (t, J = 7.0 Hz, 3H). ). HRMS (ESI+) m/z calc’d. for C26H42N3O3+ (M+H)+ 444.3221, found 444.3195.
Synthesized according to General Procedure 6. Off-white solid (73%, 73 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.24 (d, J = 8.0 Hz, 1H), 7.06 (d, J= 1.6 Hz, 1H), 6.97 (dd, J = 8.0, 1.7 Hz, 1H), 5.53 (s, 1H), 4.97 (s, 1H), 3.43 (d, J = 5.9 Hz, 2H), 2.63 (t, J = 7.7 Hz, 2H), 1.59 (q, J= 7.2 Hz, 1H), 1.43 (s, 9H), 1.33 - 1.23 (m, 14H), 0.88 (t, J= 6.9 Hz, 3H). HRMS (ESI+) m/z calc’d. for C24H39N3O3+ (M+H)+ 418.3064, found 418.3059.
Synthesized according to General Procedure 6. White solid (74%, 54 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.24 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 1.6 Hz, 1H), 6.97 (d, J = 7.9, 1H), 5.77 (s, 1H), 4.92 (t, J = 6.7 Hz, 1H), 3.52 (q, J = 6.1 Hz, 2H), 3.26 (q, J = 6.3 Hz, 2H), 2.63 (t, J= 7.7 Hz, 2H), 1.79 (p, J= 6.3 Hz, 2H), 1.64 - 1.56 (m, 2H), 1.46 (s, 9H), 1.33 - 1.20 (m, 14H), 0.88 (t, J = 6.9 Hz, 3H). HRMS (ESI+) m/z calc’d. for C25H42N3O3+ (M+H)+ 432.3221, found 432.3214.
Synthesized according to General Procedure 6. Off-white solid (76%, 83 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.25 (d, J = 7.9 Hz, 1H), 7.07 (s, 1H), 7.01 - 6.93 (m, 1H), 6.59 (s, 1H), 4.45 (s, 1H), 3.76 (dd, J = 11.4, 6.1 Hz, 1H), 3.63 - 3.32 (m, 3H), 2.63 (t, J = 7.6 Hz, 2H), 2.33 - 1.97 (m, 2H), 1.60 (p, J = 7.3 Hz, 2H), 1.46 (s, 9H), 1.34 - 1.17 (m, 14H), 0.91 - 0.83 (m, 3H). HRMS (ESI+) m/z calc’d. for C26H42N3O3+ (M+H)+ 444.3221, found 444.3216.
Synthesized according to General Procedure 6. Off-white solid (50%, 63 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.21 (d, J = 8.0 Hz, 1H), 7.04 (s, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.42 (d, J = 23.2 Hz, 1H), 4.42 (s, 1H), 3.73 (dd, J = 11.5, 6.1 Hz, 1H), 3.56 - 3.29 (m, 3H), 2.60 (t, J = 7.7 Hz, 2H), 2.30 - 2.17 (m, 1H), 2.16 - 1.93 (m, 1H), 1.57 (p, J = 7.3 Hz, 2H), 1.43 (s, 9H), 1.30 - 1.18 (m, 14H), 0.90 - 0.81 (m, 3H). HRMS (ESI+) m/z calc’d. for C26H42N3O3+ (M+H)+ 444.3221, found 444.3217.
Synthesized according to General Procedure 6. White solid (27%, 22 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.21 - 7.17 (m, 1H), 7.07 (t, J = 7.7 Hz, 1H), 6.85 - 6.83 (m, 1H), 5.89 (s, 1H), 5.10 (s, 1H), 3.59 (s, 2H), 3.47 - 3.40 (m, 2H), 2.73 (t, J = 7.7 Hz, 2H), 1.67 (p, J= 7.6 Hz, 2H), 1.43 (s, 9H), 1.35 - 1.22 (m, 14H), 0.88 (t, J= 6.9 Hz, 3H). HRMS (ESI+) m/z calc’d. for C24H40N3O3+ (M+H)+ 418.3064, found 418.3064.
Synthesized according to General Procedure 6. White solid (27%, 23 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.21 (dd, J= 7.8, 1.2 Hz, 1H), 7.08 (t, J= 7.7 Hz, 1H), 6.85 (dd, J = 7.6, 1.2 Hz, 1H), 5.92 (s, 1H), 5.02 (t, J = 6.5 Hz, 1H), 3.56 (q, J = 6.0 Hz, 2H), 3.29 (q, J = 6.3 Hz, 2H), 2.75 (t, 2H), 1.85 - 1.79 (m, 2H), 1.70 (p, J = 7.6 Hz, 2H), 1.48 (s, 9H), 1.39 - 1.26 (m, 14H), 0.90 (t, J = 6.9 Hz, 3H). HRMS (ESI+) m/z calc’d. for C25H42N3O3+ (M+H)+ 432.3221, found 432.3218.
Synthesized according to General Procedure 6. Off-white solid (67%, 107 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.09 - 7.06 (m, 1H), 7.00 - 6.93 (m, 2H), 5.50 (s, 1H), 5.23 (d, J = 6.2 Hz, 1H), 3.60 (q, J = 5.5 Hz, 2H), 3.43 (q, J = 5.8 Hz, 2H), 2.86 - 2.78 (m, 2H), 1.70 (p, J = 7.5 Hz, 2H), 1.42 (s, 9H), 1.37 - 1.23 (m, 14H), 0.88 (t, J = 6.9 Hz, 3H). HRMS (ESI+) m/z calc’d. for C24H40N3O3+ (M+H)+ 418.3064, found 418.3066.
Synthesized according to General Procedure 6. White solid (68%, 115 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.10 - 7.04 (m, 1H), 6.99 - 6.92 (m, 2H), 5.53 (s, 1H), 5.42 (s, 1H), 3.55 (q, J = 6.2 Hz, 2H), 3.24 (q, J = 6.3 Hz, 2H), 2.84 (t, J = 7.7 Hz, 2H), 1.77 (p, J= 6.2 Hz, 2H), 1.70 (p, J= 7.5 Hz, 3H), 1.46 (s, 9H), 1.35 - 1.21 (m, 14H), 0.87 (t, J= 6.9 Hz, 3H). HRMS (ESI+) m/z calc’d. for C25H42N3O3+ (M+H)+ 432.3221, found 432.3220.
Synthesized according to General Procedure 6. Clear oil (77%, 155 mg). 1H NMR (400 MHz, CDCl3) δ 7.19 (dd, J= 8.1, 2.1 Hz, 1H), 7.03 (s, 1H), 6.94 (d, J= 8.0 Hz, 1H), 5.25 (s, 2H), 3.63 (d, J = 6.4 Hz, 4H), 3.40 (q, J = 6.3 Hz, 4H), 2.61 (t, J = 7.7 Hz, 2H), 1.58 (p, J = 7.7 Hz, 2H), 1.33 (s, 16H), 1.26 (d, J = 16.8 Hz, 13H), 0.85 (t, J = 6.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 162.6, 156.3, 149.0, 140.9, 136.0, 124.3, 115.6, 108.7, 93.7, 79.4, 49.6, 39.5, 36.4, 36.0, 32.2, 32.1, 32.0, 29.7, 29.7, 29.6, 29.4, 29.2, 28.4, 26.4, 22.8, 22.1, 20.7, 14.2. HRMS (ESI+) m/z calc’d. for C31H53N4O5+ (M+H)+ 561.4010, found 561.4012.
Synthesized according to General Procedure 6. White solid (76%, 118 mg). 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 7.9 Hz, 1H), 7.08 (d, J = 1.6 Hz, 1H), 6.97 (dd, J = 8.0, 1.6 Hz, 1H), 4.71 (s, 1H), 4.36 (s, 1H), 3.87 (dd, J = 10.9, 6.0 Hz, 1H), 3.76 - 3.68 (m, 2H), 3.51 (dd, J= 11.1, 4.0 Hz, 1H), 2.66 - 2.60 (m, 2H), 2.33 - 2.24 (m, 1H), 2.05 - 1.94 (m, 1H), 1.66 - 1.55 (m, 2H), 1.45 (s, 11H), 1.33 - 1.22 (m, 17H), 0.87 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 160.7, 155.3, 149.4, 141.2, 136.0, 124.3, 115.8, 108.7, 53.4, 45.6, 36.1, 32.1, 32.0, 32.0, 29.7, 29.7, 29.5, 29.3, 28.5, 22.8, 14.2.
Synthesized according to General Procedure 6. White solid (88%, 127 mg). 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.2 Hz, 1H), 7.08 (s, 1H), 6.97 (d, J = 8.1 Hz, 1H), 4.72 (s, 1H), 4.36 (s, 1H), 3.87 (dd, J= 10.9, 6.0 Hz, 1H), 3.76 - 3.67 (m, 2H), 3.55 - 3.48 (m, 1H), 2.63 (t, J = 7.7 Hz, 2H), 2.28 (dtd, J = 13.5, 7.7, 5.9 Hz, 1H), 2.04 - 1.94 (m, 1H), 1.65 - 1.55 (m, 2H), 1.45 (s, 10H), 1.33 - 1.22 (m, 21H), 0.87 (t, J = 6.7 Hz, 4H). 13C NMR (101 MHz, CDCl3) δ 160.6, 155.3, 149.3, 141.1, 136.0, 124.3, 115.8, 108.8, 53.4, 45.6, 36.1, 32.1, 32.0, 32.0, 29.8, 29.7, 29.5, 29.3, 28.5, 22.8, 14.2.
Synthesized according to General Procedure 6. Yellow oil (83%, 102 mg). 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 7.9 Hz, 1H), 7.07 - 7.04 (m, 1H), 6.96 (dd, J = 8.0, 1.6 Hz, 1H), 5.67 (s, 1H), 3.88 (s, 1H), 2.93 (t, J = 12.4 Hz, 2H), 2.62 (t, J = 7.7 Hz, 2H), 2.10 (dd, J= 12.8, 3.8 Hz, 3H), 1.59 (h, J = 6.5 Hz, 2H), 1.46 (s, 11H), 1.34 - 1.17 (m, 17H), 0.86 (t, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 161.1, 154.8, 148.6, 140.6, 136.4, 136.4, 124.2, 115.7, 108.7, 79.8, 60.5, 50.5, 36.0, 32.5, 32.1, 32.0, 29.7, 29.7, 29.6, 29.4, 29.3, 28.5, 22.8, 14.2. HRMS (ESI+) m/z calc’d. for C27H44N3O3+ (M+H)+ 458.3383, found 458.3372
Synthesized according to General Procedure 3. White solid (90%, 42 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.46 (d, J = 8.4 Hz, 1H), 7.28 (s, 1H), 7.19 (dd, J= 8.4, 1.7 Hz, 1H), 3.87 (t, J = 6.1 Hz, 2H), 3.33 - 3.30 (m, 2H), 2.72 (t, 2H), 1.67 - 1.60 (m, 2H), 1.36 - 1.22 (m, 10H), 0.90 - 0.85 (m, 3H). 13C NMR (126 MHz, Methanol-d4) δ 160.9, 145.6, 143.3, 132.5, 125.9, 113.7, 111.5, 41.6, 39.6, 36.7, 33.0, 33.0, 30.5, 30.4, 30.2, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C17H28N3O+ (M+H)+ 290.2227, found 290.2229.
Synthesized according to General Procedure 3. White solid (60%, 48 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.23 (d, J = 8.2 Hz, 1H), 7.14 (s, 1H), 6.94 (dd, J= 8.2, 1.7 Hz, 1H), 3.70 (t, J= 5.9 Hz, 2H), 3.25 (t, J= 5.9 Hz, 2H), 2.67 - 2.62 (m, 2H), 1.65 - 1.58 (m, 2H), 1.35 - 1.21 (m, 12H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) δ 163.80, 147.82, 141.8, 140.8, 123.2, 116.2, 109.7, 41.4, 40.3, 36.9, 33.2, 33.1, 30.7, 30.6, 30.4, 30.2, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C18H30N3O+ (M+H)+ 304.2383, found 304.2381.
Synthesized according to General Procedure 3. White solid (74%, 35 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.45 (dd, J = 8.4, 3.7 Hz, 1H), 7.28 (d, J= 1.7 Hz, 1H), 7.18 (dd, J= 8.5, 1.7 Hz, 1H), 3.86 (t, J = 6.1 Hz, 2H), 3.33 - 3.30 (m, 3H), 2.74 - 2.69 (m, 2H), 1.64 (p, J= 7.5 Hz, 2H), 1.36 - 1.23 (m, 14H), 0.88 (t, J= 6.9 Hz, 3H). 13C NMR (101 MHz, Methanol-d4) δ 160.6, 145.4, 143.4, 131.6, 126.0, 113.5, 111.6, 41.7, 39.5, 36.7, 33.0, 32.9, 30.7, 30.7, 30.6, 30.4, 30.2, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C19H32N3O+ (M+H)+ 318.2540, found 318.2550.
Synthesized according to General Procedure 3. White solid (85%, 42 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.32 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 1.6 Hz, 1H), 7.04 (dd, J= 8.3, 1.7 Hz, 1H), 3.78 (t, J = 6.0 Hz, 2H), 3.30 (t, J = 6.0 Hz, 2H), 2.73 - 2.67 (m, 2H), 1.65 (p, J= 7.7 Hz, 2H), 1.32 (d, J = 25.4 Hz, 16H), 0.91 (t, J = 6.9 Hz, 3H). 13C NMR (101 MHz, Methanol-d4) δ 161.4, 145.7, 140.1, 137.2, 122.6, 113.9, 108.9, 40.0, 38.7, 35.4, 31.7, 31.6, 29.3, 29.3, 29.3, 29.2, 29.0, 28.8, 22.3, 13.0. HRMS (ESI+) m/z calc’d. for C20H34N3O+ (M+H)+ 332.2696, found 332.2702.
Synthesized according to General Procedure 3. White solid (95%, 43 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.50 (d, J = 8.4 Hz, 1H), 7.32 (s, 1H), 7.22 (dd, J= 8.5, 1.7 Hz, 1H), 3.91 (t, J = 6.1 Hz, 2H), 3.38 - 3.32 (m, 2H), 2.75 (t, J = 7.6 Hz, 2H), 1.66 (q, J = 7.3 Hz, 2H), 1.38 - 1.27 (m, 18H), 0.92 (t, J = 6.7 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) δ 159.4, 152.5, 144.2, 141.9, 124.5, 112.2, 110.1, 40.2, 38.2, 35.3, 31.7, 31.6, 29.4, 29.3, 29.3, 29.2, 29.1, 28.8, 22.3, 13.0. HRMS (ESI+) m/z calc’d. for C26H44N3O3+ (M+H)+ 346.2853, found 346.2855.
Synthesized according to General Procedure 3. Off-white solid (80%, 39 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.45 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 1.6 Hz, 1H), 7.18 (dd, J= 8.5, 1.7 Hz, 1H), 3.66 (t, J = 6.9 Hz, 2H), 3.10 (t, J = 7.7 Hz, 2H), 2.75 - 2.68 (m, 2H), 2.11 (p, J = 7.2 Hz, 2H), 1.63 (h, J = 6.7, 6.1 Hz, 2H), 1.35 - 1.24 (m, 13H), 0.91 - 0.83 (m, 3H). 13C NMR (126 MHz, Chloroform-d) δ 162.9, 147.9, 145.9, 134.0, 128.5, 115.8, 114.0, 44.0, 40.6, 39.3, 35.6, 35.5, 33.3, 33.2, 33.1, 33.0, 32.7, 30.3, 26.3, 17.0. HRMS (ESI+) m/z calc’d. for C20H34N3O+ (M+H)+ 332.2696, found 332.2674.
Synthesized according to General Procedure 3. White solid (77%, 89 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.46 - 7.42 (m, 1H), 7.26 (s, 1H), 7.19 (dt, J = 8.3, 1.6 Hz, 1H), 3.61 - 3.54 (m, 2H), 3.01 (t, J = 7.0 Hz, 2H), 2.72 (t, J = 7.7 Hz, 2H), 1.87 - 1.77 (m, 4H), 1.63 (q, J = 7.8, 7.2 Hz, 2H), 1.36 - 1.24 (m, 14H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) δ 160.1, 145.2, 143.3, 130.9, 126.0, 113.0, 111.6, 43.8, 40.2, 36.7, 33.1, 32.9, 30.7, 30.7, 30.6, 30.4, 30.2, 26.7, 25.7, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C21H36N3O+ (M+H)+ 346.2853, found 346.2862.
Synthesized according to General Procedure 3. Yellow solid (83%, 40 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.44 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 1.8 Hz, 1H), 7.18 (dd, J= 8.5, 1.7 Hz, 1H), 3.56 (t, J = 7.2 Hz, 2H), 2.96 (t, J = 7.7 Hz, 2H), 2.71 (t, J = 7.6 Hz, 2H), 1.84 - 1.70 (m, 4H), 1.63 (p, J = 7.4 Hz, 2H), 1.58 - 1.49 (m, 2H), 1.34 - 1.22 (m, 14H), 0.88 (t, J = 6.9 Hz, 3H). 13C NMR (101 MHz, Methanol-d4) δ 160.0, 145.2, 143.2, 131.0, 125.9, 113.0, 111.5, 44.2, 40.5, 36.7, 33.0, 32.9, 30.7, 30.7, 30.5, 30.4, 30.2, 29.1, 28.0, 24.5, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C22H31N3O+ (M+H)+359.2937, found 359.2927.
Synthesized according to General Procedure 3. White solid (30%, 31 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.23 (d, J= 8.2 Hz, 1H), 7.16 (d, J= 1.6 Hz, 1H), 6.94 (dd, J= 8.2, 1.7 Hz, 1H), 4.83 - 4.72 (m, 1H), 4.47 - 4.28 (m, 4H), 2.72 - 2.62 (m, 2H), 1.64 (p, J = 7.3 Hz, 2H), 1.36 - 1.27 (m, 14H), 0.94 - 0.87 (m, 2H). 13C NMR (101 MHz, Methanol-d4) δ 160.9, 146.7, 141.8, 139.0, 121.7, 115.5, 108.1, 52.5, 44.5, 35.4, 31.7, 31.6, 29.3, 29.2, 29.1, 29.0, 28.7, 22.3, 13.0. HRMS (ESI+) m/z calc’d. for C20H32N3O+ (M+H)+330.2545, found 330.2558.
Synthesized according to General Procedure 3. Off-white solid (65%, 50 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.40 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 7.12 (dd, J= 8.4, 1.7 Hz, 1H), 4.63 (tt, J = 6.7, 4.4 Hz, 1H), 3.70 (dd, J = 12.7, 6.6 Hz, 1H), 3.59 -3.45 (m, 3H), 2.70 (t, J = 7.6 Hz, 2H), 2.55 - 2.45 (m, 1H), 2.32 - 2.22 (m, 1H), 1.68 - 1.59 (m, 2H), 1.37 - 1.22 (m, 16H), 0.88 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz, Methanol-d4) δ 161.8, 147.0, 141.6, 138.4, 124.2, 115.4, 110.3, 53.5, 51.0, 45.6, 36.8, 33.0, 33.0, 31.3, 30.7, 30.7, 30.6, 30.4, 30.2, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C21H34N3O+ (M+H)+ 344.2696, found 344.2669.
Synthesized according to General Procedure 3. Off-white solid (65%, 30 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.51 (d, J = 8.5 Hz, 1H), 7.33 (s, 1H), 7.24 (dd, J = 8.5, 1.7 Hz, 1H), 4.78 - 4.69 (m, 1H), 3.79 (dd, J = 12.8, 6.8 Hz, 1H), 3.64 - 3.49 (m, 3H), 2.80 -2.71 (m, 2H), 2.62 - 2.52 (m, 1H), 2.37 - 2.26 (m, 1H), 1.73 - 1.64 (m, 2H), 1.38 - 1.25 (m, 14H), 0.94 - 0.89 (m, 3H). 13C NMR (126 MHz, Methanol-d4) δ 160.0, 145.5, 143.4, 131.7, 126.1, 113.5, 111.6, 53.9, 50.7, 45.6, 36.7, 33.1, 33.0, 31.3, 30.7, 30.7, 30.6, 30.5, 30.2, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C21H34N3O+ (M+H)+344.2696, found 344.2697.
Synthesized according to General Procedure 3. Off-white solid (82%, 69 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.47 (dd, J = 8.5, 1.3 Hz, 1H), 7.30 (d, J = 1.8 Hz, 1H), 7.19 (dd, J= 8.4, 1.8 Hz, 1H), 5.51 (dt, J = 52.8, 3.0 Hz, 1H), 4.97 - 4.89 (m, 1H), 4.01 -3.92 (m, 1H), 3.89 - 3.69 (m, 2H), 3.43 (t, J = 11.3 Hz, 1H), 2.72 (t, J = 7.7 Hz, 2H), 1.68 -1.59 (m, 2H), 1.30 (d, J = 22.6 Hz, 15H), 0.91 - 0.83 (m, 3H). 19F NMR (376 MHz, Methanol-d4) δ -196.27 - -196.71 (m). 13C NMR (126 MHz, Methanol-d4) δ 160.6, 145.7, 143.2, 132.7, 126.0, 113.9, 111.5, 91.5 (d, J = 183.1 Hz), 56.2 - 55.8 (m), 51.3 - 50.9 (m), 46.1 - 45.1 (m), 36.7, 33.0, 33.0, 30.7, 30.7, 30.6, 30.4, 30.2, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C21H33FN3O+ (M+H)+ 362.2608, found 362.2631.
Synthesized according to General Procedure 3. White solid (80%, 45 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.38 (d, J= 8.4 Hz, 1H), 7.24 (d, J= 1.6 Hz, 1H), 7.11 (dd, J = 8.4, 1.7 Hz, 1H), 4.08 (tt, J = 10.6, 4.0 Hz, 1H), 3.52 (dt, J = 12.9, 3.6 Hz, 2H), 3.27 -3.15 (m, 2H), 2.74 - 2.67 (m, 2H), 2.39 - 2.30 (m, 2H), 2.02 - 1.88 (m, 2H), 1.64 (p, J = 7.1 Hz, 2H), 1.31 (d, J = 21.6 Hz, 14H), 0.91 - 0.86 (m, 3H). 13C NMR (126 MHz, Methanol-d4) δ 160.7, 146.1, 142.4, 135.0, 125.0, 114.2, 110.9, 49.6, 43.8, 36.8, 33.1, 33.0, 30.7, 30.7, 30.6, 30.5, 30.2, 29.4, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C21H34N3O+ (M+H)+ 344.2702, found 344.2679.
Synthesized according to General Procedure 3. Off-white solid (99%, 38 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.51 (d, J = 8.5 Hz, 1H), 7.31 (d, J= 1.6 Hz, 1H), 7.22 (dd, J = 8.5, 1.7 Hz, 1H), 4.28 - 4.15 (m, 2H), 4.12 - 3.93 (m, 3H), 2.75 (t, 2H), 2.71 - 2.60 (m, 1H), 2.44 - 2.35 (m, 1H), 1.71 - 1.61 (m, 2H), 1.36 - 1.27 (m, 14H), 0.94 - 0.87 (m, 3H). 13C NMR (101 MHz, Methanol-d4) δ 158.0, 146.1, 143.5, 132.4, 125.9, 113.5, 111.6, 52.7, 51.4, 47.8, 36.7, 33.0, 32.9, 30.7, 30.7, 30.6, 30.4, 30.4, 30.2, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C21H34N3O+ (M+H)+ 344.2702, found 344.2679.
Synthesized according to General Procedure 3. Off-white solid (76%, 35 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.50 (dd, J = 8.4, 0.5 Hz, 1H), 7.29 (dd, J = 1.6, 0.6 Hz, 1H), 7.20 (dd, J = 8.5, 1.7 Hz, 1H), 4.26 - 3.90 (m, 5H), 2.77 - 2.71 (m, 2H), 2.69 - 2.59 (m, 1H), 2.43 - 2.33 (m, 1H), 1.66 (t, J = 7.6 Hz, 2H), 1.37 - 1.24 (m, 14H), 0.92 - 0.86 (m, 3H). 13C NMR (126 MHz, Methanol-d4) δ 156.8, 144.8, 141.9, 131.4, 124.4, 112.2, 110.1, 51.3, 50.0, 46.3, 35.3, 31.7, 31.6, 29.3, 29.3, 29.2, 29.1, 28.9, 28.8, 22.3, 13.0. HRMS (ESI+) m/z calc’d. for C21H34N3O+ (M+H)+ 344.2702, found 344.2679.
Synthesized according to General Procedure 3. White solid (81%, 55 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.30 (d, J = 8.2 Hz, 1H), 7.18 (d, J = 1.7 Hz, 1H), 6.99 (dd, J = 8.2, 1.7 Hz, 1H), 4.01 - 3.94 (m, 4H), 3.42 (t, J = 5.4 Hz, 5H), 2.66 (t, J = 7.6 Hz, 2H), 1.62 (t, J = 6.7 Hz, 2H), 1.34 - 1.22 (m, 14H), 0.88 (t, J = 6.9 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) δ 162.3, 148.0, 141.4, 141.2, 123.7, 116.5, 110.1, 43.7, 36.8, 33.1, 33.0, 30.7, 30.7, 30.6, 30.4, 30.2, 23.7, 14.4.
Synthesized according to General Procedure 3. White solid (88%, 51 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.42 (d, J = 1.5 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.25 (dd, J = 8.1, 1.5 Hz, 1H), 3.87 (t, J = 6.1 Hz, 2H), 3.32 (d, J = 6.1 Hz, 2H), 2.72 (t, J = 7.6 Hz, 2H), 1.63 (dd, J = 10.4, 4.7 Hz, 2H), 1.35 - 1.23 (m, 14H), 0.88 (t, J = 7.0 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) δ 160.7, 147.6, 141.8, 130.2, 127.6, 113.6, 111.6, 41.6, 39.6, 36.8, 33.1, 32.9, 30.7, 30.7, 30.6, 30.5, 30.2, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C19H32N3O+ (M+H)+ 318.2540, found 318.2540.
Synthesized according to General Procedure 3. White solid (94%, 40 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.42 (d, J = 1.4 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.26 (dd, J = 8.1 Hz, 1H), 3.65 (t, J= 6.9 Hz, 2H), 3.10 (dd, J = 9.0, 6.6 Hz, 2H), 2.72 (t, J = 7.7 Hz, 2H), 2.11 (p, J = 7.1 Hz, 2H), 1.64 (h, J = 7.1 Hz, 2H), 1.35 - 1.21 (m, 14H), 0.88 (t, J = 6.9 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) δ 158.8, 145.9, 140.5, 127.7, 126.3, 111.7, 110.3, 40.0, 36.7, 35.3, 31.7, 31.5, 29.3, 29.3, 29.2, 29.0, 28.8, 26.4, 22.3, 13.0. HRMS (ESI+) m/z calc’d. for C20H34N3O+ (M+H)+ 332.2696, found 332.2694.
Synthesized according to General Procedure 3. Off-white solid (58%, 41 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.37 - 7.30 (m, 2H), 7.22 - 7.15 (m, 1H), 4.65 - 4.55 (m, 1H), 3.73 - 3.63 (m, 1H), 3.59 - 3.46 (m, 3H), 2.74 - 2.68 (m, 2H), 2.55 - 2.45 (m, 1H), 2.32 - 2.21 (m, 1H), 1.65 (q, J = 7.0 Hz, 2H), 1.38 - 1.22 (m, 14H), 0.92 - 0.86 (m, 3H). 13C NMR (126 MHz, Methanol-d4) δ 160.9, 148.4, 140.7, 133.6, 126.9, 114.6, 111.1, 53.6, 50.9, 45.6, 36.8, 33.1, 33.0, 31.3, 30.7, 30.7, 30.6, 30.4, 30.2, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C21H34N3O+ (M+H)+ 344.2696, found 344.2679.
Synthesized according to General Procedure 3. White solid (93%, 50 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.38 - 7.30 (m, 2H), 7.24 - 7.17 (m, 1H), 4.65 - 4.57 (m, 1H), 3.72 - 3.64 (m, 1H), 3.58 - 3.43 (m, 3H), 2.74 - 2.68 (m, 2H), 2.56 - 2.44 (m, 1H), 2.33 - 2.21 (m, 1H), 1.69 - 1.58 (m, 2H), 1.37 - 1.21 (m, 14H), 0.89 (t, J = 7.0 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) δ 160.7, 148.2, 141.0, 132.9, 127.1, 114.4, 111.2, 53.7, 50.9, 45.6, 36.8, 33.1, 33.0, 31.3, 30.7, 30.7, 30.6, 30.5, 30.2, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C21H34N3O+ (M+H)+ 344.2696, found 344.2679.
Synthesized according to General Procedure 3. White solid (59%, 11 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.37 - 7.25 (m, 2H), 7.19 (d, J = 7.6 Hz, 1H), 3.89 (t, J = 6.0 Hz, 2H), 3.27 (s, 2H), 2.84 (t, J = 7.7 Hz, 2H), 1.71 (p, J = 7.3 Hz, 2H), 1.40 - 1.18 (m, 14H), 0.86 (t, J = 6.8 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) δ 160.3, 145.7, 131.1, 128.0, 127.6, 126.4, 111.3, 41.7, 39.4, 33.1, 30.8, 30.7, 30.5, 30.4, 30.4, 30.0, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C19H32N3O+ (M+H)+ 318.2540, found 318.2542.
Synthesized according to General Procedure 3. White solid (87%, 17 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.32 (t, J = 7.8 Hz, 1H), 7.26 (dd, J= 7.9, 1.2 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 3.64 (t, J = 6.9 Hz, 2H), 3.14 - 3.06 (m, 2H), 2.88 - 2.80 (m, 2H), 2.16 -2.06 (m, 2H), 1.73 (p, J = 7.4 Hz, 2H), 1.42 - 1.21 (m, 14H), 0.89 (t, J = 6.9 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) δ 158.5, 144.1, 129.3, 126.5, 126.1, 125.0, 109.6, 40.1, 36.7, 31.7, 29.4, 29.3, 29.3, 29.1, 29.0, 29.0, 28.6, 26.3, 22.3, 13.0. HRMS (ESI+) m/z calc’d. for C20H34N3O+ (M+H)+ 332.2696, found 332.2697.
Synthesized according to General Procedure 3. White solid (67%, 104 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.41 - 7.36 (m, 1H), 7.29 - 7.21 (m, 2H), 3.93 (t, J = 6.1 Hz, 2H), 3.33 (t, J= 6.0 Hz, 2H), 2.86 (t, J= 7.8 Hz, 2H), 1.73 - 1.64 (m, 2H), 1.45 - 1.17 (m, 13H), 0.87 (t, J = 6.9 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) δ 160.8, 147.2, 131.0, 130.3, 127.6, 125.6, 109.3, 41.7, 39.8, 33.1, 31.7, 31.4, 30.7, 30.7, 30.6, 30.5, 30.4, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C19H32N3O+ (M+H)+ 318.2540, found 318.2543.
Synthesized according to General Procedure 3. White solid (68%, 115 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.40 - 7.36 (m, 1H), 7.32 - 7.22 (m, 2H), 3.73 (t, J = 7.0 Hz, 2H), 3.11 (t, J = 9.0 Hz, 2H), 2.87 (t, J = 7.8 Hz, 2H), 2.16 - 2.08 (m, 2H), 1.73 - 1.64 (m, 2H), 1.45 - 1.12 (m, 14H), 0.88 (t, J = 7.0 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) δ 158.8, 145.4, 128.5, 128.3, 126.3, 124.5, 107.9, 40.1, 36.7, 31.7, 30.2, 30.0, 29.3, 29.3, 29.2, 29.0, 29.0, 26.5, 22.3, 13.0. HRMS (ESI+) m/z calc’d. for C20H34N3O+ (M+H)+ 332.2696, found 332.2699.
Synthesized according to General Procedure 3. White solid (48%, 57 mg). 1H NMR (400 MHz, CD3OD) δ 7.45 (dd, J= 1.5, 0.6 Hz, 1H), 7.41 (dd, J= 8.1, 0.5 Hz, 1H), 7.25 (dd, J= 8.2, 1.5 Hz, 1H), 4.12 (t, J = 6.4 Hz, 4H), 3.42 (t, J = 6.4 Hz, 4H), 2.78 - 2.70 (m, 2H), 1.65 (p, J = 7.2 Hz, 2H), 1.31 (d, J = 21.3 Hz, 14H), 0.94 - 0.84 (m, 3H). 13C NMR (101 MHz, CD3OD) δ 161.0, 148.4, 141.3, 132.8, 127.5, 114.7, 111.5, 48.2, 38.1, 36.8, 33.0, 32.9, 30.7, 30.7, 30.6, 30.4, 30.2, 23.7, 14.4.
Synthesized according to General Procedure 3. White solid (82%, 77 mg). 1H NMR (400 MHz, CD3OD) δ 7.48 (d, J = 1.4 Hz, 1H), 7.42 - 7.35 (m, 1H), 7.30 (dd, J = 8.1, 1.4 Hz, 1H), 4.28 - 4.17 (m, 2H), 4.12 - 4.04 (m, 1H), 4.03 - 3.95 (m, 2H), 2.79 - 2.71 (m, 2H), 2.71 - 2.60 (m, 1H), 2.46 - 2.35 (m, 1H), 1.66 (p, J = 7.0 Hz, 2H), 1.38 - 1.25 (m, 16H), 0.94 - 0.84 (m, 2H). 13C NMR (101 MHz, CD3OD) δ 157.6, 147.8, 142.0, 129.5, 127.8, 113.3, 111.9, 52.8, 51.4, 47.9, 36.7, 33.0, 32.9, 30.7, 30.7, 30.5, 30.4, 30.3, 30.2, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C21H34N3O + (M+H)+ 344.2696, found 344.2697.
Synthesized according to General Procedure 3. White solid (74%, 75 mg). 1H NMR (500 MHz, CD3OD) δ 7.48 (d, J= 1.4 Hz, 1H), 7.39 (d, J= 8.1 Hz, 1H), 7.30 (dd, J= 8.1, 1.4 Hz, 1H), 4.26 - 4.16 (m, 2H), 4.11 - 4.03 (m, 1H), 4.02 - 3.94 (m, 2H), 2.76 - 2.72 (m, 2H), 2.70 - 2.60 (m, 1H), 2.44 - 2.35 (m, 1H), 1.69 - 1.62 (m, 2H), 1.38 - 1.21 (m, 15H), 0.89 (d, J= 7.1 Hz, 3H). 13C NMR (126 MHz, CD3OD) δ 157.7, 147.9, 141.9, 129.7, 127.8, 113.3, 111.8, 52.7, 51.4, 47.8, 36.8, 33.1, 33.0, 30.8, 30.7, 30.6, 30.5, 30.3, 30.2, 23.8, 14.5. HRMS (ESI+) m/z calc’d. for C26H42N3O3+ (M+H)+ 344.2696, found 344.2694.
Synthesized according to General Procedure 3. White solid (87%, 76 mg). 1H NMR (400 MHz, CD3OD) δ 7.42 (d, J= 1.4 Hz, 1H), 7.37 (d, J= 8.1 Hz, 1H), 7.27 (dd, J= 8.1, 1.4 Hz, 1H), 4.13 (ddt, J = 10.2, 7.7, 3.7 Hz, 1H), 3.58 - 3.50 (m, 2H), 3.29 - 3.19 (m, 2H), 2.78 - 2.69 (m, 2H), 2.41 - 2.32 (m, 3H), 2.06 - 1.92 (m, 2H), 1.66 (q, J = 7.1 Hz, 2H), 1.37 - 1.22 (m, 13H), 0.94 - 0.84 (m, 3H). 13C NMR (101 MHz, CD3OD) δ 159.6, 147.3, 141.8, 129.6, 127.6, 113.3, 111.6, 43.8, 36.7, 33.0, 32.9, 30.7, 30.7, 30.5, 30.4, 30.1, 29.3, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C22H37N3O + (M+H)+ 358.2853, found 358.2855.
(a) POCl3, neat, 98° C.; (b) N-boc-amine (1.2 equiv), K2CO3 (2.0 equiv), DMF, 120° C.; (c) (i) 9-BBN (2.2 equiv), 1-decene (2.0 equiv); (ii)aryl bromide (1.0 equiv), Pd(dppf)Cl2*CH2Cl2 (0.15 equiv), 3 M KOH (3.0 equiv), THF, 70° C.; (d) 4 M HCl/Dioxane, DCM, rt.
Synthesized according to General Procedure 12. Crude mixture dried in vacuo and carried forward to the next reaction without purification.
Synthesized according to General Procedure 13. White solid (60%, 85 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.66 (s, 1H), 7.40 - 7.35 (m, 2H), 6.16 (s, 1H), 5.02 (s, 1H), 3.59 (t, J = 5.6 Hz, 2H), 3.43 (q, J = 5.8 Hz, 2H), 1.43 (s, 9H). HRMS (ESI+) m/z calc’d. for C14H19BrN3O2S+ (M+H)+372.0376, found 372.0382.
Synthesized according to General Procedure 13. White solid (96%, 37 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.66 (s, 1H), 7.38 - 7.33 (m, 2H), 6.11 (s, 1H), 4.94 (t, J = 6.5 Hz, 1H), 3.53 (t, J= 6.3 Hz, 2H), 3.25 (q, J= 6.3 Hz, 2H), 1.81 (p, J= 6.2 Hz, 2H), 1.46 (s, 9H). HRMS (ESI+) m/z calc’d. for C15H21BrN3O2S+ (M+H)+386.0532, found 386.0540.
Synthesized according to General Procedure 6. Off-white solid (50%, 50 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.43 (d, J = 8.2 Hz, 1H), 7.37 (d, J= 1.7 Hz, 1H), 7.09 (dd, J= 8.3, 1.8 Hz, 1H), 5.82 (s, 1H), 5.04 (s, 1H), 3.65 - 3.53 (m, 2H), 3.43 (q, J = 5.8 Hz, 2H), 2.66 - 2.59 (m, 2H), 1.61 (p, J = 7.2 Hz, 2H), 1.43 (s, 9H), 1.34 - 1.20 (m, 14H), 0.91 -0.85 (m, 3H). HRMS (ESI+) m/z calc’d. for C24H40N3O2S+ (M+H)+434.2836, found 434.2842.
Synthesized according to General Procedure 6. White solid (68%, 76 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.44 (d, J = 8.1 Hz, 1H), 7.37 (d, J= 1.7 Hz, 1H), 7.09 (d, J= 8.3, 1.8 Hz, 1H), 5.96 (s, 1H), 5.03 (s, 1H), 3.51 (t, J = 6.2 Hz, 2H), 3.25 (q, J = 6.3 Hz, 2H), 2.62 (t, J = 7.7 Hz, 2H), 1.81 (p, J = 6.3 Hz, 2H), 1.65 - 1.56 (m, 2H), 1.46 (s, 9H), 1.33 - 1.19 (m, 14H), 0.88 (t, J= 6.8 Hz, 3H). HRMS (ESI+) m/z calc’d. for C25H42BrN3O2S+ (M+H)+488.2992, found 488.2995.
Synthesized according to General Procedure 3. White solid (96%, 37 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.69 (d, J = 1.7 Hz, 1H), 7.57 - 7.53 (m, 1H), 7.39 (dd, J = 8.4, 1.7 Hz, 1H), 3.97 - 3.89 (m, 2H), 3.38 (t, J = 6.1 Hz, 2H), 2.74 (t, J = 7.7 Hz, 2H), 1.71 -1.62 (m, 2H), 1.39 - 1.24 (m, 14H), 0.91 (t, J = 6.9 Hz, 3H). 13C NMR (126 MHz, Methanol-d4) δ 170.3, 142.2, 138.2, 129.8, 125.1, 123.3, 115.5, 44.6, 39.0, 36.6, 33.1, 32.8, 30.7, 30.6, 30.4, 30.2, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C19H32N3S+ (M+H)+334.2311, found 334.2319.
Synthesized according to General Procedure 3. White solid (91%, 54 mg). 1H NMR (500 MHz, Methanol-d4) δ 7.65 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.35 (dd, J = 8.4, 1.6 Hz, 1H), 3.70 (t, J= 7.0 Hz, 2H), 3.12 (t, J= 9.1 Hz, 2H), 2.70 (t, J= 8.7 Hz, 2H), 2.15 (p, J = 7.2 Hz, 2H), 1.70 - 1.57 (m, 2H), 1.36 - 1.20 (m, 14H), 0.88 (t, J = 6.9 Hz, 3H).
(a) mono-N-Boc-diamine (1.05 equiv), DCM, 0 - 25° C., 18 h; (b) (i) 9-BBN (1.5 equiv), 1-decene (1.1 equiv), THF, 70° C., 2 h, (ii) aryl iodide (1.0 equiv), Pd(dppf)Cl2*CH2Cl2 (0.05 equiv), 3 M KOH (3.0 equiv), THF, 70° C., 4 h; (c) 4 M HCl/Dioxane (10 equiv), DCM, 25° C., 2 h.
Synthesized according to procedure 14. White solid (95%, 345 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.57 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 4.13 - 4.04 (m, 2H), 3.62 - 3.52 (m, 1H), 3.08 - 2.95 (m, 2H), 1.99 - 1.85 (m, 2H), 1.54 - 1.36 (m, 11H).
Synthesized according to procedure 14. White solid (92%, 316 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.55 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 3.23 (t, J = 6.7 Hz, 2H), 3.16 - 3.08 (m, 2H), 1.66 (p, J = 6.7 Hz, 2H), 1.45 (s, 9H). 13C NMR (101 MHz, cd3od) δ 158.62, 157.93, 141.04, 138.70, 121.94, 85.14, 79.94, 38.61, 38.00, 31.52, 28.77.
Synthesized according to procedure 14. White solid (96%, 347 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.67 (s, 1H), 7.49 (d, J= 8.7 Hz, 2H), 7.04 (d, J= 8.7 Hz, 2H), 5.60 (d, J= 7.6 Hz, 1H), 3.99 - 3.85 (m, 2H), 3.82 - 3.69 (m, 1H), 2.89 - 2.77 (m, 2H), 1.90 - 1.78 (m, 2H), 1.45 (s, 9H), 1.22 - 1.07 (m, 2H). 13C NMR (101 MHz, cdcl3) δ 155.22, 155.09, 139.03, 137.94, 121.28, 85.55, 80.34, 46.95, 42.42, 32.64, 28.60.
Synthesized according to procedure 7. White solid (53%, 190 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.23 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 4.14 - 4.06 (m, 2H), 3.62 - 3.53 (m, 1H), 3.06 - 2.96 (m, 2H), 2.57 (t, J = 7.6 Hz, 2H), 1.96 - 1.87 (m, 2H), 1.60 (p, J= 7.5 Hz, 2H), 1.47 (s, 9H), 1.38 - 1.25 (m, 16H), 0.91 (d, J = 6.8 Hz, 3H).
Synthesized according to procedure 7. White solid (68%, 224 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.36 (s, 1H), 7.18 (d, J= 8.0 Hz, 2H), 7.04 (d, J= 8.2 Hz, 2H), 5.80 (t, J = 7.6 Hz, 1H), 5.13 (t, J = 6.2 Hz, 1H), 3.21 (q, J = 6.2 Hz, 2H), 3.12 (q, J = 6.4 Hz, 2H), 2.51 (t, J = 7.8 Hz, 2H), 1.62 - 1.50 (m, 4H), 1.41 (s, 9H), 1.33 - 1.20 (m, 14H), 0.87 (t, J= 6.8 Hz, 3H). 13C NMR (101 MHz, cdcl3) δ 156.95, 156.69, 138.00, 136.57, 129.00, 120.69, 79.36, 37.44, 36.82, 35.40, 32.00, 31.69, 30.82, 29.74, 29.73, 29.63, 29.45, 29.44, 28.52, 22.78, 14.21.
Synthesized according to procedure 7. White solid (82%, 295 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.48 (s, 1H), 7.15 (d, J= 8.1 Hz, 2H), 7.03 (d, J= 8.2 Hz, 2H), 5.58 (d, J= 7.8 Hz, 1H), 4.01 - 3.82 (m, 2H), 3.81 - 3.67 (m, 1H), 2.88 - 2.72 (m, 2H), 2.50 (t, J= 7.8 Hz, 2H), 1.91 - 1.77 (m, 2H), 1.53 (p, J = 7.6 Hz, 2H), 1.44 (s, 9H), 1.33 - 1.09 (m, 16H), 0.87 (t, J = 6.7 Hz, 3H). 13C NMR (101 MHz, cdcl3) δ 155.87, 154.91, 137.94, 136.53, 128.99, 120.26, 79.91, 46.95, 42.51, 35.37, 32.68, 31.98, 31.70, 29.71, 29.70, 29.60, 29.43, 29.41, 28.53, 22.76, 14.20.
Synthesized according to procedure 3. White solid (86%, 140 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.23 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 4.29 - 4.22 (m, 2H), 3.41 - 3.34 (m, 1H), 3.02 - 2.92 (m, 2H), 2.56 (t, J = 7.6 Hz, 2H), 2.09 - 2.00 (m, 2H), 1.64 - 1.51 (m, 4H), 1.36 - 1.23 (m, 14H), 0.90 (t, J = 6.7 Hz, 3H). 13C NMR (101 MHz, cd3od) δ 157.87, 139.18, 138.23, 129.53, 122.53, 49.78, 43.64, 36.26, 33.06, 32.82, 31.08, 30.74, 30.72, 30.61, 30.46, 30.26, 23.73, 14.44.
Synthesized according to procedure 3. White solid (84%, 160 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.28 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 3.37 - 3.30 (m, 2H), 3.02 (t, J = 7.1 Hz, 2H), 2.56 (t, J = 7.6 Hz, 2H), 1.88 (p, J = 6.9 Hz, 2H), 1.60 (p, J = 7.5 Hz, 2H), 1.38 - 1.25 (m, 14H), 0.92 (t, J = 6.7 Hz, 3H). 13C NMR (101 MHz, cd3od) δ 159.13, 138.52, 138.19, 129.69, 120.75, 38.14, 37.13, 36.22, 33.05, 32.81, 30.73, 30.71, 30.60, 30.44, 30.26, 29.54, 23.72, 14.44. HRMS: (ESI) [M+H]+ calc. for C20H36N3O, 334.2853, observed, 334.2866.
Synthesized according to procedure 3. White solid (82%, 71 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.25 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 3.90 - 3.80 (m, 1H), 3.45 - 3.36 (m, 2H), 3.16 - 3.06 (m, 2H), 2.53 (t, J = 7.6 Hz, 2H), 2.19 - 2.09 (m, 2H), 1.81 - 1.68 (m, 2H), 1.57 (p, J = 7.2 Hz, 2H), 1.37 - 1.22 (m, 14H), 0.89 (t, J = 6.7 Hz, 3H). 13C NMR (101 MHz, cd3od) δ 157.55, 138.34, 138.17, 129.66, 120.49, 45.62, 43.99, 36.22, 33.05, 32.80, 30.73, 30.71, 30.60, 30.44, 30.27, 30.14, 23.72, 14.46.
(a) N-Boc amino-alcohol (1.05 equiv), DCM, 0 - 25° C., 18 h; (b) (i) 9-BBN (1.5 equiv), 1-decene (1.1 equiv), THF, 70° C., 2 h, (ii) aryl iodide (1.0 equiv), Pd(dppf)Cl2*CH2Cl2 (0.05 equiv), 3 M KOH (3.0 equiv), THF, 70° C., 4 h; (c) 4 M HCl/Dioxane (10 equiv), DCM, 25° C., 2 h.
Synthesized according to procedure 15. White solid (67%, 223 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.60 (d, J= 8.8 Hz, 2H), 7.27 (d, J= 8.3 Hz, 2H), 4.17 (t, J= 5.6 Hz, 2H), 3.36 (t, J= 5.6 Hz, 2H), 1.45 (s, 9H). 13C NMR (101 MHz, cd3od) δ 158.43, 155.43, 140.20, 138.80, 121.66, 86.15, 80.22, 64.81, 40.75, 28.73.
Synthesized according to procedure 15. White solid (47%, 247 mg). 1H NMR (400 MHz, Chloroform-d) δ 8.19 (d, J= 130.7 Hz, 1H), 7.56 (d, J= 8.4 Hz, 2H), 7.33 - 7.24 (m, 2H), 5.36 - 5.29 (m, 1H), 3.63 - 3.45 (m, 3H), 3.44 - 3.30 (m, 1H), 2.12 - 2.02 (m, 2H), 1.48 (d, J= 7.9 Hz, 9H). 13C NMR (101 MHz, Chloroform-d) δ 154.58 (d, J= 16.9 Hz), 152.91 (d, J= 6.8 Hz), 138.25 (d, J= 18.6 Hz), 137.74 (d, J= 4.2 Hz), 120.58, 86.02 (d, J= 13.7 Hz), 79.83, 74.11 (d, J= 106.5 Hz), 51.76 (d, J= 67.0 Hz), 43.85 (d, J= 28.8 Hz), 31.44 (d, J= 100.1 Hz), 28.52 (d, J= 3.1 Hz).
Synthesized according to procedure 15. White solid (40%, 210 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.91 - 7.49 (m, 3H), 7.29 - 7.19 (m, 2H), 5.33 - 5.26 (m, 1H), 3.61 - 3.31 (m, 4H), 2.13 - 2.00 (m, 2H), 1.46 (d, J= 5.9 Hz, 9H). 13C NMR (101 MHz, Chloroform-d) δ 154.66 (d, J= 13.9 Hz), 152.88, 138.12 (d, J= 16.9 Hz), 137.92 (d, J= 3.2 Hz), 120.63, 86.20, 79.89, 74.35 (d, J= 104.1 Hz), 51.87 (d, J= 63.9 Hz), 43.94 (d, J= 29.5 Hz), 31.52 (d, J= 97.9 Hz), 28.61.
Synthesized according to procedure 7. Yellow solid (96%, 225 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.28 (d, J= 7.4 Hz, 2H), 7.09 (d, J= 8.2 Hz, 2H), 7.04 (s, 1H), 5.04 - 4.93 (m, 1H), 4.20 (t, J= 5.3 Hz, 2H), 3.41 (q, J= 5.6 Hz, 2H), 2.53 (t, J= 7.9 Hz, 2H), 1.55 (p, J= 7.1 Hz, 2H), 1.44 (s, 9H), 1.32 - 1.21 (m, 14H), 0.87 (t, J= 6.8 Hz, 3H).
Synthesized according to procedure 7. White solid (79%, 201 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.30 (d, J= 7.9 Hz, 2H), 7.17 - 6.95 (m, 3H), 5.29 (s, 1H), 3.61 - 3.35 (m, 4H), 2.54 (t, J= 7.7 Hz, 2H), 2.12 - 2.06 (m, 2H), 1.55 (p, J= 7.3 Hz, 2H), 1.46 (s, 9H), 1.33 - 1.20 (m, 14H), 0.87 (t, J= 6.7 Hz, 3H). 13C NMR (101 MHz, cdcl3) δ 154.59, 153.13, 138.37, 135.44, 128.99, 118.84, 79.68, 74.24, 51.92, 43.95, 35.37, 32.00, 31.65, 31.01, 29.72, 29.70, 29.61, 29.43, 29.34, 28.60, 22.78, 14.21.
Synthesized according to procedure 7. White solid (92%, 200 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.29 (d, J= 7.9 Hz, 2H), 7.13 - 6.87 (m, 3H), 5.30 (s, 1H), 3.60 - 3.35 (m, 4H), 2.54 (t, J= 7.7 Hz, 2H), 2.12 - 2.06 (m, 2H), 1.55 (p, J= 7.3 Hz, 2H), 1.46 (s, 9H), 1.34 - 1.22 (m, 14H), 0.87 (t, J= 6.8 Hz, 3H). 13C NMR (101 MHz, cdcl3) δ 154.59, 153.09, 138.40, 135.48, 129.02, 118.84, 79.69, 74.21, 51.94, 43.98, 35.38, 32.01, 31.65, 31.01, 29.73, 29.71, 29.62, 29.44, 29.35, 28.61, 22.79, 14.22.
Synthesized according to procedure 3. White solid (78%, 33 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.36 (d, J= 8.1 Hz, 2H), 7.11 (d, J= 8.5 Hz, 2H), 4.42 - 4.34 (m, 2H), 3.30 - 3.26 (m, 2H), 2.57 (t, J= 7.6 Hz, 2H), 1.59 (p, J= 7.5 Hz, 2H), 1.41 - 1.23 (m, 14H), 0.91 (t, J= 6.8 Hz, 3H). 13C NMR (101 MHz, cd3od) δ 155.21, 139.20, 137.32, 129.75, 120.06, 62.19, 40.43, 36.23, 33.06, 32.77, 30.72, 30.70, 30.59, 30.45, 30.26, 23.73, 14.44.
Synthesized according to procedure 3. White solid (81%, 52 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.35 (d, J= 8.0 Hz, 2H), 7.11 (d, J= 8.4 Hz, 2H), 5.43 - 5.38 (m, 1H), 3.59 - 3.41 (m, 4H), 2.62 - 2.52 (m, 2H), 2.35 - 2.26 (m, 2H), 1.59 (p, J= 7.4 Hz, 2H), 1.37 - 1.23 (m, 14H), 0.96 - 0.87 (m, 3H). 13C NMR (101 MHz, cd3od) δ 154.57, 139.15, 137.28, 129.75, 119.98, 74.45, 52.13, 45.35, 36.23, 33.05, 32.76, 31.92, 30.72, 30.70, 30.58, 30.44, 30.26, 23.72, 14.45.
Synthesized according to procedure 3. White solid (82%, 53 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.34 (d, J= 8.0 Hz, 1H), 7.11 (d, J= 8.5 Hz, 1H), 5.43 - 5.38 (m, OH), 3.57 - 3.42 (m, 2H), 2.57 (t, J= 7.6 Hz, 1H), 2.34 - 2.28 (m, 1H), 1.59 (p, J = 7.4 Hz, 1H), 1.36 - 1.24 (m, 7H), 0.91 (t, J = 6.8 Hz, 1H). 13C NMR (101 MHz, cd3od) δ 154.59, 139.18, 137.28, 129.76, 119.99, 74.46, 52.16, 45.37, 36.23, 33.06, 32.76, 31.91, 30.72, 30.70, 30.58, 30.44, 30.26, 23.72, 14.44.
(a) 4-iodobenzoic acid (1.1 equiv), HCTU (1.1 equiv), DIEA (1.8 equiv), mono-N-Boc-protected diamine (1.0 equiv), DCM, rt, 18 h; (b) (i) 9-BBN (1.5 equiv), 1-decene (1.1 equiv), THF, 70° C., 2 h, (ii) aryl iodide (1.0 equiv), Pd(dppf)Cl2*CH2Cl2 (0.05 equiv), 3 M KOH (3.0 equiv), THF, 70° C., 4 h; (c) 4 M HCl/Dioxane (10 equiv), DCM, rt, 2 h.
Synthesized according to procedure 2. White solid (99%, 838 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.60 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.35 - 7.15 (m, 1H), 4.54 - 4.41 (m, 1H), 3.65 - 3.46 (m, 1H), 3.42 - 3.12 (m, 3H), 2.15 - 2.01 (m, 1H), 1.94 - 1.77 (m, 1H), 1.35 (s, 9H).
Synthesized according to procedure 2. Clear oil (95%, 480 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.68 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.16 - 6.74 (m, 1H), 4.61 - 4.48 (m, 1H), 3.72 - 3.52 (m, 1H), 3.50 - 3.06 (m, 3H), 2.22 - 2.08 (m, 1H), 2.00 - 1.82 (m, 1H), 1.41 (s, 9H). 13C NMR (101 MHz, cdcl3) δ 166.92, 154.54, 137.64, 133.58, 128.82, 98.59, 79.70, 51.00, 49.66, 44.07, 31.21, 28.54.
Synthesized according to procedure 2. White solid (93%, 780 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.84 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 3.79 - 3.35 (m, 8H), 1.47 (s, 9H). 13C NMR (101 MHz, cd3od) δ 171.74, 156.17, 139.05, 136.03, 129.96, 97.06, 81.67, 44.50, 43.12, 28.60. 13C NMR (101 MHz, cd3od) δ 171.74, 156.17, 139.05, 136.03, 129.96, 97.06, 81.67, 44.50, 43.12, 28.60.
Synthesized according to General Procedure 11. Tan solid (82%, 260 mg). 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J= 7.8 Hz, 2H), 7.22 (d, J= 8.2 Hz, 2H), 7.17 (s, 1H), 5.01 (d, J= 7.2 Hz, 1H), 3.49 (q, J = 6.2 Hz, 2H), 3.23 (q, J = 6.3 Hz, 2H), 2.63 (d, J = 7.7 Hz, 2H), 1.74 - 1.65 (m, 2H), 1.60 (p, J = 7.4 Hz, 2H), 1.44 (s, 9H), 1.35 - 1.20 (m, 14H), 0.86 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 167.7, 157.0, 146.8, 132.0, 128.7, 127.1, 79.6, 37.1, 36.1, 36.0, 32.0, 31.4, 30.4, 29.7, 29.7, 29.6, 29.5, 29.4, 28.5, 22.8, 14.3. HRMS: (ESI) [M+H]+ calc. for C25H43N2O3, 419.3268, observed, 419.3258.
Synthesized according to General Procedure 11. Tan solid (73%, 225 mg). 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 7.10 (s, 1H), 5.04 (t, J = 5.3 Hz, 1H), 3.59 - 3.50 (m, 2H), 3.44 - 3.35 (m, 2H), 2.62 (t, J = 7.7 Hz, 2H), 1.60 (p, J= 7.2 Hz, 2H), 1.42 (s, 9H), 1.34 - 1.19 (m, 14H), 0.87 (d, J= 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 168.0, 157.5, 146.9, 131.6, 128.6, 127.1, 80.0, 42.0, 40.2, 36.0, 32.0, 31.4, 29.7, 29.7, 29.6, 29.5, 29.4, 28.5, 22.8, 14.3. HRMS: (ESI) [M+H]+ calc. for C24H41N2O3, 405.3112, observed, 405.3108.
Synthesized according to procedure 7. White solid (80%, 691 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.64 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.77 - 6.67 (m, 1H), 4.56 (h, J = 6.1 Hz, 1H), 3.69 - 3.55 (m, 1H), 3.49 - 3.15 (m, 3H), 2.56 (t, J = 7.7 Hz, 2H), 2.18 - 2.06 (m, 1H), 1.98 - 1.79 (m, 1H), 1.54 (p, J = 7.1 Hz, 2H), 1.39 (s, 9H), 1.29 - 1.15 (m, 14H), 0.82 (t, J = 6.7 Hz, 3H). 13C NMR (101 MHz, cdcl3) δ 167.50, 154.46, 146.89, 131.46, 128.42, 127.05, 79.45, 51.02, 49.64, 43.81, 35.75, 31.82, 31.16, 31.10, 29.53, 29.51, 29.39, 29.25, 29.16, 28.42, 22.61, 14.05.
Synthesized according to procedure 7. White solid (98%, 490 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.65 (d, J= 8.1 Hz, 2H), 7.16 (d, J= 8.0 Hz, 2H), 6.67 (d, J= 7.0 Hz, 1H), 4.58 (h, J = 6.0 Hz, 1H), 3.72 - 3.59 (m, 1H), 3.51 - 3.16 (m, 3H), 2.58 (t, J = 7.7 Hz, 2H), 2.27 - 2.09 (m, 1H), 1.96 - 1.85 (m, 1H), 1.57 (p, J = 7.8, 7.3 Hz, 2H), 1.41 (s, 9H), 1.29 - 1.12 (m, 14H), 0.84 (t, J = 6.7 Hz, 3H). 13C NMR (101 MHz, cdcl3) δ 167.57, 154.56, 147.01, 131.55, 128.53, 127.12, 79.56, 51.21, 49.39, 43.96, 35.84, 31.91, 31.63, 31.25, 29.62, 29.60, 29.49, 29.34, 29.25, 28.51, 22.70, 14.14.
Synthesized according to procedure 7. White solid (92%, 740 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.30 (d, J = 7.8 Hz, 2H), 7.20 (d, J = 7.8 Hz, 2H), 3.81 - 3.29 (m, 8H), 2.61 (t, J= 7.7 Hz, 2H), 1.60 (p, J = 7.1 Hz, 2H), 1.46 (s, 9H), 1.35 - 1.20 (m, 14H), 0.87 (t, J = 6.7 Hz, 3H). 13C NMR (101 MHz, cdcl3) δ 170.97, 154.70, 145.28, 132.75, 128.66, 127.28, 80.42, 43.73, 42.28, 35.94, 32.01, 31.40, 29.73, 29.69, 29.59, 29.44, 29.37, 28.49, 22.80, 14.24.
Synthesized according to procedure 3. White solid (77%, 99 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.77 (d, J = 1.9 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 4.65 - 4.54 (m, 1H), 3.62 - 3.50 (m, 2H), 3.41 - 3.33 (m, 2H), 2.64 (t, J = 7.6 Hz, 2H), 2.44 - 2.32 (m, 1H), 2.22 - 2.13 (m, 1H), 1.61 (p, J= 7.4 Hz, 2H), 1.36 - 1.18 (m, 14H), 0.87 (t, J= 6.8 Hz, 3H). 13C NMR (101 MHz, cd3od) δ 170.48, 148.70, 132.27, 129.60, 128.59, 51.16, 50.84, 45.84, 36.73, 33.04, 32.38, 30.93, 30.69, 30.68, 30.54, 30.43, 30.26, 23.71, 14.44. HRMS: (ESI) [M+H]+ calc. for C21H35N2O, 331.2744, observed, 331.2731.
Synthesized according to procedure 3. White solid (79%, 101 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.80 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 4.69 - 4.59 (m, 1H), 3.64 - 3.53 (m, 2H), 3.44 - 3.35 (m, 2H), 2.66 (t, J = 7.7 Hz, 2H), 2.46 - 2.35 (m, 1H), 2.27 - 2.15 (m, 1H), 1.63 (p, J = 7.0 Hz, 2H), 1.36 - 1.23 (m, 14H), 0.89 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, cd3od) δ 170.44, 148.68, 132.26, 129.59, 128.59, 51.14, 50.83, 45.83, 36.73, 33.04, 32.38, 30.94, 30.68, 30.67, 30.54, 30.43, 30.26, 23.71, 14.44. HRMS: (ESI) [M+H]+ calc. for C21H35N2O, 331.2744, observed, 331.2731.
Synthesized according to procedure 3. White solid (74%, 95 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.42 (d, J= 8.1 Hz, 2H), 7.33 (d, J= 7.9 Hz, 2H), 4.00 - 3.80 (m, 4H), 3.36 -3.26 (m, 4H), 2.68 (t, J = 7.7 Hz, 2H), 1.65 (p, J = 7.1 Hz, 2H), 1.39 - 1.25 (m, 14H), 0.91 (t, J= 6.7 Hz, 3H). 13C NMR (101 MHz, cd3od) δ 172.92, 147.31, 132.74, 129.87, 128.46, 44.42, 36.75, 33.06, 32.51, 30.71, 30.71, 30.58, 30.45, 30.31, 23.73, 14.44. HRMS: (ESI) [M+H]+ calc. for C21H35N2O, 331.2744, observed, 331.2731.
Synthesized according to General Procedure 3. White solid (77%, 164 mg). 1H NMR (400 MHz, CD3OD) δ 7.77 (d, J= 8.5 Hz, 2H), 7.29 (d, J= 8.6 Hz, 2H), 3.50 (t, J= 6.5 Hz, 2H), 2.99 (t, J = 7.3 Hz, 2H), 2.67 (t, J = 7.7 Hz (2, H), 1.96 (p, J = 7.0 Hz, 2H), 1.63 (p, J = 6.3 Hz, 2H), 1.38 - 1.21 (m, 14H), 0.89 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 170.9, 148.6, 132.4, 129.7, 128.4, 38.3, 37.3, 36.7, 33.1, 32.4, 30.7, 30.6, 30.5, 30.3, 29.0, 23.7, 14.5. HRMS: (ESI) [M+H]+ calc. for C20H35N2O, 319.2744, observed, 319.2736.
Synthesized according to General Procedure 3. White solid (66%, 120 mg). 1H NMR (400 MHz, CD3OD) δ 7.80 (d, J= 8.3 Hz, 2H), 7.30 (d, J= 8.3 Hz, 2H), 3.66 (t, J = 5.9 Hz, 2H), 3.17 (t, J= 5.9 Hz, 2H), 2.67 (t, J= 7.6 Hz, 2H), 1.63 (p, J= 6.7 Hz, 2H), 1.40 -1.20 (m, 14H), 0.89 (t, J= 6.8 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 171.2, 148.7, 132.2, 129.6, 128.6, 41.1, 38.7, 36.7, 33.1, 32.4, 30.7, 30.7, 30.6, 30.5, 30.3, 23.7, 14.5. HRMS: (ESI) [M+H]+ calc. for C19H33N2O, 305.2587, observed, 305.2584.
(a) (i) 9-BBN (2.2 equiv), 1-decene (2.0 equiv) THF, 70° C., (ii) Pd(dppf)Cl2*CH2Cl2 (0.075 equiv), 3 M KOH (3.0 equiv), THF, 70° C.; (b) SnCl2 (5.0 equiv), HCl (10 equiv), EtOH, 80° C.; (c) N-Boc amino acid (1.3 equiv), DIEA (4.0 equiv), HCTU (1.0 equiv), DMF, 0 - 25° C.; (d) 13.7 M AcOH (70 equiv), neat, 65° C.; (e) 4 M HCl/Dioxane (10 equiv), DCM, rt.
Synthesized according to General Procedure 6. Orange solid (36%, 560 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J = 2.1 Hz, 1H), 7.20 (dd, J = 8.5, 2.1 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 5.92 (s, 2H), 2.58 - 2.46 (m, 2H), 1.56 (q, J = 7.3, 6.5 Hz, 4H), 1.32 - 1.21 (m, 14H), 0.99 - 0.81 (m, 3H).
Synthesized according to General Procedure 16. Brown solid (54%, 24 mg). 1H NMR (500 MHz, Chloroform-d) δ 6.63 (d, J = 7.6 Hz, 1H), 6.55 - 6.51 (m, 2H), 3.32 (s, 4H), 2.48 - 2.42 (m, 2H), 1.54 (p, J = 7.3 Hz, 2H), 1.30 - 1.21 (m, 14H), 0.88 (t, J = 6.9 Hz, 3H).
Synthesized according to General Procedure 1. Reaction carried forward crude with no further purification.
Synthesized according to General Procedure 17. Clear oil (73%, 46 mg). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.2 Hz, 1H), 7.35 (s, 1H), 7.03 (d, J = 8.2 Hz, 1H), 5.07 (t, J = 6.6 Hz, 1H), 3.21 (q, J = 6.3 Hz, 2H), 2.92 (t, J = 6.6 Hz, 2H), 2.69 (t, J = 7.8 Hz, 2H), 1.96 - 1.87 (m, 2H), 1.63 (q, J = 7.4 Hz, 2H), 1.45 (s, 9H), 1.35 - 1.20 (m, 16H), 0.87 (t, J= 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 157.4, 154.4, 137.2, 123.0, 79.9, 39.1, 38.7, 36.3, 32.3, 32.0, 29.7, 29.7, 29.5, 29.4, 28.5, 25.7, 22.8, 14.2. HRMS (ESI+) m/z calc’d. for C25H42N3O2+ (M+H)+ 416.3277, found 416.3256.
Synthesized according to General Procedure 6. White solid (90%, 35 mg). 1H NMR (400 MHz, CD3OD) δ 7.67 (dd, J = 8.5, 0.7 Hz, 1H), 7.56 (dt, J= 1.5, 0.7 Hz, 1H), 7.44 (dd, J= 8.5, 1.5 Hz, 1H), 3.17 - 3.08 (m, 2H), 2.86 - 2.77 (m, 2H), 2.35 - 2.23 (m, 2H), 1.68 (q, J= 7.2 Hz, 2H), 1.37 - 1.26 (m, 15H), 0.93 - 0.86 (m, 3H). 13C NMR (101 MHz, CD3OD) δ 153.4, 143.2, 132.8, 130.8, 128.3, 114.4, 113.8, 39.7, 36.9, 33.0, 32.9, 30.7, 30.7, 30.6, 30.4, 30.2, 25.9, 24.9, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C2oH34N3+ (M+H)+ 316.2747, found 316.2757.
Synthesized according to procedure 2. Purified via column chromatography (40% ethyl acetate/hexanes). White solid (92%, 799 mg). 1HNMR (400 MHz, Chloroform-d) δ 7.82 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 4.16 - 3.95 (m, 3H), 2.97 - 2.85 (m, 2H), 2.01 - 1.84 (m, 2H), 1.46 (s, 11H). 13C NMR (101 MHz, Chloroform-d) δ 168.79, 156.42, 138.83, 135.32, 130.09, 99.09, 81.14, 48.83, 43.97, 32.54, 28.67.
Synthesized according to procedure 14. Purified via column chromatography (50-70% ethyl acetate/hexanes). White solid (95%, 670 mg). 1HNMR (400 MHz, Chloroform-d) δ 7.88 (d, J= 35.1 Hz, 1H), 7.47 (d, J= 8.9 Hz, 2H), 7.08 (d, J= 8.7 Hz, 2H), 6.07 (dd, J= 38.0, 7.0 Hz, 1H), 4.38 - 4.27 (m, 1H), 3.50 (dd, J= 11.5, 5.6 Hz, 1H), 3.46 -3.26 (m, 2H), 3.15 (dd, J= 11.5, 2.2 Hz, 1H), 2.12 - 1.95 (m, 1H), 1.94 - 1.73 (m, 1H), 1.45 (d, J = 12.5 Hz, 9H). 13C NMR (101 MHz, Chloroform-d) δ 155.32, 155.23, 139.16, 137.75, 120.76, 85.01, 80.38 (d, J = 8.4 Hz), 52.08 (d, J = 68.3 Hz), 49.49 (d, J = 69.0 Hz), 44.00 (d, J = 18.7 Hz), 31.80 (d, J= 107.6 Hz), 28.60.
Synthesized according to procedure 14. Purified via column chromatography (40-50% ethyl acetate/hexanes). White solid (97%, 512 mg). 1HNMR (400 MHz, Chloroform-d) δ 7.47 (d, J = 8.7 Hz, 2H), 7.17 (s, 1H), 7.07 (d, J = 8.8 Hz, 2H), 3.43 - 3.32 (m, 8H), 1.44 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ 155.01, 154.62, 138.96, 137.57, 122.34, 86.16, 80.44, 43.78, 42.92, 28.43.
Synthesized according to procedure 6. Purified via column chromatography (30% ethyl acetate/hexanes). White solid (87%, 721 mg). 1HNMR (400 MHz, Chloroform-d) δ 7.65 (d, J = 8.2 Hz, 2H), 7.13 (d, J= 8.2 Hz, 2H), 6.59 (d, J = 7.9 Hz, 1H), 4.11 - 3.97 (m, 3H), 2.79 (t, J = 12.8 Hz, 2H), 2.57 (t, J = 7.7 Hz, 2H), 1.94 - 1.86 (m, 2H), 1.54 (p, J= 7.0 Hz, 2H), 1.40 (s, 11H), 1.29 - 1.13 (m, 14H), 0.83 (t, J= 6.9 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 166.89, 154.64, 146.68, 131.90, 128.41, 127.05, 79.53, 47.13, 42.75, 35.76, 32.02, 31.85, 31.22, 29.56, 29.54, 29.42, 29.28, 29.19, 28.39, 22.64, 14.09.
Synthesized according to procedure 6. Purified via column chromatography (30-40% ethyl acetate/hexanes). Off-white solid (73%, 505 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J = 24.8 Hz, 1H), 7.20 (d, J = 6.3 Hz, 2H), 7.03 (d, J = 8.5 Hz, 2H), 5.98 (dd, J= 38.9, 7.1 Hz, 1H), 4.41 - 4.29 (m, 1H), 3.53 (dd, J = 11.4, 5.8 Hz, 1H), 3.46 -3.29 (m, 2H), 3.16 (dd, J = 11.2, 3.6 Hz, 1H), 2.50 (t, J = 7.7 Hz, 2H), 2.12 - 1.95 (m, 1H), 1.93 - 1.70 (m, 1H), 1.60 - 1.43 (m, 11H), 1.35 - 1.17 (m, 14H), 0.87 (t, J = 6.9 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 155.96, 155.16, 137.51, 136.76, 128.91, 119.58, 80.09 (d, J = 8.8 Hz), 52.07 (d, J= 81.3 Hz), 49.60 (d, J = 70.2 Hz), 44.09 (d, J = 23.3 Hz), 35.35, 31.98, 31.84 (d, J = 120.6 Hz), 31.69, 29.71, 29.70, 29.61, 29.41, 29.39, 28.62, 22.76, 14.19.
Synthesized according to procedure 6. Purified via column chromatography (60-70% ethyl acetate/hexanes). Brown solid (22%, 122 mg). 1HNMR (400 MHz, Chloroform-d) δ 7.22 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 6.48 (s, 1H), 3.49 - 3.41 (m, 8H), 2.53 (t, J = 7.7 Hz, 2H), 1.56 (p, J= 7.6 Hz, 2H), 1.47 (s, 9H), 1.33 - 1.22 (m, 14H), 0.87 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 155.41, 154.76, 138.23, 136.40, 128.89, 120.47, 80.40, 43.98, 43.00, 35.40, 32.01, 31.66, 29.74, 29.72, 29.63, 29.44, 29.38, 28.50, 22.79, 14.23.
To a round bottom flask SM (0.20 g, 0.62 mmol), anhydrous THF (10 mL) was added under argon. The solution was then cooled to -78° C. To the cold solution, n-butyllithium (0.39 mL, 0.62 mmol) was added drop wise and allowed to stir at -78° C. for 10 min. To this solution, iodomethane (0.038 mL, 0.62 mmol) was added drop wise at -78° C. The solution was then allowed to warm to room temperature and then refluxed for 24 h. Purified via column chromatography (40-60% ethyl acetate/hexanes). Clear oil (67%, 103 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.29 (d, J= 8.1 Hz, 2H), 7.20 (d, J= 8.2 Hz, 2H), 5.27 -4.35 (m, 1H), 3.68 - 3.46 (m, 2H), 3.42 - 3.17 (m, 2H), 2.94 (s, 3H), 2.62 (t, J = 7.5 Hz, 2H), 2.12 - 1.98 (m, 2H), 1.60 (p, J= 7.6 Hz, 2H), 1.44 (s, 9H), 1.37 - 1.19 (m, 14H), 0.87 (t, J= 6.8 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 172.48, 154.45, 145.04, 133.65, 128.66, 126.93, 79.79, 46.99 (d, J = 41.6 Hz), 44.43 (d, J = 37.4 Hz), 35.92, 32.00, 31.38, 29.71, 29.68, 29.58, 29.42, 29.37, 28.58, 28.14 (d, J = 53.4 Hz), 22.78, 14.22.
Synthesized according to procedure 6. Purified via column chromatography (40% ethyl acetate/hexanes). Yellow oil (69%, 151 mg). 1HNMR (400 MHz, Chloroform-d) δ 7.86 (d, J = 38.3 Hz, 1H), 7.63 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 5.17 - 5.03 (m, 1H), 3.80 - 3.63 (m, 1H), 3.53 - 3.30 (m, 3H), 2.60 (t, J= 7.7 Hz, 2H), 2.29 (h, J = 7.2 Hz, 1H), 2.19 - 2.00 (m, 1H), 1.58 (p, J= 7.2 Hz, 2H), 1.43 (s, 9H), 1.34 - 1.20 (m, 14H), 0.86 (t, J= 6.8 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 199.35, 154.55, 146.89, 139.05, 128.52, 126.88, 79.89, 55.66 (d, J= 59.1 Hz), 50.76 (d, J= 54.2 Hz), 44.11 (d, J = 24.4 Hz), 35.78, 31.94, 31.29, 30.68 (d, J = 76.7 Hz), 29.66, 29.63, 29.53, 29.37, 29.27, 28.52, 22.74, 14.18.
Synthesized according to procedure 3. Purified via trituration with ethyl acetate and diethyl ether. White solid (84%, 72 mg). 1HNMR (400 MHz, Methanol-d4) δ 8.44 (d, J= 7.4 Hz, 1H), 7.77 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 4.24 - 4.11 (m, 1H), 3.48 (dt, J = 14.1, 4.2 Hz, 2H), 3.15 (td, J= 12.8, 3.1 Hz, 2H), 2.65 (t, J = 7.7 Hz, 2H), 2.23 - 2.12 (m, 2H), 2.00 - 1.85 (m, 2H), 1.61 (p, J= 7.4 Hz, 2H), 1.37 - 1.20 (m, 14H), 0.89 (t, J = 6.8 Hz, 3H).13C NMR (101 MHz, Methanol-d4) δ 169.86 (d, J = 7.6 Hz), 148.35, 132.77 (d, J = 3.8 Hz), 129.53, 128.52, 46.28 (d, J = 10.7 Hz), 44.35, 36.72, 33.03, 32.39, 30.68, 30.67, 30.53, 30.42, 30.27, 29.46 (d, J = 2.7 Hz), 23.71, 14.46.
Synthesized according to procedure 3. Purified via trituration with ethyl acetate and diethyl ether. White solid (77%, 66 mg). 1HNMR (400 MHz, Methanol-d4) δ 7.27 (d, J= 8.5 Hz, 2H), 7.08 (d, J = 8.6 Hz, 2H), 4.44 - 4.33 (m, 1H), 3.57 - 3.45 (m, 2H), 3.40 - 3.28 (m, 2H), 2.55 (t, J = 7.6 Hz, 2H), 2.36 (ddt, J = 13.9, 8.3, 7.0 Hz, 1H), 2.14 - 1.99 (m, 1H), 1.59 (p, J = 7.5 Hz, 2H), 1.36 - 1.26 (m, 14H), 0.91 (t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, Methanol-d4) δ 157.95, 138.63, 137.98, 129.71, 120.65, 51.84, 50.81, 45.63, 36.23, 33.06, 32.80, 31.37, 30.73, 30.71, 30.60, 30.44, 30.26, 23.72, 14.44.
Synthesized according to procedure 3. Purified via trituration with ethyl acetate and diethyl ether. White solid (63%, 27 mg). 1HNMR (400 MHz, Methanol-d4) δ 7.26 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 3.78 (t, J = 5.5 Hz, 4H), 3.28 (t, J = 5.3 Hz, 4H), 2.56 (t, J = 7.6 Hz, 2H), 1.59 (p, J = 7.5 Hz, 2H), 1.36 - 1.23 (m, 14H), 0.90 (t, J= 7.0 Hz, 3H). 13C NMR (101 MHz, Methanol-d4) δ 157.61, 139.47, 137.92, 129.61, 122.43, 44.49, 42.39, 36.26, 33.06, 32.80, 30.74, 30.71, 30.60, 30.45, 30.26, 23.73, 14.43.
Synthesized according to procedure 3. Purified via column chromatography (10% methanol/dichloromethane). White solid (46%, 41 mg). 1HNMR (400 MHz, Methanol-d4) δ 7.38 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 4.68 (p, J = 7.5 Hz, 1H), 3.73 - 3.45 (m, 3H), 3.30 - 3.20 (m, 1H), 3.04 (s, 3H), 2.66 (t, J = 7.7 Hz, 2H), 2.52 - 2.23 (m, 2H), 1.63 (p, J= 7.6 Hz, 2H), 1.38 - 1.21 (m, 14H), 0.90 (t, J= 6.9 Hz, 3H). 13C NMR (101 MHz, Methanol-d4) δ 174.72, 146.90, 134.41, 129.72, 128.22, 58.31, 46.74, 36.73, 33.04, 32.49, 30.70, 30.69, 30.56, 30.43, 30.29, 28.53, 23.72, 14.43.
Synthesized according to procedure 3. Purified via trituration with ethyl acetate and diethyl ether. Yellow solid (94%, 122 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.77 (d, J= 8.2 Hz, 2H), 7.23 (d, J= 8.3 Hz, 2H), 5.22 (tt, J= 7.2, 4.9 Hz, 1H), 3.77 (dd, J= 12.5, 7.1 Hz, 1H), 3.63 - 3.39 (m, 3H), 2.66 (t, J= 7.6 Hz, 2H), 2.50 (dq, J= 13.7, 7.5 Hz, 1H), 2.40 - 2.27 (m, 1H), 1.64 (p, J= 7.1 Hz, 2H), 1.39 - 1.22 (m, 14H), 0.91 (t, J= 6.9 Hz, 3H). 13C NMR (101 MHz, Methanol-d4) δ 201.81, 147.79, 140.13, 129.16, 128.60, 56.24, 50.63, 45.88, 36.63, 33.04, 32.40, 30.71, 30.69, 30.56, 30.44, 30.27, 30.26, 23.72, 14.46.
Synthesized according to General Procedure 13. White solid (71%, 108 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.45 (s, 1H), 7.19 - 7.04 (m, 2H), 5.95 (d, J= 63.8 Hz, 1H), 3.63 - 3.30 (m, 5H), 3.23 - 3.05 (m, 1H), 2.62 (p, J= 7.3 Hz, 1H), 2.12 - 2.00 (m, 1H), 1.70 (q, J= 10.4 Hz, 1H), 1.46 (s, 9H). HRMS (ESI+) m/z calc’d. for C18H25BrN3O3+ (M+H)+ 396.0917, found 396.0919.
Synthesized according to General Procedure 13. White solid (75%, 113 mg). 1H NMR (500 MHz, Chloroform-d) δ 7.45 (s, 1H), 7.17 - 7.07 (m, 2H), 5.75 (d, J= 78.7 Hz, 1H), 3.63 - 3.27 (m, 5H), 3.21 - 3.06 (m, 1H), 2.62 (q, J= 7.1 Hz, 1H), 2.14 - 1.99 (m, 1H), 1.78 - 1.64 (m, 1H), 1.46 (s, 9H). HRMS (ESI+) m/z calc’d. for C18H25BrN3O3+ (M+H)+ 396.0917, found 396.0913.
Synthesized according to General Procedure 13. White solid (72%, 116 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.45 (t, J= 1.8 Hz, 1H), 7.14 (dt, J= 8.4, 1.9 Hz, 1H), 7.09 (dd, J= 8.4, 1.6 Hz, 1H), 5.67 (s, 1H), 4.13 (s, 3H), 3.45 - 3.32 (m, 2H), 2.71 (t, J= 12.9 Hz, 2H), 1.88 - 1.71 (m, 4H), 1.46 (s, 9H). HRMS (ESI+) m/z calc’d. for C18H25BrN3O3+ (M+H)+ 410.1074, found 410.1076.
Synthesized according to General Procedure 6. Yellow oil (69%, 72 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.16 - 7.06 (m, 2H), 6.82 (d, J= 8.1 Hz, 1H), 6.44 (s, 1H), 3.65 - 3.38 (m, 4H), 3.39 - 3.25 (m, 1H), 3.24 - 3.04 (m, 1H), 2.63 (t, J= 7.7 Hz, 2H), 2.09 -1.96 (m, 1H), 1.81 - 1.55 (m, 3H), 1.45 (s, 9H), 1.35 - 1.20 (m, 14H), 0.88 (t, J= 6.7 Hz, 3H). HRMS (ESI+) m/z calc’d. for C27H44N3O3+ (M+H)+ 458.3377, found 458.3371.
Synthesized according to General Procedure 6. Yellow oil (67%, 79 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.19 - 7.05 (m, 2H), 6.82 (d, J= 8.1 Hz, 1H), 6.60 (s, 2H), 3.62 - 3.39 (m, 4H), 3.39 - 3.23 (m, 1H), 3.24 - 3.04 (m, 1H), 2.62 (t, J= 7.7 Hz, 3H), 2.10 -1.97 (m, 1H), 1.80 - 1.65 (m, 1H), 1.64 - 1.56 (m, 2H), 1.45 (s, 9H), 1.33 - 1.20 (m, 15H), 0.88 (t, J= 6.9 Hz, 3H). HRMS (ESI+) m/z calc’d. for C27H44N3O3+ (M+H)+ 458.3377, found 458.3381.
Synthesized according to General Procedure 6. Yellow oil (77%, 88 mg). 1H NMR (400 MHz, Chloroform-d) δ 7.15 (d, J= 1.6 Hz, 1H), 7.09 (d, J= 8.1 Hz, 1H), 6.81 (dd, J= 8.1, 1.7 Hz, 1H), 5.76 (s, 1H), 4.10 (s, 2H), 3.33 (d, J= 6.7 Hz, 2H), 2.72 - 2.57 (m, 4H), 1.88 - 1.70 (m, 3H), 1.58 (p, J= 7.4 Hz, 2H), 1.43 (s, 9H), 1.31 - 1.20 (m, 17H), 0.85 (t, J= 6.8 Hz, 3H). HRMS (ESI+) m/z calc’d. for C28H46N3O3+ (M+H)+ 472.3534, found 472.3526.
Synthesized according to General Procedure 3. Off-white solid (71%, 44 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.44 - 7.38 (m, 1H), 7.26 - 7.21 (m, 1H), 7.19 - 7.12 (m, 1H), 3.66 - 3.59 (m, 2H), 3.54 (dd, J= 11.9, 7.9 Hz, 1H), 3.48 - 3.39 (m, 1H), 3.36 -3.30 (m, 1H), 3.14 - 3.03 (m, 1H), 2.79 (p, J= 7.9 Hz, 1H), 2.70 (t, J= 7.6 Hz, 2H), 2.36 -2.25 (m, 1H), 1.91 - 1.77 (m, 1H), 1.63 (t, J= 7.5 Hz, 3H), 1.34 - 1.23 (m, 14H), 0.87 (t, J= 6.5 Hz, 3H). 13C NMR (101 MHz, Methanol-d4) δ 160.6, 145.5, 143.1, 132.0, 125.8, 113.4, 111.4, 49.2, 46.4, 45.9, 38.7, 36.7, 33.0, 32.9, 30.7, 30.7, 30.6, 30.4, 30.2, 29.1, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C22H36N3O+ (M+H)+ 358.2853, found 358.2849.
Synthesized according to General Procedure 3. Off-white solid (68%, 46 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.43 (dd, J= 8.4, 3.3 Hz, 1H), 7.30 - 7.24 (m, 1H), 7.19 - 7.13 (m, 1H), 3.67 - 3.62 (m, 2H), 3.58 - 3.50 (m, 1H), 3.49 - 3.40 (m, 1H), 3.37 - 3.27 (m, 1H), 3.14 - 3.04 (m, 1H), 2.87 - 2.74 (m, 1H), 2.71 (t, J= 7.7 Hz, 2H), 2.40 - 2.23 (m, 1H), 1.90 - 1.76 (m, 1H), 1.62 (q, J= 7.2 Hz, 2H), 1.35 - 1.21 (m, 14H), 0.87 (t, J= 6.7 Hz, 3H). 13C NMR (101 MHz, Methanol-d4) δ 160.6, 145.4, 143.2, 131.9, 125.8, 113.4, 111.4, 49.2, 46.4, 46.0, 38.7, 36.7, 33.0, 32.9, 30.7, 30.7, 30.6, 30.4, 30.2, 29.1, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C22H36N3O+ (M+H)+ 358.2853, found 358.2854.
Synthesized according to General Procedure 3. White solid (70%, 53 mg). 1H NMR (400 MHz, Methanol-d4) δ 7.46 (d, J= 8.4 Hz, 1H), 7.29 (s, 1H), 7.20 (d, J= 8.5, 1H), 3.55 - 3.40 (m, 4H), 3.04 (t, J= 13.0, 2.8 Hz, 2H), 2.72 (t, J= 7.6 Hz, 2H), 2.18 - 2.04 (m, 3H), 1.73 - 1.50 (m, 4H), 1.37 - 1.22 (m, 14H), 0.88 (t, J= 6.6 Hz, 3H). 13C NMR (101 MHz, Methanol-d4) δ 160.28, 145.21, 143.34, 131.02, 126.02, 113.09, 111.54, 44.73, 36.70, 34.58, 33.04, 32.90, 30.70, 30.7, 30.6, 30.4, 30.2, 27.3, 23.7, 14.4. HRMS (ESI+) m/z calc’d. for C23H38N3O+ (M+H)+ 372.3009, found 372.3012.
Transporter assays are vectorial and therefore require measurement of the transported analyte in different compartments. The S1P transporter SPNS2 only exports S1P, which obviates measuring uptake of S1P into transporter-expressing cells. Thus, transporter activity was determined by quantifying S1P release from whole cells expressing SPNS2. SPNS2 inhibitor potency was assessed using whole cell assays. HeLa cells expressing mouse SPNS2 were used to determine inhibitor potency (IC50). Cells were plated onto 12 well plates and assayed when the cell monolayers became confluent. Cell growth media (RPMI-1640 containing 10% fetal bovine serum) was replaced with 2 mL of serum-free media (RPMI-1640) containing fatty acid free bovine serum albumin (BSA) (0.2 % w/v) and supplemented with 4-deoxypyridoxine (DOP) (1 mM), NaF (2 mM), Na3VO4 (0.2 mM) to inhibit S1P degradation. Test articles (1 × 10-9 - 1 × 10-4 M) were assayed in duplicate or triplicate. After 18 hours, media was collected, an internal recovery standard (0.005 mL of 5 × 10-7 M deuterated (d7) S 1P in methanol) was added, the BSA was precipitated with trichloroacetic acid and the bound S1P extracted with methanol. S1P and S1P-d7 were measured by liquid chromatography mass spectrometry. Inhibitor potency at the human SPNS2 ortholog was determined by an analogous assay using U-937 cells, which endogenously express human SPNS2.
This application claims priority to U.S. Pat. Application Serial No. 63/076,105, filed Sep. 9, 2020, the disclosure of which is incorporated herein in its entirety by reference.
This invention was made with government support under R01GM121075 and R01AI144026 awarded by the National Institutes of Health. The government has certain rights in the invention.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2021/049534 | 9/8/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63076105 | Sep 2020 | US |
